bluuebunny/crossref_metadata_2025_split huggingface dataset:
Refractory Dissolved Organic Matter has Similar Chemical Characteristics but Different Radiocarbon Signatures With Depth in the Marine Water Column
Authors: White Margot E. , Nguyen Tran B. , Koester Irina , Lardie Gaylord Mary C. , Beman J. Michael , Smith Kenneth L. , McNichol Ann P. , Beaupré Steven R. , Aluwihare Lihini I. 
Published: April 2023

AbstractThe >5,000‐year radiocarbon age (14C‐age) of much of the 630 ± 30 Pg C oceanic dissolved organic carbon (DOC) reservoir remains an enigma in the marine carbon cycle. The fact that DOC is significantly older than dissolved inorganic carbon at every depth in the ocean forms the basis of our current framing of the marine DOC cycle, where some component persists over multiple cycles of ocean mixing. As a result, 14C‐depleted, aged DOC is hypothesized to be present as a uniform reservoir with a constant 14C signature and concentration throughout the water column. However, key requirements of this model, including direct observations of DOC with similar 14C signatures in the surface and deep ocean, have never been met. Despite decades of research, the distribution of Δ14C values in marine DOC remains a mystery. Here, we applied a thermal fractionation method to compare operationally defined refractory DOC (RDOC) from different depths in the North Pacific Ocean. We found that RDOC shares chemical characteristics (as recorded by OC bond strength) throughout the water column but does not share the same 14C signature. Our results support one part of the current paradigm—that RDOC is comprised of structurally related components throughout the ocean that form a “background” reservoir. However, in contrast to the current paradigm, our results are consistent with a vertical concentration gradient and a vertical and inter‐ocean Δ14C gradient for RDOC. The observed Δ14C gradient is compatible with the potential addition of pre‐aged DOC to the upper ocean.
Magnetic Perturbations in Electron Phase‐Space Holes: Contribution of Electron Polarization Drift
Authors: Yang Fan , Zhou Xu‐Zhi , Zhuang Yan , Yue Chao , Zong Qiu‐Gang , Liu Zhi‐Yang , Artemyev Anton V. 
Published: April 2023

AbstractElectron phase‐space holes, sometimes referred to as electron holes, are Debye‐scale plasma structures commonly observed in space plasmas. Although they are usually thought of as electrostatic structures, recent observations have shown that these structures are often accompanied by magnetic field perturbations. Such magnetic perturbations may originate from Lorentz transformation of the electric field, although it has been also suggested that localized currents caused by the electron E × B motion may also play a role. In this paper, we consider the contribution of electron polarization drift to the current and therefore the magnetic field perturbations, which is validated by comparison to Magnetospheric MultiScale observations of 69 electron holes based on a superposed epoch technique. Our results show that the magnetic perturbations caused by the electron polarization drift can be significant compared to Lorentz transformation effect, especially in regions with low magnetic strength and large electron density.
How Bi‐Modal Are Jupiter's Main Aurora Zones?
Authors: Mauk B. H. , Szalay J. R. , Allegrini F. , Bagenal F. , Bolton S. J. , Clark G. , Connerney J. E. P. , Gladstone G. R. , Haggerty D. K. , Kollmann P. , Kurth W. S. , Paranicas C. P. , Sulaiman A. H. 
Published: April 2023

AbstractUsing Juno‐measured >30 keV electrons, three regions with substantial ultraviolet emissions were identified previously for Jupiter's main aurora (excluding the polar cap): low‐latitude diffuse aurora, mid‐latitude Zone I of downward acceleration, and higher latitude Zone II of bi‐directional acceleration. Zone I, associated with upward magnetic field‐aligned currents, was represented as bimodal: sometimes supporting coherent downward electron electrostatic acceleration and sometimes downward electron broadband acceleration, with broadband acceleration usually delivering the most intense electron energy flux at Juno. Recent observations of up‐going ion beams within Zone I represent a challenge as to whether coherent electrostatic acceleration invariably accompanies broadband acceleration. Is this region strictly bi‐modal, or is there a continuum between these two modes? We address these questions by combining multiple ion and electron data sources to diagnose electrostatic potentials both above and below the spacecraft. We find: (a) During Zone I downward electron broadband events, there are examples where evidence of downward electron electrostatic acceleration completely disappears and examples where it endures at some level. (b) Most often, evidence of downward electron electrostatic acceleration is strongly suppressed with strong downward electron broadband acceleration. Residual potentials most often (not always) have values small (<10 kV) compared to the electron characteristic energies of 100–400 keV. (c) Care must be exercised in these studies because plasmasheet electron precipitation spectra can mimic broadband acceleration spectra. At least for weaker auroral broadband accelerations, there is likely to be a continuum of electrostatic and broadband participation. Why either process is favored at any one time is unknown.
Assessing the Deep Carbon Release in an Active Volcanic Field Using Hydrochemistry, δ13CDIC and Δ14CDIC
Authors: Zhong Jun , Wang Linan , Caracausi Antonio , Galy Albert , Li Si‐Liang , Wang Wanfa , Zhang Maoliang , Liu Cong‐Qiang , Liu Guo‐Ming , Xu Sheng 
Published: April 2023

