bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo
Authors: Huang Hai , Park Song , Zhang Haibo , Park Sijun , Kwon Wookbong , Kim Enugyung , Zhang Xiujuan , Jang Soyoung , Yoon Duhak , Choi Seong-Kyoon , Yi Jun-koo , Kim Sung-hyun , Dong Zigang , Lee Mee-hyun , Ryoo Zaeyoung , Kim Myoung Ok 
Published: March 2021

Abstract
Background
Colorectal cancer (CRC) is a clinically challenging malignant tumor worldwide. As a natural product and sesquiterpene lactone, Costunolide (CTD) has been reported to possess anticancer activities. However, the regulation mechanism and precise target of this substance remain undiscovered in CRC. In this study, we found that CTD inhibited CRC cell proliferation in vitro and in vivo by targeting AKT.

Methods
Effects of CTD on colon cancer cell growth in vitro were evaluated in cell proliferation assays, migration and invasion, propidium iodide, and annexin V-staining analyses. Targets of CTD were identified utilizing phosphoprotein-specific antibody array; Costunolide-sepharose conjugated bead pull-down analysis and knockdown techniques. We investigated the underlying mechanisms of CTD by ubiquitination, immunofluorescence staining, and western blot assays. Cell-derived tumour xenografts (CDX) in nude mice and immunohistochemistry were used to assess anti-tumour effects of CTD in vivo.

Results
CTD suppressed the proliferation, anchorage-independent colony growth and epithelial-mesenchymal transformation (EMT) of CRC cells including HCT-15, HCT-116 and DLD1. Besides, the CTD also triggered cell apoptosis and cell cycle arrest at the G2/M phase. The CTD activates and induces p53 stability by inhibiting MDM2 ubiquitination via the suppression of AKT’s phosphorylation in vitro. The CTD suppresses cell growth in a p53-independent fashion manner; p53 activation may contribute to the anticancer activity of CTD via target AKT. Finally, the CTD decreased the volume of CDX tumors without of the body weight loss and reduced the expression of AKT-MDM2-p53 signaling pathway in xenograft tumors.

Conclusions
Our project has uncovered the mechanism underlying the biological activity of CTD in colon cancer and confirmed the AKT is a directly target of CTD. All of which These results revealed that CTD might be a new AKT inhibitor in colon cancer treatment, and CTD is worthy of further exploration in preclinical and clinical trials.
Emergence and evolution of antimicrobial resistance genes and mutations in Neisseria gonorrhoeae
Authors: Yahara Koji , Ma Kevin C. , Mortimer Tatum D. , Shimuta Ken , Nakayama Shu-ichi , Hirabayashi Aki , Suzuki Masato , Jinnai Michio , Ohya Hitomi , Kuroki Toshiro , Watanabe Yuko , Yasuda Mitsuru , Deguchi Takashi , Eldholm Vegard , Harrison Odile B. , Maiden Martin C. J. , Grad Yonatan H. , Ohnishi Makoto 
Published: March 2021

Abstract
Background
Antimicrobial resistance in Neisseria gonorrhoeae is a global health concern. Strains from two internationally circulating sequence types, ST-7363 and ST-1901, have acquired resistance to third-generation cephalosporins, mainly due to mosaic penA alleles. These two STs were first detected in Japan; however, the timeline, mechanism, and process of emergence and spread of these mosaic penA alleles to other countries remain unknown.

Methods
We studied the evolution of penA alleles by obtaining the complete genomes from three Japanese ST-1901 clinical isolates harboring mosaic penA allele 34 (penA-34) dating from 2005 and generating a phylogenetic representation of 1075 strains sampled from 35 countries. We also sequenced the genomes of 103 Japanese ST-7363 N. gonorrhoeae isolates from 1996 to 2005 and reconstructed a phylogeny including 88 previously sequenced genomes.

