bluuebunny/crossref_metadata_2025_split huggingface dataset:
FROM ANGELS TO ALIENS: HUMANKIND'S ONGOING ENCOUNTERS WITH, AND EVOLVING INTERPRETATIONS OF, THE GENUINE CELESTIAL UNKNOWN
Authors: Lomas Tim , Case Brendan 
Published: April 2023

AbstractThroughout history, people have observed aerial events that appeared extraordinary and anomalous. In earlier eras, these were often interpreted through a lens that invoked special classes of divine beings, such as angels (who, compared with gods, are regarded as more likely to interact with humans). Today, in our ostensibly secular scientific age, there is a tendency to assume such observers were mistaken, and that with the benefit of modern knowledge, these events can be “debunked” and attributed to conventional naturalistic explanations. However, recent years have seen a burgeoning interest and even concern over the issue of unidentified aerial phenomena. Through the lens of our “space age,” these are sometimes interpreted using notions such as extraterrestrial agents. Ultimately though, this article suggests that both categories of explanation, from angels to aliens, may be the perennial human quest to render comprehensible, through the prism of prevailing beliefs and traditions, an ongoing encounter with celestial phenomena that remain genuinely unknown but deeply significant.
Multifidelity Algorithm for the Sensitivity Analysis of Multidisciplinary Problems
Authors: Drouet Vincent , Balesdent Mathieu , Brevault Loïc , Dubreuil Sylvain , Morio Jérôme 
Published: April 2023

AbstractThe present article proposes an algorithm for the sensitivity analysis of a multidisciplinary problem, in which the derivative-based global sensitivity indices are computed with multifidelity Gaussian process models. Two levels of fidelity are used to estimate the indices, where the low-fidelity samples are obtained by stopping the multidisciplinary analysis solver before convergence. A dedicated refinement strategy for the multifidelity Gaussian process is proposed to ensure the accuracy of the sensitivity index estimation. This algorithm is tested on three multidisciplinary problems of increasing complexity (one analytical and two representative engineering design problems), and proved to be both reliable in detecting the noninfluential variables and computationally efficient, compared to classical Monte Carlo integration and to three other candidate algorithms.
Twist-Coupled Flapping Mechanism for Bird-Type Flapping-Wing Air Vehicles
Authors: Han Yu-Jeong , Yang Hyeon-Ho , Han Jae-Hung 
Published: April 2023

Abstract
In flapping-wing air vehicles, the flapping mechanism is directly related to the movement of the wing making it one of the major factors in determining aerodynamic performance. In this study, a method to increase aerodynamic performance using the flapping mechanism is discussed. This paper presents a twist-coupled mechanism that can increase thrust by combining twisting motion with flapping motion. The proposed mechanism generates twisting motion by the 4-bar planar link mechanism and flapping motion by the 4-bar spatial link mechanism. The mechanism can be driven by only one actuator by connecting two crankshafts with a pair of gears and rotating them at once. Here, we define the design parameters and constraints and search for the optimal design parameters to maximize aerodynamic force. Optimization is carried out by a genetic algorithm, a global optimization algorithm, combining kinematic and aerodynamic analyses. We then search for the design parameters that maximize thrust. Based on our optimization results, the proposed mechanism has the figure-of-eight wingtip trajectory motion like the flying animals. The aerodynamic efficiency of the proposed mechanism was validated by an aerodynamic measurement test comparing a reference mechanism that can only generate flapping motion without twisting motion. For comparative validation, prototypes of the proposed mechanism and the reference mechanism were designed and fabricated. Thrust and lift were measured by the wind tunnel test. From the wind tunnel test, it is confirmed that the proposed mechanism can generate aerodynamic loads more efficiently than the reference mechanism.
Metabolic Reprogramming Driven by IGF2BP3 Promotes Acquired Resistance to EGFR Inhibitors in Non–Small Cell Lung Cancer
Authors: Lin Ziyou , Li Jingwei , Zhang Jian , Feng Weineng , Lu Jiaye , Ma Xiaofan , Ding Wen , Ouyang Shumin , Lu Jinjian , Yue Peibin , Wan Guohui , Liu Peiqing , Zhang Xiaolei 
Published: April 2023

