bluuebunny/crossref_metadata_2025 huggingface dataset:
Climate Impact Comparison of Electric and Gas‐Powered End‐User Appliances
Authors: Dietrich Florian , Chen Jia , Shekhar Ankit , Lober Sebastian , Krämer Konstantin , Leggett Graham , van der Veen Carina , Velzeboer Ilona , Denier van der Gon Hugo , Röckmann Thomas
Published: January 2023

Natural gas is considered a bridging technology in the energy transition because it produces fewer carbon emissions than coal, for example. However, when leaks exist, methane is released into the atmosphere, leading to a dramatic increase in the carbon footprint of natural gas, as methane is a much stronger greenhouse gas than carbon dioxide. Therefore, we conducted a detailed study of methane emissions from gas‐powered end‐use appliances and then compared their climate impacts with those of electricity‐powered appliances. We used the Munich Oktoberfest as a case study and then extended the study to 25 major natural gas consuming countries. This showed that electricity has been the more climate‐friendly energy source at Oktoberfest since 2005, due to the extensive use of renewable electricity at the festival and the presence of methane emissions, particularly caused by the incomplete combustion and leakages of natural gas in cooking and heating appliances. By contrast, at the global level, our study shows that natural gas still produces lower carbon emissions for end‐user appliances than electricity in 18 of the 25 countries studied. However, as the share of renewable energy in the electricity mix steadily increases in most countries, the carbon footprint of electricity will be lower than that of natural gas in these countries in the near future. These findings from our comparison of the total carbon emissions of electric and gas‐powered end‐use appliances can help inform the debate on how to effectively address climate change.
Short‐Lived and Voluminous Fluid‐Flow in a Single Fracture Related to Seismic Events in the Middle Crust
Authors: Mindaleva D. , Uno M. , Tsuchiya N.
Published: January 2023

This study focuses on samples that underwent rapid hydration (∼10 hr) and evolved in permeability (∼10−9 to 10−8 m2) as a result of crustal fracturing. A coupled reactive transport model and thermodynamic analyses, focusing on Si alteration processes within reaction zones, are used to estimate the fluid volume required to induce fluid‐driven seismic activity. Estimated fluid volumes (101–104 m3) are used to approximate the moment magnitudes of potential seismic events. The resulting moment magnitudes (−0.6 to 3.8) and short timescales of fluid infiltration (∼10 hr) are comparable to some slow‐slip events, such as tremors and low‐frequency earthquakes. This indicates that the voluminous fluid flow in a single fracture could be a key control on the generation of crustal fracturing and the induction of seismic activity above the tremor and slow slip events source regions in the lower–middle crust.
Seismic Attenuation Extraction From Traffic Signals Recorded by a Single Seismic Station
Authors: Zhao Yumin , Nilot Enhedelihai Alex , Li Bei , Fang Gang , Luo Wei , Li Yunyue Elita
Published: January 2023

Seismic ambient noise contains rich information about the physical properties of the critical zone. From the motor vehicle noise, we extract the daily seismic attenuation by quantifying the linear relationship between the frequency and amplitude ratio of paired instantaneous spectra. After verifying the reliability of the proposed method, we apply it to seismic ambient noise data collected at three urban sites. The estimated attenuation is compared against three environmental variables: rainfall, temperature, and traffic volume. The results show that the estimated seismic attenuation correlates most strongly with precipitation with positive time lags, suggesting a high attenuation sensitivity to changes in soil moisture and groundwater system. Furthermore, differences in attenuation‐precipitation correlations indicate that near‐surface physical properties may vary significantly due to local site conditions. Our statistical method extracts reliable near‐surface information from highly complex urban ambient noise data, achieving unprecedented spatial and temporal resolution compared to existing ambient noise imaging methods.
Global Self‐Similar Scaling of Terrestrial Carbon With Aridity
Authors: Yin Jun , Porporato Amilcare
Published: January 2023