Results
Based on an estimate of the time-of-emergence of ST-1901 (harboring mosaic penA-34) and ST-7363 (harboring mosaic penA-10), and > 300 additional genome sequences of Japanese strains representing multiple STs isolated in 1996–2015, we suggest that penA-34 in ST-1901 was generated from penA-10 via recombination with another Neisseria species, followed by recombination with a gonococcal strain harboring wildtype penA-1. Following the acquisition of penA-10 in ST-7363, a dominant sub-lineage rapidly acquired fluoroquinolone resistance mutations at GyrA 95 and ParC 87-88, by independent mutations rather than horizontal gene transfer. Data in the literature suggest that the emergence of these resistance determinants may reflect selection from the standard treatment regimens in Japan at that time.

Conclusions
Our findings highlight how antibiotic use and recombination across and within Neisseria species intersect in driving the emergence and spread of drug-resistant gonorrhea.
Evaluation of hydrological and cryospheric angular momentum estimates based on GRACE, GRACE-FO and SLR data for their contributions to polar motion excitation
Authors: Śliwińska Justyna , Nastula Jolanta , Wińska Małgorzata 
Published: March 2021

AbstractIn geodesy, a key application of data from the Gravity Recovery and Climate Experiment (GRACE), GRACE Follow-On (GRACE-FO), and Satellite Laser Ranging (SLR) is an interpretation of changes in polar motion excitation due to variations in the Earth’s surficial fluids, especially in the continental water, snow, and ice. Such impacts are usually examined by computing hydrological and cryospheric polar motion excitation (hydrological and cryospheric angular momentum, HAM/CAM). Three types of GRACE and GRACE-FO data can be used to determine HAM/CAM, namely degree-2 order-1 spherical harmonic coefficients of geopotential, gridded terrestrial water storage anomalies computed from spherical harmonic coefficients, and terrestrial water storage anomalies obtained from mascon solutions. This study compares HAM/CAM computed from these three kinds of gravimetric data. A comparison of GRACE-based excitation series with HAM/CAM obtained from SLR is also provided. A validation of different HAM/CAM estimates is conducted here using the so-called geodetic residual time series (GAO), which describes the hydrological and cryospheric signal in the observed polar motion excitation. Our analysis of GRACE mission data indicates that the use of mascon solutions provides higher consistency between HAM/CAM and GAO than the use of other datasets, especially in the seasonal spectral band. These conclusions are confirmed by the results obtained for data from first 2 years of GRACE-FO. Overall, after 2 years from the start of GRACE-FO, the high consistency between HAM/CAM and GAO that was achieved during the best GRACE period has not yet been repeated. However, it should be remembered that with the systematic appearance of subsequent GRACE-FO observations, this quality can be expected to increase. SLR data can be used for determination of HAM/CAM to fill the one-year-long data gap between the end of GRACE and the start of the GRACE-FO mission. In addition, SLR series could be particularly useful in determination of HAM/CAM in the non-seasonal spectral band. Despite its low seasonal amplitudes, SLR-based HAM/CAM provides high phase consistency with GAO for annual and semiannual oscillation.
Autonomous elastic microswimmer
Authors: Era Katsutomo , Koyano Yuki , Hosaka Yuto , Yasuda Kento , Kitahata Hiroyuki , Komura Shigeyuki 
Published: March 2021

Abstract
A model of an autonomous three-sphere microswimmer is proposed by implementing a coupling effect between the two natural lengths of an elastic microswimmer. Such a coupling mechanism is motivated by the previous models for synchronization phenomena in coupled oscillator systems. We numerically show that a microswimmer can acquire a nonzero steady state velocity and a finite phase difference between the oscillations in the natural lengths. These velocity and phase differences are almost independent of the initial phase difference. There is a finite range of the coupling parameter for which a microswimmer can have an autonomous directed motion. The stability of the phase difference is investigated both numerically and analytically in order to determine its bifurcation structure.
Molecular-shape- and size-independent power-law dependence of percolation thresholds on radius of gyration in ideal molecular systems
Authors: Norizoe Yuki , Kawakatsu Toshihiro , Morita Hiroshi 
Published: March 2021

