bluuebunny/crossref_metadata_2025_split huggingface dataset:
Late Cretaceous Crustal Shortening in the Northern Snake Range Metamorphic Core Complex: Constraints on the Structural Geometry and Magnitude of Pre‐Extensional Footwall Burial
Authors: Wrobel A. J. , Gans P. B. , Womer J. B. 
Published: June 2021

AbstractDetailed geologic mapping and structural investigation of the footwall of the northern Snake Range (NSR) metamorphic core complex reveal km‐scale Late Cretaceous fold and thrust relationships of the northern Snake Range Fold and Thrust System (NSRFTS) that are broadly coeval with the deep burial and amphibolite facies metamorphism of Eocambrian strata. The O'Neill Peak Recumbent Syncline (OPRS) ‐ an NNW‐trending, non‐cylindrical, eastward‐opening, inclined to recumbent syncline and its overlying anticlinal closure, the O'Neill Peak Anticline, affect the entire Middle to Upper Cambrian stratigraphy, effectively doubling its structural thickness from ∼3.5 to ∼8 km. West of the OPRS, pervasive isoclinal folding in lower Cambrian schistose units and local thrust duplication of lower and middle Cambrian units of the Eightmile Thrust System record layer‐parallel shear and shortening. Detailed cross sections are used to create an interpretive pre‐extensional reconstruction of the NSR that integrates the NSRFTS with associated supracrustal shortening structures now exposed in the Confusion Range to the east. We conclude that the NSRFTS and overlying structures accommodated ≥10 km of horizontal shortening, resulting in ≥7 km of structural burial of the deepest structural levels in the NSR footwall, thus explaining the localized kyanite‐grade metamorphism and elevated thermobarometric P‐T estimates. This burial was apparently quite localized as evidenced by decreasing metamorphism to the north and south. The highest magnitude of subsequent extensional exhumation of the NSR footwall appears to coincides with the area of deepest burial, suggesting that Mesozoic crustal thickening influenced both the magnitudes and geometry of subsequent Cenozoic extensional exhumation.
Automated Technique for the Detection of Step‐Like Solar Wind Dynamic Pressure Changes: Application to the Response of the Transpolar Potential to Solar Wind Dynamic Pressure Fronts
Authors: Boudouridis A. , Zesta E. 
Published: June 2021

AbstractThe input from the solar wind (SW) and the accompanying Interplanetary Magnetic Field (IMF) is the defining feature of the solar wind‐magnetosphere interactions. One of the most important SW drivers is the solar wind dynamic pressure, and most significantly its sharp changes known as pressure fronts. Sudden enhancements in solar wind dynamic pressure, , have been shown to lead to intensification of the auroral electrojets (and Region 1 field‐aligned currents), increase in auroral emissions, and significant enhancement in ionospheric convection and the transpolar potential. Case studies of the interaction between pressure fronts and the terrestrial space environment shed great light on their importance to the structure and dynamics of the system. However, thorough understanding of the interaction requires fully statistical investigations. These statistical studies require a large number of suitable pressure front events. In the past these have been obtained through laborious manual inspection of solar wind data. We present an automated procedure that identifies sudden step enhancements in that satisfy a desired set of limiting step‐like characteristics, such as magnitude of the change, sign of the change (positive/negative), and rate of change. The procedure yields a list of suitable events, along with their step features within minutes. The technique is tested for missed events and false positives by direct comparison to manual inspection of the data. Its utility is illustrated by application to the statistical effect of pressure fronts to the transpolar potential as measured by the Assimilative Mapping of Ionospheric Electrodynamics (AMIE) technique.
A 22‐Year Evaluation of Convection Reaching the Stratosphere Over the United States
Authors: Homeyer Cameron R. , Bowman Kenneth P. 
Published: June 2021