While it is well known that water availability controls vegetation growth and soil microbial activity, how aridity affects ecosystem carbon patterns is not completely understood. Toward a more quantitative assessment of terrestrial carbon stocks, here we apply dimensional analysis and scaling to the global joint distribution of terrestrial carbon stock, obtained from international survey data and harmonized global maps. The results show a remarkable self‐similar behavior of the global carbon stock with dryness index, whereby the key statistics (e.g., mean, quantiles, and standard deviation) of carbon stock tend to scale with the hydroclimatic regime (i.e., aridity) via a universal exponent. Such a scaling reflects the strong coupling between the hydrological cycle and biogeochemical process and enables robust predictions of carbon stocks as a function of aridity only. When normalized by its averages in the corresponding hydroclimatic regime, the carbon stock distributions collapse onto a single double Pareto lognormal distribution, often used in economics to describe income. The presence of this distribution in completely different physical contexts, such as biogeochemistry and economics, hints at generating mechanisms that transcend the details of the specific stock being considered.
Modelling the Apparent von Kármán Parameter in Thermally and Sedimentologically Stratified Air Flows
Authors: Li Bailiang , Yan Dongyue , He Yanyu , Liu Jianhui
Published: January 2023

Through a field experiment on a sandy beach at Pingtan, China, we propose the first model to characterize the variability of apparent von Kármán parameter in the thermally and sedimentologically stratified air flows. The model shows that is negatively correlated to flux Richardson number as well as sediment transport rate. The atmospheric stability can be either from thermal stratification or sedimentological stratification, neglecting either of them can lead to substantial errors in predicting shear velocity and sediment transport rate.
Comparison of TIDI Line of Sight Winds With ICON‐MIGHTI Measurements
Authors: Wu Chen , Ridley Aaron J.
Published: January 2023

The Thermosphere‐Ionosphere‐Mesosphere Energetics and Dynamics (TIMED) satellite has been making observations of the mesosphere and lower thermosphere (MLT) region for two decades. The TIMED Doppler Interferometer (TIDI) measures the neutral winds using four orthogonal telescopes. In this study, the line of sight (LOS) winds from individual telescopes are compared to the measurements from the Ionospheric Connection Explorer's (ICON's) Michelson Interferometer for Global High‐resolution Thermospheric Imaging (MIGHTI) instrument from 90 to 100 km altitude during 2020. With the MIGHTI vector winds projected onto the LOS direction of each TIDI telescope, coincidences of the two data sets are found. The four telescopes perform differently and the performance depends on the satellite configuration and local solar zenith angle. Measurements from the coldside telescopes, Telescope 1 (Tel1) and Telescope 2 (Tel2), are better correlated with the MIGHTI winds in general with Tel2 having higher correlation coefficients across all conditions. The performance of Tel1 is comparable to that of Tel2 during backward flight while showing systematic errors larger than the average wind speeds during forward flight. The warmside LOS winds from Telescope 3 (Tel3) and Telescope 4 (Tel4) vary widely in magnitude, especially on the nightside. Compared with MIGHTI winds, the Tel4 measurements have the weakest correlation, while the Tel3 performance is comparable to that of the coldside telescopes during the ascending phase but deteriorates during the descending phase. Based on the TIDI/MIGHTI comparisons, figures of merit are generated to quantify the quality of measurements from individual telescopes in different configurations.
Altimetry‐Derived Gravity Gradients Using Spectral Method and Their Performance in Bathymetry Inversion Using Back‐Propagation Neural Network
Authors: Wan Xiaoyun , Annan Richard Fiifi , Ziggah Yao Yevenyo
Published: January 2023

Variations in bathymetry produce gravity gradients; therefore, gravity gradients should be suitable for inverting bathymetry. However, classical bathymetry inversion methods often use gravity anomalies. Studies wherein gravity gradients are employed always use only vertical gravity gradients, ; however, the remaining five gravity gradients also contain bathymetric information. This study presents a spectral method of inverting gravity gradients from altimetry‐derived deflection of the vertical. The accuracy of derived gravity gradients is first evaluated by Laplace's equation. Results show that, except the Arctic region, the mean and standard deviation (STD) of the Laplace operator are, respectively, less than 0.001 and 0.06 E in the Atlantic, Indian and Pacific oceans. Computed was compared with from Scripps Institution of Oceanography. The differences have means and STDs smaller than 0.06 and 6.7 E, respectively, in all study areas, except the Arctic which registered an STD of 13.81 E. All six tensors were then fed into a back‐propagation neural network to predict bathymetries of each study area. The resultant bathymetries compare well with reference models from ship‐borne depths, SRTM15+V2 and GEBCO_2021. Relative to ship‐borne depths, the Atlantic, Pacific, Indian and Arctic study areas yielded mean errors, error STDs and correlation coefficients of 5.40, 3.28, 0.92, 3.07 m; 110.03, 76.23, 104.58, 132.41 m; and 0.9861, 0.9615, 0.9760, 0.9803; respectively. The bathymetries were inverted again, however, with each gravity gradient component omitted. Analysis showed that was not the most influential component across the study regions; rather, each gravity gradient component can significantly contribute to bathymetry inversion.
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

