bluuebunny/crossref_metadata_2025 huggingface dataset:
New Insights Into the Heterogeneity of the Lithosphere‐Asthenosphere System Beneath South China From Teleseismic Body‐Wave Attenuation
Authors: Deng Yangfan , Byrnes Joseph S. , Bezada Maximiliano
Published: February 2021

Teleseismic body‐wave attenuation provides an independent constraint on the architecture of the lithosphere‐asthenosphere system. We obtain the first map of teleseismic attenuation across South China, which correlates well with previous estimates of lithospheric thickness. The weakest attenuation occurs in the Sichuan Basin, where continental lithosphere is thick, and in the adjacent Chuandian region, which we attribute to delaminated lithosphere, or lithosphere strengthened by an ancient plume based on comparison with previous studies. Smaller batches of remnant or delaminated lithosphere may cause local minima along the eastern coast. Pronounced negative anomalies occur in the Hengyang, Jianghan and Nanchang basins, motivating the hypothesis that the basins occur where locally strong blocks within the lithosphere resisted the pervasive deformation of South China. The strongest attenuation occurs in a broad region in the vicinity of the Hainan plume, which is consistent with high temperatures and possibly partial melt in the upper mantle.
Circulation Over the South‐East Greenland Shelf and Potential for Liquid Freshwater Export: A Drifter Study
Authors: Duyck Elodie , De Jong Marieke Femke
Published: February 2021

Freshwater input into deep convection regions could affect the overturning circulation. With a set of 15 Consortium for Advanced Research for the Transport of Hydrocarbon in the Environment (CARTHE) drifters and 15 Surface Velocity Program (SVP) drifters, we investigate the circulation over the south‐east Greenland shelf and the potential for off‐shelf freshwater export. Part of the East Greenland Current flow is steered into the East Greenland Coastal Current immediately upstream of Sermilik Trough. Between the trough and Cape Farewell, two separate cores are visible. Just past Cape Farewell drifters are redistributed into a shelfbreak core and a slow eddying shelf flow. A coastal core is reestablished downstream. Exchanges between the shelfbreak and coastal flows take place both on the east and west Greenland shelf, allowing fresher water to be diverted away from the coast. Five of 15 shallower CARTHE drifters were exported, mainly at Cape Farewell. CARTHE motion shows a higher correlation with local winds, which are more favorable for off‐shelf transport in this area.
A Possible Mechanism on the Detachment Between a Subauroral Proton Arc and the Auroral Oval
Authors: Zhou Su , Luan Xiaoli , Burch J. L. , Yao Zhonghua , Han De‐Sheng , Tian Chenjing , Chen Yuqing , Zhang Jin , Yu Xiaoyan , Dai Tianjun
Published: February 2021

Subauroral proton arcs are a type of terrestrial auroral phenomena, which are often detached equatorially from the auroral oval. This work presents evolution of a subauroral proton arc using observations of the Special Sensor Ultraviolet Spectrographic Imager and Special Sensor J (SSJ) on board Defense Meteorological Satellite Program (DMSP) spacecraft. The arc was observed in the afternoon sector and was located within 60°–70° geomagnetic latitude during the recovery phase of a moderate magnetic storm with the minimum SYM‐H index of −55 nT. Particle measurements from DMSP F17/SSJ indicate that the arc was detached from the normal oval and produced by energetic ring current ions with energies above 10 keV. These energetic ions were likely scattered into the magnetic loss cone by electromagnetic ion cyclotron waves in the frequency range between 0.1 and 0.5 Hz, as confirmed by Pc1 waves derived from the observations of a ground station. Continuous auroral observations directly show that the subauroral proton arc was detached from the oval during evolution. Following a northward interplanetary magnetic field turning, the auroral oval moved toward higher latitudes. We propose that the equatorward edge of the auroral oval is less influenced by the convection electric field, and thus moves more slowly than the poleward edge. This mechanism is proposed for producing a separation between the equatorward and poleward parts of the auroral oval, with the former evolving into the subauroral proton arc.
Saturn's Nightside Ring Current During Cassini's Grand Finale
Authors: Provan G. , Bradley T. J. , Bunce E. J. , Cowley S. W. H. , Cao H. , Dougherty M. , Hunt G. J. , Roussos E. , Staniland N. R. , Tao C.
Published: February 2021

During Cassini's Grand Finale proximal orbits, the spacecraft traversed the nightside magnetotail to ∼21 Saturn radii. Clear signatures of Saturn's equatorial current sheet are observed in the magnetic field data. An axisymmetric model of the ring current is fitted to these data, amended to take into account the tilt of the current layer by solar wind forcing, its teardrop‐shaped nature and the magnetotail and magnetopause fringing fields. Variations in ring current parameters are examined in relation to external driving of the magnetosphere by the solar wind and internal driving by the two planetary period oscillations (PPOs), and compared with previous dawn and dayside observations. We find that the relative phasing of the PPOs determines the ring current's response to solar wind conditions. During solar wind compressions when the PPOs are in antiphase, a thick partial ring current is formed on the nightside, dominated by hot plasma injected by tail reconnection. This partial ring current should close partly via magnetopause currents and possibly via field‐aligned currents into the ionosphere. However, during solar wind compressions when the PPOs are in phase, this partial ring current is not detected. During solar wind rarefactions an equatorial “magnetodisc” configuration is observed in the dayside/dawn/nightside regions, with similar total currents flowing at these local times. During very quiet intervals of prolonged solar wind rarefaction, a thin current sheet with an enhanced current density is formed, indicative of a ring current dominated by cool, dense, Enceladus water group ions.
Alpine Ice‐Core Evidence of a Large Increase in Vanadium and Molybdenum Pollution in Western Europe During the 20th Century
Authors: Arienzo Monica M. , Legrand Michel , Preunkert Susanne , Stohl Andreas , Chellman Nathan , Eckhardt Sabine , Gleason Kelly E. , McConnell Joseph R.
Published: February 2021

