bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paul Williams: The Cage Mix
Authors: DAVENPORT MARK 
Published: April 2020

AbstractDemystifying a largely misunderstood chapter in John Cage's biographical narrative, this article explores the pivotal role architect and philanthropist Paul Williams played in Cage's life, and for whom Cage named his famous magnetic tape composition Williams Mix (1952–53). Retracing the activities of both men, beginning with their earliest encounter at the experimental Black Mountain College in North Carolina in 1948, this investigation documents for the first time the extent of their mutually devoted relationship. Newly uncovered source material and photographs also reveal the valuable contributions Williams made as primary benefactor and mastermind of the intentional community called the Gatehill Cooperative (a.k.a. “Stony Point”), a place Cage called home for seventeen years (1954–71). There Cage developed a “hunger for nature,” wrote his widely read and influential book Silence (1961), and undertook some of his most significant musical projects.
Achieving sustainability requires systemic business transformation
Authors: Waddock Sandra 
Published: April 2020

Non-technical summaryAchieving sustainability requires that businesses transform; however, it is virtually impossible in today's competitive environment for individual businesses to do what is needed to bring about systemic transformation. Instead, it is the context around businesses, including the public policy environment and changes by major actors, which must shift so that the pressures, constraints and demands on businesses can epimimetically drive their competitive instincts in the direction of wellbeing for all.
Horse purslane (Trianthema portulacastrum) control in pigeonpea with PRE and POST herbicides
Authors: Mahajan Gulshan , Rachaputi R. C. N. , Chauhan Bhagirath Singh 
Published: April 2020

AbstractPigeonpea has great potential as a profitable summer legume rotational crop in cereal farming systems of subtropical Australia. Pigeonpea requires season-long weed control, but options for controlling broadleaf weeds in pigeonpea with POST herbicides are limited. The objective of this study was to evaluate the performance of different herbicides (PRE: pendimethalin; POST: acifluorfen, bentazon, and imazapic) applied singly or in sequence for horse purslane control in pigeonpea and their impact on pigeonpea yield. Field experiments were conducted in 2017 and 2018 at Gatton, Australia. Pendimethalin applied PRE at 1.14 kg ai ha−1 reduced horse purslane biomass by 87% and 92% and produced 32% and 105% higher grain yield compared with the nontreated control in 2017 and 2018, respectively. Imazapic applied POST at 0.10 kg ai ha−1 reduced horse purslane biomass by 79% and 82% and increased grain yield by 60% and 88% compared with the nontreated control in 2017 and 2018, respectively. Acifluorfen applied POST (0.34 and 0.42 kg ai ha−1) caused 16% to 48% injury to pigeonpea at 45 d after treatment. Control of horse purslane ranged from 87% to 92% (biomass reduction) with pendimethalin applied PRE at 1.14 kg ai ha−1 and was comparable with pendimethalin applied PRE at 0.91 kg ai ha−1 in the sequential application, and imazapic at 0.08 kg ai ha−1 or bentazon at 0.96 kg ai ha−1. The study findings suggest if farmers miss the PRE application of pendimethalin or are unable to achieve season-long weed control, POST application of imazapic is an alternate. This research provided herbicide options for control of horse purslane in pigeonpea that could be used in rotations for reducing the selection pressure of weeds.
Spatiotemporal Seismic Structure Variations Associated With the 2018 Kīlauea Eruption Based on Temporary Dense Geophone Arrays
Authors: Wu Sin‐Mei , Lin Fan‐Chi , Farrell Jamie , Shiro Brian , Karlstrom Leif , Okubo Paul , Koper Keith 
Published: April 2020