The 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.
Scientists Decipher the Seismic Dance of the Southern Alps
Authors: Rehnberg Morgan
Published: January 2023

Most of the Alps are considered tectonically dead, but according to new research, the southeastern region—home to prosecco wine—is very much alive.
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

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

A 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

The 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

Urinary 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

Patients 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

As 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

Pancreatic 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

We 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

The 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

The 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

The 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

DNA-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

Apical 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.
Active learning to overcome exponential-wall problem for effective structure prediction of chemical-disordered materials
Authors: Yuan Xiaoze , Zhou Yuwei , Peng Qing , Yang Yong , Li Yongwang , Wen Xiaodong
Published: January 2023

Chemical-disordered materials have a wide range of applications whereas the determination of their structures or configurations is one of the most important and challenging problems. Traditional methods are extremely inefficient or intractable for large systems due to the notorious exponential-wall issue that the number of possible structures increase exponentially for N-body systems. Herein, we introduce an efficient approach to predict the thermodynamically stable structures of chemical-disordered materials via active-learning accompanied by first-principles calculations. Our method, named LAsou, can efficiently compress the sampling space and dramatically reduce the computational cost. Three distinct and typical finite-size systems are investigated, including the anion-disordered BaSc(OxF1−x)3 (x = 0.667), the cation-disordered Ca1−xMnxCO3 (x = 0.25) with larger size and the defect-disordered ε-FeCx (x = 0.5) with larger space. The commonly used enumeration method requires to explicitly calculate 2664, 1033, and 10496 configurations, respectively, while the LAsou method just needs to explicitly calculate about 15, 20, and 10 configurations, respectively. Besides the finite-size system, our LAsou method is ready for quasi-infinite size systems empowering materials design.
Systems level analysis of sex-dependent gene expression changes in Parkinson’s disease
Authors: Tranchevent Léon-Charles , Halder Rashi , Glaab Enrico
Published: January 2023

Parkinson’s disease (PD) is a heterogeneous disorder, and among the factors which influence the symptom profile, biological sex has been reported to play a significant role. While males have a higher age-adjusted disease incidence and are more frequently affected by muscle rigidity, females present more often with disabling tremors. The molecular mechanisms involved in these differences are still largely unknown, and an improved understanding of the relevant factors may open new avenues for pharmacological disease modification. To help address this challenge, we conducted a meta-analysis of disease-associated molecular sex differences in brain transcriptomics data from case/control studies. Both sex-specific (alteration in only one sex) and sex-dimorphic changes (changes in both sexes, but with opposite direction) were identified. Using further systems level pathway and network analyses, coordinated sex-related alterations were studied. These analyses revealed significant disease-associated sex differences in mitochondrial pathways and highlight specific regulatory factors whose activity changes can explain downstream network alterations, propagated through gene regulatory cascades. Single-cell expression data analyses confirmed the main pathway-level changes observed in bulk transcriptomics data. Overall, our analyses revealed significant sex disparities in PD-associated transcriptomic changes, resulting in coordinated modulations of molecular processes. Among the regulatory factors involved, NR4A2 has already been reported to harbor rare mutations in familial PD and its pharmacological activation confers neuroprotective effects in toxin-induced models of Parkinsonism. Our observations suggest that NR4A2 may warrant further research as a potential adjuvant therapeutic target to address a subset of pathological molecular features of PD that display sex-associated profiles.
A randomized clinical trial of mindfulness meditation versus exercise in Parkinson’s disease during social unrest
Authors: Kwok Jojo Yan Yan , Choi Edmond Pui Hang , Wong Janet Yuen Ha , Lok Kris Yuet Wan , Ho Mu-Hsing , Fong Daniel Yee Tak , Kwan Jackie Cheuk Yin , Pang Shirley Yin Yu , Auyeung Man
Published: January 2023