Abstract

Acquired resistance represents a bottleneck for effective molecular targeted therapy in lung cancer. Metabolic adaptation is a distinct hallmark of human lung cancer that might contribute to acquired resistance. In this study, we discovered a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) mediated by IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3–COX6B2 axis. IGF2BP3 was upregulated in patients with TKI-resistant non–small cell lung cancer, and high IGF2BP3 expression correlated with reduced overall survival. Upregulated expression of the RNA binding protein IGF2BP3 in lung cancer cells reduced sensitivity to TKI treatment and exacerbated the development of drug resistance via promoting oxidative phosphorylation (OXPHOS). COX6B2 mRNA bound IGF2BP3, and COX6B2 was required for increased OXPHOS and acquired EGFR-TKI resistance mediated by IGF2BP3. Mechanistically, IGF2BP3 bound to the 3′-untranslated region of COX6B2 in an m6A-dependent manner to increase COX6B2 mRNA stability. Moreover, the IGF2BP3–COX6B2 axis regulated nicotinamide metabolism, which can alter OXPHOS and promote EGFR-TKI acquired resistance. Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in strong growth suppression in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, these findings suggest that metabolic reprogramming by the IGF2BP3–COX6B2 axis plays a critical role in TKI resistance and confers a targetable metabolic vulnerability to overcome acquired resistance to EGFR-TKIs in lung cancer.

Significance:
IGF2BP3 stabilizes COX6B2 to increase oxidative phosphorylation and to drive resistance to EGFR inhibitors in lung cancer, which provides a therapeutic strategy to overcome acquired resistance by targeting metabolic transitions.
Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression
Authors: DeBlasi Janine M. , Falzone Aimee , Caldwell Samantha , Prieto-Farigua Nicolas , Prigge Justin R. , Schmidt Edward E. , Chio Iok In Christine , Karreth Florian A. , DeNicola Gina M. 
Published: April 2023

Abstract

Mutations in the KEAP1–NRF2 (Kelch-like ECH-associated protein 1–nuclear factor-erythroid 2 p45-related factor 2) pathway occur in up to a third of non–small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic NRF2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors, p53 or LKB1. When combined with KrasG12D/+, constitutive NRF2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by NRF2 deletion. Finally, NRF2 overexpression in KEAP1 mutant human NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, these results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process.

Significance:
Stabilization of the transcription factor NRF2 promotes oncogene-driven tumor initiation but blocks tumor progression, indicating distinct, threshold-dependent effects of the KEAP1/NRF2 pathway in different stages of lung tumorigenesis.
Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model
Authors: Chen Shih-Shih , Barrientos Jacqueline C. , Ferrer Gerardo , King-Richards Morgan , Chen Yu-Ju , Ravichandran Priyadarshini , Ibrahim Michael , Kieso Yasmine , Waters Sheila , Kutok Jeffery L. , Peluso Marisa , Sharma Sujata , Weaver David T. , Pachter Jonathan A. , Rai Kanti R. , Chiorazzi Nicholas 
Published: April 2023

Abstract

Purpose:
Inhibitors of Bruton's tyrosine kinase (BTKi) and PI3K (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Hence, we sought evidence for essential roles of PI3K-δi and PI3K-γi in treatment-naïve and BTKi-refractory CLL.

Experimental Design:
Responses to PI3K-δi, PI3K-γi, and the dual-inhibitor duvelisib in each B, T, and myeloid cell compartments of CLL were studied in vitro, and in a xenograft mouse model using primary cells from treatment-naïve and ibrutinib-resistant patients, and finally, in a patient with ibrutinib-resistant CLL treated with duvelisib.

Results:
We demonstrate the essential roles of PI3K-δ for CLL B-cell survival and migration, of PI3K-γ for T-cell migration and macrophage polarization, and of dual inhibition of PI3K-δ,γ for efficacious reduction of leukemia burden. We also show that samples from patients whose disease progressed on ibrutinib were responsive to duvelisib therapy in a xenograft model, irrespective of BTK mutations. In support of this, we report a patient with ibrutinib-resistant CLL, bearing a clone with BTK and PLCγ2 mutations, who responded immediately to single-agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with modulation of T and myeloid cells.