AbstractVolcanic activities have great implications on the geological carbon cycle, and ascertaining the deep carbon contribution in the Earth's surface that runs along the volcanic edifices is important to understand the relationship between solid Earth degassing and global climate change. This study reports analytical results of major dissolved ions concentrations, carbon isotopic compositions (δ13CDIC and Δ14CDIC) of dissolved inorganic carbon (DIC) of rivers, cold springs, and hot springs from Changbaishan volcanic area, Northeast China. The hydrothermal fluids had a significant impact on solutes budgets, as well as carbon isotopes for the rivers. The changes in concentrations of major ions are mainly controlled by mixing of high‐temperature water/rock interaction and low‐temperature water/rock interaction, and low‐temperature water/rock interaction can be explained by the change of chemical composition between volcanic cone (trachyte) and basaltic shield. Because Δ14CDIC is conservative to CO2 outgassing, we used Δ14CDIC to figure out the contributions of deep carbon and surface carbon. While δ13CDIC is sensitive to CO2 outgassing, we thus estimated the minimum deep CO2 outgassing yield (1.24 × 104 t C yr−1) based on DIC flux corrected for outgassing by a Rayleigh model. In the Changbaishan volcanic area, deep carbon release flux was higher than CO2 consumption flux by silicate weathering, while the deep CO2 outgassing flux was an underestimate, consistent with the hypothesis that deep CO2 release regulates climate on geological timescales. This study calls for a better understanding of the effects of volcanic activities on Earth's surface carbon cycling, which has great implications on studying global climate change.
The KMT2A recombinome of acute leukemias in 2023
Authors: Meyer C. , Larghero P. , Almeida Lopes B. , Burmeister T. , Gröger D. , Sutton R. , Venn N. C. , Cazzaniga G. , Corral Abascal L. , Tsaur G. , Fechina L. , Emerenciano M. , Pombo-de-Oliveira M. S. , Lund-Aho T. , Lundán T. , Montonen M. , Juvonen V. , Zuna J. , Trka J. , Ballerini P. , Lapillonne H. , Van der Velden V. H. J. , Sonneveld E. , Delabesse E. , de Matos R. R. C. , Silva M. L. M. , Bomken S. , Katsibardi K. , Keernik M. , Grardel N. , Mason J. , Price R. , Kim J. , Eckert C. , Lo Nigro L. , Bueno C. , Menendez P. , zur Stadt U. , Gameiro P. , Sedék L. , Szczepański T. , Bidet A. , Marcu V. , Shichrur K. , Izraeli S. , Madsen H. O. , Schäfer B. W. , Kubetzko S. , Kim R. , Clappier E. , Trautmann H. , Brüggemann M. , Archer P. , Hancock J. , Alten J. , Möricke A. , Stanulla M. , Lentes J. , Bergmann A. K. , Strehl S. , Köhrer S. , Nebral K. , Dworzak M. N. , Haas O. A. , Arfeuille C. , Caye-Eude A. , Cavé H. , Marschalek R. 
Published: April 2023

AbstractChromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’-KMT2A, two patients had a 5’-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.
RAF1 contributes to cell proliferation and STAT3 activation in colorectal cancer independently of microsatellite and KRAS status
Authors: Dorard Coralie , Madry Claire , Buhard Olivier , Toifl Stefanie , Didusch Sebastian , Ratovomanana Toky , Letourneur Quentin , Dolznig Helmut , Garnett Mathew J. , Duval Alex , Baccarini Manuela 
Published: April 2023

