bluuebunny/crossref_metadata_2025 huggingface dataset:
Hydrodynamic Analysis of CO2 Migration in Heterogeneous Rocks: Conventional and Micro‐Bubble CO2 Flooding Experiments and Pore‐Scale Numerical Simulations
Authors: Wang Dayong , Fan Jiarui , Xue Ziqiu
Published: May 2022

The hydrodynamics of CO2 flooding determine its capacity and efficiency in CO2 geological storage; however, this is not sufficiently understood. In this study, a medical X‐ray CT was used to visualize CO2 flooding in a Berea sandstone sample, and the migration pattern and distribution of injected CO2 were carefully analyzed in a series of comparison experiments. For conventional flooding, CO2 migrated mostly along the high‐porosity and large‐pore‐size layers, leaving a large area of low‐porosity and small‐pore‐size regions undisplaced. Comparatively, before CO2 broke through, CO2 fingering developed and migrated slowly for micro‐bubble flooding, showing that CO2 micro‐bubbles infiltrated into more regions than the CO2 continuous fluid. After CO2 breakthrough began, the micro‐bubble CO2 continued to enter some previously undisplaced regions; however, this was inconspicuous for conventional flooding. Finally, micro‐bubble flooding increased CO2 saturation by 6.1% over conventional flooding. Compared to conventional flooding, an essential hydrodynamic change by micro‐bubble flooding weakened the resistance of interface tension over CO2 infiltration into the small pores. Accordingly, two types of hydrodynamic models were proposed for conventional and micro‐bubble CO2 flooding, and their simulated pore‐scale CO2 migration results in a cluster of heterogeneous pores were compatible with the aforementioned core‐scale experimental observations. According to these models, both the small sizes and high injection rates of micro‐bubble CO2 were instrumental in enhancing the displacement effect. The filter for micro‐bubble CO2 injection in our experiment achieved even injection of the small CO2 micro‐bubbles at a relatively high rate, ensuring its practical potential in field applications.
Observations of Modulation of Ion Flux in the Coma of Comet 67P/Churyumov‐Gerasimenko
Authors: Goldstein R. , Burch J. L. , Llera K. , Altwegg K. , Rubin M. , Eriksson A. I. , Nilsson H.
Published: May 2022

On 6–8 June 2015, the Ion and Electron Sensor on board Rosetta observed keV‐range water‐group pickup ions arriving from the solar direction. Based on magnetic field intensification and variations, the appearance of the ions was likely to have been caused by a coronal mass ejection. During the 3‐day period when Rosetta was 200 km from the comet, peak ion energy/charge (E/q) varied over a range from 50 eV to 1 keV in concert with neutral gas density variations caused by the rotation of the comet and its variable solar illumination. Thermal ion densities showed the same variations. The neutral density variations provided a unique opportunity to observe the repeated slowing of the solar wind by mass loading caused by charge exchange between energetic water‐group ions and thermal water‐group molecules. Such solar wind slowing was observed previously only by flyby missions that provided single events.
Evidence of Transient Energy and Enstrophy Cascades in Tidal Flows: A Scale to Scale Analysis
Authors: De Leo A. , Stocchino A.
Published: May 2022

Tidal currents are predominant in coastal areas, causing the generation of vortices at different scales. We reproduce the main process of vortex shedding generated in tidal systems with inlets and channels using a laboratory large‐scale model. A filter‐space technique is implemented to analyze nonlinear energy/enstrophy transfer rates and map out the energy pathways through the flow scales of the measured velocity fields. We provide sound evidence of the transitional character of the energy cascades during a tidal period. The periodic generation and destruction of tidal vortices plays a relevant role in the transition from an inverse to a direct energy cascade within a tidal period. The period‐averaged energy budget shows the coexistence of multiple cascades. Small scales follow a direct energy cascade, whereas a split‐energy cascade is found at intermediate and large scales, where part of the injected energy goes to small scales and part to a larger flow scale.
Signatures of Auroral Potential Structure Extending Through the Near‐Equatorial Inner Magnetosphere
Authors: Imajo S. , Miyoshi Y. , Asamura K. , Shinohara I. , Nosé M. , Shiokawa K. , Kasahara Y. , Kasaba Y. , Matsuoka A. , Kasahara S. , Yokota S. , Keika K. , Hori T. , Shoji M. , Nakamura S. , Teramoto M.
Published: May 2022

The auroral acceleration region plays an important role in the magnetosphere‐ionosphere coupling system. In this study, signatures of an auroral U‐shaped potential structure were found for the first time in the near‐equatorial inner magnetosphere by the Arase satellite at ∼6.0 RE geocentric distance and 11° magnetic latitude. The observed magnetic and electric field variations corresponded to the equatorward motion of the upward field‐aligned current and converging perpendicular electric field. Examining the three‐dimensional velocity distribution function of H+ and O+ ions, we demonstrate that upflowing ion beams were significantly deflected in an east‐west direction with a perpendicular velocity up to ∼80 km/s, which is consistent with the ExB drift velocity. A simple particle drift model with the inferred auroral perpendicular potential presents a new kink‐like drift path of ions from the magnetotail, implying that the auroral potential structure has a great impact on particle dynamics in the near‐earth plasma sheet.
Occurrence Statistics of Horse Collar Aurora
Authors: Bower G. E. , Milan S. E. , Paxton L. J. , Anderson B. J.
Published: May 2022

