bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship Between Active Faulting/Fracturing and Magmatism Around Santorini: Seismic Anisotropy From an Active Source Tomography Experiment
Authors: Heath B. A. , Hooft E. E. E. , Toomey D. R. , Paulatto M. , Papazachos C. B. , Nomikou P. , Morgan J. V. 
Published: July 2021

AbstractIn extending volcanic arcs such as the Aegean, tectonic processes exert a significant control on magmatism. Spanning scales from 1 to 10s of km, volcanic vents, edifices, and eruptive centers follow the orientation of, and are located near, fault zones. Whether this tectonic control on magmatism results from individual faults/fractures weakening the crust or because regional stresses control magma input into the crust is debated. Here we investigate the scales of tectonic and magmatic interactions, specifically focusing on the role of local‐scale (<10 km) faults/fractures in controlling magmatism. We infer local‐scale fault/fracture orientations from anisotropic active‐source P‐wave travel‐time tomography to investigate tectonic and magmatic interactions in the upper crust of Santorini Volcano, Greece, and the actively deforming region to the east. We use the anisotropy magnitude and seismic velocity reduction to model the relative distribution of both consistently oriented and randomly oriented faults/fractures. Our results show that oriented faulting/fracturing resulting from regional‐scale (>10 km) tectonic stresses is distributed broadly across the region at 2–3 km depth, approximately paralleling volcanic/magmatic features. On a local‐scale, magmatism is neither localized in areas of higher oriented fault/fracture density, nor is it accommodating enough extensional strain to inhibit oriented faulting/fracturing of host rock. The alignment of magmatic features shows strong tectonic control despite the lack of correlation with local oriented fault/fracture density. These results suggest that magmatic processes are strongly influenced by regional‐scale, not local‐scale, tectonic processes. We infer regional processes have a greater impact on magmatism than local features due to their greater effect at depth.
Hydrological Modeling of the Effect of the Transition From Flood to Drip Irrigation on Groundwater Recharge Using Multi‐Objective Calibration
Authors: Pool Sandra , Francés Félix , Garcia‐Prats Alberto , Puertes Cristina , Pulido‐Velazquez Manuel , Sanchis‐Ibor Carles , Schirmer Mario , Yang Hong , Jiménez‐Martínez Joaquín 
Published: July 2021

AbstractThe replacement of flood‐irrigation systems by drip‐irrigation technology has been widely promoted with the aim of a more sustainable use of freshwater resources in irrigated agriculture. However, evidence for an irrigation efficiency paradox emphasizes the need to improve our understanding of the impacts of irrigation transformations on water resources. Here, we developed a distributed hydrological modeling approach to investigate the spatiotemporal effect of flood and drip irrigation on groundwater recharge. The approach recognizes differences in the water balance resulting from the localized application of water in surface drip‐irrigated fields and the more extensive application of water in flood irrigation. The approach was applied to the semi‐arid Mediterranean region of Valencia (Spain) and calibrated using a multi‐objective framework. Multiple process scales were addressed within the framework by considering the annual evaporative index, monthly groundwater level dynamics, and daily soil moisture dynamics. Daily simulations from 1994 to 2015 suggested that, in our hydroclimatic conditions, (a) annual recharge is strongly related to annual rainfall, which had a four times higher impact on recharge than the type of irrigation practice, (b) flood‐irrigated recharge tends to exceed drip‐irrigated recharge by 10% at annual time scales, (c) however, recharge response to a particular precipitation event is smaller in flood irrigation than in drip irrigation, and (d) 8–18 rainfall events could generate more than half of the annual recharge in drip and flood irrigation, respectively. Our results highlight the importance of understanding the hydrological dynamics under different irrigation practices for supporting irrigation infrastructure policies.
ETV7 regulates breast cancer stem-like cell features by repressing IFN-response genes
Authors: Pezzè Laura , Meškytė Erna Marija , Forcato Mattia , Pontalti Stefano , Badowska Kalina Aleksandra , Rizzotto Dario , Skvortsova Ira-Ida , Bicciato Silvio , Ciribilli Yari 
Published: July 2021

