bluuebunny/crossref_metadata_2025_split huggingface dataset:
Syn-rift carbonate platforms in space and time: testing and refining conceptual models using stratigraphic and seismic numerical forward modelling
Authors: Masiero Isabella , Burgess Peter , Hollis Cathy , Manifold Lucy , Gawthorpe Rob , Lecomte Isabelle , Marshall Jim , Rotevatn Atle 
Published: December 2020

Abstract
Understanding and predicting architecture and facies distribution of syn-rift carbonates is challenging owing to complex control by climatic, tectonic, biological and sedimentological factors. CarboCAT is a three-dimensional stratigraphic forward model of carbonate and mixed carbonate–siliciclastic systems that has recently been developed to include processes controlling carbonate platform development in extensional settings. CarboCAT has been used here to perform numerical experiment investigations of the various processes and factors hypothesized to control syn-rift carbonates sedimentation. Models representing three tectonic scenarios have been calculated and investigated, to characterize facies distribution and architecture of carbonate platforms developed on half-grabens, horsts and transfer zones. For each forward stratigraphic model, forward seismic models have also been calculated, so that modelled stratal geometries presented as synthetic seismic images can be directly compared with seismic images of subsurface carbonate strata. The CarboCAT models and synthetic seismic images corroborate many elements of the existing syn-rift and early-post-rift conceptual model, but also expand these models by describing how platform architecture and spatial facies distributions vary along-strike between hanging-wall, footwall and transfer zone settings. Synthetic seismic images show how platform margins may appear in seismic data, showing significant differences in overall seismic character between prograding and backstepping stacking patterns.
Targeting p300/CBP Attenuates Hepatocellular Carcinoma Progression through Epigenetic Regulation of Metabolism
Authors: Cai Ling-Yan , Chen Shi-Jie , Xiao Sen-Hao , Sun Qin-Juan , Ding Chen-Hong , Zheng Bai-Nan , Zhu Xin-Yan , Liu Shu-Qing , Yang Feng , Yang Ya-Xi , Zhou Bing , Luo Cheng , Zhang Xin , Xie Wei-Fen 
Published: December 2020

AbstractTargeting epigenetics in cancer has emerged as a promising anticancer strategy. p300/CBP is a central regulator of epigenetics and plays an important role in hepatocellular carcinoma (HCC) progression. Tumor-associated metabolic alterations contribute to the establishment and maintenance of the tumorigenic state. In this study, we used a novel p300 inhibitor, B029-2, to investigate the effect of targeting p300/CBP in HCC and tumor metabolism. p300/CBP–mediated acetylation of H3K18 and H3K27 increased in HCC tissues compared with surrounding noncancerous tissues. Conversely, treatment with B029-2 specifically decreased H3K18Ac and H3K27Ac and displayed significant antitumor effects in HCC cells in vitro and in vivo. Importantly, ATAC-seq and RNA-seq integrated analysis revealed that B029-2 disturbed metabolic reprogramming in HCC cells. Moreover, B029-2 decreased glycolytic function and nucleotide synthesis in Huh7 cells by reducing H3K18Ac and H3K27Ac levels at the promoter regions of amino acid metabolism and nucleotide synthesis enzyme genes, including PSPH, PSAT1, ALDH18A1, TALDO1, ATIC, and DTYMK. Overexpression of PSPH and DTYMK partially reversed the inhibitory effect of B029-2 on HCC cells. These findings suggested that p300/CBP epigenetically regulates the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC and highlights the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy.Significance:This study demonstrates p300/CBP as a critical epigenetic regulator of glycolysis-related metabolic enzymes in HCC and identifies the p300/CBP inhibitor B029-2 as a potential therapeutic strategy in this disease.
Improved Antitumor Activity of the Fluoropyrimidine Polymer CF10 in Preclinical Colorectal Cancer Models through Distinct Mechanistic and Pharmacologic Properties
Authors: Gmeiner William H. , Dominijanni Anthony , Haber Alex O. , Ghiraldeli Lais P. , Caudell David L. , D’Agostino Ralph , Pasche Boris C. , Smith Thomas L. , Deng Zhiyong , Kiren Sezgin , Mani Chinnadurai , Palle Komaraiah , Brody Jonathan R. 
Published: December 2020

