bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractModel 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

AbstractA 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

Abstract
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

AbstractPrevious 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

AbstractCOVID-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

AbstractIn 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

AbstractEdge 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

AbstractIn 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

AbstractThe 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

AbstractProtein 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

AbstractA 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

AbstractCystinuria 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

AbstractMultisystem 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

AbstractInhibited 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

AbstractSoluble 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.