AbstractCancer stem cells (CSCs) represent a population of cells within the tumor able to drive tumorigenesis and known to be highly resistant to conventional chemotherapy and radiotherapy. In this work, we show a new role for ETV7, a transcriptional repressor member of the ETS family, in promoting breast cancer stem-like cells plasticity and resistance to chemo- and radiotherapy in breast cancer (BC) cells. We observed that MCF7 and T47D BC-derived cells stably over-expressing ETV7 showed reduced sensitivity to the chemotherapeutic drug 5-fluorouracil and to radiotherapy, accompanied by an adaptive proliferative behavior observed in different culture conditions. We further noticed that alteration of ETV7 expression could significantly affect the population of breast CSCs, measured by CD44+/CD24low cell population and mammosphere formation efficiency. By transcriptome profiling, we identified a signature of Interferon-responsive genes significantly repressed in cells over-expressing ETV7, which could be responsible for the increase in the breast CSCs population, as this could be partially reverted by the treatment with IFN-β. Lastly, we show that the expression of the IFN-responsive genes repressed by ETV7 could have prognostic value in breast cancer, as low expression of these genes was associated with a worse prognosis. Therefore, we propose a novel role for ETV7 in breast cancer stem cells’ plasticity and associated resistance to conventional chemotherapy and radiotherapy, which involves the repression of a group of IFN-responsive genes, potentially reversible upon IFN-β treatment. We, therefore, suggest that an in-depth investigation of this mechanism could lead to novel breast CSCs targeted therapies and to the improvement of combinatorial regimens, possibly involving the therapeutic use of IFN-β, with the aim of avoiding resistance development and relapse in breast cancer.
Tissue-specific expression of p73 and p63 isoforms in human tissues
Authors: Marshall Clayton B. , Beeler J. Scott , Lehmann Brian D. , Gonzalez-Ericsson Paula , Sanchez Violeta , Sanders Melinda E. , Boyd Kelli L. , Pietenpol Jennifer A. 
Published: July 2021

Abstractp73 and p63 are members of the p53 family that exhibit overlapping and distinct functions in development and homeostasis. The evaluation of p73 and p63 isoform expression across human tissue can provide greater insight to the functional interactions between family members. We determined the mRNA isoform expression patterns of TP73 and TP63 across a panel of 36 human tissues and protein expression within the highest-expressing tissues. TP73 and TP63 expression significantly correlated across tissues. In tissues with concurrent mRNA expression, nuclear co-expression of both proteins was observed in a majority of cells. Using GTEx data, we quantified p73 and p63 isoform expression in human tissue and identified that the α-isoforms of TP73 and TP63 were the predominant isoform expressed in nearly all tissues. Further, we identified a previously unreported p73 mRNA product encoded by exons 4 to 14. In sum, these data provide the most comprehensive tissue-specific atlas of p73 and p63 protein and mRNA expression patterns in human and murine samples, indicating coordinate expression of these transcription factors in the majority of tissues in which they are expressed.
Super-resolution microscopy reveals that Na+/K+-ATPase signaling protects against glucose-induced apoptosis by deactivating Bad
Authors: Bernhem Kristoffer , Fontana Jacopo M. , Svensson Daniel , Zhang Liang , Nilsson Linnéa M. , Scott Lena , Blom Hans , Brismar Hjalmar , Aperia Anita 
Published: July 2021

AbstractActivation of the apoptotic pathway is a major cause of progressive loss of function in chronic diseases such as neurodegenerative and diabetic kidney diseases. There is an unmet need for an anti-apoptotic drug that acts in the early stage of the apoptotic process. The multifunctional protein Na+,K+-ATPase has, in addition to its role as a transporter, a signaling function that is activated by its ligand, the cardiotonic steroid ouabain. Several lines of evidence suggest that sub-saturating concentrations of ouabain protect against apoptosis of renal epithelial cells, a common complication and major cause of death in diabetic patients. Here, we induced apoptosis in primary rat renal epithelial cells by exposing them to an elevated glucose concentration (20 mM) and visualized the early steps in the apoptotic process using super-resolution microscopy. Treatment with 10 nM ouabain interfered with the onset of the apoptotic process by inhibiting the activation of the BH3-only protein Bad and its translocation to mitochondria. This occurred before the pro-apoptotic protein Bax had been recruited to mitochondria. Two ouabain regulated and Akt activating Ca2+/calmodulin-dependent kinases were found to play an essential role in the ouabain anti-apoptotic effect. Our results set the stage for further exploration of ouabain as an anti-apoptotic drug in diabetic kidney disease as well as in other chronic diseases associated with excessive apoptosis.
Chromatin remodeler ARID1A binds IRF3 to selectively induce antiviral interferon production in macrophages
Authors: Hu Ye , Wang Xin , Song Jiaying , Wu Jiacheng , Xu Jia , Chai Yangyang , Ding Yuanyuan , Wang Bingjing , Wang Chunmei , Zhao Yong , Shen Zhongyang , Xu Xiaoqing , Cao Xuetao 
Published: July 2021

