bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Unprecedented Arctic Ozone Depletion Event During Spring 2020 and Its Impacts Across Europe
Authors: Petkov Boyan H. , Vitale Vito , Di Carlo Piero , Drofa Oxana , Mastrangelo Daniele , Smedley Andrew R. D. , Diémoz Henri , Siani Anna Maria , Fountoulakis Ilias , Webb Ann R. , Bais Alkiviadis , Kift Richard , Rimmer John , Casale Giuseppe Rocco , Hansen Georg H. , Svendby Tove , Pazmiño Andrea , Werner Rolf , Atanassov Atanas M. , Láska Kamil , De Backer Hugo , Mangold Alexander , Köhler Ulf , Velazco Voltaire A. , Stübi René , Solomatnikova Anna , Pavlova Kseniya , Sobolewski Piotr S. , Johnsen Bjørn , Goutail Florence , Mišaga Oliver , Aruffo Eleonora , Metelka Ladislav , Tóth Zoltán , Fekete Dénes , Aculinin Alexandr A. , Lupi Angelo , Mazzola Mauro , Zardi Federico 
Published: January 2023

AbstractThe response of the ozone column across Europe to the extreme 2020 Arctic ozone depletion was examined by analyzing ground‐based observations at 38 European stations. The ozone decrease at the northernmost site, Ny‐Ålesund (79°N) was about 43% with respect to a climatology of more than 30 years. The magnitude of the decrease declined by about 0.7% deg−1 moving south to reach nearly 15% at 40°N. In addition, it was found that the variations of the ozone column at each of the selected stations in March‐May were similar to those observed at Ny‐Ålesund but with a delay increasing to about 20 days at mid‐latitudes with a gradient of approximately 0.5 days deg−1. The distributions of reconstructed ozone column anomalies over a sector covering a large European area show decreasing ozone that started from the north at the beginning of April 2020 and spread south. Such behavior was shown to be similar to that observed after the Arctic ozone depletion in 2011. Stratospheric dynamical patterns in March–May 2011 and during 2020 suggested that the migration of ozone‐poor air masses from polar areas to the south after the vortex breakup caused the observed ozone responses. A brief survey of the ozone mass mixing ratios at three stratospheric levels showed the exceptional strength of the 2020 episode. Despite the stronger and longer‐lasting Arctic ozone loss in 2020, the analysis in this work indicates a similar ozone response at latitudes below 50°N to both 2011 and 2020 phenomena.
An assessment of the ECETOC TRA Consumer tool performance as a screening level tool
Authors: Zaleski Rosemary T. , Dudzina Tatsiana , Keller Detlef , Money Chris , Qian Hua , Rodriguez Carlos , Schnöder Frank 
Published: January 2023

Abstract
Background
The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) Consumer tool was developed to fill in a methodology gap for a high throughput, screening level tool to support industry compliance with the European Union’s Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) regulation.

Objective
To evaluate if the TRA Consumer tool has met its design of being a screening level tool (i.e., one which does not under-predict potential exposures).

Methods
The TRA Consumer tool algorithms and defaults were reviewed and performance benchmarked vs. other consumer models and/or empirical data. Findings from existing reviews of the TRA consumer tool were also considered and addressed.

Results
TRA predictions based on its default inputs exceeded measured exposures when available, typically by orders of magnitude, and were generally greater than or similar to those of other consumer exposure tools. For dermal exposure from articles, there was no evidence that a diffusivity approach would provide more appropriate exposure estimates than those of the TRA. When default values are refined using more specific data, the refined values must be considered holistically to reflect the situation being modeled as some parameters may be correlated.

Significance
This is the first evaluation of the ECETOC TRA consumer tool in its entirety, considering algorithms, input defaults, and associated predictions for consumer products and articles. The evaluation confirmed its design as a screening level tool.

Impact Statement

The ECETOC TRA Consumer tool has been widely applied to generate exposure estimates to support chemical registrations under the EU REACH regulation. This evaluation supports the appropriateness of the TRA as a screening level exposure assessment tool. It also warrants additional measurements of consumer exposure, especially for article use scenarios, to aid the development of consumer exposure tools and chemical risk assessment.
Disruption to the FOXO-PRDM1 axis resulting from deletions of chromosome 6 in acute lymphoblastic leukaemia
Authors: Sinclair Paul B. , Cranston Ruth E. , Raninga Prahlad , Cheng Joanna , Hanna Rebecca , Hawking Zoe , Hair Steven , Ryan Sarra L. , Enshaei Amir , Nakjang Sirintra , Rand Vikki , Blair Helen J. , Moorman Anthony V. , Heidenreich Olaf , Harrison Christine J. 
Published: January 2023