Horse collar aurora (HCA) are an auroral feature where the dawn and dusk sector auroral oval moves polewards and the polar cap becomes teardrop shaped. They form during prolonged periods of northward interplanetary magnetic field (IMF), when the IMF clock angle is small. Their formation has been linked to dual‐lobe reconnection (DLR) closing magnetic flux at the dayside magnetopause. The conditions necessary for DLR are currently not well‐understood therefore understanding HCA statistics will allow DLR to be studied in more detail. We have identified over 600 HCA events between 2010 and 2016 in UV images captured by the Special Sensor Ultraviolet Spectrographic Imager instrument on‐board the Defense Meteorological Satellite Program spacecraft F16, F17 and F18. As expected, there is a clear preference for HCA occurring during northward IMF. We find no clear seasonal dependence in their occurrence, with an average of 8 HCA events per month. The occurrence of HCA events does not appear to depend on the Bx component of the IMF. Considering the average radiance intensity across the dusk‐dawn meridian shows the HCA as a separate bulge inside the auroral oval and that the dawn side arc of the HCA is usually brighter than the dusk in the Lyman‐Birge‐Hopfield short band. We relate this to the expected field aligned current pattern of HCA formation. We further suggest that transpolar arcs observed in the dawn sector simultaneously in both northern and southern hemispheres are misidentified HCA.
InSight Pressure Data Recalibration, and Its Application to the Study of Long‐Term Pressure Changes on Mars
Authors: Lange L. , Forget F. , Banfield D. , Wolff M. , Spiga A. , Millour E. , Viúdez‐Moreiras D. , Bierjon A. , Piqueux S. , Newman C. , Pla‐García J. , Banerdt W. B.
Published: May 2022

Observations of the South Polar Residual Cap suggest a possible erosion of the cap, leading to an increase of the global mass of the atmosphere. We test this assumption by making the first comparison between Viking 1 and InSight surface pressure data, which were recorded 40 years apart. Such a comparison also allows us to determine changes in the dynamics of the seasonal ice caps between these two periods. To do so, we first had to recalibrate the InSight pressure data because of their unexpected sensitivity to the sensor temperature. Then, we had to design a procedure to compare distant pressure measurements. We propose two surface pressure interpolation methods at the local and global scale to do the comparison. The comparison of Viking and InSight seasonal surface pressure variations does not show changes larger than ±8 Pa in the CO2 cycle. Such conclusions are supported by an analysis of Mars Science Laboratory (MSL) pressure data. Further comparisons with images of the south seasonal cap taken by the Viking 2 orbiter and MARCI camera do not display significant changes in the dynamics of this cap over a 40 year period. Only a possible larger extension of the North Cap after the global storm of MY 34 is observed, but the physical mechanisms behind this anomaly are not well determined. Finally, the first comparison of MSL and InSight pressure data suggests a pressure deficit at Gale crater during southern summer, possibly resulting from a large presence of dust suspended within the crater.
Deep Learning to Estimate Model Biases in an Operational NWP Assimilation System
Authors: Laloyaux Patrick , Kurth Thorsten , Dueben Peter Dominik , Hall David
Published: May 2022

Model bias is one of the main obstacles to improved accuracy and reliability in numerical weather prediction conducted with state‐of‐the‐art atmospheric models. To deal with model bias, a modification of the standard four‐dimensional variational (4D‐Var) algorithm, called weak‐constraint 4D‐Var, has been developed where a forcing term is introduced into the model to correct for the bias that accumulates along the model trajectory. This approach reduced the temperature bias in the stratosphere by up to 50% and is implemented in the European Centre for Medium‐Range Weather Forecasts operational forecasting system. Despite different origins and applications, data assimilation (DA) and Deep Learning are both able to learn about the Earth system from observations. In this paper, a deep learning approach for model bias correction is developed using temperature retrievals from radio occultation (RO) measurements. Neural networks (NNs) require a large number of samples to properly capture the relationship between the temperature first‐guess trajectory and the model bias. As running the Integrated Forecasting System (IFS) DA system for extended periods of time with a fixed model version and at realistic resolutions is computationally very expensive, we have chosen to train, the initial NNs are trained using the ERA5 reanalysis before using transfer learning on 1 year of the current IFS model. Preliminary results show that convolutional NNs are adequate to estimate model bias from RO temperature retrievals. The different strengths and weaknesses of both deep learning and weak constraint 4D‐Var are discussed, highlighting the potential for each method to learn model biases effectively and adaptively.
The Potential for a Networked Ionospheric Sounding Constellation
Authors: Chartier A. T.
Published: May 2022

A novel networked sounding constellation mission concept is proposed. Radio sounding is the original sensing method that proved the existence of the ionosphere. Satellite‐borne sounders provided the first global observations of the terrestrial ionosphere and plasmasphere, as well as the Martian ionosphere. Networked sounding, where signals are transmitted and received across multiple instruments, has been used on the ground since the first days of ionospheric observation. This paper proposes networked sounding from space, to produce measurements of the F‐layer peak, enhanced E‐layers, regions of turbulent structuring, the topside scale height (or transition height) and potentially the plasmapause. The principal advantage of sounding over other methods is direct measurement of the peak density, where a networked implementation greatly increases spatial data coverage because it provides multiple unique signal paths through the ionosphere at different frequencies. Major advances in satellite software‐defined radio, deployable antennas, signal processing and data analysis have been made in recent years, such that a networked sounding constellation could be built at realistic cost—either as a hosted payload on commercial buses or on dedicated CubeSats.
Protozoal food vacuoles enhance transformation in Vibrio cholerae through SOS-regulated DNA integration
Authors: Rahman Md Hafizur , Mahbub Khandaker Rayhan , Espinoza-Vergara Gustavo , Ritchie Angus , Hoque M Mozammel , Noorian Parisa , Cole Louise , McDougald Diane , Labbate Maurizio
Published: May 2022