AbstractStratosphere‐reaching moist convection can significantly alter the dynamics, chemistry, and climate of the Earth system. This study seeks to add to the emerging understanding of the frequency, depth, and stratospheric impact of such events using 22 years (1996–2017) of ground‐based radar observations in the contiguous United States. While most prior studies identify such storms using the temperature lapse‐rate tropopause (LRT) as a troposphere‐stratosphere boundary, this study is the first to identify convection that reaches into stratospheric air below the LRT (tropopause depressions, excluding folds) as well. It is found that tropopause depression (TD) overshooting and LRT overshooting occur at similar frequency over the United States, with TD overshooting being more episodic in nature than LRT overshooting. TD overshooting is also found more often throughout the cooler months of the year, while LRT overshooting dominates all overshooting in the summer months. Stratospheric residence of overshoot material, as estimated using trajectory calculations driven by large‐scale winds, suggests that the vast majority of TD overshoot material does not remain in the stratosphere within 5 days downstream and rarely impacts altitudes more than 1 km above the LRT. Conversely, the majority of LRT overshoot material remains in the stratosphere downstream and routinely impacts altitudes >1 and >2 km above the tropopause.
MUC1-C activates the PBAF chromatin remodeling complex in integrating redox balance with progression of human prostate cancer stem cells
Authors: Hagiwara Masayuki , Fushimi Atsushi , Yamashita Nami , Bhattacharya Atrayee , Rajabi Hasan , Long Mark D. , Yasumizu Yota , Oya Mototsugu , Liu Song , Kufe Donald 
Published: June 2021

AbstractThe polybromo-associated PBAF (SWI/SNF) chromatin remodeling complex, which includes PBRM1, ARID2, and BRD7, regulates cell differentiation and genomic integrity. MUC1-C is an oncogenic protein that drives lineage plasticity in prostate cancer (PC) progression. The present work demonstrates that MUC1-C induces PBRM1, ARID2, and BRD7 expression by the previously unrecognized E2F1-mediated activation of their respective promoters. The functional significance of the MUC1-C→PBAF pathway is supported by demonstrating involvement of MUC1-C in associating with nuclear PBAF and driving the NRF2 antioxidant gene transcriptome in PC cells. Mechanistically, MUC1-C forms a complex with NRF2 and PBRM1 on the NRF2 target SLC7A11 gene that encodes the xCT cystine-glutamate antiporter, increases chromatin accessibility and induces SLC7A11/xCT expression. We also show that MUC1-C and PBRM1 are necessary for induction of other NRF2 target genes, including G6PD and PGD that regulate the pentose phosphate pathway. Our results further demonstrate that MUC1-C integrates activation of PBRM1 with the regulation of antioxidant genes, ROS levels, pluripotency factor expression and the cancer stem cell (CSC) state. These findings reveal a role for MUC1-C in regulating PBAF, redox balance and lineage plasticity of PC CSC progression. Our findings also uncover involvement of MUC1-C in integrating the PBAF and BAF pathways in cancer.
NF-κB-activated SPRY4-IT1 promotes cancer cell metastasis by downregulating TCEB1 mRNA via Staufen1-mediated mRNA decay
Authors: Zhao Lin , Jiang Longyang , Zhang Ming , Zhang Qiang , Guan Qiutong , Li Yalun , He Miao , Zhang Jingdong , Wei Minjie 
Published: June 2021