Pollutants emitted by industrial processes are deposited across the landscape. Ice core records from mid‐latitude glaciers located close to emission sources document the history of local‐to‐regional pollution since preindustrial times. Such records underpin attribution of pollutants to specific emission sources critical to developing abatement policies. Previous ice core studies from the Alps document the overall magnitude and timing of pollution related to nitrogen and sulfur‐derived species, as well as a few metals including lead. Here, we used subannually resolved measurements of vanadium (V) and molybdenum (Mo) in two ice cores from Col du Dome (French Alps), as well as atmospheric transport and deposition modeling, to investigate sources of pollution in the free European troposphere. The noncrustal V and Mo (ncV, ncMo) components were calculated by subtracting the crustal component from the total concentration. These ice core results showed a 32‐fold increase in ncV and a 69‐fold increase in ncMo from the preindustrial era (pre‐1860) to the industrial concentration peaks. Anthropogenic V and Mo emissions in Europe were estimated using emission factors from oil and coal consumption and atmospheric transport and deposition modeling. When comparing ice core data to estimated anthropogenic V and Mo emissions in Europe, V was found to be sourced primarily from oil combustion emissions. Conversely, coal and oil combustion estimated emissions did not agree with the measured ice core Mo concentrations, suggesting that other anthropogenic Mo sources dominated coal‐burning emissions, particularly after the 1950s. Noncoal‐burning sources of Mo may include metallurgy although emission factors are poorly known.
Seasonal Precipitation and Soil Moisture Relationships Across Forests and Woodlands in the Southwestern United States
Authors: Koehn C. R. , Petrie M. D. , Bradford J. B. , Litvak M. E. , Strachan S.
Published: February 2021

Precipitation [P: mm] controls forest and woodland dynamics in the southwestern United States (SWUS) by altering soil moisture [θ: mm3 mm−3] availability, but the influence of P on θ is complex, varying across space and time. We evaluated seasonal P and θ relationships at shallow (0–20 cm) and intermediate (50 cm) soil depths for nine semiarid forest and woodland sites (56 total years), which comprised three elevation gradients in the SWUS. We developed time‐varying definitions of winter (snow accumulation), spring (moisture recharge), and summer (moisture deficit), and determined how these sites exhibited similar P influence on θ across depths in the soil profile, between seasons, and in seasons with above‐ and below‐average P. Higher elevation sites (>2,800 m) experienced greater winter P, longer springs, and shorter summers compared to lower elevation sites (<2,500 m). Seasons with above‐ and below‐average P reduced elevation‐associated differences. θ at 0–20 cm was generally decoupled from θ at 50 cm in seasons with average and below‐average P, imparted by differences in spring and summer rainfall versus winter snowfall. Notably, across‐season influence of θ (e.g., a season’s similarity to subsequent seasons) was high when the first season experienced above‐ or below‐average P, and the subsequent season experienced average P, illustrating an important temporal connection initiated by wet and dry conditions. These results illustrate similarities in P‐θ relationships across widely differing ecosystems in the SWUS, and elucidate how these relationships may be altered in a changing climate.
Diatoms in Hyporheic Sediments Trace Organic Matter Retention and Processing in the McMurdo Dry Valleys, Antarctica
Authors: Heindel Ruth C. , Darling Josh P. , Singley Joel G. , Bergstrom Anna J. , McKnight Diane M. , Lukkari Braeden M. , Welch Kathleen A. , Gooseff Michael N.
Published: February 2021

In low‐nutrient streams in cold and arid ecosystems, the spiraling of autochthonous particulate organic matter (POM) may provide important nutrient subsidies downstream. Because of its lability and the spatial heterogeneity of processing in hyporheic sediments, the downstream transport and fate of autochthonous POM can be difficult to trace. In Antarctic McMurdo Dry Valley (MDV) streams, any POM retained in the hyporheic zone is expected to be derived from surface microbial mats that contain diatoms with long‐lasting silica frustules. We tested whether diatom frustules can be used to trace the retention of autochthonous POM in the hyporheic zone and whether certain geomorphic locations promote this process. The accumulation of diatom frustules in hyporheic sediments, measured as biogenic silica, was correlated with loss‐on‐ignition organic matter and sorbed ammonium, suggesting that diatoms can be used to identify locations where POM has been retained and processed over long timescales, regardless of whether the POM remains intact. In addition, by modeling the upstream sources of hyporheic diatom assemblages, we found that POM was predominantly derived from N‐fixing microbial mats of the genus Nostoc. In terms of spatial variability, we conclude that the hyporheic sediments adjacent to the stream channel that are regularly inundated by daily flood pulses are where the most POM has been retained over long timescales. Autochthonous POM is retained in hyporheic zones of low‐nutrient streams beyond the MDVs, and we suggest that biogenic silica and diatom composition can be used to identify locations where this transfer is most prevalent.
Neogene Tectono‐Stratigraphic Evolution of the Intermontane Tarom Basin: Insights Into Basin Filling and Plateau Building Processes Along the Northern Margin of the Iranian Plateau (Arabia‐Eurasia Collision Zone)
Authors: Paknia M. , Ballato P. , Heidarzadeh G. , Cifelli F. , Hassanzadeh J. , Vezzoli G. , Mirzaie Ataabadi M. , Ghassemi M. R. , Mattei M.
Published: February 2021