Conclusions:
Our data define the mechanism of action whereby dual inhibition of PI3K-δ,γ affects CLL B-cell numbers and T and myeloid cell pro-leukemia functions and support the use of duvelisib as a valuable approach for therapeutic interventions, including for patients refractory to BTKi.
FDA Oncology Center of Excellence Crowdsourcing Initiative: Outreach to the Scientific Community to Identify Research Questions for Pooled Analyses of Oncology Clinical Trial Data
Authors: Schneider Julie A. , Eckstein Julia , Goldberg Kirsten B. , Ascione Mark C. , Bailey Thamar , Taylor Kimberly , Coffey Aisha M. , Satchi Darshini , Philips Howard , Sridhara Rajeshwari , Nair Abhilasha , Pazdur Richard , Theoret Marc R. 
Published: April 2023

Abstract
The FDA Oncology Center of Excellence recently launched a crowdsourcing pilot to request ideas from the scientific community for research questions that FDA could address with pooled analyses of clinical trial data submitted to the agency for regulatory purposes. This effort builds on FDA's track record of publishing pooled analyses to explore scientific questions that cannot be addressed in a single trial due to limited sample size. The research crowdsourcing pilot tested a new approach for obtaining external input on regulatory science activities, because FDA is generally unable to share patient-level data outside of the agency due to federal disclosure laws and regulations protecting different types of data submitted in regulatory applications. We received 29 submissions over the 28-day crowdsourcing campaign, including one research idea that we are exploring for possible follow-up. Based on our experience with this pilot, we learned that crowdsourcing is a promising new approach to gather external input and feedback. We identified opportunities to build understanding in the external oncology community about the types of data typically included in regulatory applications and expand the dissemination of published FDA pooled analyses to help inform future drug development and clinical practice.
Critical Role of 6-Phosphogluconate Dehydrogenase in TAp73-Mediated Cancer Cell Proliferation
Authors: Qiao Rui , Wei Mengmeng , Chen Hui , Zhang Xianhong , Zhang Jie , Gao Liyang , Ma Haijun , Wang Yujiong , Li Le 
Published: April 2023

Abstract

Cancer cells frequently alter their metabolism to support biogenesis and proliferation and survive specific metabolic stressors. The glucose-associated pentose phosphate pathway (PPP) is crucial for cancer cell proliferation. In particular, 6-phosphogluconate dehydrogenase (6PGD), the second dehydrogenase in the PPP, catalyzes the decarboxylation of 6-phosphogluconate into ribulose 5-phosphate (Ru5P). However, the mechanisms controlling 6PGD expression in cancer cells remain unclear. Herein, we show that TAp73 increases Ru5P and NADPH production through 6PGD activation to counteract reactive oxygen species and protects cells from apoptosis. Moreover, 6PGD overexpression rescues the proliferation and tumorigenic ability of TAp73-deficient cells. These findings further establish the critical role of TAp73 on glucose metabolism regulation, demonstrating that TAp73 can activate 6PGD expression to support oncogenic cell growth.

Implications:
By transcriptional upregulation of 6PGD, TAp73 promotes the generation of Ru5P and NADPH, and enhances tumor cell proliferation.
Os Commonwealthmen a serviço da liberdade: a oposição a Guilherme III e ao “cânone republicano”
Authors: Herrmann Frédéric , Vargas Thiago 
Published: April 2023

A historiografia neo-republicana de Cambridge estabeleceu uma franca distinção entre republicanismo e liberalismo que merece ser reexaminada. Este artigo busca contribuir para esse debate, propondo um estudo de caso dos commonwealthmen ou republicanos que apoiaram a revolução de 1688 na Inglaterra, mas que se opuseram à nova cultura política e à nova “economia de crédito” do reino de Guilherme III na década de 1690. Ao desviarmos nosso olhar do republicanismo enquanto linguagem para situá-lo sob o republicanismo enquanto cultura, bem como modo de ação política, é possível constatar uma porosidade entre direitos naturais e virtude cívica, mas também entre liberdade negativa e liberdade positiva.
Effects of Atrial Fibrillation Screening According to N-Terminal Pro-B-Type Natriuretic Peptide: A Secondary Analysis of the Randomized LOOP Study
Authors: Xing Lucas Yixi , Diederichsen Søren Zöga , Højberg Søren , Krieger Derk W. , Graff Claus , Frikke-Schmidt Ruth , Olesen Morten S. , Brandes Axel , Køber Lars , Haugan Ketil Jørgen , Svendsen Jesper Hastrup 
Published: April 2023

Background:
Research suggests NT-proBNP (N-terminal pro-B-type natriuretic peptide) to be a strong predictor of incident atrial fibrillation (AF) and stroke. However, its utility in AF screening remains unknown. The aim of this study was to investigate NT-proBNP as a potential marker for screening efficacy with respect to AF yield and stroke prevention.