Vibrio cholerae, the bacterial pathogen responsible for the diarrheal disease cholera, resides in the aquatic environment between outbreaks. For bacteria, genetic variation by lateral gene transfer (LGT) is important for survival and adaptation. In the aquatic environment, V. cholerae is predominantly found in biofilms associated with chitinous organisms or with chitin “rain”. Chitin induces competency in V. cholerae, which can lead to LGT. In the environment, V. cholerae is also subjected to predation pressure by protist. Here we investigated whether protozoal predation affected LGT using the integron as a model. Integrons facilitate the integration of mobile DNA (gene cassettes) into the bacterial chromosome. We report that protozoal predation enhances transformation of a gene cassette by as much as 405-fold. We show that oxidative radicals produced in the protozoal phagosome induces the universal SOS response, which in turn upregulates the integron-integrase, the recombinase that facilitates cassette integration. Additionally, we show that during predation, V. cholerae requires the type VI secretion system to acquire the gene cassette from Escherichia coli. These results show that protozoal predation enhances LGT thus producing genetic variants that may have increased capacity to survive grazing. Additionally, the conditions in the food vacuole may make it a “hot spot” for LGT by accumulating diverse bacteria and inducing the SOS response helping drive genetic diversification and evolution.
Systemic DNA and RNA damage from oxidation after serotonergic treatment of unipolar depression
Authors: Jorgensen Anders , Köhler-Forsberg Kristin , Henriksen Trine , Weimann Allan , Brandslund Ivan , Ellervik Christina , Poulsen Henrik E. , Knudsen Gitte Moos , Frokjaer Vibe G. , Jorgensen Martin B.
Published: May 2022

Previous studies have indicated that antidepressants that inhibit the serotonin transporter reduces oxidative stress. DNA and RNA damage from oxidation is involved in aging and a range of age-related pathophysiological processes. Here, we studied the urinary excretion of markers of DNA and RNA damage from oxidation, 8-oxodG and 8-oxoGuo, respectively, in the NeuroPharm cohort of 100 drug-free patients with unipolar depression and in 856 non-psychiatric community controls. Patients were subsequently treated for 8 weeks with escitalopram in flexible doses of 5–20 mg; seven of these switched to duloxetine by week 4, as allowed by the protocol. At week 8, 82 patients were followed up clinically and with measurements of 8-oxodG/8-oxoGuo. Contextual data were collected in patients, including markers of cortisol excretion and low-grade inflammation. The intervention was associated with a substantial reduction in both 8-oxodG/8-oxoGuo excretion (25% and 10%, respectively). The change was not significantly correlated to measures of clinical improvement. Both markers were strongly and negatively correlated to cortisol, as measured by the area under the curve for the full-day salivary cortisol excretion. Surprisingly, patients had similar levels of 8-oxodG excretion and lower levels of 8-oxoGuo excretion at baseline compared to the controls. We conclude that intervention with serotonin reuptake inhibitors in unipolar depression is associated with a reduction in systemic DNA and RNA damage from oxidation. To our knowledge, this to date the largest intervention study to characterize this phenomenon, and the first to include a marker of RNA oxidation.
A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection
Authors: Jamison David A. , Anand Narayanan S. , Trovão Nídia S. , Guarnieri Joseph W. , Topper Michael J. , Moraes-Vieira Pedro M. , Zaksas Viktorija , Singh Keshav K. , Wurtele Eve Syrkin , Beheshti Afshin
Published: May 2022

COVID-19, the disease caused by SARS-CoV-2, has claimed approximately 5 million lives and 257 million cases reported globally. This virus and disease have significantly affected people worldwide, whether directly and/or indirectly, with a virulent pathogen that continues to evolve as we race to learn how to prevent, control, or cure COVID-19. The focus of this review is on the SARS-CoV-2 virus’ mechanism of infection and its proclivity at adapting and restructuring the intracellular environment to support viral replication. We highlight current knowledge and how scientific communities with expertize in viral, cellular, and clinical biology have contributed to increase our understanding of SARS-CoV-2, and how these findings may help explain the widely varied clinical observations of COVID-19 patients.
Recommendations for whole genome sequencing in diagnostics for rare diseases
Authors: Souche Erika , Beltran Sergi , Brosens Erwin , Belmont John W. , Fossum Magdalena , Riess Olaf , Gilissen Christian , Ardeshirdavani Amin , Houge Gunnar , van Gijn Marielle , Clayton-Smith Jill , Synofzik Matthis , de Leeuw Nicole , Deans Zandra C. , Dincer Yasemin , Eck Sebastian H. , van der Crabben Saskia , Balasubramanian Meena , Graessner Holm , Sturm Marc , Firth Helen , Ferlini Alessandra , Nabbout Rima , De Baere Elfride , Liehr Thomas , Macek Milan , Matthijs Gert , Scheffer Hans , Bauer Peter , Yntema Helger G. , Weiss Marjan M.
Published: May 2022

In 2016, guidelines for diagnostic Next Generation Sequencing (NGS) have been published by EuroGentest in order to assist laboratories in the implementation and accreditation of NGS in a diagnostic setting. These guidelines mainly focused on Whole Exome Sequencing (WES) and targeted (gene panels) sequencing detecting small germline variants (Single Nucleotide Variants (SNVs) and insertions/deletions (indels)). Since then, Whole Genome Sequencing (WGS) has been increasingly introduced in the diagnosis of rare diseases as WGS allows the simultaneous detection of SNVs, Structural Variants (SVs) and other types of variants such as repeat expansions. The use of WGS in diagnostics warrants the re-evaluation and update of previously published guidelines. This work was jointly initiated by EuroGentest and the Horizon2020 project Solve-RD. Statements from the 2016 guidelines have been reviewed in the context of WGS and updated where necessary. The aim of these recommendations is primarily to list the points to consider for clinical (laboratory) geneticists, bioinformaticians, and (non-)geneticists, to provide technical advice, aid clinical decision-making and the reporting of the results.
A mathematical perspective on edge-centric brain functional connectivity
Authors: Novelli Leonardo , Razi Adeel
Published: May 2022