AbstractMore than 30% of all human cancers are driven by RAS mutations and activating KRAS mutations are present in 40% of colorectal cancer (CRC) in the two main CRC subgroups, MSS (Microsatellite Stable) and MSI (Microsatellite Instable). Studies in RAS-driven tumors have shown essential roles of the RAS effectors RAF and specifically of RAF1, which can be dependent or independent of RAF’s ability to activate the MEK/ERK module. In this study, we demonstrate that RAF1, but not its kinase activity, plays a crucial role in the proliferation of both MSI and MSS CRC cell line-derived spheroids and patient-derived organoids, and independently of KRAS mutation status. Moreover, we could define a RAF1 transcriptomic signature which includes genes that contribute to STAT3 activation, and could demonstrate that RAF1 ablation decreases STAT3 phosphorylation in all CRC spheroids tested. The genes involved in STAT3 activation as well as STAT3 targets promoting angiogenesis were also downregulated in human primary tumors expressing low levels of RAF1. These results indicate that RAF1 could be an attractive therapeutic target in both MSI and MSS CRC regardless of their KRAS status and support the development of selective RAF1 degraders rather than RAF1 inhibitors for clinical use in combination therapies.
The MEF2A transcription factor interactome in cardiomyocytes
Authors: Moustafa Amira , Hashemi Sara , Brar Gurnoor , Grigull Jörg , Ng Siemon H. S. , Williams Declan , Schmitt-Ulms Gerold , McDermott John C. 
Published: April 2023

AbstractTranscriptional regulators encoded by the Myocyte Enhancer Factor 2 (MEF2) gene family play a fundamental role in cardiac development, homeostasis and pathology. Previous studies indicate that MEF2A protein-protein interactions serve as a network hub in several cardiomyocyte cellular processes. Based on the idea that interactions with regulatory protein partners underly the diverse roles of MEF2A in cardiomyocyte gene expression, we undertook a systematic unbiased screen of the MEF2A protein interactome in primary cardiomyocytes using an affinity purification-based quantitative mass spectrometry approach. Bioinformatic processing of the MEF2A interactome revealed protein networks involved in the regulation of programmed cell death, inflammatory responses, actin dynamics and stress signaling in primary cardiomyocytes. Further biochemical and functional confirmation of specific protein-protein interactions documented a dynamic interaction between MEF2A and STAT3 proteins. Integration of transcriptome level data from MEF2A and STAT3-depleted cardiomyocytes reveals that the balance between MEF2A and STAT3 activity exerts a level of executive control over the inflammatory response and cardiomyocyte cell survival and experimentally ameliorates Phenylephrine induced cardiomyocyte hypertrophy. Lastly, we identified several MEF2A/STAT3 co-regulated genes, including the MMP9 gene. Herein, we document the cardiomyocyte MEF2A interactome, which furthers our understanding of protein networks involved in the hierarchical control of normal and pathophysiological cardiomyocyte gene expression in the mammalian heart.
Aberrant RNA m6A modification in gastrointestinal malignancies: versatile regulators of cancer hallmarks and novel therapeutic opportunities
Authors: Shen Li-Ting , Che Lin-Rong , He Zongsheng , Lu Qian , Chen Dong-Feng , Qin Zhong-yi , Wang Bin 
Published: April 2023

AbstractGastrointestinal (GI) cancer is one of the most common malignancies, and a leading cause of cancer-related death worldwide. However, molecular targeted therapies are still lacking, leading to poor treatment efficacies. As an important layer of epigenetic regulation, RNA N6-Methyladenosine (m6A) modification is recently linked to various biological hallmarks of cancer by orchestrating RNA metabolism, including RNA splicing, export, translation, and decay, which is partially involved in a novel biological process termed phase separation. Through these regulatory mechanisms, m6A dictates gene expression in a dynamic and reversible manner and may play oncogenic, tumor suppressive or context-dependent roles in GI tumorigenesis. Therefore, regulators and effectors of m6A, as well as their modified substrates, represent a novel class of molecular targets for cancer treatments. In this review, we comprehensively summarize recent advances in this field and highlight research findings that documented key roles of RNA m6A modification in governing hallmarks of GI cancers. From a historical perspective, milestone findings in m6A machinery are integrated with a timeline of developing m6A targeting compounds. These available chemical compounds, as well as other approaches that target core components of the RNA m6A pathway hold promises for clinical translational to treat human GI cancers. Further investigation on several outstanding issues, e.g. how oncogenic insults may disrupt m6A homeostasis, and how m6A modification impacts on the tumor microenvironment, may dissect novel mechanisms underlying human tumorigenesis and identifies next-generation anti-cancer therapeutics.
Well-TEMP-seq as a microwell-based strategy for massively parallel profiling of single-cell temporal RNA dynamics
Authors: Lin Shichao , Yin Kun , Zhang Yingkun , Lin Fanghe , Chen Xiaoyong , Zeng Xi , Guo Xiaoxu , Zhang Huimin , Song Jia , Yang Chaoyong 
Published: April 2023