Abstract
Three-dimensional single-component ideal gas systems composed of model homogeneous rigid molecules in various molecular shapes and sizes are simulated by a molecular Monte Carlo simulation technique. We reveal that percolation thresholds of such single-component systems result in, when the molecular volume is fixed, power-law decreasing functions of the radius of gyration (gyradius) of the molecules. The systems with the same parameter set of the molecular volume and radius of gyration, but in different molecular shapes, show the identical value of the percolation threshold. Moreover, we also reveal that a dimensionless scale-free parameter, which is the ratio between the radius of gyration and the real cube root of the molecular volume, uniquely determines the percolation threshold.
The Role of Incretins on Insulin Function and Glucose Homeostasis
Authors: Holst Jens Juul , Gasbjerg Lærke Smidt , Rosenkilde Mette Marie 
Published: March 2021

AbstractThe incretin effect—the amplification of insulin secretion after oral vs intravenous administration of glucose as a mean to improve glucose tolerance—was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of 2 insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.
Archerfish coordinate fin maneuvers with their shots
Authors: Gerullis Peggy , Reinel Caroline P. , Schuster Stefan 
Published: March 2021

ABSTRACT
Archerfish down a variety of aerial prey from a range of distances using water jets that they adjust to the size and distance of their prey. We describe here that characteristic rapid fin maneuvers, most notably of the pectoral and pelvic fins, are precisely coordinated with the release of the jet. We discovered these maneuvers in two fish, the jets of which had been characterized in detail, that had been trained to shoot from fixed positions at targets at different heights and that remained stable during their shots. Based on the findings in these individuals, we examined shooting-associated fin movement in 28 further archerfish of two species that could shoot from freely chosen positions at targets at different heights. Slightly before the onset of the water jet, at a time when the shooter remains stable, the pectoral fins of all shooters switched from asynchronous low-amplitude beating to a synchronized rapid forward flap. The onset and duration of the forward and subsequent backward flap were robust across all individuals and shooting angles but depended on target height. The pelvic fins were slowly adducted at the start of the jet and stopped moving after its release. All other fins also showed a characteristic sequence of activation, some starting ∼0.5 s before the shot. Our findings suggest that shooting-related fin maneuvers are needed to stabilize the shooter, and that these maneuvers are an important component in the precise and powerful far-distance shooting in archerfish.
Conflict Analysis for MINLP
Authors: Berthold Timo , Witzig Jakob 
Published: March 2021

The generalization of mixed integer program (MIP) techniques to deal with nonlinear, potentially nonconvex, constraints has been a fruitful direction of research for computational mixed integer nonlinear programs (MINLPs) in the last decade. In this paper, we follow that path in order to extend another essential subroutine of modern MIP solvers toward the case of nonlinear optimization: the analysis of infeasible subproblems for learning additional valid constraints. To this end, we derive two different strategies, geared toward two different solution approaches. These are using local dual proofs of infeasibility for LP-based branch-and-bound and the creation of nonlinear dual proofs for NLP-based branch-and-bound, respectively. We discuss implementation details of both approaches and present an extensive computational study, showing that both techniques can significantly enhance performance when solving MINLPs to global optimality. Summary of Contribution: This original article concerns the advancement of exact general-purpose algorithms for solving one of the largest and most prominent problem classes in optimization, mixed integer nonlinear programs (MINLPs). It demonstrates how methods for conflict analysis that learn from infeasible subproblems can be transferred to nonlinear optimization. Further, it develops theory for how nonlinear dual infeasibility proofs can be derived from a nonlinear relaxation. This paper features a thoroughly computational study regarding the impact of conflict analysis techniques on the overall performance of a state-of-the-art MINLP solver when solving MINLPs to global optimality.
How Florist Apprentices Explore Bouquet Designs: Supporting Design Space Exploration for Vocational Students
Authors: Kim Kevin Gonyop , Oertel Catharine , Dillenbourg Pierre 
Published: March 2021