The intermontane Tarom Basin of NW Iran (Arabia‐Eurasia collision zone) is located at the transition between the Iranian Plateau (IP) to the SW and the Alborz Mountains to the NE. This basin was filled by upper Cenozoic synorogenic red beds that retain first‐order information on the erosional history of adjacent topography, the vertical growth of the plateau margin and its orogen perpendicular expansion. Here, we perform a multidisciplinary study including magnetostratigraphy, sedimentology, geochronology and sandstone petrography on these red beds. Our data show that Eocene arc volcanism in the region terminated at 38‐36 Ma, while intrabasinal synorogenic sedimentation (endorheic conditions) occurred from at least 16.2 to <7.6 Ma, implying that the red beds are stratigraphically equivalent to the Upper Red Formation. After 7.6 Ma, the basin experienced intrabasinal deformation, uplift and erosion with the establishment of external drainage. Fluvial connectivity with the Caspian Sea, however, was interrupted by at least four episodes of basin aggradation. During endorheic conditions, the basin fill did not reach the elevation of the plateau interior and hence the Tarom Basin was never integrated into the plateau. Furthermore, our provenance data indicate that the northern margin of the basin (Alborz Mountains) experienced a greater magnitude of Miocene deformation and erosional exhumation than the southern one (IP margin). This agrees with recent Moho depth estimates, suggesting that crustal shortening and thickening cannot be responsible for the vertical growth of the northern margin of the IP, and hence surface uplift must have been driven by deep‐seated processes.
Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab
Authors: Zhu Andrew X. , Finn Richard S. , Kang Yoon-Koo , Yen Chia-Jui , Galle Peter R. , Llovet Josep M. , Assenat Eric , Brandi Giovanni , Motomura Kenta , Ohno Izumi , Daniele Bruno , Vogel Arndt , Yamashita Tatsuya , Hsu Chih-Hung , Gerken Guido , Bilbruck John , Hsu Yanzhi , Liang Kun , Widau Ryan C. , Wang Chunxiao , Abada Paolo , Kudo Masatoshi
Published: February 2021

Background

Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).

Methods

Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.

Results

Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6–12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354–0.574; p < 0.0001).

Conclusions

AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.

Clinical Trial Registration

ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).
CREPT/RPRD1B promotes tumorigenesis through STAT3-driven gene transcription in a p300-dependent manner
Authors: Zhai Wanli , Ye Xiongjun , Wang Yinyin , Feng Yarui , Wang Ying , Lin Yuting , Ding Lidan , Yang Liu , Wang Xuning , Kuang Yanshen , Fu Xinyuan , Eugene Chin Y. , Jia Baoqing , Zhu Bingtao , Ren Fangli , Chang Zhijie
Published: February 2021

Background

Signal transducer and activator of transcription 3 (STAT3) has been shown to upregulate gene transcription during tumorigenesis. However, how STAT3 initiates transcription remains to be exploited. This study is to reveal the role of CREPT (cell cycle-related and elevated-expression protein in tumours, or RPRD1B) in promoting STAT3 transcriptional activity.

Methods

BALB/c nude mice, CREPT overexpression or deletion cells were employed for the assay of tumour formation, chromatin immunoprecipitation, assay for transposase-accessible chromatin using sequencing.

Results

We demonstrate that CREPT, a recently identified oncoprotein, enhances STAT3 transcriptional activity to promote tumorigenesis. CREPT expression is positively correlated with activation of STAT3 signalling in tumours. Deletion of CREPT led to a decrease, but overexpression of CREPT resulted in an increase, in STAT3-initiated tumour cell proliferation, colony formation and tumour growth. Mechanistically, CREPT interacts with phosphorylated STAT3 (p-STAT3) and facilitates p-STAT3 to recruit p300 to occupy at the promoters of STAT3-targeted genes. Therefore, CREPT and STAT3 coordinately facilitate p300-mediated acetylation of histone 3 (H3K18ac and H3K27ac), further augmenting RNA polymerase II recruitment. Accordingly, depletion of p300 abolished CREPT-enhanced STAT3 transcriptional activity.