Methods:
In the LOOP Study (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals), 6004 AF-naïve individuals at least 70 years old and with additional stroke risk factors were randomized 1:3 to either screening with an implantable loop recorder (ILR) and initiation of anticoagulation upon detection of AF episodes lasting ≥6 minutes or usual care (control). This post hoc analysis included study participants with available NT-proBNP measurement at baseline.

Results:

A total of 5819 participants (96.9% of the trial population) were included. The mean age was 74.7 years (SD, 4.1 years) and 47.5% were female. The median NT-proBNP level was 15 pmol/L (interquartile range, 9–28 pmol/L) corresponding to 125 pg/mL (interquartile range, 76–233 pg/mL). NT-proBNP above median was associated with an increased risk of AF diagnosis both in the ILR group (hazard ratio, 1.84 [95% CI, 1.51–2.25]) and the control group (hazard ratio, 2.79 [95% CI, 2.30–3.40]). Participants with NT-proBNP above the median were also at higher risk of clinical events compared with those having lower levels (hazard ratio, 1.21 [95% CI, 0.96–1.54] for stroke or systemic embolism [SE], 1.60 [95% CI, 1.32–1.95] for stroke/SE/cardiovascular death, and 1.91 [95% CI, 1.61–2.26] for all-cause death). Compared with usual care, ILR screening was associated with significant reductions in stroke/SE and stroke/SE/cardiovascular death among participants with NT-proBNP above median (hazard ratio, 0.60 [95% CI, 0.40–0.90] and 0.70 [95% CI, 0.53–0.94], respectively) but not among those with lower levels (
P
interaction
=0.029 for stroke/SE and 0.045 for stroke/SE/cardiovascular death). No risk reduction in all-cause death was observed in either NT-proBNP subgroup for ILR versus control (
P
interaction
=0.68). Analyzing NT-proBNP as a continuous variable yielded similar findings.

Conclusions:
In an older population with additional stroke risk factors, ILR screening for AF was associated with a significant reduction in stroke risk among individuals with higher NT-proBNP levels but not among those with lower levels. These findings should be considered hypothesis generating and warrant further study before clinical implementation.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02036450.
Theorising in Educational Children’s Rights Research
Authors: Gillett-Swan Jenna , Quennerstedt Ann , Moody Zoe 
Published: April 2023

Abstract
Child rights research has increased since the adoption of the Convention on the Rights of the Child (crc) in 1989. Reviews of the research has indicated a lack of criticality and a reluctance to interrogate or challenge dominant views. Some scholars argue that this results from under theorisation, whereas other maintain that theorisation is abundant. The paradox suggesting that children’s rights research can be both abundant and deficient in theory calls for a thorough discussion about theorisation. This systematic review engages in this debate by exploring what is positioned as “theory” in educational children’s rights research, and what function theory has. Analysis determined that alignment with established theoretical approaches is uncommon. Previous research literature is instead often positioned as theory, mostly in combination with policy, law or an established theory. Main functions of theory are to construct the object of study and to provide analysis support. Some uses of theory appear to be more powerful than others.
Hickman, Buddhism, and Algorithmic Technology
Authors: Garrison Jim 
Published: April 2023