AbstractPrevious study demonstrated that most long non-coding RNAs (lncRNAs) function as competing endogenous RNAs or molecular sponges to negatively modulate miRNA and regulate tumor development. However, the molecular mechanisms of lncRNAs in cancer are not fully understood. Our study describes the role of the lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) in cancer metastasis by mechanisms related to Staufen1 (STAU1)-mediated mRNA decay (SMD). Briefly, we found that, high SPRY4-IT1 expression was associated with aggressiveness and poor outcome in human colorectal, breast and ovarian cancer tissues. In addition, functional assays revealed that SPRY4-IT1 significantly promoted colorectal, breast and ovarian cancer metastasis in vitro and in vivo. Mechanistically, microarray analyses identified several differentially-expressed genes upon SPRY4-IT1 overexpression in HCT 116 colorectal cancer cells. Among them, the 3′-UTR of transcription elongation factor B subunit 1 (TCEB1) mRNA can base-pair with the Alu element in the 3′-UTR of SPRY4-IT1. Moreover, SPRY4-IT1 was found to bind STAU1, promote STAU1 recruitment to the 3′-UTR of TCEB1 mRNA, and affect TCEB1 mRNA stability and expression, resulting in hypoxia-inducible factor 1α (HIF-1α) upregulation, and thereby affecting cancer cell metastasis. In addition, STAU1 depletion abrogated TCEB1 SMD and alleviated the pro-metastatic effect of SPRY4-IT1 overexpression. Significantly, we revealed that SPRY4-IT1 is also transactivated by NF-κB/p65, which activates SPRY4-IT1 to inhibit TCEB1 expression, and subsequently upregulate HIF-1α. In conclusion, our results highlight a novel mechanism of cytoplasmic lncRNA SPRY4-IT1 in which SPRY4-IT1 affecting TCEB1 mRNA stability via STAU1-mediated degradation during cancer metastasis.
AAV-mediated in vivo CAR gene therapy for targeting human T-cell leukemia
Authors: Nawaz Waqas , Huang Bilian , Xu Shijie , Li Yanlei , Zhu Linjing , Yiqiao Hu , Wu Zhiwei , Wu Xilin 
Published: June 2021

AbstractChimeric antigen receptor (CAR) T-cell therapy is the most active field in immuno-oncology and brings substantial benefit to patients with B cell malignancies. However, the complex procedure for CAR T-cell generation hampers its widespread applications. Here, we describe a novel approach in which human CAR T cells can be generated within the host upon injecting an Adeno-associated virus (AAV) vector carrying the CAR gene, which we call AAV delivering CAR gene therapy (ACG). Upon single infusion into a humanized NOD.Cg-Prkdcscid Il2rgem26/Nju tumor mouse model of human T-cell leukemia, AAV generates sufficient numbers of potent in vivo CAR cells, resulting in tumor regression; these in vivo-generated CAR cells produce antitumor immunological characteristics. This instantaneous generation of in vivo CAR T cells may bypass the need for patient lymphodepletion, as well as the β processes of traditional CAR T-cell production, which may make CAR therapy simpler and less expensive. It may allow the development of intricate, individualized treatments in the form of on-demand and diverse therapies.
Clinical stage drugs targeting inhibitor of apoptosis proteins purge episomal Hepatitis B viral genome in preclinical models
Authors: Clark Michelle P. , Huynh Thao , Rao Shringar , Mackiewicz Liana , Mason Hugh , Romal Shahla , Stutz Michael D. , Ahn Sang H. , Earnest Linda , Sozzi Vitina , Littlejohn Margaret , Tran Bang M. , Wiedemann Norbert , Vincan Elizabeth , Torresi Joseph , Netter Hans J. , Mahmoudi Tokameh , Revill Peter , Pellegrini Marc , Ebert Gregor 
Published: June 2021

AbstractA major unmet clinical need is a therapeutic capable of removing hepatitis B virus (HBV) genome from the liver of infected individuals to reduce their risk of developing liver cancer. A strategy to deliver such a therapy could utilize the ability to target and promote apoptosis of infected hepatocytes. Presently there is no clinically relevant strategy that has been shown to effectively remove persistent episomal covalently closed circular HBV DNA (cccDNA) from the nucleus of hepatocytes. We used linearized single genome length HBV DNA of various genotypes to establish a cccDNA-like reservoir in immunocompetent mice and showed that clinical-stage orally administered drugs that antagonize the function of cellular inhibitor of apoptosis proteins can eliminate HBV replication and episomal HBV genome in the liver. Primary human liver organoid models were used to confirm the clinical relevance of these results. This study underscores a clinically tenable strategy for the potential elimination of chronic HBV reservoirs in patients.
Expression of CYP24A1 and other multiple sclerosis risk genes in peripheral blood indicates response to vitamin D in homeostatic and inflammatory conditions
Authors: Law Samantha P. L. , Gatt Prudence N. , Schibeci Stephen D. , McKay Fiona C. , Vucic Steve , Hart Prue , Byrne Scott N. , Brown David , Stewart Graeme J. , Liddle Christopher , Parnell Grant P. , Booth David R. 
Published: June 2021