Conclusions

We propose that CREPT is a co-activator of STAT3 for recruiting p300. Our study provides an alternative strategy for the therapy of cancers related to STAT3.
A Sarcina bacterium linked to lethal disease in sanctuary chimpanzees in Sierra Leone
Authors: Owens Leah A. , Colitti Barbara , Hirji Ismail , Pizarro Andrea , Jaffe Jenny E. , Moittié Sophie , Bishop-Lilly Kimberly A. , Estrella Luis A. , Voegtly Logan J. , Kuhn Jens H. , Suen Garret , Deblois Courtney L. , Dunn Christopher D. , Juan-Sallés Carles , Goldberg Tony L.
Published: February 2021

Human and animal infections with bacteria of the genusSarcina(familyClostridiaceae) are associated with gastric dilation and emphysematous gastritis. However, the potential roles of sarcinae as commensals or pathogens remain unclear. Here, we investigate a lethal disease of unknown etiology that affects sanctuary chimpanzees (Pan troglodytes verus) in Sierra Leone. The disease, which we have named “epizootic neurologic and gastroenteric syndrome” (ENGS), is characterized by neurologic and gastrointestinal signs and results in death of the animals, even after medical treatment. Using a case-control study design, we show that ENGS is strongly associated withSarcinainfection. The microorganism is distinct fromSarcina ventriculiand other known members of its genus, based on bacterial morphology and growth characteristics. Whole-genome sequencing confirms this distinction and reveals the presence of genetic features that may account for the unusual virulence of the bacterium. Therefore, we propose that this organism be considered the representative of a new species, named “CandidatusSarcina troglodytae”. Our results suggest that a heretofore unrecognized complex of related sarcinae likely exists, some of which may be highly virulent. However, the potential role of “Ca. S. troglodytae” in the etiology of ENGS, alone or in combination with other factors, remains a topic for future research.
Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia
Authors: Gasca-Salas Carmen , Fernández-Rodríguez Beatriz , Pineda-Pardo José A. , Rodríguez-Rojas Rafael , Obeso Ignacio , Hernández-Fernández Frida , del Álamo Marta , Mata David , Guida Pasqualina , Ordás-Bandera Carlos , Montero-Roblas J. Ignacio , Martínez-Fernández Raúl , Foffani Guglielmo , Rachmilevitch Itay , Obeso José A.
Published: February 2021

MR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary BBB opening in patients with neurodegenerative disorders and brain tumors. MRgFUS could become a therapeutic tool for drug delivery of putative neurorestorative therapies. Treatment for Parkinson’s disease with dementia (PDD) is an important unmet need. We initiated a prospective, single-arm, non-randomized, proof-of-concept, safety and feasibility phase I clinical trial (NCT03608553), which is still in progress. The primary outcomes of the study were to demonstrate the safety, feasibility and reversibility of BBB disruption in PDD, targeting the right parieto-occipito-temporal cortex where cortical pathology is foremost in this clinical state. Changes in β-amyloid burden, brain metabolism after treatments and neuropsychological assessments, were analyzed as exploratory measurements. Five patients were recruited from October 2018 until May 2019, and received two treatment sessions separated by 2–3 weeks. The results are set out in a descriptive manner. Overall, this procedure was feasible and reversible with no serious clinical or radiological side effects. We report BBB opening in the parieto-occipito-temporal junction in 8/10 treatments in 5 patients as demonstrated by gadolinium enhancement. In all cases the procedures were uneventful and no side effects were encountered associated with BBB opening. From pre- to post-treatment, mild cognitive improvement was observed, and no major changes were detected in amyloid or fluorodeoxyglucose PET. MRgFUS-BBB opening in PDD is thus safe, reversible, and can be performed repeatedly. This study provides encouragement for the concept of BBB opening for drug delivery to treat dementia in PD and other neurodegenerative disorders.
Cyclodextrin-based host-guest complexes loaded with regorafenib for colorectal cancer treatment
Authors: Bai Hongzhen , Wang Jianwei , Phan Chi Uyen , Chen Qi , Hu Xiurong , Shao Guoqiang , Zhou Jun , Lai Lihua , Tang Guping
Published: February 2021

The malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG’s anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment.
The molecular basis of socially mediated phenotypic plasticity in a eusocial paper wasp
Authors: Taylor Benjamin A. , Cini Alessandro , Wyatt Christopher D. R. , Reuter Max , Sumner Seirian
Published: February 2021

Phenotypic plasticity, the ability to produce multiple phenotypes from a single genotype, represents an excellent model with which to examine the relationship between gene expression and phenotypes. Analyses of the molecular foundations of phenotypic plasticity are challenging, however, especially in the case of complex social phenotypes. Here we apply a machine learning approach to tackle this challenge by analyzing individual-level gene expression profiles of Polistes dominula paper wasps following the loss of a queen. We find that caste-associated gene expression profiles respond strongly to queen loss, and that this change is partly explained by attributes such as age but occurs even in individuals that appear phenotypically unaffected. These results demonstrate that large changes in gene expression may occur in the absence of outwardly detectable phenotypic changes, resulting here in a socially mediated de-differentiation of individuals at the transcriptomic level but not at the levels of ovarian development or behavior.
IgA transcytosis and antigen recognition govern ovarian cancer immunity
Authors: Biswas Subir , Mandal Gunjan , Payne Kyle K. , Anadon Carmen M. , Gatenbee Chandler D. , Chaurio Ricardo A. , Costich Tara Lee , Moran Carlos , Harro Carly M. , Rigolizzo Kristen E. , Mine Jessica A. , Trillo-Tinoco Jimena , Sasamoto Naoko , Terry Kathryn L. , Marchion Douglas , Buras Andrea , Wenham Robert M. , Yu Xiaoqing , Townsend Mary K. , Tworoger Shelley S. , Rodriguez Paulo C. , Anderson Alexander R. , Conejo-Garcia Jose R.
Published: February 2021