AbstractSingle-cell RNA sequencing (scRNA-seq) reveals the transcriptional heterogeneity of cells, but the static snapshots fail to reveal the time-resolved dynamics of transcription. Herein, we develop Well-TEMP-seq, a high-throughput, cost-effective, accurate, and efficient method for massively parallel profiling the temporal dynamics of single-cell gene expression. Well-TEMP-seq combines metabolic RNA labeling with scRNA-seq method Well-paired-seq to distinguish newly transcribed RNAs marked by T-to-C substitutions from pre-existing RNAs in each of thousands of single cells. The Well-paired-seq chip ensures a high single cell/barcoded bead pairing rate (~80%) and the improved alkylation chemistry on beads greatly alleviates chemical conversion-induced cell loss (~67.5% recovery). We further apply Well-TEMP-seq to profile the transcriptional dynamics of colorectal cancer cells exposed to 5-AZA-CdR, a DNA-demethylating drug. Well-TEMP-seq unbiasedly captures the RNA dynamics and outperforms the splicing-based RNA velocity method. We anticipate that Well-TEMP-seq will be broadly applicable to unveil the dynamics of single-cell gene expression in diverse biological processes.
Structural mechanism of a drug-binding process involving a large conformational change of the protein target
Authors: Ayaz Pelin , Lyczek Agatha , Paung YiTing , Mingione Victoria R. , Iacob Roxana E. , de Waal Parker W. , Engen John R. , Seeliger Markus A. , Shan Yibing , Shaw David E. 
Published: April 2023

AbstractProteins often undergo large conformational changes when binding small molecules, but atomic-level descriptions of such events have been elusive. Here, we report unguided molecular dynamics simulations of Abl kinase binding to the cancer drug imatinib. In the simulations, imatinib first selectively engages Abl kinase in its autoinhibitory conformation. Consistent with inferences drawn from previous experimental studies, imatinib then induces a large conformational change of the protein to reach a bound complex that closely resembles published crystal structures. Moreover, the simulations reveal a surprising local structural instability in the C-terminal lobe of Abl kinase during binding. The unstable region includes a number of residues that, when mutated, confer imatinib resistance by an unknown mechanism. Based on the simulations, NMR spectra, hydrogen-deuterium exchange measurements, and thermostability measurements and estimates, we suggest that these mutations confer imatinib resistance by exacerbating structural instability in the C-terminal lobe, rendering the imatinib-bound state energetically unfavorable.
Localized nuclear reaction breaks boron drug capsules loaded with immune adjuvants for cancer immunotherapy
Authors: Shi Yaxin , Guo Zhibin , Fu Qiang , Shen Xinyuan , Zhang Zhongming , Sun Wenjia , Wang Jinqiang , Sun Junliang , Zhang Zizhu , Liu Tong , Gu Zhen , Liu Zhibo 
Published: April 2023

AbstractBoron neutron capture therapy (BNCT) was clinically approved in 2020 and exhibits remarkable tumour rejection in preclinical and clinical studies. It is binary radiotherapy that may selectively deposit two deadly high-energy particles (4He and 7Li) within a cancer cell. As a radiotherapy induced by localized nuclear reaction, few studies have reported its abscopal anti-tumour effect, which has limited its further clinical applications. Here, we engineer a neutron-activated boron capsule that synergizes BNCT and controlled immune adjuvants release to provoke a potent anti-tumour immune response. This study demonstrates that boron neutron capture nuclear reaction forms considerable defects in boron capsule that augments the drug release. The following single-cell sequencing unveils the fact and mechanism that BNCT heats anti-tumour immunity. In female mice tumour models, BNCT and the controlled drug release triggered by localized nuclear reaction causes nearly complete regression of both primary and distant tumour grafts.
Selection and adaptive introgression guided the complex evolutionary history of the European common bean
Authors: Bellucci Elisa , Benazzo Andrea , Xu Chunming , Bitocchi Elena , Rodriguez Monica , Alseekh Saleh , Di Vittori Valerio , Gioia Tania , Neumann Kerstin , Cortinovis Gaia , Frascarelli Giulia , Murube Ester , Trucchi Emiliano , Nanni Laura , Ariani Andrea , Logozzo Giuseppina , Shin Jin Hee , Liu Chaochih , Jiang Liang , Ferreira Juan José , Campa Ana , Attene Giovanna , Morrell Peter L. , Bertorelle Giorgio , Graner Andreas , Gepts Paul , Fernie Alisdair R. , Jackson Scott A. , Papa Roberto 
Published: April 2023