AbstractTranscription factor IRF3 is critical for the induction of antiviral type I interferon (IFN-I). The epigenetic regulation of IFN-I production in antiviral innate immunity needs to be further identified. Here, we reported that epigenetic remodeler ARID1A, a critical component of the mSWI/SNF complex, could bind IRF3 and then was recruited to the Ifn-I promoter by IRF3, thus selectively promoting IFN-I but not TNF-α, IL-6 production in macrophages upon viral infection. Myeloid cell-specific deficiency of Arid1a rendered mice more susceptible to viral infection, accompanied with less IFN-I production. Mechanistically, ARID1A facilitates chromatin accessibility of IRF3 at the Ifn-I promoters by interacting with histone methyltransferase NSD2, which methylates H3K4 and H3K36 of the promoter regions. Our findings demonstrated the new roles of ARID1A and NSD2 in innate immunity, providing insight into the crosstalks of chromatin remodeling, histone modification, and transcription factors in the epigenetic regulation of antiviral innate immunity.
GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms
Authors: Ward Lucas D. , Tu Ho-Chou , Quenneville Chelsea B. , Tsour Shira , Flynn-Carroll Alexander O. , Parker Margaret M. , Deaton Aimee M. , Haslett Patrick A. J. , Lotta Luca A. , Verweij Niek , Ferreira Manuel A. R. ,   Regeneron Genetics Center,   RGC Management and Leadership Team, Abecasis Goncalo , Cantor Michael , Coppola Giovanni , Reid Jeffrey G. , Shuldiner Alan , Karalis Katia , Siminovitch Katherine ,   Sequencing and Lab Operations, Beechert Christina , Forsythe Caitlin , Fuller Erin D. , Gu Zhenhua , Lattari Michael , Lopez Alexander , Schleicher Thomas D. , Padilla Maria Sotiropoulos , Widom Louis , Wolf Sarah E. , Pradhan Manasi , Manoochehri Kia , Ulloa Ricardo H. ,   Genome Informatics, Bai Xiaodong , Balasubramanian Suganthi , Blumenfeld Andrew , Boutkov Boris , Eom Gisu , Habegger Lukas , Hawes Alicia , Khalid Shareef , Krasheninina Olga , Lanche Rouel , Mansfield Adam J. , Maxwell Evan K. , Nafde Mrunali , O’Keeffe Sean , Orelus Max , Panea Razvan , Polanco Tommy , Rasool Ayesha , Salerno William , Staples Jeffrey C. ,   Clinical Informatics, Li Dadong , Sharma Deepika , Kury Fabricio ,   Translational Genetics, Nielsen Jonas , De Tanima ,   Research Program Management, Jones Marcus B. , Mighty Jason , LeBlanc Michelle G. , Mitnaul Lyndon J. ,   Geisinger-Regeneron DiscovEHR Collaboration, Baras Aris , Cantor Michael , Economides Aris , Reid Jeffrey G. , Deubler Andrew , Siminovitch Katherine , Adams Lance J. , Blank Jackie , Bodian Dale , Boris Derek , Buchanan Adam , Carey David J. , Colonie Ryan D. , Davis F. Daniel , Hartzel Dustin N. , Kelly Melissa , Kirchner H. Lester , Leader Joseph B. , Ledbetter David H. , Manus J. Neil , Martin Christa L. , Metpally Raghu P. , Meyer Michelle , Mirshahi Tooraj , Oetjens Matthew , Person Thomas Nate , Still Christopher , Strande Natasha , Sturm Amy , Wagner Jen , Williams Marc , Baras Aris , Hinkle Gregory , Nioi Paul 
Published: July 2021

AbstractUnderstanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variantSLC30A10Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia,SLC30A10Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation inSLC30A10adversely affects more individuals than patients with diagnosed HMNDYT1.
Transporter characterisation reveals aminoethylphosphonate mineralisation as a key step in the marine phosphorus redox cycle
Authors: Murphy Andrew R. J. , Scanlan David J. , Chen Yin , Adams Nathan B. P. , Cadman William A. , Bottrill Andrew , Bending Gary , Hammond John P. , Hitchcock Andrew , Wellington Elizabeth M. H. , Lidbury Ian D. E. A. 
Published: July 2021

AbstractThe planktonic synthesis of reduced organophosphorus molecules, such as alkylphosphonates and aminophosphonates, represents one half of a vast global oceanic phosphorus redox cycle. Whilst alkylphosphonates tend to accumulate in recalcitrant dissolved organic matter, aminophosphonates do not. Here, we identify three bacterial 2-aminoethylphosphonate (2AEP) transporters, named AepXVW, AepP and AepSTU, whose synthesis is independent of phosphate concentrations (phosphate-insensitive). AepXVW is found in diverse marine heterotrophs and is ubiquitously distributed in mesopelagic and epipelagic waters. Unlike the archetypal phosphonate binding protein, PhnD, AepX has high affinity and high specificity for 2AEP (Stappia stellulata AepX Kd 23 ± 4 nM; methylphosphonate Kd 3.4 ± 0.3 mM). In the global ocean, aepX is heavily transcribed (~100-fold>phnD) independently of phosphate and nitrogen concentrations. Collectively, our data identifies a mechanism responsible for a major oxidation process in the marine phosphorus redox cycle and suggests 2AEP may be an important source of regenerated phosphate and ammonium, which are required for oceanic primary production.
NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1
Authors: Zhang Xiaozhen , Huang Xing , Xu Jian , Li Enliang , Lao Mengyi , Tang Tianyu , Zhang Gang , Guo Chengxiang , Zhang Xiaoyu , Chen Wen , Yadav Dipesh Kumar , Bai Xueli , Liang Tingbo 
Published: July 2021

AbstractDespite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically “hot” pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy.
The upstream 5′ splice site remains associated to the transcription machinery during intron synthesis
Authors: Leader Yodfat , Lev Maor Galit , Sorek Matan , Shayevitch Ronna , Hussein Maram , Hameiri Ofir , Tammer Luna , Zonszain Jonathan , Keydar Ifat , Hollander Dror , Meshorer Eran , Ast Gil 
Published: July 2021

AbstractIn the earliest step of spliceosome assembly, the two splice sites flanking an intron are brought into proximity by U1 snRNP and U2AF along with other proteins. The mechanism that facilitates this intron looping is poorly understood. Using a CRISPR interference-based approach to halt RNA polymerase II transcription in the middle of introns in human cells, we discovered that the nascent 5′ splice site base pairs with a U1 snRNA that is tethered to RNA polymerase II during intron synthesis. This association functionally corresponds with splicing outcome, involves bona fide 5′ splice sites and cryptic intronic sites, and occurs transcriptome-wide. Overall, our findings reveal that the upstream 5′ splice sites remain attached to the transcriptional machinery during intron synthesis and are thus brought into proximity of the 3′ splice sites; potentially mediating the rapid splicing of long introns.
Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome
Authors: Smith Amanda M. , LaValle Taylor A. , Shinawi Marwan , Ramakrishnan Sai M. , Abel Haley J. , Hill Cheryl A. , Kirkland Nicole M. , Rettig Michael P. , Helton Nichole M. , Heath Sharon E. , Ferraro Francesca , Chen David Y. , Adak Sangeeta , Semenkovich Clay F. , Christian Diana L. , Martin Jenna R. , Gabel Harrison W. , Miller Christopher A. , Ley Timothy J. 
Published: July 2021