Abstract
Chemotherapy regimens that include 5-fluorouracil (5-FU) are central to colorectal cancer treatment; however, risk/benefit concerns limit 5-FU’s use, necessitating development of improved fluoropyrimidine (FP) drugs. In our study, we evaluated a second-generation nanoscale FP polymer, CF10, for improved antitumor activity. CF10 was more potent than the prototype FP polymer F10 and much more potent than 5-FU in multiple colorectal cancer cell lines including HCT-116, LS174T, SW480, and T84D. CF10 displayed improved stability to exonuclease degradation relative to F10 and reduced susceptibility to thymidine antagonism due to extension of the polymer with arabinosyl cytidine. In colorectal cancer cells, CF10 strongly inhibited thymidylate synthase (TS), induced Top1 cleavage complex formation and caused replication stress, while similar concentrations of 5-FU were ineffective. CF10 was well tolerated in vivo and invoked a reduced inflammatory response relative to 5-FU. Blood chemistry parameters in CF10-treated mice were within normal limits. In vivo, CF10 displayed antitumor activity in several colorectal cancer flank tumor models including HCT-116, HT-29, and CT-26. CF10’s antitumor activity was associated with increased plasma levels of FP deoxynucleotide metabolites relative to 5-FU. CF10 significantly reduced tumor growth and improved survival (84.5 days vs. 32 days; P &lt; 0.0001) relative to 5-FU in an orthotopic HCT-116-luc colorectal cancer model that spontaneously metastasized to liver. Improved survival in the orthotopic model correlated with localization of a fluorescent CF10 conjugate to tumor. Together, our preclinical data support an early-phase clinical trial of CF10 for treatment of colorectal cancer.
Genomic Alterations during the In Situ to Invasive Ductal Breast Carcinoma Transition Shaped by the Immune System
Authors: Trinh Anne , Gil Del Alcazar Carlos R. , Shukla Sachet A. , Chin Koei , Chang Young Hwan , Thibault Guillaume , Eng Jennifer , Jovanović Bojana , Aldaz C. Marcelo , Park So Yeon , Jeong Joon , Wu Catherine , Gray Joe , Polyak Kornelia 
Published: December 2020

Abstract

The drivers of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) transition are poorly understood. Here, we conducted an integrated genomic, transcriptomic, and whole-slide image analysis to evaluate changes in copy-number profiles, mutational profiles, expression, neoantigen load, and topology in 6 cases of matched pure DCIS and recurrent IDC. We demonstrate through combined copy-number and mutational analysis that recurrent IDC can be genetically related to its pure DCIS despite long latency periods and therapeutic interventions. Immune “hot” and “cold” tumors can arise as early as DCIS and are subtype-specific. Topologic analysis showed a similar degree of pan-leukocyte-tumor mixing in both DCIS and IDC but differ when assessing specific immune subpopulations such as CD4 T cells and CD68 macrophages. Tumor-specific copy-number aberrations in MHC-I presentation machinery and losses in 3p, 4q, and 5p are associated with differences in immune signaling in estrogen receptor (ER)-negative IDC. Common oncogenic hotspot mutations in genes including TP53 and PIK3CA are predicted to be neoantigens yet are paradoxically conserved during the DCIS-to-IDC transition, and are associated with differences in immune signaling. We highlight both tumor and immune-specific changes in the transition of pure DCIS to IDC, including genetic changes in tumor cells that may have a role in modulating immune function and assist in immune escape, driving the transition to IDC.

Implications:
We demonstrate that the in situ to IDC evolutionary bottleneck is shaped by both tumor and immune cells.
Clinical and Anatomic Complexity of Patients Undergoing Coronary Intervention With and Without On-Site Surgical Capabilities
Authors: Waldo Stephen W. , Hebbe Annika , Grunwald Gary K. , Doll Jacob A. , Schofield Richard 
Published: December 2020

Background:
Professional society consensus statements articulate the clinical and anatomic complexity of patients that may undergo percutaneous coronary intervention (PCI) without on-site cardiothoracic surgery, although compliance with these recommendations has not been assessed. We sought to evaluate the clinical and anatomic complexity of patients undergoing PCI with and without cardiothoracic surgery on-site.

Methods:
We identified all patients undergoing PCI in the Veterans Affairs health care system between October 2009 and September 2017. The clinical and anatomic complexity of patients treated at sites with or without cardiothoracic surgery was evaluated with a comparative interrupted time series, and mortality was ascertained in a propensity-matched cohort.