Edge time series are increasingly used in brain imaging to study the node functional connectivity (nFC) dynamics at the finest temporal resolution while avoiding sliding windows. Here, we lay the mathematical foundations for the edge-centric analysis of neuroimaging time series, explaining why a few high-amplitude cofluctuations drive the nFC across datasets. Our exposition also constitutes a critique of the existing edge-centric studies, showing that their main findings can be derived from the nFC under a static null hypothesis that disregards temporal correlations. Testing the analytic predictions on functional MRI data from the Human Connectome Project confirms that the nFC can explain most variation in the edge FC matrix, the edge communities, the large cofluctuations, and the corresponding spatial patterns. We encourage the use of dynamic measures in future research, which exploit the temporal structure of the edge time series and cannot be replicated by static null models.
Identification of a modulator of the actin cytoskeleton, mitochondria, nutrient metabolism and lifespan in yeast
Authors: Sing Cierra N. , Garcia Enrique J. , Lipkin Thomas G. , Huckaba Thomas M. , Tsang Catherine A. , Coughlin Arielle C. , Yang Emily J. , Boldogh Istvan R. , Higuchi-Sanabria Ryo , Pon Liza A.
Published: May 2022

In yeast, actin cables are F-actin bundles that are essential for cell division through their function as tracks for cargo movement from mother to daughter cell. Actin cables also affect yeast lifespan by promoting transport and inheritance of higher-functioning mitochondria to daughter cells. Here, we report that actin cable stability declines with age. Our genome-wide screen for genes that affect actin cable stability identified the open reading frame YKL075C. Deletion of YKL075C results in increases in actin cable stability and abundance, mitochondrial fitness, and replicative lifespan. Transcriptome analysis revealed a role for YKL075C in regulating branched-chain amino acid (BCAA) metabolism. Consistent with this, modulation of BCAA metabolism or decreasing leucine levels promotes actin cable stability and function in mitochondrial quality control. Our studies support a role for actin stability in yeast lifespan, and demonstrate that this process is controlled by BCAA and a previously uncharacterized ORF YKL075C, which we refer to as actin, aging and nutrient modulator protein 1 (AAN1).
Cooperative regulation of PBI1 and MAPKs controls WRKY45 transcription factor in rice immunity
Authors: Ichimaru Kota , Yamaguchi Koji , Harada Kenichi , Nishio Yusaku , Hori Momoka , Ishikawa Kazuya , Inoue Haruhiko , Shigeta Shusuke , Inoue Kento , Shimada Keita , Yoshimura Satomi , Takeda Takumi , Yamashita Eiki , Fujiwara Toshimichi , Nakagawa Atsushi , Kojima Chojiro , Kawasaki Tsutomu
Published: May 2022

The U-box type ubiquitin ligase PUB44 positively regulates pattern-triggered immunity in rice. Here, we identify PBI1, a protein that interacts with PUB44. Crystal structure analysis indicates that PBI1 forms a four-helix bundle structure. PBI1 also interacts with WRKY45, a master transcriptional activator of rice immunity, and negatively regulates its activity. PBI1 is degraded upon perception of chitin, and this is suppressed by silencing of PUB44 or expression of XopP, indicating that PBI1 degradation depends on PUB44. These data suggest that PBI1 suppresses WRKY45 activity when cells are in an unelicited state, and during chitin signaling, PUB44-mediated degradation of PBI1 leads to activation of WRKY45. In addition, chitin-induced MAP kinase activation is required for WRKY45 activation and PBI1 degradation. These results demonstrate that chitin-induced activation of WRKY45 is regulated by the cooperation between MAP kinase-mediated phosphorylation and PUB44-mediated PBI1 degradation.
POD1-SUN-CRT3 chaperone complex guards the ER sorting of LRR receptor kinases in Arabidopsis
Authors: Xue Yong , Meng Jiang-Guo , Jia Peng-Fei , Zhang Zheng-Rong , Li Hong-Ju , Yang Wei-Cai
Published: May 2022

Protein sorting in the secretory pathway is essential for cellular compartmentalization and homeostasis in eukaryotic cells. The endoplasmic reticulum (ER) is the biosynthetic and folding factory of secretory cargo proteins. The cargo transport from the ER to the Golgi is highly selective, but the molecular mechanism for the sorting specificity is unclear. Here, we report that three ER membrane localized proteins, SUN3, SUN4 and SUN5, regulate ER sorting of leucine-rich repeat receptor kinases (LRR-RKs) to the plasma membrane. The triple mutant sun3/4/5 displays mis-sorting of these cargo proteins to acidic compartments and therefore impairs the growth of pollen tubes and the whole plant. Furthermore, the extracellular LRR domain of LRR-RKs is responsible for the correct sorting. Together, this study reports a mechanism that is important for the sorting of cell surface receptors.
Efficient access to general α-tertiary amines via water-accelerated organocatalytic multicomponent allylation
Authors: Goswami Prithwish , Cho Sung Yeon , Park Jin Hyun , Kim Woo Hee , Kim Hyun Jin , Shin Myoung Hyeon , Bae Han Yong
Published: May 2022