Context: Exploring the design space is an important process in a design task. In this study, we considered design space exploration for the learners in vocational education and training (VET). The goal of the study was to investigate how they explore the design space while focusing on the effect of a graph-like interface on the learner’s understanding of the design space. With florists as the target profession, we investigated how the apprentices explore design variations, what they would gain from such activity, and how we can support this process. Approach: We developed a web application called BloomGraph that allows learners to explore design variations. It provides a graph-based interface that enables the systematic variation of design. Using the BloomGraph application, we conducted an experimental study with 44 florist apprentices in Switzerland to investigate the effect of the graph-based interface which provides a structured way of exploring the design space. The experimental group was given the graph-based interface to explore design variations while the control group had a linear-based interface. We compared them in terms of the number of bouquets explored, time of exploration, diversity of bouquets explored, and the learning gain in terms of the understanding of the design space measured using pre and post-tests. We also analyzed the strategies adopted by the participants for the graph navigation and the visual exploration behavior using the eye gaze data. Findings: Our analysis shows that the graph-based interface fosters a better understanding of the size of the design space and more efficient navigation towards a goal design in terms of the number of intermediate designs but with longer exploration of each intermediate design compared to the linear-based interface. Regarding the behavioral patterns in graph exploration, the participants who showed more strategic behavior in the design choices acquired a better understanding of the design space. Additionally, we trained a model that predicts the next choice of a learner using eye tracking data. It provides a reasonable accuracy that opens new possibilities for future studies.Conclusion: The findings of this study support the feasibility of design space exploration as a digital activity for VET learners and show how the learners can benefit from it. The contribution of the paper includes the validation of the idea with florist apprentices and the demonstration of how the process can be supported using a structured interface and the learner behavior analysis. This paper shows how a design exploration activity can provide an added value in the learning of an apprentice in a design-related VET system.
Phase-sensitive nonclassical properties in quantum metrology with a displaced squeezed vacuum state
Authors: Tao Zhiwei , Ren Yichong , Abdukirim Azezigul , Liu Shiwei , Rao Ruizhong 
Published: March 2021

We predict that the phase-dependent error distribution of locally unentangled quantum states directly affects quantum parameter estimation accuracy. Therefore, we employ the displaced squeezed vacuum (DSV) state as a probe state and investigate an interesting question of the phase-sensitive nonclassical properties in the DSV’s metrology. We found that the accuracy limit of parameter estimation is a function of the phase-sensitive parameter

ϕ
−
θ

/

2

with a period

π

. We show that when

ϕ
−
θ

/

2

∈
[
k
π

/

2
,
3
k
π

/

4
)
(
k
∈

Z

)

, we can obtain the accuracy of parameter estimation approaching the ultimate quantum limit through the use of the DSV state with the larger displacement and squeezing strength, whereas when

ϕ
−
θ

/

2

∈
(
3
k
π

/

4
,
k
π
]
(
k
∈

Z

)

, the optimal estimation accuracy can be acquired only when the DSV state degenerates to a squeezed vacuum state.
Dual-frequency Doppler velocimeter based on delay interferometric optical phase-locking
Authors: Feng Yuxiang , Xie Weilin , Meng Yinxia , Zhang Ling , Yang Jiang , Wei Wei , Dong Yi 
Published: March 2021

We present a dual-frequency laser Doppler velocimeter (DF-LDV) relying on a DF laser source (DFLS) generated by optical phase-locking two individual lasers to a common unbalanced Mach–Zehnder interferometer, which allows achieving high stability regardless of the DF separation of the lasers. This DFLS is evaluated using an optical frequency comb, testifying to the generation of DFLS with large DF separation up to terahertz with flexible tunability and high stability. Demonstration of DF-LDV using the DFLS of