AbstractDuring the 2018 Kīlauea volcanic eruption, lava erupted from a series of new fissures in the lower East Rift Zone more than 30 km away from the summit through a dike intrusion. Between late May and early August, variations in the effusion rate at the persistent eruptive vent (Fissure 8) were observed following near‐daily summit caldera collapse events. Targeting the ongoing eruptive activity and the subsurface magma movement, we deployed a temporary dense seismic array. The observed time‐lapse changes in seismic velocity associated with the response of the summit collapse in three areas are presented in this study. The results show (1) clear spatially dependent co‐collapse velocity reductions across the newly‐intruded dike structure, (2) a gradual post‐collapse velocity increase near Fissure 8 correlated with the surge of magma supply, and (3) a gradual post‐collapse velocity increase on the summit likely associated with reservoir pressurization and crustal welding.
Optimization of Deep Learning Precipitation Models Using Categorical Binary Metrics
Authors: Larraondo Pablo R. , Renzullo Luigi J. , Van Dijk Albert I. J. M. , Inza Inaki , Lozano Jose A. 
Published: April 2020

AbstractThis work introduces a methodology for optimizing neural network models using a combination of continuous and categorical binary indices in the context of precipitation forecasting. Probability of detection and false alarm rate are popular metrics used in the verification of precipitation models. However, machine learning models trained using gradient descent cannot be optimized based on these metrics, as they are not differentiable. We propose an alternative formulation for these categorical indices that are differentiable and we demonstrate how they can be used to optimize the skill of precipitation neural network models defined as a multiobjective optimization problem. To our knowledge, this is the first proposal of a methodology for optimizing weather neural network models based on categorical indices.
Chronic inhibition of GABA synthesis in the infralimbic cortex facilitates conditioned safety memory and reduces contextual fear
Authors: Kreutzmann Judith C. , Fendt Markus 
Published: April 2020

AbstractAccurate discrimination between danger and safety cues is essential for survival. Recent findings in humans indicate that patients suffering from anxiety disorders cannot reliably use safety cues in order to inhibit fear responses. However, the neuroanatomical pathways of conditioned safety are still unclear. Aim of the present study was to investigate whether chronic inhibition of GABA synthesis in the infralimbic (IL) cortex, a critical region for fear inhibition, would lead to enhanced conditioned safety memory. Male Sprague Dawley rats were equipped with osmotic mini-pumps attached to an infusion cannula aimed at the IL. Mini-pumps were either filled with the glutamate decarboxylase (GAD) inhibitor l-allylglycine (l-AG) or the inactive enantiomer d-allylglycine (d-AG). Previous studies demonstrated that chronic infusions of l-AG lead to lower GABA levels and overall enhanced neural activity. The effect of IL disinhibition on conditioned safety was investigated utilizing the acoustic startle response. Chronic disinhibition of the IL facilitated conditioned safety memory, along with reduced contextual fear and lower corticosterone levels. The present findings suggest that the IL is a key brain region for conditioned safety memory. Because anxiety disorder patients are often not capable to use safety cues to inhibit unnecessary fear responses, the present findings are of clinical relevance and could potentially contribute to therapy optimization.
Statin as anti-cancer therapy in autochthonous T-lymphomas expressing stabilized gain-of-function mutant p53 proteins
Authors: Tutuska Karis , Parrilla-Monge Laura , Di Cesare Erica , Nemajerova Alice , Moll Ute M. 
Published: April 2020

AbstractAn important component of missense mutant p53 gain-of-function (mutp53 GOF) activities is the ability of stabilized mutp53 proteins to upregulate the mevalonate pathway, providing a rationale for exploring the statin family of HMG-CoA reductase inhibitors as anticancer agents in mutp53 tumors. In this small exploratory study we report on the effects of statin treatment in autochthonous mouse models of clinically advanced T-cell lymphoma expressing two different GOF mutp53 alleles. We find that Rosuvastatin monotherapy shows a modest, p53 allele-selective and transient anti-tumor effect in autochthonous T-lymphomas expressing the p53 R248Q DNA contact mutant, but not in tumors expressing the p53 R172H conformational mutant. p53 null mice also do not benefit. In vitro statin sensitivity is not a strong predictor for in vivo sensitivity, while subcutaneous allografts are. Future explorations of statins in combination therapies are justified to improve its anti-tumor effects and to better define the most statin-sensitive alleles and tumor types among mutp53-stabilized cancers.
LncRNA KCNQ1OT1 sponges miR-34c-5p to promote osteosarcoma growth via ALDOA enhanced aerobic glycolysis
Authors: Shen Yifei , Xu Jingwen , Pan Xiaohui , Zhang Yunkun , Weng Yiping , Zhou Dong , He Shisheng 
Published: April 2020