Most ovarian cancers are infiltrated by prognostically relevant activated T cells1–3, yet exhibit low response rates to immune checkpoint inhibitors4. Memory B cell and plasma cell infiltrates have previously been associated with better outcomes in ovarian cancer5,6, but the nature and functional relevance of these responses are controversial. Here, using 3 independent cohorts that in total comprise 534 patients with high-grade serous ovarian cancer, we show that robust, protective humoral responses are dominated by the production of polyclonal IgA, which binds to polymeric IgA receptors that are universally expressed on ovarian cancer cells. Notably, tumour B-cell-derived IgA redirects myeloid cells against extracellular oncogenic drivers, which causes tumour cell death. In addition, IgA transcytosis through malignant epithelial cells elicits transcriptional changes that antagonize the RAS pathway and sensitize tumour cells to cytolytic killing by T cells, which also contributes to hindering malignant progression. Thus, tumour-antigen-specific and -antigen-independent IgA responses antagonize the growth of ovarian cancer by governing coordinated tumour cell, T cell and B cell responses. These findings provide a platform for identifying targets that are spontaneously recognized by intratumoural B-cell-derived antibodies, and suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors.
Author Correction: A structural variation reference for medical and population genetics
Authors:   Genome Aggregation Database Production Team, Collins Ryan L. ,   Genome Aggregation Database Consortium, Brand Harrison , Karczewski Konrad J. , Zhao Xuefang , Alföldi Jessica , Francioli Laurent C. , Khera Amit V. , Lowther Chelsea , Gauthier Laura D. , Wang Harold , Watts Nicholas A. , Solomonson Matthew , O’Donnell-Luria Anne , Baumann Alexander , Munshi Ruchi , Walker Mark , Whelan Christopher W. , Huang Yongqing , Brookings Ted , Sharpe Ted , Stone Matthew R. , Valkanas Elise , Fu Jack , Tiao Grace , Laricchia Kristen M. , Ruano-Rubio Valentin , Stevens Christine , Gupta Namrata , Cusick Caroline , Margolin Lauren , Taylor Kent D. , Lin Henry J. , Rich Stephen S. , Post Wendy S. , Chen Yii-Der Ida , Rotter Jerome I. , Nusbaum Chad , Philippakis Anthony , Lander Eric , Gabriel Stacey , Neale Benjamin M. , Kathiresan Sekar , Daly Mark J. , Banks Eric , MacArthur Daniel G. , Talkowski Michael E.
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03176-6.
Edge states of Floquet–Dirac semimetal in a laser-driven semiconductor quantum-well
Authors: Zhang Boyuan , Maeshima Nobuya , Hino Ken-ichi
Published: February 2021

Band crossings observed in a wide range of condensed matter systems are recognized as a key to understand low-energy fermionic excitations that behave as massless Dirac particles. Despite rapid progress in this field, the exploration of non-equilibrium topological states remains scarce and it has potential ability of providing a new platform to create unexpected massless Dirac states. Here we show that in a semiconductor quantum-well driven by a cw-laser with linear polarization, the optical Stark effect conducts bulk-band crossing, and the resulting Floquet-Dirac semimetallic phase supports an unconventional edge state in the projected one-dimensional Brillouin zone under a boundary condition that an electron is confined in the direction perpendicular to that of the laser polarization. Further, we reveal that this edge state mediates a transition between topological and non-topological edge states that is caused by tuning the laser intensity. We also show that the properties of the edge states are strikingly changed under a different boundary condition. It is found that such difference originates from that nearly fourfold-degenerate points exist in a certain intermediate region of the bulk Brillouin zone between high-symmetry points.
Understanding structure/function relationships in nitrifying microbial communities after cross-transfer between freshwater and seawater
Authors: Gonzalez-Silva Blanca M. , Jonassen Kjell Rune , Bakke Ingrid , Østgaard Kjetill , Vadstein Olav
Published: February 2021

In this study, nitrification before and after abrupt cross-transfer in salinity was investigated in two moving bed biofilm reactors inoculated with nitrifying cultures that had adaptation to freshwater (FR) and seawater salinities (SR). FR and SR MBRRs were exposed to short and long term cross-transfer in salinity, and the functional capacity of nitrifying microbial communities was quantified by the estimation of ammonia and nitrite oxidation rates. Salinity induced successions were evaluated before and after salinity change by deep sequencing of 16S rRNA gene amplicons and statistical analysis. The bacterial community structure was characterized and Venn diagrams were included. The results indicated that after salinity cross-transfer, the FR was not significantly recovered at seawater salinity whereas SR showed high resistance to stress caused by low-salt. Succession and physiological plasticity were the main mechanisms of the long-term adaption of the nitrifying communities exposed to abrupt salinity changes. Independently of salinity, some nitrifiers presented high physiological plasticity towards salinity and were very successful at both zero and full seawater salinity. SR culture is robust and suitable inoculum for ammonium removal from recirculating aquaculture systems and industrial wastewaters with variable and fast salinity changes. Our findings contradict the current perspective of the significance of salinity on the structure of nitrifying communities.
B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF
Authors: Bakhuraysah Maha M. , Theotokis Paschalis , Lee Jae Young , Alrehaili Amani A. , Aui Pei-Mun , Figgett William A. , Azari Michael F. , Abou-Afech John-Paul , Mackay Fabienne , Siatskas Christopher , Alderuccio Frank , Strittmatter Stephen M. , Grigoriadis Nikolaos , Petratos Steven
Published: February 2021