AbstractA common problem in the study of human malignancy is the elucidation of cancer driver mechanisms associated with recurrent deletion of regions containing multiple genes. Taking B-cell acute lymphoblastic leukaemia (B-ALL) and large deletions of 6q [del(6q)] as a model, we integrated analysis of functional cDNA clone tracking assays with patient genomic and transcriptomic data, to identify the transcription factors FOXO3 and PRDM1 as candidate tumour suppressor genes (TSG). Analysis of cell cycle and transcriptomic changes following overexpression of FOXO3 or PRDM1 indicated that they co-operate to promote cell cycle exit at the pre-B cell stage. FOXO1 abnormalities are absent in B-ALL, but like FOXO3, FOXO1 expression suppressed growth of TCF3::PBX1 and ETV6::RUNX1 B-ALL in-vitro. While both FOXOs induced PRDM1 and other genes contributing to late pre-B cell development, FOXO1 alone induced the key transcription factor, IRF4, and chemokine, CXCR4. CRISPR-Cas9 screening identified FOXO3 as a TSG, while FOXO1 emerged as essential for B-ALL growth. We relate this FOXO3-specific leukaemia-protective role to suppression of glycolysis based on integrated analysis of CRISPR-data and gene sets induced or suppressed by FOXO1 and FOXO3. Pan-FOXO agonist Selinexor induced the glycolysis inhibitor TXNIP and suppressed B-ALL growth at low dose (ID50 < 50 nM).
Immunological and metabolic characteristics of the Omicron variants infection
Authors: Geng Jiejie , Yang Xu , Wang Kun , Wang Ke , Chen Ruo , Chen Zhi-Nan , Qin Chuan , Wu Guizhen , Wang Youchun , Xu Ke , Du Peng , Liu Jiangning , Chen Shirui , Zhang Tao , Sun Xiuxuan , Guo Ting , Shi Ying , Zhang Zheng , Wei Ding , Lin Peng , Wang Qingyi , Yuan Jing , Qu Jiuxin , Zou Jin , Liu Yingxia , Lu Hongzhou , Zhu Ping , Bian Huijie , Chen Liang 
Published: January 2023

AbstractThe Omicron variants of SARS-CoV-2, primarily authenticated in November 2021 in South Africa, has initiated the 5th wave of global pandemics. Here, we systemically examined immunological and metabolic characteristics of Omicron variants infection. We found Omicron resisted to neutralizing antibody targeting receptor binding domain (RBD) of wildtype SARS-CoV-2. Omicron could hardly be neutralized by sera of Corona Virus Disease 2019 (COVID-19) convalescents infected with the Delta variant. Through mass spectrometry on MHC-bound peptidomes, we found that the spike protein of the Omicron variants could generate additional CD8 + T cell epitopes, compared with Delta. These epitopes could induce robust CD8 + T cell responses. Moreover, we found booster vaccination increased the cross-memory CD8 + T cell responses against Omicron. Metabolic regulome analysis of Omicron-specific T cell showed a metabolic profile that promoted the response of memory T cells. Consistently, a greater fraction of memory CD8 + T cells existed in Omicron stimulated peripheral blood mononuclear cells (PBMCs). In addition, CD147 was also a receptor for the Omicron variants, and CD147 antibody inhibited infection of Omicron. CD147-mediated Omicron infection in a human CD147 transgenic mouse model induced exudative alveolar pneumonia. Taken together, our data suggested that vaccination booster and receptor blocking antibody are two effective strategies against Omicron.
Application of metabolomics in urolithiasis: the discovery and usage of succinate
Authors: Zhang Xiu-zhen , Lei Xiong-xin , Jiang Yan-lin , Zhao Long-mei , Zou Chen-yu , Bai Yun-jin , Li Ya-xing , Wang Rui , Li Qian-jin , Chen Qiu-zhu , Fan Ming-hui , Song Yu-ting , Zhang Wen-qian , Zhang Yi , Li-Ling Jesse , Xie Hui-qi 
Published: January 2023

AbstractUrinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events. It has been shown that the occurrence of calcium oxalate monohydrate (COM) during stone formation is regulated by crystal growth modifiers. Although crystallization inhibitors have been recognized as a therapeutic modality for decades, limited progress has been made in the discovery of effective modifiers to intervene with stone disease. In this study, we have used metabolomics technologies, a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model. By in-depth mining and analysis of metabolomics data, we have screened five differential metabolites. Through density functional theory studies and bulk crystallization, we found that three of them (salicyluric, gentisic acid and succinate) could effectively inhibit nucleation in vitro. We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones. Notably, succinate, a key player in the tricarboxylic acid cycle, could decrease kidney calcium deposition and injury in the model. Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation, inhibition of cell adhesion and osteogenic differentiation. These findings indicated that succinate may provide a new therapeutic option for urinary stones.
Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation
Authors: Wu Pei-Rung , Chiang Shang-Yin , Midence Robert , Kao Wen-Chao , Lai Chun-Lun , Cheng I-Cheng , Chou Shen-Ju , Chen Chih-Cheng , Huang Chih-Yang , Chen Ruey-Hwa 
Published: January 2023

AbstractPatients with mutations of WDR4, a substrate adaptor of the CUL4 E3 ligase complex, develop cerebellar atrophy and gait phenotypes. However, the underlying mechanisms remain unexplored. Here, we identify a crucial role of Wdr4 in cerebellar development.Wdr4deficiency in granule neuron progenitors (GNPs) not only reduces foliation and the sizes of external and internal granular layers but also compromises Purkinje neuron organization and the size of the molecular layer, leading to locomotion defects. Mechanistically, Wdr4 supports the proliferation of GNPs by preventing their cell cycle exit. This effect is mediated by Wdr4-induced ubiquitination and degradation of Arhgap17, thereby activating Rac1 to facilitate cell cycle progression. Disease-associated Wdr4 variants, however, cannot provide GNP cell cycle maintenance. Our study identifies Wdr4 as a previously unappreciated participant in cerebellar development and locomotion, providing potential insights into treatment strategies for diseases withWDR4mutations, such as primordial dwarfism and Galloway-Mowat syndrome.
Neuroprotective effect of astragalin via activating PI3K/Akt-mTOR-mediated autophagy on APP/PS1 mice
Authors: Yang Cui-Zhu , Wang Shu-Han , Zhang Run-Heng , Lin Jia-Hong , Tian Ying-Hong , Yang Ya-Qi , Liu Jing , Ma Yu-Xin 
Published: January 2023

AbstractAs a small molecule flavonoid, astragalin (AST) has anti-inflammatory, anti-cancer, and anti-oxidation effects. However, the impact and molecular mechanism of AST in Alzheimer’s disease (AD) are still not clear. This study aims to investigate the neuroprotective effect and mechanism of AST on APP/PS1 mice and Aβ25-35-injured HT22 cells. In this study, we found that AST ameliorated cognitive dysfunction, reduced hippocampal neuronal damage and loss, and Aβ pathology in APP/PS1 mice. Subsequently, AST activated autophagy and up-regulated the levels of autophagic flux-related protein in APP/PS1 mice and Aβ25-35-induced injury in HT22 cells. Interestingly, AST down-regulated the phosphorylation level of PI3K/Akt-mTOR pathway-related proteins, which was reversed by autophagy inhibitors 3-Methyladenine (3-MA) or Bafilomycin A1 (Baf A1). At the same time, consistent with the impacts of Akt inhibitor MK2206 and mTOR inhibitor rapamycin, inhibited levels of autophagy in Aβ25-35-injured HT22 cells were activated by the administration of AST. Taken together, these results suggested that AST played key neuroprotective roles on AD via stimulating PI3K/Akt-mTOR pathway-mediated autophagy and autophagic flux. This study revealed a new mechanism of autophagy regulation behind the neuroprotection impact of AST for AD treatment.
A microfluidic-based PDAC organoid system reveals the impact of hypoxia in response to treatment
Authors: Geyer Marlene , Schreyer Daniel , Gaul Lisa-Marie , Pfeffer Susanne , Pilarsky Christian , Queiroz Karla 
Published: January 2023