AbstractMetabolic switch from oxidative phosphorylation to aerobic glycolysis, which is also called the Warburg effect, is a hallmark of osteosarcoma (OS) and leads to the enhancement of cell chemoresistance, growth, metastasis, and invasion. Emerging evidence indicates that long non-coding RNA (lncRNA) plays a crucial role in the Warburg effect of cancer cells. Here, we report that lncRNA KCNQ1OT1 was upregulated in OS. Meanwhile, functional experiments demonstrated that the KCNQ1OT1 facilitated proliferation and suppressed apoptosis of OS cells. In addition, KCNQ1OT1 contributed to the Warburg effect by stimulating aldolase A (ALDOA) expression. Furthermore, using bioinformatics analysis, luciferase reporter, RNA immunoprecipitation, and RNA pull-down assay, we identified that KCNQ1OT1 functions as a competing endogenous RNA (ceRNA) by sponging miR-34c-5p, which inhibited ALDOA expression by directly targeting its 3ʹUTR. Taken together, these data identified a key role of KCNQ1OT1 in glucose metabolism reprogramming of OS. Targeting the KCNQ1OT1/miR-34c-5p/ALDOA axis may be a potential therapeutic target in OS treatment.
Escape mutations circumvent a tradeoff between resistance to a beta-lactam and resistance to a beta-lactamase inhibitor
Authors: Russ Dor , Glaser Fabian , Shaer Tamar Einat , Yelin Idan , Baym Michael , Kelsic Eric D. , Zampaloni Claudia , Haldimann Andreas , Kishony Roy 
Published: April 2020

AbstractBeta-lactamase inhibitors are increasingly used to counteract antibiotic resistance mediated by beta-lactamase enzymes. These inhibitors compete with the beta-lactam antibiotic for the same binding site on the beta-lactamase, thus generating an evolutionary tradeoff: mutations that increase the enzyme’s beta-lactamase activity tend to increase also its susceptibility to the inhibitor. Here, we investigate how common and accessible are mutants that escape this adaptive tradeoff. Screening a deep mutant library of theblaampCbeta-lactamase gene ofEscherichia coli, we identified mutations that allow growth at beta-lactam concentrations far exceeding those inhibiting growth of the wildtype strain, even in the presence of the enzyme inhibitor (avibactam). These escape mutations are rare and drug-specific, and some combinations of avibactam with beta-lactam drugs appear to prevent such escape phenotypes. Our results, showing differential adaptive potential ofblaampCto combinations of avibactam and different beta-lactam antibiotics, suggest that it may be possible to identify treatments that are more resilient to evolution of resistance.
Methylation of Salmonella Typhimurium flagella promotes bacterial adhesion and host cell invasion
Authors: Horstmann Julia A. , Lunelli Michele , Cazzola Hélène , Heidemann Johannes , Kühne Caroline , Steffen Pascal , Szefs Sandra , Rossi Claire , Lokareddy Ravi K. , Wang Chu , Lemaire Laurine , Hughes Kelly T. , Uetrecht Charlotte , Schlüter Hartmut , Grassl Guntram A. , Stradal Theresia E. B. , Rossez Yannick , Kolbe Michael , Erhardt Marc 
Published: April 2020