AbstractGermline pathogenic variants inDNMT3Awere recently described in patients with overgrowth, obesity, behavioral, and learning difficulties (DNMT3AOvergrowthSyndrome/DOS). Somatic mutations in theDNMT3Agene are also the most common cause of clonal hematopoiesis, and can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation in peripheral blood cells of 11 DOS patients and found a focal, canonical hypomethylation phenotype, which is most severe with the dominant negativeDNMT3AR882Hmutation. A germline mouse model expressing the homologousDnmt3aR878Hmutation phenocopies most aspects of the human DOS syndrome, including the methylation phenotype and an increased incidence of spontaneous hematopoietic malignancies, suggesting that all aspects of this syndrome are caused by this mutation.
Gαq activation modulates autophagy by promoting mTORC1 signaling
Authors: Cabezudo Sofía , Sanz-Flores Maria , Caballero Alvaro , Tasset Inmaculada , Rebollo Elena , Diaz Antonio , Aragay Anna M. , Cuervo Ana María , Mayor Federico , Ribas Catalina 
Published: July 2021

AbstractThe mTORC1 node plays a major role in autophagy modulation. We report a role of the ubiquitous Gαq subunit, a known transducer of plasma membrane G protein-coupled receptors signaling, as a core modulator of mTORC1 and autophagy. Cells lacking Gαq/11 display higher basal autophagy, enhanced autophagy induction upon different types of nutrient stress along with a decreased mTORC1 activation status. They are also unable to reactivate mTORC1 and thus inactivate ongoing autophagy upon nutrient recovery. Conversely, stimulation of Gαq/11 promotes sustained mTORC1 pathway activation and reversion of autophagy promoted by serum or amino acids removal. Gαq is present in autophagic compartments and lysosomes and is part of the mTORC1 multi-molecular complex, contributing to its assembly and activation via its nutrient status-sensitive interaction with p62, which displays features of a Gαq effector. Gαq emerges as a central regulator of the autophagy machinery required to maintain cellular homeostasis upon nutrient fluctuations.
Individual environmental niches in mobile organisms
Authors: Carlson Ben S. , Rotics Shay , Nathan Ran , Wikelski Martin , Jetz Walter 
Published: July 2021

AbstractIndividual variation is increasingly recognized as a central component of ecological processes, but its role in structuring environmental niche associations remains largely unknown. Species’ responses to environmental conditions are ultimately determined by the niches of single individuals, yet environmental associations are typically captured only at the level of species. Here, we develop scenarios for how individual variation may combine to define the compound environmental niche of populations, use extensive movement data to document individual environmental niche variation, test associated hypotheses of niche configuration, and examine the consistency of individual niches over time. For 45 individual white storks (Ciconia ciconia;116 individual-year combinations), we uncover high variability in individual environmental associations, consistency of individual niches over time, and moderate to strong niche specialization. Within populations, environmental niches follow a nested pattern, with individuals arranged along a specialist-to-generalist gradient. These results reject common assumptions of individual niche equivalency among conspecifics, as well as the separation of individual niches into disparate parts of environmental space. These findings underscore the need for a more thorough consideration of individualistic environmental responses in global change research.
Stiff and tough PDMS-MMT layered nanocomposites visualized by AIE luminogens
Authors: Peng Jingsong , Tomsia Antoni P. , Jiang Lei , Tang Ben Zhong , Cheng Qunfeng 
Published: July 2021

AbstractPolydimethylsiloxane (PDMS) is a widely used soft material that exhibits excellent stability and transparency. But the difficulty of fine-tuning its Young’s modulus and its low toughness significantly hinder its application in fields such as tissue engineering and flexible devices. Inspired by nacre, here we report on the development of PDMS-montmorillonite layered (PDMS-MMT-L) nanocomposites via the ice-templating technique, resulting in 23 and 12 times improvement in Young’s modulus and toughness as compared with pure PDMS. Confocal fluorescence microscopy assisted by aggregation-induced emission (AIE) luminogens reveals three-dimensional reconstruction and in situ crack tracing of the nacre-inspired PDMS-MMT-L nanocomposite. The PDMS-MMT-L nanocomposite is toughened with mechanisms such as crack deflection and bridging. The AIE-assisted visualization of the crack propagation for nacre-inspired layered nanocomposites provides an advanced and universal characterization technique for organic-inorganic nanocomposites.