AbstractPancreatic Ductal Adenocarcinoma (PDAC) is estimated to become the second leading cause of cancer-related deaths by 2030 with mortality rates of up to 93%. Standard of care chemotherapeutic treatment only prolongs the survival of patients for a short timeframe. Therefore, it is important to understand events driving treatment failure in PDAC as well as identify potential more effective treatment opportunities. PDAC is characterized by a high-density stroma, high interstitial pressure and very low oxygen tension. The aim of this study was to establish a PDAC platform that supported the understanding of treatment response of PDAC organoids in mono-, and co-culture with pancreatic stellate cells (PSCs) under hypoxic and normoxic conditions. Cultures were exposed to Gemcitabine in combination with molecules targeting relevant molecular programs that could explain treatment specific responses under different oxygen pressure conditions. Two groups of treatment responses were identified, showing either a better effect in monoculture or co-culture. Moreover, treatment response also differed between normoxia and hypoxia. Modulation of response to Gemcitabine was also observed in presence of a Hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) inhibitor and HIF inhibitors. Altogether this highlights the importance of adjusting experimental conditions to include relevant oxygen levels in drug response studies in PDAC.
Cancer-associated fibroblast-secreted IGFBP7 promotes gastric cancer by enhancing tumor associated macrophage infiltration via FGF2/FGFR1/PI3K/AKT axis
Authors: Li Dandan , Xia Lingyun , Huang Pan , Wang Zidi , Guo Qiwei , Huang Congcong , Leng Weidong , Qin Shanshan 
Published: January 2023

AbstractWe previously reported that IGFBP7 plays a role in maintaining mRNA stability of oncogenic lncRNA UBE2CP3 by RNA-RNA interaction in gastric cancer (GC). Clinical cohort studies had implied an oncogenic role of IGFBP7 in GC. However, the molecular mechanism of IGFBP7 in GC progression remains unknown. In this study, clinical analysis based on two independent cohorts showed that IGFBP7 was positively associated with poor prognosis and macrophage infiltration in GC. Loss-of-function studies confirmed the oncogenic properties of IGFBP7 in regulating GC cell proliferation and invasion. Mechanismly, IGFBP7 was highly expressed in cancer-associated fibroblasts (CAF) and mesenchymal cells, and was induced by epithelial-to-mesenchymal transition (EMT) signaling, since its expression was increased by TGF-beta treatment and reduced by overexpression of OVOL2 in GC. RNA sequencing, qRT-PCR, ELISA assay showed that IGFBP7 positively regulated FGF2 expression and secretion in GC. Transcriptome analysis revealed that FGFR1 was downregulated in M1 polarization but upregulated in M2 polarization. Exogenous recombinant IGFBP7 treatment in macrophages and GC cells further identified that IGFBP7 promotes tumor associated macrophage (TAM) polarization via FGF2/FGFR1/PI3K/AKT axis. Our finding here represented the first evidence that IGFBP7 promotes GC by enhancing TAM/M2 macrophage polarization through FGF2/FGFR1/PI3K/AKT axis.
Uncovering a miltiradiene biosynthetic gene cluster in the Lamiaceae reveals a dynamic evolutionary trajectory
Authors: Bryson Abigail E. , Lanier Emily R. , Lau Kin H. , Hamilton John P. , Vaillancourt Brieanne , Mathieu Davis , Yocca Alan E. , Miller Garret P. , Edger Patrick P. , Buell C. Robin , Hamberger Björn 
Published: January 2023

AbstractThe spatial organization of genes within plant genomes can drive evolution of specialized metabolic pathways. Terpenoids are important specialized metabolites in plants with diverse adaptive functions that enable environmental interactions. Here, we report the genome assemblies of Prunella vulgaris, Plectranthus barbatus, and Leonotis leonurus. We investigate the origin and subsequent evolution of a diterpenoid biosynthetic gene cluster (BGC) together with other seven species within the Lamiaceae (mint) family. Based on core genes found in the BGCs of all species examined across the Lamiaceae, we predict a simplified version of this cluster evolved in an early Lamiaceae ancestor. The current composition of the extant BGCs highlights the dynamic nature of its evolution. We elucidate the terpene backbones generated by the Callicarpa americana BGC enzymes, including miltiradiene and the terpene (+)-kaurene, and show oxidization activities of BGC cytochrome P450s. Our work reveals the fluid nature of BGC assembly and the importance of genome structure in contributing to the origin of metabolites.
Active mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress
Authors: Sandoz Jérémy , Cigrang Max , Zachayus Amélie , Catez Philippe , Donnio Lise-Marie , Elly Clèmence , Nieminuszczy Jadwiga , Berico Pietro , Braun Cathy , Alekseev Sergey , Egly Jean-Marc , Niedzwiedz Wojciech , Giglia-Mari Giuseppina , Compe Emmanuel , Coin Frédéric 
Published: January 2023