Clinical practice guidelines support resilience training and exercise for patients with Parkinson’s disease (PD). This assessor-blinded, randomized clinical trial aimed to compare the effects of a modified mindfulness meditation program versus stretching and resistance training exercise (SRTE) in patients with mild-to-moderate PD. A total of 126 potential participants were enrolled via convenience sampling, of which 68 eligible participants were randomized 1:1 to receive eight weekly 90-min sessions of mindfulness meditation or SRTE. Compared to the SRTE group, generalized estimating equation analyses revealed that the mindfulness group had significantly better improvement in outcomes, particularly for improving depressive symptoms (d, −1.66; 95% CI, −3.31 to −0.02) at week 8 and maintaining emotional non-reactivity at week 20 (d, 2.08; 95% CI, 0.59 to 3.56). Both groups demonstrated significant immediate, small-moderate effects on cognition (effect size [d] = 0.36–0.37, p = 0.006–0.011). Compared with the SRTE, mindfulness meditation appeared to be a feasible and promising strategy for managing depressive symptoms and maintaining emotional stability, with comparable benefits on cognitive performance. To combat the psychospiritual and cognitive sequelae of social unrest and COVID-19 pandemic, the integration of mindfulness training into motor-oriented PD rehabilitation protocols is recommended to strengthen the resilience and minimize the psycho-cognitive comorbidities among patients with mild-to-moderate PD.

Trial Registration: HKU Clinical Trials Registry identifier: HKUCTR-2681.
Understanding the feasibility and environmental effectiveness of a pilot postal inhaler recovery and recycling scheme
Authors: Murphy Anna , Howlett David , Gowson Aaron , Lewis Harriet
Published: January 2023

All inhalers have an environmental impact; the majority are not recycled, with many disposed of inappropriately through domestic waste. To assess the feasibility of a method for recovering and recycling inhalers, Chiesi Limited (Chiesi) set up and funded ‘Take AIR (Action for Inhaler Recycling)’, a 12-month pilot postal scheme facilitated by community pharmacies across Leicester, Leicestershire, and Rutland, and hospitals in Leicestershire. All inhalers were accepted in the scheme. The recovered pressurised metered-dose inhalers (pMDIs) were dismantled and component parts recycled where possible; the remaining propellant gas was extracted for reuse in refrigeration and air conditioning industries. Other inhaler types were incinerated in an ‘energy-from-waste’ facility. From February 2021 to February 2022, 20,049 inhalers were returned; most (77%) were pMDIs. So far, Take AIR has saved the equivalent of an estimated 119.3 tonnes of carbon dioxide emissions from entering the atmosphere. Our experience demonstrates the feasibility and effectiveness of a postal inhaler recovery and recycling scheme, which could be used as a foundation to build future initiatives.
A large scale 16S ribosomal RNA gene amplicon dataset of hand, foot and mouth patients and healthy individuals
Authors: Guo Xiaoying , Yan Min , Huang Dongyi , Chen Siyi , Zhang Dantao , Li Zhifeng , Yang Xingfen , Wu Wei
Published: January 2023

There is evidence linking hand, foot and mouth disease (HFMD) to gut microbiota dysbiosis, and this relationship was corroborated in a large HFMD patient population in our previous study. Here, we present a bacterial 16S rRNA gene dataset from faecal samples of 713 individuals (254 HFMD patients, 459 healthy controls) aged 2 to 7 years residing in Heyuan and Jiangmen counties, Guangdong Province, southern China. Microbiome analysis indicated a significant increase in genus Prevotella, Cetobacterium, and Megamonas was observed in patients with HFMD, whereas a large increase in genus Bacteroides, Ruminococcus, and Faecalibacterium were seen in the control group. We also share the bioinformatic analytical pipeline for this analysis, from data preprocessing to data filtering and amplicon sequence variant (ASV) table generation. We expect that the dataset will be reprocessed, evaluated and fully analysed with various analysis methods to further elucidate the role of the gut microbiota in HFMD development.
Vitamin D level, pain severity and quality of life among hemodialysis patients: a cross-sectional study
Authors: Ishtawi Shaima , Jomaa Dana , Nizar Aisha , Abdalla Mazen , Hamdan Zakaria , Nazzal Zaher
Published: January 2023