AbstractDomesticated crops have been disseminated by humans over vast geographic areas. Common bean (Phaseolus vulgaris L.) was introduced in Europe after 1492. Here, by combining whole-genome profiling, metabolic fingerprinting and phenotypic characterisation, we show that the first common bean cultigens successfully introduced into Europe were of Andean origin, after Francisco Pizarro’s expedition to northern Peru in 1529. We reveal that hybridisation, selection and recombination have shaped the genomic diversity of the European common bean in parallel with political constraints. There is clear evidence of adaptive introgression into the Mesoamerican-derived European genotypes, with 44 Andean introgressed genomic segments shared by more than 90% of European accessions and distributed across all chromosomes except PvChr11. Genomic scans for signatures of selection highlight the role of genes relevant to flowering and environmental adaptation, suggesting that introgression has been crucial for the dissemination of this tropical crop to the temperate regions of Europe.
Structure and function of the metagenomic plastic-degrading polyester hydrolase PHL7 bound to its product
Authors: Richter P. Konstantin , Blázquez-Sánchez Paula , Zhao Ziyue , Engelberger Felipe , Wiebeler Christian , Künze Georg , Frank Ronny , Krinke Dana , Frezzotti Emanuele , Lihanova Yuliia , Falkenstein Patricia , Matysik Jörg , Zimmermann Wolfgang , Sträter Norbert , Sonnendecker Christian 
Published: April 2023

AbstractThe recently discovered metagenomic-derived polyester hydrolase PHL7 is able to efficiently degrade amorphous polyethylene terephthalate (PET) in post-consumer plastic waste. We present the cocrystal structure of this hydrolase with its hydrolysis product terephthalic acid and elucidate the influence of 17 single mutations on the PET-hydrolytic activity and thermal stability of PHL7. The substrate-binding mode of terephthalic acid is similar to that of the thermophilic polyester hydrolase LCC and deviates from the mesophilicIsPETase. The subsite I modifications L93F and Q95Y, derived from LCC, increased the thermal stability, while exchange of H185S, derived fromIsPETase, reduced the stability of PHL7. The subsite II residue H130 is suggested to represent an adaptation for high thermal stability, whereas L210 emerged as the main contributor to the observed high PET-hydrolytic activity. Variant L210T showed significantly higher activity, achieving a degradation rate of 20 µm h−1with amorphous PET films.
Lunar eclipses illuminate timing and climate impact of medieval volcanism
Authors: Guillet Sébastien , Corona Christophe , Oppenheimer Clive , Lavigne Franck , Khodri Myriam , Ludlow Francis , Sigl Michael , Toohey Matthew , Atkins Paul S. , Yang Zhen , Muranaka Tomoko , Horikawa Nobuko , Stoffel Markus 
Published: April 2023

AbstractExplosive volcanism is a key contributor to climate variability on interannual to centennial timescales1. Understanding the far-field societal impacts of eruption-forced climatic changes requires firm event chronologies and reliable estimates of both the burden and altitude (that is, tropospheric versus stratospheric) of volcanic sulfate aerosol2,3. However, despite progress in ice-core dating, uncertainties remain in these key factors4. This particularly hinders investigation of the role of large, temporally clustered eruptions during the High Medieval Period (HMP, 1100–1300 ce), which have been implicated in the transition from the warm Medieval Climate Anomaly to the Little Ice Age5. Here we shed new light on explosive volcanism during the HMP, drawing on analysis of contemporary reports of total lunar eclipses, from which we derive a time series of stratospheric turbidity. By combining this new record with aerosol model simulations and tree-ring-based climate proxies, we refine the estimated dates of five notable eruptions and associate each with stratospheric aerosol veils. Five further eruptions, including one responsible for high sulfur deposition over Greenland circa 1182 ce, affected only the troposphere and had muted climatic consequences. Our findings offer support for further investigation of the decadal-scale to centennial-scale climate response to volcanic eruptions.