AbstractAlthough genetic and epidemiological evidence indicates vitamin D insufficiency contributes to multiple sclerosis (MS), and serum levels of vitamin D increase on treatment with cholecalciferol, recent metanalyses indicate that this vitamin D form does not ameliorate disease. Genetic variation in genes regulating vitamin D, and regulated by vitamin D, affect MS risk. We evaluated if the expression of vitamin D responsive MS risk genes could be used to assess vitamin D response in immune cells. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls and people with MS treated with dimethyl fumarate. We assayed changes in expression of vitamin D responsive MS risk (VDRMS) genes in response to treatment with 25 hydroxy vitamin D in the presence or absence of inflammatory stimuli. Expression of CYP24A1 and other VDRMS genes was significantly altered in PBMCs treated with vitamin D in the homeostatic and inflammatory models. Gene expression in MS samples had similar responses to controls, but lower initial expression of the risk genes. Vitamin D treatment abrogated these differences. Expression of CYP24A1 and other MS risk genes in blood immune cells indicate vitamin D response and could enable assessment of immunological response to vitamin D in clinical trials and on therapy.
Single cell derived mRNA signals across human kidney tumors
Authors: Young Matthew D. , Mitchell Thomas J. , Custers Lars , Margaritis Thanasis , Morales-Rodriguez Francisco , Kwakwa Kwasi , Khabirova Eleonora , Kildisiute Gerda , Oliver Thomas R. W. , de Krijger Ronald R. , van den Heuvel-Eibrink Marry M. , Comitani Federico , Piapi Alice , Bugallo-Blanco Eva , Thevanesan Christine , Burke Christina , Prigmore Elena , Ambridge Kirsty , Roberts Kenny , Braga Felipe A. Vieira , Coorens Tim H. H. , Del Valle Ignacio , Wilbrey-Clark Anna , Mamanova Lira , Stewart Grant D. , Gnanapragasam Vincent J. , Rampling Dyanne , Sebire Neil , Coleman Nicholas , Hook Liz , Warren Anne , Haniffa Muzlifah , Kool Marcel , Pfister Stefan M. , Achermann John C. , He Xiaoling , Barker Roger A. , Shlien Adam , Bayraktar Omer A. , Teichmann Sarah A. , Holstege Frank C. , Meyer Kerstin B. , Drost Jarno , Straathof Karin , Behjati Sam 
Published: June 2021

AbstractTumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we quantify reference “cellular signals” in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of “fetalness” with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.
Correlator convolutional neural networks as an interpretable architecture for image-like quantum matter data
Authors: Miles Cole , Bohrdt Annabelle , Wu Ruihan , Chiu Christie , Xu Muqing , Ji Geoffrey , Greiner Markus , Weinberger Kilian Q. , Demler Eugene , Kim Eun-Ah 
Published: June 2021

AbstractImage-like data from quantum systems promises to offer greater insight into the physics of correlated quantum matter. However, the traditional framework of condensed matter physics lacks principled approaches for analyzing such data. Machine learning models are a powerful theoretical tool for analyzing image-like data including many-body snapshots from quantum simulators. Recently, they have successfully distinguished between simulated snapshots that are indistinguishable from one and two point correlation functions. Thus far, the complexity of these models has inhibited new physical insights from such approaches. Here, we develop a set of nonlinearities for use in a neural network architecture that discovers features in the data which are directly interpretable in terms of physical observables. Applied to simulated snapshots produced by two candidate theories approximating the doped Fermi-Hubbard model, we uncover that the key distinguishing features are fourth-order spin-charge correlators. Our approach lends itself well to the construction of simple, versatile, end-to-end interpretable architectures, thus paving the way for new physical insights from machine learning studies of experimental and numerical data.
The perpetual fragility of creeping hillslopes
Authors: Deshpande Nakul S. , Furbish David J. , Arratia Paulo E. , Jerolmack Douglas J. 
Published: June 2021