AbstractThe long external filament of bacterial flagella is composed of several thousand copies of a single protein, flagellin. Here, we explore the role played by lysine methylation of flagellin in Salmonella, which requires the methylase FliB. We show that both flagellins of Salmonella enterica serovar Typhimurium, FliC and FljB, are methylated at surface-exposed lysine residues by FliB. A Salmonella Typhimurium mutant deficient in flagellin methylation is outcompeted for gut colonization in a gastroenteritis mouse model, and methylation of flagellin promotes bacterial invasion of epithelial cells in vitro. Lysine methylation increases the surface hydrophobicity of flagellin, and enhances flagella-dependent adhesion of Salmonella to phosphatidylcholine vesicles and epithelial cells. Therefore, posttranslational methylation of flagellin facilitates adhesion of Salmonella Typhimurium to hydrophobic host cell surfaces, and contributes to efficient gut colonization and host infection.
HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells
Authors: Nguyen Diu T. T. , Lu Yuheng , Chu Eren L. , Yang Xuejing , Park Sun-Mi , Choo Zi-Ning , Chin Christopher R. , Prieto Camila , Schurer Alexandra , Barin Ersilia , Savino Angela M. , Gourkanti Saroj , Patel Payal , Vu Ly P. , Leslie Christina S. , Kharas Michael G. 
Published: April 2020

AbstractThe cell-context dependency for RNA binding proteins (RBPs) mediated control of stem cell fate remains to be defined. Here we adapt the HyperTRIBE method using an RBP fused to a Drosophila RNA editing enzyme (ADAR) to globally map the mRNA targets of the RBP MSI2 in mammalian adult normal and malignant stem cells. We reveal a unique MUSASHI-2 (MSI2) mRNA binding network in hematopoietic stem cells that changes during transition to multipotent progenitors. Additionally, we discover a significant increase in RNA binding activity of MSI2 in leukemic stem cells compared with normal hematopoietic stem and progenitor cells, resulting in selective regulation of MSI2’s oncogenic targets. This provides a basis for MSI2 increased dependency in leukemia cells compared to normal cells. Moreover, our study provides a way to measure RBP function in rare cells and suggests that RBPs can achieve differential binding activity during cell state transition independent of gene expression.
Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity
Authors: He Yonghan , Zhang Xuan , Chang Jianhui , Kim Ha-Neui , Zhang Peiyi , Wang Yingying , Khan Sajid , Liu Xingui , Zhang Xin , Lv Dongwen , Song Lin , Li Wen , Thummuri Dinesh , Yuan Yaxia , Wiegand Janet S. , Ortiz Yuma T. , Budamagunta Vivekananda , Elisseeff Jennifer H. , Campisi Judith , Almeida Maria , Zheng Guangrong , Zhou Daohong 
Published: April 2020

AbstractSmall molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.
Ethanol consumption inhibits TFH cell responses and the development of autoimmune arthritis
Authors: Azizov Vugar , Dietel Katharina , Steffen Franziska , Dürholz Kerstin , Meidenbauer Julia , Lucas Sébastien , Frech Michael , Omata Yasunori , Tajik Narges , Knipfer Lisa , Kolenbrander Anne , Seubert Silvia , Lapuente Dennis , Sokolova Maria V. , Hofmann Jörg , Tenbusch Matthias , Ramming Andreas , Steffen Ulrike , Nimmerjahn Falk , Linker Ralf , Wirtz Stefan , Herrmann Martin , Temchura Vladimir , Sarter Kerstin , Schett Georg , Zaiss Mario M. 
Published: April 2020

AbstractAlcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by TFHcells, preventing proper spatial organization of TFHcells to form TFH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption.
The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions
Authors: Mitra Anita , MacIntyre David A. , Ntritsos George , Smith Ann , Tsilidis Konstantinos K. , Marchesi Julian R. , Bennett Phillip R. , Moscicki Anna-Barbara , Kyrgiou Maria 
Published: April 2020