AbstractThe transcriptional response to genotoxic stress involves gene expression arrest, followed by recovery of mRNA synthesis (RRS) after DNA repair. We find that the lack of the EXD2 nuclease impairs RRS and decreases cell survival after UV irradiation, without affecting DNA repair. Overexpression of wild-type, but not nuclease-dead EXD2, restores RRS and cell survival. We observe that UV irradiation triggers the relocation of EXD2 from mitochondria to the nucleus. There, EXD2 is recruited to chromatin where it transiently interacts with RNA Polymerase II (RNAPII) to promote the degradation of nascent mRNAs synthesized at the time of genotoxic attack. Reconstitution of the EXD2-RNAPII partnership on a transcribed DNA template in vitro shows that EXD2 primarily interacts with an elongation-blocked RNAPII and efficiently digests mRNA. Overall, our data highlight a crucial step in the transcriptional response to genotoxic attack in which EXD2 interacts with elongation-stalled RNAPII on chromatin to potentially degrade the associated nascent mRNA, allowing transcription restart after DNA repair.
Explainable deep learning for insights in El Niño and river flows
Authors: Liu Yumin , Duffy Kate , Dy Jennifer G. , Ganguly Auroop R. 
Published: January 2023

AbstractThe El Niño Southern Oscillation (ENSO) is a semi-periodic fluctuation in sea surface temperature (SST) over the tropical central and eastern Pacific Ocean that influences interannual variability in regional hydrology across the world through long-range dependence or teleconnections. Recent research has demonstrated the value of Deep Learning (DL) methods for improving ENSO prediction as well as Complex Networks (CN) for understanding teleconnections. However, gaps in predictive understanding of ENSO-driven river flows include the black box nature of DL, the use of simple ENSO indices to describe a complex phenomenon and translating DL-based ENSO predictions to river flow predictions. Here we show that eXplainable DL (XDL) methods, based on saliency maps, can extract interpretable predictive information contained in global SST and discover SST information regions and dependence structures relevant for river flows which, in tandem with climate network constructions, enable improved predictive understanding. Our results reveal additional information content in global SST beyond ENSO indices, develop understanding of how SSTs influence river flows, and generate improved river flow prediction, including uncertainty estimation. Observations, reanalysis data, and earth system model simulations are used to demonstrate the value of the XDL-CN based methods for future interannual and decadal scale climate projections.
SPRTN patient variants cause global-genome DNA-protein crosslink repair defects
Authors: Weickert Pedro , Li Hao-Yi , Götz Maximilian J. , Dürauer Sophie , Yaneva Denitsa , Zhao Shubo , Cordes Jacqueline , Acampora Aleida C. , Forne Ignasi , Imhof Axel , Stingele Julian 
Published: January 2023

AbstractDNA-protein crosslinks (DPCs) are pervasive DNA lesions that are induced by reactive metabolites and various chemotherapeutic agents. Here, we develop a technique for the Purification of x-linked Proteins (PxP), which allows identification and tracking of diverse DPCs in mammalian cells. Using PxP, we investigate DPC repair in cells genetically-engineered to express variants of the SPRTN protease that cause premature ageing and early-onset liver cancer in Ruijs-Aalfs syndrome patients. We find an unexpected role for SPRTN in global-genome DPC repair, that does not rely on replication-coupled detection of the lesion. Mechanistically, we demonstrate that replication-independent DPC cleavage by SPRTN requires SUMO-targeted ubiquitylation of the protein adduct and occurs in addition to proteasomal DPC degradation. Defective ubiquitin binding of SPRTN patient variants compromises global-genome DPC repair and causes synthetic lethality in combination with a reduction in proteasomal DPC repair capacity.
Wnt4 and ephrinB2 instruct apical constriction via Dishevelled and non-canonical signaling
Authors: Yoon Jaeho , Sun Jian , Lee Moonsup , Hwang Yoo-Seok , Daar Ira O. 
Published: January 2023

AbstractApical constriction is a cell shape change critical to vertebrate neural tube closure, and the contractile force required for this process is generated by actin-myosin networks. The signaling cue that instructs this process has remained elusive. Here, we identify Wnt4 and the transmembrane ephrinB2 protein as playing an instructive role in neural tube closure as members of a signaling complex we termed WERDS (Wnt4, EphrinB2, Ror2, Dishevelled (Dsh2), and Shroom3). Disruption of function or interaction among members of the WERDS complex results in defects of apical constriction and neural tube closure. The mechanism of action involves an interaction of ephrinB2 with the Dsh2 scaffold protein that enhances the formation of the WERDS complex, which in turn, activates Rho-associated kinase to induce apical constriction. Moreover, the ephrinB2/Dsh2 interaction promotes non-canonical Wnt signaling and shows how cross-talk between two major signal transduction pathways, Eph/ephrin and Wnt, coordinate morphogenesis of the neural tube.