This cross-sectional study aims to find the prevalence of chronic pain and its correlation with the quality of life and vitamin D levels among hemodialysis patients in Palestine. We used the brief pain inventory, the medical outcomes study 36-item short-form health survey, and Serum 25-hydroxyvitamin D to assess chronic pain, quality of life, and vitamin D levels, respectively. The study included 200 patients, 38.1% (95% confidence interval 31.3–45.4%) of whom had chronic pain, and 77.7% (95% confidence interval 71.0–83.4%) had deficient Vitamin D levels. Quality of life scores were generally low, with the lowest in role emotional and physical functioning. Sex, comorbidities, and vitamin D level significantly correlate with pain severity. Employment, number of comorbidities, pain severity, and albumin level are significantly associated with the Physical component of quality of life. On the other hand, employment and pain severity are significantly related to the mental component of quality of life. In conclusion, low vitamin D levels, chronic pain, and low quality of life scores are common among hemodialysis patients. In addition, vitamin D is negatively correlated with pain severity. Therefore, healthcare workers should assess and manage hemodialysis patients' chronic pain to improve their quality of life and reduce suffering.
Comparative analysis of Australian climate change and COVID-19 vaccine audience segments shows climate skeptics can be vaccine enthusiasts
Authors: Richardson Lucy M. , Thaker Jagadish , Holmes David C.
Published: January 2023

Denialism and the spreading of misinformation have occurred regarding both climate change and COVID-19, delaying uptake of urgent actions. Audience segmentation analysis identifies audience subgroups likely to have similar responses to messaging, and is a valuable tool for effective campaigns encouraging critical behaviors in both contexts. This study compared audience segmentations based on a representative sample of 1054 Australians. One segmentation was based on the ‘Global Warming’s Six Americas’ online SASSY tool. The second segmentation applied the Theory of Planned Behavior and found five distinct COVID-19 vaccine segments. Both studies showed those most concerned and those most skeptical in the climate change segmentation tended to be in more enthusiastic COVID-19 vaccine segments, while those in the center on climate change were more skeptical on COVID-19 vaccines. Differences identified relating to age, gender, and political views may be explained by a combination of the specific nature and histories of these issues. These findings have implications for effective communication on science and health issues across diverse disciplines.
Pharmacokinetics and bioequivalence evaluation of omeprazole and sodium bicarbonate dry suspensions in healthy Chinese volunteers
Authors: Zhang Rui , Guo Pengpeng , Zhou Jinping , Li Peixia , Wan Jing , Yang Chunxiao , Zhou Jiali , Liu Yani , Shi Shaojun
Published: January 2023

Omeprazole and sodium bicarbonate dry suspension are effective treatments for acid-related disorders. This study compared the bioequivalence and safety of the two formulations of omeprazole and sodium bicarbonate powder and assessed how CYP2C19 gene polymorphisms affect pharmacokinetics (PK). A single-center, randomized, single-dose, 2-sequence and 2-period crossover method was performed in forty healthy Chinese subjects. Blood samples were collected after a single dose for PK (AUC0–∞, AUC0–t, and Cmax) analysis. The concentrations of Omeprazole in human plasma were determined by HPLC–MS/MS. Besides, the gene polymorphisms of CYP2C19 were assessed by Sanger sequencing. The geometric mean ratios (90% confidence interval) [GMR (95% CI)] of Test/Reference preparation for Cmax: 95.2% (88.48%, 102.43%), AUC0–t: 97.47% (94.4%, 101.02%), AUC0–∞: 97.68% (94.27%, 101.21%) were within the range of 80.00–125.00%. The non-parametric test showed no statistical difference in Tmax between the two groups (p > 0.05). All drugs were well tolerated, no severe adverse reactions occurred, and no significant differences in adverse events between the two drugs. For CYP2C19 gene polymorphisms, the results showed that of 40 subjects, 12 subjects were extensive metabolizers, 24 were intermediate metabolizers, and 4 were poor metabolizers, the frequency of metabolic genotypes were 30%, 60%, and 10%. And the allele distributions for CYP2C19 were *1, *2, and *3 at 60%, 38.75%, and 1.25%. Both the CYP2C19 alleles and metabolic genotypes were consistent with other studies in Chinese. The results of PK parameters showed that different genotypes of CYP2C19 lead to significant differences in t1/2, AUC0–t, AUC0–∞ and Cmax, but no significant differences in Tmax in each group. At the same time, we confirmed that the PK parameters of the test and reference had no differences between the males and females. This study has shown that the pharmacokinetic parameters of the two formulations are not significantly different, which showed bioequivalence and exemplary safety. CYP2C19 gene polymorphism significantly differed in the PK parameters of omeprazole sodium bicarbonate powder.