A tetrasubstituted carbon atom connected by three sp3 or sp2-carbons with single nitrogen, i.e., the α-tertiary amine (ATA) functional group, is an essential structure of diverse naturally occurring alkaloids and pharmaceuticals. The synthetic approach toward ATA structures is intricate, therefore, a straightforward catalytic method has remained a substantial challenge. Here we show an efficient water-accelerated organocatalytic method to directly access ATA incorporating homoallylic amine structures by exploiting readily accessible general ketones as useful starting material. The synergistic action of a hydrophobic Brønsted acid in combination with a squaramide hydrogen-bonding donor under aqueous condition enabled the facile formation of the desired moiety. The developed exceptionally mild but powerful system facilitated a broad substrate scope, and enabled efficient multi-gram scalability.
Ca2+-mediated higher-order assembly of heterodimers in amino acid transport system b0,+ biogenesis and cystinuria
Authors: Lee Yongchan , Wiriyasermkul Pattama , Kongpracha Pornparn , Moriyama Satomi , Mills Deryck J. , Kühlbrandt Werner , Nagamori Shushi
Published: May 2022

Cystinuria is a genetic disorder characterized by overexcretion of dibasic amino acids and cystine, causing recurrent kidney stones and kidney failure. Mutations of the regulatory glycoprotein rBAT and the amino acid transporter b0,+AT, which constitute system b0,+, are linked to type I and non-type I cystinuria respectively and they exhibit distinct phenotypes due to protein trafficking defects or catalytic inactivation. Here, using electron cryo-microscopy and biochemistry, we discover that Ca2+ mediates higher-order assembly of system b0,+. Ca2+ stabilizes the interface between two rBAT molecules, leading to super-dimerization of b0,+AT–rBAT, which in turn facilitates N-glycan maturation and protein trafficking. A cystinuria mutant T216M and mutations of the Ca2+ site of rBAT cause the loss of higher-order assemblies, resulting in protein trapping at the ER and the loss of function. These results provide the molecular basis of system b0,+ biogenesis and type I cystinuria and serve as a guide to develop new therapeutic strategies against it. More broadly, our findings reveal an unprecedented link between transporter oligomeric assembly and protein-trafficking diseases.
An Artificial Intelligence-guided signature reveals the shared host immune response in MIS-C and Kawasaki disease
Authors: Ghosh Pradipta , Katkar Gajanan D. , Shimizu Chisato , Kim Jihoon , Khandelwal Soni , Tremoulet Adriana H. , Kanegaye John T. ,   Pediatric Emergency Medicine Kawasaki Disease Research Group, Abe Naomi , Austin-Page Lukas , Bryl Amy , Donofrio-Ödmann J. Joelle , Ekpenyong Atim , Gardiner Michael , Gutglass David J. , Nguyen Margaret B. , Schwartz Kristy , Ulrich Stacey , Vayngortin Tatyana , Zimmerman Elise , Bocchini Joseph , Das Soumita , Burns Jane C. , Sahoo Debashis
Published: May 2022

Multisystem inflammatory syndrome in children (MIS-C) is an illness that emerged amidst the COVID-19 pandemic but shares many clinical features with the pre-pandemic syndrome of Kawasaki disease (KD). Here we compare the two syndromes using a computational toolbox of two gene signatures that were developed in the context of SARS-CoV-2 infection, i.e., the viral pandemic (ViP) and severe-ViP signatures and a 13-transcript signature previously demonstrated to be diagnostic for KD, and validated our findings in whole blood RNA sequences, serum cytokines, and formalin fixed heart tissues. Results show that KD and MIS-C are on the same continuum of the host immune response as COVID-19. Both the pediatric syndromes converge upon an IL15/IL15RA-centric cytokine storm, suggestive of shared proximal pathways of immunopathogenesis; however, they diverge in other laboratory parameters and cardiac phenotypes. The ViP signatures reveal unique targetable cytokine pathways in MIS-C, place MIS-C farther along in the spectrum in severity compared to KD and pinpoint key clinical (reduced cardiac function) and laboratory (thrombocytopenia and eosinopenia) parameters that can be useful to monitor severity.
Multifunctional metal-organic framework-based nanoreactor for starvation/oxidation improved indoleamine 2,3-dioxygenase-blockade tumor immunotherapy
Authors: Dai Liangliang , Yao Mengjiao , Fu Zhenxiang , Li Xiang , Zheng Xinmin , Meng Siyu , Yuan Zhang , Cai Kaiyong , Yang Hui , Zhao Yanli
Published: May 2022

Inhibited immune response and low levels of delivery restrict starvation cancer therapy efficacy. Here, we report on the co-delivery of glucose oxidase (GOx) and indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan using a metal-organic framework (MOF)-based nanoreactor, showing an amplified release for tumor starvation/oxidation immunotherapy. The nanosystem significantly overcomes the biobarriers associated with tumor penetration and improves the cargo bioavailability owing to the weakly acidic tumor microenvironment-activated charge reversal and size reduction strategy. The nanosystem rapidly disassembles and releases cargoes in response to the intracellular reactive oxygen species (ROS). GOx competitively consumes glucose and generates ROS, further inducing the self-amplifiable MOF disassembly and drug release. The starvation/oxidation combined IDO-blockade immunotherapy not only strengthens the immune response and stimulates the immune memory through the GOx-activated tumor starvation and recruitment of effector T cells, but also effectively relieves the immune tolerance by IDO blocking, remarkably inhibiting the tumor growth and metastasis in vivo.
Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses
Authors: Meng Jonathan X. , Zhang Yu , Saman Dominik , Haider Arshad M. , De Suman , Sang Jason C. , Brown Karen , Jiang Kun , Humphrey Jane , Julian Linda , Hidari Eric , Lee Steven F. , Balmus Gabriel , Floto R. Andres , Bryant Clare E. , Benesch Justin L. P. , Ye Yu , Klenerman David
Published: May 2022