Abstract
This paper is a further reflection on my dialogue with Larry Hickman, director emeritus of the Center for Dewey Studies, and Daisaku Ikeda, president of the lay Buddhist organization Soka Gakkai International (sgi). One surprising outcome of this dialogue is how similar Deweyan pragmatism is to many forms of Mahayana Buddhism such as sgi. Here I survey some similarities between Hickman’s philosophy of technology and Buddhism by emphasizing value creation and criticism. (Soka Gakkai means value creating society.) I then explore Peter D. Herschock’s, Buddhism and Intelligent Technology relying on Hickman to rectify Herschock’s philosophy of technology before discussing how Herschock’s insightful application of Buddhist ethics to ai and the internet accord with Hickman.
Temporal Variability of Global Surface Eddy Diffusivities: Estimates and Machine Learning Prediction
Authors: Zhang Guangchuang , Chen Ru , Li Xichen , Li Laifang , Wei Hao , Guan Wenting 
Published: April 2023

Abstract
Mesoscale eddies, ubiquitous in the global ocean, play a key role in the climate system by stirring and mixing key tracers. Estimating, understanding, and predicting eddy diffusivity is of great significance for designing suitable eddy parameterization schemes for coarse-resolution climate models. This is because climate model results are sensitive to the choice of eddy diffusivity magnitudes. Using 24-yr satellite altimeter data and a Lagrangian approach, we estimate time-dependent global surface cross-stream eddy diffusivities. We found that eddy diffusivity has nonnegligible temporal variability, and the regionally averaged eddy diffusivity is significantly correlated with the climate indices, including the North Pacific Gyre Oscillation, Atlantic multidecadal oscillation, El Niño–Southern Oscillation, Pacific decadal oscillation, and dipole mode index. We also found that, compared to the suppressed mixing length theory, random forest (RF) is more effective in capturing the temporal variability of regionally averaged eddy diffusivity. Our results indicate the need for using time-dependent eddy mixing coefficients in climate models and demonstrate the advantage of RF in predicting mixing temporal variability.

Significance Statement
Mixing induced by ocean eddies can greatly modulate the ocean circulation and climate variability. Steady eddy mixing coefficients are often specified in coarse-resolution climate models. However, using satellite observations, we show that the eddy mixing rate has significant temporal variability at the global ocean surface. The regional temporal variability of eddy mixing is linked with large-scale climate variability (e.g., North Pacific Gyre Oscillation and Atlantic multidecadal oscillation). We found that random forest, a user-friendly machine learning algorithm, is a better tool to predict the mixing temporal variability than the conventional mixing theory. This study suggests the possibility of improving climate model performance by using time-dependent eddy mixing coefficients inferred from machine learning methods.
Early impacts of the ‘National Suicide Prevention Trial’ on trends in suicide and hospital admissions for self-harm in Australia
Authors: Page Andrew , Pirkis Jane , Bandara Piumee , Oostermeijer Sanne , Hall Teresa , Burgess Philip M , Harris Meredith , Currier Dianne 
Published: April 2023

Objectives: The National Suicide Prevention Trial was announced by the Australian Government in 2016 and aimed to prevent suicidal behaviour in 12 trial sites (representing a population of ~8 million). This study investigated the early population-level impact of the National Suicide Prevention Trial activity on rates of suicide and hospital admissions for self-harm in comparison to control areas. Methods: Relative and absolute differences in monthly rates of suicide and hospital admissions for self-harm were compared in the period after the National Suicide Prevention Trial implementation (July 2017–November 2020) to the period prior to implementation (January 2010–June 2017) in (1) ‘National Suicide Prevention Trial areas’ and (2) ‘Control areas’, using a difference-in-difference method in a series of negative binomial models. Analyses also investigated whether associations for suicide and self-harm rates differed by key socio-demographic factors, namely sex, age group, area socio-economic status and urban–rural residence. Results: There were no substantial differences between ‘National Suicide Prevention Trial areas’ and ‘Control areas’ in rates of suicide (2% relative decrease, relative risk = 0.98, 95% confidence interval = [0.91, 1.06]) or self-harm (1% relative decrease, relative risk = 0.99, 95% confidence interval = [0.96, 1.02]), adjusting for sex, age group and socio-economic status. Stronger relative decreases in self-harm only were evident for those aged 50–64 years, high socio-economic status areas, metropolitan and remote geographic areas. Conclusion: There was limited evidence that the National Suicide Prevention Trial resulted in reductions in suicide or hospital admissions for self-harm during the first 4 years of implementation. Continued monitoring of trends with timely data is imperative over the next 2–3 years to ascertain whether there are any subsequent impacts of National Suicide Prevention Trial activities.