AbstractEmerging evidence suggests associations between the vaginal microbiota (VMB) composition, human papillomavirus (HPV) infection, and cervical intraepithelial neoplasia (CIN); however, causal inference remains uncertain. Here, we use bacterial DNA sequencing from serially collected vaginal samples from a cohort of 87 adolescent and young women aged 16–26 years with histologically confirmed, untreated CIN2 lesions to determine whether VMB composition affects rates of regression over 24 months. We show that women with a Lactobacillus-dominant microbiome at baseline are more likely to have regressive disease at 12 months. Lactobacillus spp. depletion and presence of specific anaerobic taxa including Megasphaera, Prevotella timonensis and Gardnerella vaginalis are associated with CIN2 persistence and slower regression. These findings suggest that VMB composition may be a future useful biomarker in predicting disease outcome and tailoring surveillance, whilst it may offer rational targets for the development of new prevention and treatment strategies.
Changing role of coral reef marine reserves in a warming climate
Authors: Graham Nicholas A. J. , Robinson James P. W. , Smith Sarah E. , Govinden Rodney , Gendron Gilberte , Wilson Shaun K. 
Published: April 2020

AbstractCoral reef ecosystems are among the first to fundamentally change in structure due to climate change, which leads to questioning of whether decades of knowledge regarding reef management is still applicable. Here we assess ecological responses to no-take marine reserves over two decades, spanning a major climate-driven coral bleaching event. Pre-bleaching reserve responses were consistent with a large literature, with higher coral cover, more species of fish, and greater fish biomass, particularly of upper trophic levels. However, in the 16 years following coral mortality, reserve effects were absent for the reef benthos, and greatly diminished for fish species richness. Positive fish biomass effects persisted, but the groups of fish benefiting from marine reserves profoundly changed, with low trophic level herbivores dominating the responses. These findings highlight that while marine reserves still have important roles on coral reefs in the face of climate change, the species and functional groups they benefit will be substantially altered.
Topography and human pressure in mountain ranges alter expected species responses to climate change
Authors: Elsen Paul R. , Monahan William B. , Merenlender Adina M. 
Published: April 2020

AbstractClimate change is leading to widespread elevational shifts thought to increase species extinction risk in mountains. We integrate digital elevation models with a metric of human pressure to examine changes in the amount of intact land area available for species undergoing elevational range shifts in all major mountain ranges globally (n = 1010). Nearly 60% of mountainous area is under intense human pressure, predominantly at low elevations and mountain bases. Consequently, upslope range shifts generally resulted in modeled species at lower elevations expanding into areas of lower human pressure and, due to complex topography, encountering more intact land area relative to their starting position. Such gains were often attenuated at high elevations as land-use constraints diminished and topographic constraints increased. Integrating patterns of topography and human pressure is essential for accurate species vulnerability assessments under climate change, as priorities for protecting, connecting, and restoring mountain landscapes may otherwise be misguided.
Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts
Authors: Kim Kwanghee , Hu Wenhuo , Audenet François , Almassi Nima , Hanrahan Aphrothiti J. , Murray Katie , Bagrodia Aditya , Wong Nathan , Clinton Timothy N. , Dason Shawn , Mohan Vishnu , Jebiwott Sylvia , Nagar Karan , Gao Jianjiong , Penson Alex , Hughes Chris , Gordon Benjamin , Chen Ziyu , Dong Yiyu , Watson Philip A. , Alvim Ricardo , Elzein Arijh , Gao Sizhi P. , Cocco Emiliano , Santin Alessandro D. , Ostrovnaya Irina , Hsieh James J. , Sagi Irit , Pietzak Eugene J. , Hakimi A. Ari , Rosenberg Jonathan E. , Iyer Gopa , Vargas Herbert A. , Scaltriti Maurizio , Al-Ahmadie Hikmat , Solit David B. , Coleman Jonathan A. 
Published: April 2020

AbstractTreatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.