Soluble aggregates of the microtubule-associated protein tau have been challenging to assemble and characterize, despite their important role in the development of tauopathies. We found that sequential hyperphosphorylation by protein kinase A in conjugation with either glycogen synthase kinase 3β or stress activated protein kinase 4 enabled recombinant wild-type tau of isoform 0N4R to spontaneously polymerize into small amorphous aggregates in vitro. We employed tandem mass spectrometry to determine the phosphorylation sites, high-resolution native mass spectrometry to measure the degree of phosphorylation, and super-resolution microscopy and electron microscopy to characterize the morphology of aggregates formed. Functionally, compared with the unmodified aggregates, which require heparin induction to assemble, these self-assembled hyperphosphorylated tau aggregates more efficiently disrupt membrane bilayers and induce Toll-like receptor 4-dependent responses in human macrophages. Together, our results demonstrate that hyperphosphorylated tau aggregates are potentially damaging to cells, suggesting a mechanism for how hyperphosphorylation could drive neuroinflammation in tauopathies.
Electronic cigarettes versus nicotine patches for smoking cessation in pregnancy: a randomized controlled trial
Authors: Hajek Peter , Przulj Dunja , Pesola Francesca , Griffiths Chris , Walton Robert , McRobbie Hayden , Coleman Tim , Lewis Sarah , Whitemore Rachel , Clark Miranda , Ussher Michael , Sinclair Lesley , Seager Emily , Cooper Sue , Bauld Linda , Naughton Felix , Sasieni Peter , Manyonda Isaac , Myers Smith Katie
Published: May 2022

Nicotine replacement therapy, in the form of nicotine patches, is commonly offered to pregnant women who smoke to help them to stop smoking, but this approach has limited efficacy in this population. Electronic cigarettes (e-cigarettes) are also used by pregnant women who smoke but their safety and efficacy in pregnancy are unknown. Here, we report the results of a randomized controlled trial in 1,140 participants comparing refillable e-cigarettes with nicotine patches. Pregnant women who smoked were randomized to e-cigarettes (n = 569) or nicotine patches (n = 571). In the unadjusted analysis of the primary outcome, validated prolonged quit rates at the end of pregnancy in the two study arms were not significantly different (6.8% versus 4.4% in the e-cigarette and patch arms, respectively; relative risk (RR) = 1.55, 95%CI: 0.95–2.53, P = 0.08). However, some participants in the nicotine patch group also used e-cigarettes during the study. In a pre-specified sensitivity analysis excluding abstinent participants who used non-allocated products, e-cigarettes were more effective than patches (6.8% versus 3.6%; RR = 1.93, 95%CI: 1.14–3.26, P = 0.02). Safety outcomes included adverse events and maternal and birth outcomes. The safety profile was found to be similar for both study products, however, low birthweight (<2,500 g) was less frequent in the e-cigarette arm (14.8% versus 9.6%; RR = 0.65, 95%CI: 0.47–0.90, P = 0.01). Other adverse events and birth outcomes were similar in the two study arms. E-cigarettes might help women who are pregnant to stop smoking, and their safety for use in pregnancy is similar to that of nicotine patches. ISRCTN62025374.
Optimal precision and accuracy in 4Pi-STORM using dynamic spline PSF models
Authors: Bates Mark , Keller-Findeisen Jan , Przybylski Adrian , Hüper Andreas , Stephan Till , Ilgen Peter , Cereceda Delgado Angel R. , D’Este Elisa , Egner Alexander , Jakobs Stefan , Sahl Steffen J. , Hell Stefan W.
Published: May 2022

Coherent fluorescence imaging with two objective lenses (4Pi detection) enables single-molecule localization microscopy with sub-10 nm spatial resolution in three dimensions. Despite its outstanding sensitivity, wider application of this technique has been hindered by complex instrumentation and the challenging nature of the data analysis. Here we report the development of a 4Pi-STORM microscope, which obtains optimal resolution and accuracy by modeling the 4Pi point spread function (PSF) dynamically while also using a simpler optical design. Dynamic spline PSF models incorporate fluctuations in the modulation phase of the experimentally determined PSF, capturing the temporal evolution of the optical system. Our method reaches the theoretical limits for precision and minimizes phase-wrapping artifacts by making full use of the information content of the data. 4Pi-STORM achieves a near-isotropic three-dimensional localization precision of 2–3 nm, and we demonstrate its capabilities by investigating protein and nucleic acid organization in primary neurons and mammalian mitochondria.
Cryo-EM structure of an active central apparatus
Authors: Han Long , Rao Qinhui , Yang Renbin , Wang Yue , Chai Pengxin , Xiong Yong , Zhang Kai
Published: May 2022