∼

1.024

T
H
z

separation has achieved

1.62
×

10

−
2

mm/s velocity resolution even for a slow velocity of

1.8

m
m

/

s

in a mere 5 s acquisition time, confirming the high resolution and efficient speckle noise suppression enabled by the proposed DF-LDV. Featuring high precision, flexibility, and robustness, this method is particularly attractive from the practical point of view.
Thyroid function analysis in COVID-19: A retrospective study from a single center
Authors: Malik Jahanzeb , Malik Asmara , Javaid Muhammad , Zahid Tayyaba , Ishaq Uzma , Shoaib Muhammad 
Published: March 2021

Background and objective
Coronavirus disease 2019 (COVID-19) is an on-going epidemic with a multitude of long-ranging effects on the physiological balance of the human body. It can cause several effects on thyroid functions as well. We aimed to assess the lasting sequelae of COVID-19 on thyroid hormone and the clinical course of the disease as a result.

Methods
Out of 76 patients, 48 patients of COVID-19 positive and 28 patients of COVID-19 negative polymerase chain reaction (PCR) were assessed for thyroid functions, IL-6, and Procalcitonin between moderate, severe, and critical pneumonia on HRCT.

Results
Seventy-five percent of patients with COVID-19 had thyroid abnormalities and higher IL-6 levels (76.10 ± 82.35 vs. 6.99 ± 3.99, 95% CI 52.18–100.01, P-value <0.01). Logistic regression analysis suggested TT3 (P-value 0.01), IL-6 (P-value <0.01), and Procalcitonin (P-value 0.03) as independent risk factors for COVID-19. ROC curve demonstrated IL-6 as the most sensitive marker (P-value <0.01), and TT3, and Procalcitonin as the predictor for COVID-19 disease.

Conclusion
This pilot study from Pakistan demonstrates that changes in serum TSH and TT3 levels may be important manifestations of the courses of COVID-19 pneumonia.
DIREITO A MEDICAMENTOS DO COMPONENTE ESPECIALIZADO DA ASSISTÊNCIA FARMACÊUTICA: COMPREENSÃO DE TRABALHADORES DA ATENÇÃO BÁSICA
Authors: Brito Acácia da Hora , Araujo Mariana de Oliveira , Araujo Bianca de Oliveira , De Oliveira Luciane Cristina Feltrin 
Published: March 2021

O Componente Especializado de Assistência Farmacêutica (CEAF) procura garantir a integralidade do tratamento medicamentoso para todas as doenças por ele contempladas, a partir das diferentes linhas de cuidado apresentadas nos Protocolos Clínicos e Diretrizes Terapêuticas (PCDT). Este estudo teve por objetivo analisar a compreensão dos trabalhadores da Atenção Básica de um município do interior da Bahia sobre o direito ao acesso a medicamentos do CEAF e identificar o conhecimento desses trabalhadores sobre os medicamentos disponibilizados por esse componente e os procedimentos necessários para a sua aquisição. Trata-se de um estudo descritivo, com abordagem qualitativa, que utilizou para a coleta de dados a entrevista semiestruturada. O campo de estudo foram duas Unidades de Saúde da Família (USF), situadas no município de Feira de Santana, BA, localizadas na zona urbana. Participaram desse estudo dois agentes comunitários de saúde (ACS) e duas enfermeiras. Para a análise dos dados foi utilizada a Técnica de Análise de Conteúdo Temática. Há limitações em relação ao conhecimento dos trabalhadores de saúde da Atenção Básica sobre o CEAF, quando questionados sobre a compreensão acerca do componente, os procedimentos necessários para aquisição e os medicamentos que são disponibilizados. A deficiência no conhecimento dos trabalhadores de saúde sobre o componente especializado poderá prejudicar a integralidade da atenção à saúde pois leva a dificuldades de acesso a esses medicamentos pelos usuários.