Results:

We identified 75 564 patients who underwent PCI, with the majority (53 708, 71%) treated at sites with cardiothoracic surgery. The overall clinical complexity was statistically greater for those treated at sites with cardiothoracic surgery (National Cardiovascular Data Registries CathPCI: 18.4) compared with those at sites without (17.8,
P
<0.001) throughout the study, with similar annual increases in complexity before (2% versus 3%;
P
=0.107) and after (3% versus 3%;
P
=0.704) January 2014. The anatomic complexity of patients treated was also statistically greater (Veterans Affairs SYNTAX: 11.0 versus 10.2;
P
<0.001) and increased at comparable rates (2% versus 1%,
P
=0.731) before 2014. After publication of the consensus statement, anatomic complexity declined at sites with cardiothoracic surgery (−2%) but increased at sites without on-site surgery (5%,
P
=0.025) such that it was similar at the end of the study (
P
=0.622). Referrals for emergent cardiothoracic surgery were rare regardless of treatment venue (61, 0.08%) and the hazard for mortality was similar (hazard ratio, 0.883 [95% CI, 0.662–1.176]) after propensity matching.

Conclusions:
There are minor differences in complexity of patients undergoing coronary intervention at sites with and without cardiothoracic surgery. Clinical outcomes are similar regardless of treatment venue, suggesting an opportunity to improve access to complex interventional care without sacrificing quality.
SIRT6 Protects Smooth Muscle Cells From Senescence and Reduces Atherosclerosis
Authors: Grootaert Mandy O.J. , Finigan Alison , Figg Nichola L. , Uryga Anna K. , Bennett Martin R. 
Published: December 2020

Rationale:
Vascular smooth muscle cell (VSMC) senescence promotes atherosclerosis and features of plaque instability, in part, through lipid-mediated oxidative DNA damage and telomere dysfunction. SIRT6 (Sirtuin 6) is a nuclear deacetylase involved in DNA damage response signaling, inflammation, and metabolism; however, its role in regulating VSMC senescence and atherosclerosis is unclear.

Objective:
We examined SIRT6 expression in human VSMCs, the role, regulation, and downstream pathways activated by SIRT6, and how VSMC SIRT6 regulates atherogenesis.

Methods and Results:

SIRT6 protein, but not mRNA, expression was markedly reduced in VSMCs in human and mouse atherosclerotic plaques, and in human VSMCs derived from plaques or undergoing replicative or palmitate-induced senescence versus healthy aortic VSMCs. The ubiquitin ligase CHIP (C terminus of HSC70-interacting protein) promoted SIRT6 stability, but CHIP expression was reduced in human and mouse plaque VSMCs and by palmitate in a p38- and c-Jun N-terminal kinase-dependent manner. SIRT6 bound to telomeres, while SIRT6 inhibition using shRNA or a deacetylase-inactive mutant (SIRT6
H133Y
) shortened human VSMC lifespan and induced senescence, associated with telomeric H3K9 (histone H3 lysine 9) hyperacetylation and 53BP1 (p53 binding protein 1) binding, indicative of telomere damage. In contrast, SIRT6 overexpression preserved telomere integrity, delayed cellular senescence, and reduced inflammatory cytokine expression and changes in VSMC metabolism associated with senescence. SIRT6, but not SIRT6
H133Y
, promoted proliferation and lifespan of mouse VSMCs, and prevented senescence-associated metabolic changes. ApoE
−/−
(apolipoprotein E) mice were generated that overexpress SIRT6 or SIRT6
H133Y
in VSMCs only. SM22α-hSIRT6/ApoE
−/−
mice had reduced atherosclerosis, markers of senescence and inflammation compared with littermate controls, while plaques of SM22α-hSIRT6
H133Y
/ApoE
−/−
mice showed increased features of plaque instability.

Conclusions:
SIRT6 protein expression is reduced in human and mouse plaque VSMCs and is positively regulated by CHIP. SIRT6 regulates telomere maintenance and VSMC lifespan and inhibits atherogenesis, all dependent on its deacetylase activity. Our data show that endogenous SIRT6 deacetylase is an important and unrecognized inhibitor of VSMC senescence and atherosclerosis.
Wrestling with Spirits: A Medieval Internal Jewish Debate on the Nature of Biblical Angels and its Arabic and Latin Sources
Authors: Schwartz Yossef 
Published: December 2020