Accurately regulated ciliary beating in time and space is critical for diverse cellular activities, which impact the survival and development of nearly all eukaryotic species. An essential beating regulator is the conserved central apparatus (CA) of motile cilia, composed of a pair of microtubules (C1 and C2) associated with hundreds of protein subunits per repeating unit. It is largely unclear how the CA plays its regulatory roles in ciliary motility. Here, we present high-resolution structures of Chlamydomonas reinhardtii CA by cryo-electron microscopy (cryo-EM) and its dynamic conformational behavior at multiple scales. The structures show how functionally related projection proteins of CA are clustered onto a spring-shaped scaffold of armadillo-repeat proteins, facilitated by elongated rachis-like proteins. The two halves of the CA are brought together by elastic chain-like bridge proteins to achieve coordinated activities. We captured an array of kinesin-like protein (KLP1) in two different stepping states, which are actively correlated with beating wave propagation of cilia. These findings establish a structural framework for understanding the role of the CA in cilia.
A global 0.05° dataset for gross primary production of sunlit and shaded vegetation canopies from 1992 to 2020
Authors: Bi Wenjun , He Wei , Zhou Yanlian , Ju Weimin , Liu Yibo , Liu Yang , Zhang Xiaoyu , Wei Xiaonan , Cheng Nuo
Published: May 2022

Distinguishing gross primary production of sunlit and shaded leaves (GPPsun and GPPshade) is crucial for improving our understanding of the underlying mechanisms regulating long-term GPP variations. Here we produce a global 0.05°, 8-day dataset for GPP, GPPshade and GPPsun over 1992–2020 using an updated two-leaf light use efficiency model (TL-LUE), which is driven by the GLOBMAP leaf area index, CRUJRA meteorology, and ESA-CCI land cover. Our products estimate the mean annual totals of global GPP, GPPsun, and GPPshade over 1992–2020 at 125.0 ± 3.8 (mean ± std) Pg C a−1, 50.5 ± 1.2 Pg C a−1, and 74.5 ± 2.6 Pg C a−1, respectively, in which EBF (evergreen broadleaf forest) and CRO (crops) contribute more than half of the totals. They show clear increasing trends over time, in which the trend of GPP (also GPPsun and GPPshade) for CRO is distinctively greatest, and that for DBF (deciduous broadleaf forest) is relatively large and GPPshade overwhelmingly outweighs GPPsun. This new dataset advances our in-depth understanding of large-scale carbon cycle processes and dynamics.
Multiscale mechanical consequences of ocean acidification for cold-water corals
Authors: Wolfram Uwe , Peña Fernández Marta , McPhee Samuel , Smith Ewan , Beck Rainer J. , Shephard Jonathan D. , Ozel Ali , Erskine Craig S. , Büscher Janina , Titschack Jürgen , Roberts J. Murray , Hennige Sebastian J.
Published: May 2022

Ocean acidification is a threat to deep-sea corals and could lead to dramatic and rapid loss of the reef framework habitat they build. Weakening of structurally critical parts of the coral reef framework can lead to physical habitat collapse on an ecosystem scale, reducing the potential for biodiversity support. The mechanism underpinning crumbling and collapse of corals can be described via a combination of laboratory-scale experiments and mathematical and computational models. We synthesise data from electron back-scatter diffraction, micro-computed tomography, and micromechanical experiments, supplemented by molecular dynamics and continuum micromechanics simulations to predict failure of coral structures under increasing porosity and dissolution. Results reveal remarkable mechanical properties of the building material of cold-water coral skeletons of 462 MPa compressive strength and 45–67 GPa stiffness. This is 10 times stronger than concrete, twice as strong as ultrahigh performance fibre reinforced concrete, or nacre. Contrary to what would be expected, CWCs retain the strength of their skeletal building material despite a loss of its stiffness even when synthesised under future oceanic conditions. As this is on the material length-scale, it is independent of increasing porosity from exposure to corrosive water or bioerosion. Our models then illustrate how small increases in porosity lead to significantly increased risk of crumbling coral habitat. This new understanding, combined with projections of how seawater chemistry will change over the coming decades, will help support future conservation and management efforts of these vulnerable marine ecosystems by identifying which ecosystems are at risk and when they will be at risk, allowing assessment of the impact upon associated biodiversity.
A genome-wide scan of wastewater E. coli for genes under positive selection: focusing on mechanisms of antibiotic resistance
Authors: Malekian Negin , Agrawal Amay A. , Berendonk Thomas U. , Al-Fatlawi Ali , Schroeder Michael
Published: May 2022

Antibiotic resistance is a global health threat and consequently, there is a need to understand the mechanisms driving its emergence. Here, we hypothesize that genes and mutations under positive selection may contribute to antibiotic resistance. We explored wastewater E. coli, whose genomes are highly diverse. We subjected 92 genomes to a statistical analysis for positively selected genes. We obtained 75 genes under positive selection and explored their potential for antibiotic resistance. We found that eight genes have functions relating to antibiotic resistance, such as biofilm formation, membrane permeability, and bacterial persistence. Finally, we correlated the presence/absence of non-synonymous mutations in positively selected sites of the genes with a function in resistance against 20 most prescribed antibiotics. We identified mutations associated with antibiotic resistance in two genes: the porin ompC and the bacterial persistence gene hipA. These mutations are located at the surface of the proteins and may hence have a direct effect on structure and function. For hipA, we hypothesize that the mutations influence its interaction with hipB and that they enhance the capacity for dormancy as a strategy to evade antibiotics. Overall, genomic data and positive selection analyses uncover novel insights into mechanisms driving antibiotic resistance.
Identification of QTLs for root color and carotenoid contents in Japanese orange carrot F2 populations
Authors: Shibaya Taeko , Kuroda Chika , Tsuruoka Hisano , Minami Chiharu , Obara Akiko , Nakayama Shinobu , Kishida Yoshie , Fujii Takayoshi , Isobe Sachiko
Published: May 2022