AbstractSoil creeps imperceptibly but relentlessly downhill, shaping landscapes and the human and ecological communities that live within them. What causes this granular material to ‘flow’ at angles well below repose? The unchallenged dogma is churning of soil by (bio)physical disturbances. Here we experimentally render slow creep dynamics down to micron scale, in a laboratory hillslope where disturbances can be tuned. Surprisingly, we find that even an undisturbed sandpile creeps indefinitely, with rates and styles comparable to natural hillslopes. Creep progressively slows as the initially fragile pile relaxes into a lower energy state. This slowing can be enhanced or reversed with different imposed disturbances. Our observations suggest a new model for soil as a creeping glass, wherein environmental disturbances maintain soil in a perpetually fragile state.
Tumor-associated hematopoietic stem and progenitor cells positively linked to glioblastoma progression
Authors: Lu I-Na , Dobersalske Celia , Rauschenbach Laurèl , Teuber-Hanselmann Sarah , Steinbach Anita , Ullrich Vivien , Prasad Shruthi , Blau Tobias , Kebir Sied , Siveke Jens T. , Becker Jürgen C. , Sure Ulrich , Glas Martin , Scheffler Björn , Cima Igor 
Published: June 2021

AbstractBrain tumors are typically immunosuppressive and refractory to immunotherapies for reasons that remain poorly understood. The unbiased profiling of immune cell types in the tumor microenvironment may reveal immunologic networks affecting therapy and course of disease. Here we identify and validate the presence of hematopoietic stem and progenitor cells (HSPCs) within glioblastoma tissues. Furthermore, we demonstrate a positive link of tumor-associated HSPCs with malignant and immunosuppressive phenotypes. Compared to the medullary hematopoietic compartment, tumor-associated HSPCs contain a higher fraction of immunophenotypically and transcriptomically immature, CD38- cells, such as hematopoietic stem cells and multipotent progenitors, express genes related to glioblastoma progression and display signatures of active cell cycle phases. When cultured ex vivo, tumor-associated HSPCs form myeloid colonies, suggesting potential in situ myelopoiesis. In experimental models, HSPCs promote tumor cell proliferation, expression of the immune checkpoint PD-L1 and secretion of tumor promoting cytokines such as IL-6, IL-8 and CCL2, indicating concomitant support of both malignancy and immunosuppression. In patients, the amount of tumor-associated HSPCs in tumor tissues is prognostic for patient survival and correlates with immunosuppressive phenotypes. These findings identify an important element in the complex landscape of glioblastoma that may serve as a target for brain tumor immunotherapies.
Atomically-resolved interlayer charge ordering and its interplay with superconductivity in YBa2Cu3O6.81
Authors: Hsu Chun-Chih , Huang Bo-Chao , Schnedler Michael , Lai Ming-Yu , Wang Yuh-Lin , Dunin-Borkowski Rafal E. , Chang Chia-Seng , Lee Ting-Kuo , Ebert Philipp , Chiu Ya-Ping 
Published: June 2021

AbstractHigh-temperature superconductive (SC) cuprates exhibit not only a SC phase, but also competing orders, suppressing superconductivity. Charge order (CO) has been recognized as an important competing order, but its microscopic spatial interplay with SC phase as well as the interlayer coupling in CO and SC phases remain elusive, despite being essential for understanding the physical mechanisms of competing orders and hence superconductivity. Here we report the achievement of direct real-space imaging with atomic-scale resolution of cryogenically cleaved YBa2Cu3O6.81 using cross-sectional scanning tunneling microscopy/spectroscopy. CO nanodomains are found embedded in the SC phase with a proximity-like boundary region characterized by mutual suppression of CO and superconductivity. Furthermore, SC coherence as well as CO occur on both CuO chain and plane layers, revealing carrier transport and density of states mixing between layers. The CO antiphase correlation along the c direction suggests a dominance of Coulomb repulsion over Josephson tunneling between adjacent layers.
CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function
Authors: Sethna Saumil , Scott Patrick A. , Giese Arnaud P. J. , Duncan Todd , Jian Xiaoying , Riazuddin Sheikh , Randazzo Paul A. , Redmond T. Michael , Bernstein Steven L. , Riazuddin Saima , Ahmed Zubair M. 
Published: June 2021

AbstractAge-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling—a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to ‘nucleotide empty’ or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.