We have previously reported evidence that Nogo-A activation of Nogo-receptor 1 (NgR1) can drive axonal dystrophy during the neurological progression of experimental autoimmune encephalomyelitis (EAE). However, the B-cell activating factor (BAFF/BlyS) may also be an important ligand of NgR during neuroinflammation. In the current study we define that NgR1 and its homologs may contribute to immune cell signaling during EAE. Meningeal B-cells expressing NgR1 and NgR3 were identified within the lumbosacral spinal cords ofngr1+/+EAE-induced mice at clinical score 1. Furthermore, increased secretion of immunoglobulins that bound to central nervous system myelin were shown to be generated from isolated NgR1- and NgR3-expressing B-cells ofngr1+/+EAE-induced mice. In vitro BAFF stimulation of NgR1- and NgR3-expressing B cells, directed them into the cell cycle DNA synthesis phase. However, when we antagonized BAFF signaling by co-incubation with recombinant BAFF-R, NgR1-Fc, or NgR3 peptides, the B cells remained in the G0/G1 phase. The data suggest that B cells express NgR1 and NgR3 during EAE, being localized to infiltrates of the meninges and that their regulation is governed by BAFF signaling.
Specific inhibition of FGF5-induced cell proliferation by RNA aptamers
Authors: Amano Ryo , Namekata Masato , Horiuchi Masataka , Saso Minami , Yanagisawa Takuya , Tanaka Yoichiro , Ghani Farhana Ishrat , Yamamoto Masakuni , Sakamoto Taiichi
Published: February 2021

Fibroblast growth factor 5 (FGF5) is a crucial regulator of hair growth and an oncogenic factor in several human cancers. To generate FGF5 inhibitors, we performed Systematic Evolution of Ligands by EXponential enrichment and obtained novel RNA aptamers that have high affinity to human FGF5. These aptamers inhibited FGF5-induced cell proliferation, but did not inhibit FGF2-induced cell proliferation. Surface plasmon resonance demonstrated that one of the aptamers, F5f1, binds to FGF5 tightly (Kd = 0.7 ± 0.2 nM), but did not fully to FGF1, FGF2, FGF4, FGF6, or FGFR1. Based on sequence and secondary structure similarities of the aptamers, we generated the truncated aptamer, F5f1_56, which has higher affinity (Kd = 0.118 ± 0.003 nM) than the original F5f1. Since the aptamers have high affinity and specificity to FGF5 and inhibit FGF5-induced cell proliferation, they may be candidates for therapeutic use with FGF5-related diseases or hair disorders.
Evidence for strong environmental control on bacterial microbiomes of Antarctic springtails
Authors: Leo Chiara , Nardi Francesco , Cucini Claudio , Frati Francesco , Convey Peter , Weedon James T. , Roelofs Dick , Carapelli Antonio
Published: February 2021

Collembola are a key component of the soil biota globally, playing an important role in community and ecosystem dynamics. Equally significant are their associated microbiomes, that can contribute to key metabolic functions. In the present study, we investigated the bacterial community composition of four Antarctic springtail species to assess if and how the extreme Antarctic environment has shaped the collembolans’ microbiomes. Springtails were collected from two biogeographical regions, the maritime and the continental Antarctic. From each region, two endemic species, belonging to the generaCryptopygus(Isotomidae, Entomobryomorpha) andFriesea(Neanuridae, Poduromorpha), were included. This experimental design allowed us to quantify the relative importance of ecological factors (different regions of occurrence) and/or phylogenetic divergence in the host (different Orders) in shaping the Collembola microbiome. The diversity and richness of springtail microbiomes was lower in the Antarctic taxa compared to published information from species from temperate regions. The microbiome composition was predominantly species-specific, with a limited core microbiome shared across the four species examined. While both geographic origin and host species influenced the associated microbiomes, the former was the prevalent driver, with closer similarity between springtails from the same bioregion than between those belonging to the same genus.
Unravelling the local crystallographic structure of ferromagnetic $$\gamma '$$-$$\hbox {Ga}_y \hbox {Fe}_{4-y}$$N nanocrystals embedded in GaN
Authors: Navarro-Quezada Andrea , Gas Katarzyna , Spindlberger Anna , Karimi Fahim , Sawicki Maciej , Ciatto Gianluca , Bonanni Alberta
Published: February 2021

In the Fe-doped GaN phase-separated magnetic semiconductor Ga$$\delta $$
δ
FeN, the presence of embedded $$\gamma '$$

γ
′

-$$\hbox {Ga}_y \hbox {Fe}_{4-y}$$

Ga
y

Fe

4
-
y

N nanocrystals determines the magnetic properties of the system. Here, through a combination of anomalous X-ray diffraction and diffraction anomalous fine structure, the local structure of Ga in self-assembled face-centered cubic (fcc) $$\gamma '$$