Carrot is a major source of provitamin A in a human diet. Two of the most important traits for carrot breeding are carotenoid contents and root color. To examine genomic regions related to these traits and develop DNA markers for carrot breeding, we performed an association analysis based on a general liner model using genome-wide single nucleotide polymorphism (SNPs) in two F2 populations, both derived from crosses of orange root carrots bred in Japan. The analysis revealed 21 significant quantitative trait loci (QTLs). To validate the detection of the QTLs, we also performed a QTL analysis based on a composite interval mapping of these populations and detected 32 QTLs. Eleven of the QTLs were detected by both the association and QTL analyses. The physical position of some QTLs suggested two possible candidate genes, an Orange (Or) gene for visual color evaluation, and the α- and β-carotene contents and a chromoplast-specific lycopene β-cyclase (CYC-B) gene for the β/α carotene ratio. A KASP marker developed on the Or distinguished a quantitative color difference in a different, related breeding line. The detected QTLs and the DNA marker will contribute to carrot breeding and the understanding of carotenoid biosynthesis and accumulation in orange carrots.
Accuracy of a surface-based fusion method when integrating digital models and the cone beam computed tomography scans with metal artifacts
Authors: Zou Bingshuang , Kim Jung-Hoon , Kim So-Hyun , Choi Tae-Hyun , Shin Yonsoo , Kook Yoon-Ah , Lee Nam-Ki
Published: May 2022

The aim of this study was to evaluate the intra- and inter-observer reliability of maxillary digital dental model integration into cone-beam computed tomography (CBCT) scans to reconstruct three-dimensional (3D) skeletodental models for orthognathic patients. This retrospective study consisted of CBCT and digital maxillary dentition images of 20 Class III orthognathic patients. After two repeated fusions of digital cast images with reconstructed CBCT images by a digital engineer and an orthodontist respectively, the 3D coordinate values of the canines, first molars, and central incisors were evaluated. The intra- and inter-observer reliability of 3D positions of maxillary teeth were compared using intraclass correlation coefficients (ICCs). Intra-observer reliability of x-, y-, and z-coordinate values of maxillary teeth showed significant and excellent agreement in an engineer (0.946 ≤ ICC ≤ 1.000) and an orthodontist (0.876 ≤ ICC ≤ 1.000). The inter-observer reliability of the y- and z-coordinates of each tooth was significantly excellent or good, but that of the x-coordinates showed insignificantly poor to moderate agreement. This study showed that the integration of maxillary digital models into CBCT scans was clinically reliable. However, considering the low inter-observer reliability on the x-coordinates of dentition, clinical experience and repeated learning are needed for accurate application of digital skeletodental model in orthognathic patients.
Gain roll-off in cadmium selenide colloidal quantum wells under intense optical excitation
Authors: Diroll Benjamin T. , Brumberg Alexandra , Schaller Richard D.
Published: May 2022

Colloidal quantum wells, or nanoplatelets, show among the lowest thresholds for amplified spontaneous emission and lasing among solution-cast materials and among the highest modal gains of any known materials. Using solution measurements of colloidal quantum wells, this work shows that under photoexcitation, optical gain increases with pump fluence before rolling off due to broad photoinduced absorption at energies lower than the band gap. Despite the common occurrence of gain induced by an electron–hole plasma found in bulk materials and epitaxial quantum wells, under no measurement conditions was the excitonic absorption of the colloidal quantum wells extinguished and gain arising from a plasma observed. Instead, like gain, excitonic absorption reaches a minimum intensity near a photoinduced carrier sheet density of 2 × 1013 cm−2 above which the absorption peak begins to recover. To understand the origins of these saturation and reversal effects, measurements were performed with different excitation energies, which deposit differing amounts of excess energy above the band gap. Across many samples, it was consistently observed that less energetic excitation results in stronger excitonic bleaching and gain for a given carrier density. Transient and static optical measurements at elevated temperatures, as well as transient X-ray diffraction of the samples, suggest that the origin of gain saturation and reversal is a heating and disordering of the colloidal quantum wells which produces sub-gap photoinduced absorption.
Analysis of circRNAs and circRNA-associated competing endogenous RNA networks in β-thalassemia
Authors: Yang Fang , Ruan Heyun , Li Shuquan , Hou Wei , Qiu Yuling , Deng Lingjie , Su Sha , Chen Ping , Pang Lihong , Lai Ketong
Published: May 2022

The involvement of circRNAs in β-thalassemia and their actions on fetal hemoglobin (HbF) is unclear. Here, the circRNAs in β-thalassemia carriers with high HbF levels were comprehensively analyzed and compared with those of healthy individuals. Differential expression of 2183 circRNAs was observed and their correlations with hematological parameters were investigated. Down-regulated hsa-circRNA-100466 had a strong negative correlation with HbF and HbA2. Bioinformatics was employed to construct a hsa-circRNA-100466‑associated competing endogenous RNA (ceRNA) network to identify hub genes and associated miRNAs. The hsa-circRNA-100466▁miR-19b-3p▁SOX6 pathway was identified using both present and previously published data. The ceRNA network was verified by qRT-PCR analysis of β-thalassemia samples, RNA immunoprecipitation of K562 cell lysates, and dual-luciferase reporter analysis. qRT-PCR confirmed that hsa-circRNA-100466 and SOX6 were significantly down-regulated, while miR-19b-3p was up-regulated. Hsa-circRNA-100466, miR-19b-3p, and SOX6 were co-immunoprecipitated by anti-argonaute antibodies, indicating involvement with HbF induction. A further dual-luciferase reporter assay verified that miR-19b-3p interacted directly with hsa-circRNA-100466 and SOX6. Furthermore, spearman correlation coefficients revealed their significant correlations with HbF. In conclusion, a novel hsa-circRNA-100466▁miR-19b-3p▁SOX6 pathway was identified, providing insight into HbF induction and suggesting targets β-thalassemia treatment.