Abstract
The article’s point of departure is a debate that took place in about 1290 between Zeraḥyah b. Isaac Ḥen and Hillel b. Samuel, two Jewish-Italian thinkers, that presents us with a surprisingly great variety of Arab, Jewish, and Latin-Christian exegetical and cosmological approaches regarding angelic nature. Zeraḥyah, following the dominant attitude among Arab, Muslim, and Jewish philosophers, strives to interpret the biblical angel-figure either naturalistically or allegorically. Conversely, Hillel cleaves more closely to Christian scholastic conceptions, adhering to the biblical narrative in the literal sense. The struggle between Jacob and the angel (Gen 32) posed one of the most challenging cases, presenting the interpreter with a situation in which an angel did not only appear but was also engaged in bodily contact. In the case of Hillel, his dual commitment as a Jewish Maimonidean heavily influenced by Latin Scholasticism led to the development of a highly unique solution.
Analogism vs. Anomalism in Jewish Linguistic Thought. The 18th-Century Controversy between Zalman Hanau and Jacob Emden
Authors: Wormser Yehonatan 
Published: December 2020

Abstract
This article presents an analysis of the controversy between two 18th-century leading figures: Rabbi Zalman Hanau and Rabbi Jacob Emden. The stances expressed in this controversy, which was held over changes in the traditional prayer versions suggested by Hanau, reveal opposing fundamental attitudes of the two rivals towards basic questions concerning the origin of Hebrew and its linguistic essence. It is being suggested that this controversy resembles the ancient linguistic dispute between the analogist school and anomalist school in Greek and Latin linguistics, even though these two 18th-century figures were not familiar with it.
Sinicizing Islam: Translating the Gulistan of Saʿdi in Modern China
Authors: Jabbari Alexander , Tsai Tiffany Yun-Chu 
Published: December 2020

Abstract
This article examines the translation and domestication of an important piece of Persian didactic literature, the Gulistan of Saʿdi, into modern Chinese. We address all of the Chinese translations of this text, focusing on Yang Wanbao’s translation published in 2000. Yang transforms the text according to the imperatives of the Chinese state, altering the homoerotic scenes of the original and rendering Sufi Islamic concepts into a Confucian or Buddhist idiom. The result is a translation that serves as a significant text for the Jahriyya Sufi order in China, but also an articulation of Chinese Islam countenanced by the People’s Republic.
Seasonal Sensitivity of the Cross-Equatorial Hadley Cell Response to Extratropical Thermal Forcings
Authors: Hwang Yen-Ting , Chung Po-Chun 
Published: December 2020

AbstractThis study explores the seasonal sensitivity of tropical circulation responses to an idealized extratropical thermal forcing using the Community Atmosphere Model version 5 coupled to a slab ocean. The thermal heating over the Southern Ocean is held constant, and the tropical responses in each month of the year are investigated. An anomalous cross-equatorial cell and a southward tropical rain belt shift occur every month. The anomalous cross-equatorial cell has a strong influence on the strengths of the Hadley cell and the subtropical jet in the winter hemisphere; in contrast, it has nearly no impact on the Hadley cell and the subtropical jet strengths in the summer hemisphere. The seasonal variation of the anomalous cross-equatorial cell is small ( of the annual mean change), and could be understood via the energetic and the sea surface temperature gradient perspectives. Both perspectives point to the seasonality of the anomalous ocean heat uptake within the deep tropics as the key factor explaining the weak seasonality of the anomalous cross-equatorial cell. We propose a hypothesis explaining about 75% of this seasonal variation via the climatological position of the ITCZ relative to the anomalous cross-equatorial cell. The results suggest a modest seasonality in tropical precipitation and circulation responses to extratropical forcing. Also, such seasonality may be partly predicted by the climatological seasonal cycle of the tropical circulations.
Compatible Fossil Fuel CO2 Emissions in the CMIP6 Earth System Models’ Historical and Shared Socioeconomic Pathway Experiments of the Twenty-First Century
Authors: Liddicoat Spencer K. , Wiltshire Andy J. , Jones Chris D. , Arora Vivek K. , Brovkin Victor , Cadule Patricia , Hajima Tomohiro , Lawrence David M. , Pongratz Julia , Schwinger Jörg , Séférian Roland , Tjiputra Jerry F. , Ziehn Tilo 
Published: December 2020