γ
′

-$$\hbox {Ga}_y \hbox {Fe}_{4-y}$$

Ga
y

Fe

4
-
y

N nanocrystals embedded in wurtzite GaN thin layers is investigated in order to shed light onto the correlation between fabrication parameters, local structural arrangement and overall magnetic properties of the material system. It is found, that by adjusting the growth parameters and thus, the crystallographic surroundings, the Ga atoms can be induced to incorporate into 3c positions at the faces of the fcc crystal lattice, reaching a maximum occupancy of 30%. The magnetic response of the embedded nanocrystals is ferromagnetic with Curie temperature increasing from 450 to 500 K with the Ga occupation. These results demonstrate the outstanding potential of the employed experimental protocol for unravelling the local structure of magnetic multi-phase systems, even when embedded in a matrix containing the same element under investigation.
Human leukocyte antigen B*0702 is protective against ocular Stevens–Johnson syndrome/toxic epidermal necrolysis in the UK population
Authors: Butt Gibran F. , Hassan Ali , Wallace Graham R. , Kinoshita Shigeru , Ahmad Sajjad , Ueta Mayumi , Rauz Saaeha
Published: February 2021

Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) are part of a disease continuum of vesiculobullous mucocutaneous reactions affecting the skin and mucous membranes including the ocular surface. Manifestations of disease range from mild dry eye to progressive conjunctival cicatrisation, limbal epithelial stem cell failure and corneal blindness. In Far Eastern and South East Asian populations where SJS/TEN is prevalent, numerous human leukocyte antigen (HLA) gene variants at the A, B and C loci have been identified as risk factors for developing SJS/TEN with severe ocular complications (SOC). By contrast, the incidence of SJS/TEN with SOC in European countries is relatively low. To date, ocular SJS/TEN risk altering alleles have not been widely investigated in European populations. In this study, we analysed the association of HLA -A, -B and -C alleles with SJS/TEN in 33 patients residing in the UK with age matched controls. The data showed statistically significant novel negative allele association with HLA-B*0702 and a trend with HLA-C*0702 in the patient group, indicating these alleles are protective. Further characterisation of protective and risk alleles in other ethnic groups is required to fully elucidate the putative role of these alleles in the susceptibility of SJS/TEN with or without severe ocular complications in patients in the UK.
Characterization of a green Stentor with symbiotic algae growing in an extremely oligotrophic environment and storing large amounts of starch granules in its cytoplasm
Authors: Hoshina Ryo , Tsukii Yuuji , Harumoto Terue , Suzaki Toshinobu
Published: February 2021

The genus Stentor is a relatively well-known ciliate owing to its lucid trumpet shape. Stentor pyriformis represents a green, short, and fat Stentor, but it is a little-known species. We investigated 124 ponds and wetlands in Japan and confirmed the presence of S. pyriformis at 23 locations. All these ponds were noticeably oligotrophic. With the improvement of oligotrophic culture conditions, we succeeded in long-term cultivation of three strains of S. pyriformis. The cytoplasm of S. piriformis contains a large number of 1–3 μm refractive granules that turn brown by Lugol’s staining. The granules also show a typical Maltese-cross pattern by polarization microscopy, strongly suggesting that the granules are made of amylopectin-rich starch. By analyzing the algal rDNA, it was found that all S. pyriformis symbionts investigated in this study were Chlorella variabilis. This species is known as the symbiont of Paramecium bursaria and is physiologically specialized for endosymbiosis. Genetic discrepancies between C. variabilis of S. pyriformis and P. bursaria may indicate that algal sharing was an old incident. Having symbiotic algae and storing carbohydrate granules in the cytoplasm is considered a powerful strategy for this ciliate to withstand oligotrophic and cold winter environments in highland bogs.
A molecularly defined skin test reagent for the diagnosis of bovine tuberculosis compatible with vaccination against Johne’s Disease
Authors: Middleton Sonya , Steinbach Sabine , Coad Michael , McGill Kevina , Brady Colm , Duignan Anthony , Wiseman Jimmy , Gormley Eamonn , Jones Gareth J. , Vordermeier H. Martin
Published: February 2021

Tuberculin Purified Protein Derivatives (PPDs) exhibit multiple limitations: they are crude extracts from mycobacterial cultures with largely unknown active components; their production depends on culture of mycobacteria requiring expensive BCL3 production facilities; and their potency depends on the technically demanding guinea pig assay. To overcome these limitations, we developed a molecularly defined tuberculin (MDT) by adding further antigens to our prototype reagent composed of ESAT-6, CFP-10 and Rv3615c (DIVA skin test, DST). In vitro screening using PBMC from infected and uninfected cattle shortlisted four antigens from a literature-based list of 18 to formulate the MDT. These four antigens plus the previously identified Rv3020c protein, produced as recombinant proteins or overlapping synthetic peptides, were formulated together with the three DST antigens into the MDT to test cattle experimentally and naturally infected with M. bovis, uninfected cattle and MAP vaccinated calves. We demonstrated significant increases in MDT-induced skin responses compared to DST in infected animals, whilst maintaining high specificity in unvaccinated or MAP vaccinated calves. Further, MDT can also be applied in in vitro blood-based interferon-gamma release assays. Thus, MDT promises to be a robust diagnostic skin and blood test reagent overcoming some of the limitations of PPDs and warrants full validation.
Urine lipoarabinomannan in HIV uninfected, smear negative, symptomatic TB patients: effective sample pretreatment for a sensitive immunoassay and mass spectrometry
Authors: Amin Anita G. , De Prithwiraj , Graham Barbara , Calderon Roger I. , Franke Molly F. , Chatterjee Delphi
Published: February 2021