AbstractWe present the compatible CO2 emissions from fossil fuel (FF) burning and industry, calculated from the historical and Shared Socioeconomic Pathway (SSP) experiments of nine Earth system models (ESMs) participating in phase 6 of the Coupled Model Intercomparison Project (CMIP6). The multimodel mean FF emissions match the historical record well and are close to the data-based estimate of cumulative emissions (394 ± 59 GtC vs 400 ± 20 GtC, respectively). Only two models fall inside the observed uncertainty range; while two exceed the upper bound, five fall slightly below the lower bound, due primarily to the plateau in CO2 concentration in the 1940s. The ESMs’ diagnosed FF emission rates are consistent with those generated by the integrated assessment models (IAMs) from which the SSPs’ CO2 concentration pathways were constructed; the simpler IAMs’ emissions lie within the ESMs’ spread for seven of the eight SSP experiments, the other being only marginally lower, providing confidence in the relationship between the IAMs’ FF emission rates and concentration pathways. The ESMs require fossil fuel emissions to reduce to zero and subsequently become negative in SSP1-1.9, SSP1-2.6, SSP4-3.4, and SSP5-3.4over. We also present the ocean and land carbon cycle responses of the ESMs in the historical and SSP scenarios. The models’ ocean carbon cycle responses are in close agreement, but there is considerable spread in their land carbon cycle responses. Land-use and land-cover change emissions have a strong influence over the magnitude of diagnosed fossil fuel emissions, with the suggestion of an inverse relationship between the two.
FGF-23 from erythroblasts promotes hematopoietic progenitor mobilization
Authors: Ishii Shinichi , Suzuki Tomohide , Wakahashi Kanako , Asada Noboru , Kawano Yuko , Kawano Hiroki , Sada Akiko , Minagawa Kentaro , Nakamura Yukio , Mizuno Seiya , Takahashi Satoru , Matsui Toshimitsu , Katayama Yoshio 
Published: December 2020

Abstract
Fibroblast growth factor 23 (FGF-23) hormone is produced by bone-embedded osteocytes and regulates phosphate homeostasis in kidneys. We found that administration of granulocyte colony-stimulating factor (G-CSF) to mice induced a rapid, substantial increase in FGF-23 messenger RNA in bone marrow (BM) cells. This increase originated mainly from CD45−Ter119+CD71+ erythroblasts. FGF-23 protein in BM extracellular fluid was markedly increased during G-CSF–induced hematopoietic progenitor cell (HPC) mobilization, but remained stable in the blood, with no change in the phosphate level. Consistent with the BM hypoxia induced by G-CSF, low oxygen concentration induced FGF-23 release from human erythroblast HUDEP-2 cells in vitro. The efficient mobilization induced by G-CSF decreased drastically in both FGF-23−/− and chimeric mice with FGF-23 deficiency, only in hematopoietic cells, but increased in osteocyte-specific FGF-23−/− mice. This finding suggests that erythroblast-derived, but not bone-derived, FGF-23 is needed to release HPCs from BM into the circulation. Mechanistically, FGF-23 did not influence CXCL-12 binding to CXCR-4 on progenitors but interfered with their transwell migration toward CXCL-12, which was canceled by FGF receptor inhibitors. These results suggest that BM erythroblasts facilitate G-CSF–induced HPC mobilization via FGF-23 production as an intrinsic suppressor of chemoattraction.
Venetoclax and dexamethasone synergize with inotuzumab ozogamicin–induced DNA damage signaling in B-lineage ALL
Authors: Kirchhoff Hanna , Karsli Uemran , Schoenherr Caroline , Battmer Karin , Erschow Sergej , Talbot Steven R. , Steinemann Doris , Heuser Michael , Heidenreich Olaf , Hilfiker-Kleiner Denise , Ganser Arnold , Eder Matthias , Scherr Michaela 
Published: December 2020

Abstract
Adult patients with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a dismal prognosis. To improve pharmacotherapy, we analyzed induction of apoptosis by venetoclax and inotuzumab ozogamicin in terms of cytotoxicity and mode of action. Flow cytometry–based analyses of mitochondrial outer membrane permeabilization (MOMP) and ataxia telangiectasia mutated activation demonstrate rapid induction of MOMP by venetoclax and DNA damage signaling by inotuzumab ozogamicin, respectively. In primary ALL samples and patient-derived xenograft (PDX) models, venetoclax and inotuzumab ozogamicin cooperated and synergized in combination with dexamethasone in vitro in all tested samples of ALL. In murine PDX models, inotuzumab ozogamicin, but not venetoclax, induced complete remission in a dose-dependent manner but constantly failed to achieve relapse-free survival. In contrast, combination therapy with venetoclax, dexamethasone, and inotuzumab ozogamicin induced long-term leukemia-free survival and treatment-free survival in all 3 ALL-PDX models tested. These data demonstrate synergistic and highly efficient pharmacotherapy in preclinical models that qualify for evaluation in clinical trials.