Our study sought to determine whether urine lipoarabinomannan (LAM) could be validated in a sample cohort that consisted mainly of HIV uninfected individuals that presented with tuberculosis symptoms. We evaluated two tests developed in our laboratory, and used them on clinical samples from Lima, Peru where incidence of HIV is low. ELISA analysis was performed on 160 samples (from 140 adult culture-confirmed TB cases and 20 symptomatic TB-negative child controls) using 100 μL of urine after pretreatment with Proteinase K. Two different mouse monoclonal antibodies-CS35 and CHCS9-08 were used individually for capture of urine LAM. Among cases, optical density (OD450) values had a positive association with higher bacillary loads. The 20 controls had negative values (below the limit of detection). The assay correctly identified all samples (97–100% accuracy confidence interval). For an alternate validation of the ELISA results, we analyzed all 160 urine samples using an antibody independent chemoanalytical approach. Samples were called positive only when LAM surrogates—tuberculostearic acid (TBSA) and d-arabinose (d-ara)—were found to be present in similar amounts. All TB cases, including the 40 with a negative sputum smear had LAM in detectable quantities in urine. None of the controls had detectable amounts of LAM. Our study shows that urinary LAM detection is feasible in HIV uninfected, smear negative TB patients.
Unravelling the involvement of cilevirus p32 protein in the viral transport
Authors: Leastro Mikhail Oliveira , Freitas-Astúa Juliana , Kitajima Elliot Watanabe , Pallás Vicente , Sánchez-Navarro Jesús A.
Published: February 2021

Citrus leprosis (CL) is a severe disease that affects citrus orchards mainly in Latin America. It is caused by Brevipalpus-transmitted viruses from genera Cilevirus and Dichorhavirus. Currently, no reports have explored the movement machinery for the cilevirus. Here, we have performed a detailed functional study of the p32 movement protein (MP) of two cileviruses. Citrus leprosis-associated viruses are not able to move systemically in neither their natural nor experimental host plants. However, here we show that cilevirus MPs are able to allow the cell-to-cell and long-distance transport of movement-defective alfalfa mosaic virus (AMV). Several features related with the viral transport were explored, including: (i) the ability of cilevirus MPs to facilitate virus movement on a nucleocapsid assembly independent-manner; (ii) the generation of tubular structures from transient expression in protoplast; (iii) the capability of the N- and C- terminus of MP to interact with the cognate capsid protein (p29) and; (iv) the role of the C-terminus of p32 in the cell-to-cell and long-distance transport, tubule formation and the MP-plasmodesmata co-localization. The MP was able to direct the p29 to the plasmodesmata, whereby the C-terminus of MP is independently responsible to recruit the p29 to the cell periphery. Furthermore, we report that MP possess the capacity to enter the nucleolus and to bind to a major nucleolar protein, the fibrillarin. Based on our findings, we provide a model for the role of the p32 in the intra- and intercellular viral spread.
Data-driven identification of ageing-related diseases from electronic health records
Authors: Kuan Valerie , Fraser Helen C. , Hingorani Melanie , Denaxas Spiros , Gonzalez-Izquierdo Arturo , Direk Kenan , Nitsch Dorothea , Mathur Rohini , Parisinos Constantinos A. , Lumbers R. Thomas , Sofat Reecha , Wong Ian C. K. , Casas Juan P. , Thornton Janet M. , Hemingway Harry , Partridge Linda , Hingorani Aroon D.
Published: February 2021

Reducing the burden of late-life morbidity requires an understanding of the mechanisms of ageing-related diseases (ARDs), defined as diseases that accumulate with increasing age. This has been hampered by the lack of formal criteria to identify ARDs. Here, we present a framework to identify ARDs using two complementary methods consisting of unsupervised machine learning and actuarial techniques, which we applied to electronic health records (EHRs) from 3,009,048 individuals in England using primary care data from the Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics admitted patient care dataset between 1 April 2010 and 31 March 2015 (mean age 49.7 years (s.d. 18.6), 51% female, 70% white ethnicity). We grouped 278 high-burden diseases into nine main clusters according to their patterns of disease onset, using a hierarchical agglomerative clustering algorithm. Four of these clusters, encompassing 207 diseases spanning diverse organ systems and clinical specialties, had rates of disease onset that clearly increased with chronological age. However, the ages of onset for these four clusters were strikingly different, with median age of onset 82 years (IQR 82–83) for Cluster 1, 77 years (IQR 75–77) for Cluster 2, 69 years (IQR 66–71) for Cluster 3 and 57 years (IQR 54–59) for Cluster 4. Fitting to ageing-related actuarial models confirmed that the vast majority of these 207 diseases had a high probability of being ageing-related. Cardiovascular diseases and cancers were highly represented, while benign neoplastic, skin and psychiatric conditions were largely absent from the four ageing-related clusters. Our framework identifies and clusters ARDs and can form the basis for fundamental and translational research into ageing pathways.