bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction of biodegradable core cross-linked nanoparticles from near infrared dyes encoded in polyprodrug amphiphiles and investigation of their synergistic anticancer activity
Authors: Mao Xiaoxu , Hu Shoukui , Shang Ke , Yang Guangwei , Yan Jinhao , Ma Chao , Yin Jun
Published: March 2021

Amphiphilic polyprodrugs with reduction-responsive camptothecin prodrug and photothermal converted IR780 dyes was performedviacore cross-linking protocol. The nanoparticles could be served as a nanocarrier and presented severe cytotoxicity to HeLa cells.
Mathematical model of heat transfer through a conductive pipe
Authors: Ljulj Matko , Marušić-Paloka Eduard , Pažanin Igor , Tambača Josip
Published: March 2021

The standard engineer’s model for heat transfer between the fluid flowing through the pipe and the exterior medium neglects the effects of the pipe’s wall. The goal of this paper is to prove that they are not always negligible. Comparing the ratio between diffusivities of the fluid and the wall with the wall’s thickness, using rigorous asymptotic analysis, we find five different models for effective description of the heat exchange process.
Probabilistic error estimation for non-intrusive reduced models learned from data of systems governed by linear parabolic partial differential equations
Authors: Uy Wayne Isaac Tan , Peherstorfer Benjamin
Published: March 2021

This work derives a residual-based a posteriori error estimator for reduced models learned with non-intrusive model reduction from data of high-dimensional systems governed by linear parabolic partial differential equations with control inputs. It is shown that quantities that are necessary for the error estimator can be either obtained exactly as the solutions of least-squares problems in a non-intrusive way from data such as initial conditions, control inputs, and high-dimensional solution trajectories or bounded in a probabilistic sense. The computational procedure follows an offline/online decomposition. In the offline (training) phase, the high-dimensional system is judiciously solved in a black-box fashion to generate data and to set up the error estimator. In the online phase, the estimator is used to bound the error of the reduced-model predictions for new initial conditions and new control inputs without recourse to the high-dimensional system. Numerical results demonstrate the workflow of the proposed approach from data to reduced models to certified predictions.
Predicting neurological deficit in patients with spinal tuberculosis – A single-center retrospective case-control study
Authors: Mittal Samarth , Yadav Gagandeep , Ahuja Kaustubh , Ifthekar Syed , Sarkar Bhaskar , Kandwal Pankaj
Published: March 2021

Background: Identifying the risk factors for the neurological deficit in spine tuberculosis would help surgeons in deciding on early surgery, thus reducing the morbidity related to neurological deficit. The main objective of our study was to predict the risk of neurological deficit in patients with spinal tuberculosis (TB). Methods: The demographic, clinical, radiological (X-ray and MRI) data of 105 patients with active spine TB were retrospectively analyzed. Patients were divided into two groups – with a neurological deficit (n = 52) as Group A and those without deficit (n = 53) as Group B. Univariate and multivariate logistic regression analysis was used to predict the risk factors for the neurological deficit. Results: The mean age of the patients was 38.1 years. The most common location of disease was dorsal region (35.2%). Paradiscal (77%) was the most common type of involvement. A statistically significant difference (p < 0.05) was noted in the location of disease, presence of cord compression, kyphosis, cord oedema, loss of CSF anterior to the cord, and degree of canal compromise or canal encroachment between two groups. Multivariate analysis revealed kyphosis > 30° (OR – 3.92, CI – 1.21–12.7, p – 0.023), canal encroachment > 50% (OR – 7.34, CI – 2.32–23.17, p – 0.001), and cord oedema (OR – 11.93, CI – 1.24–114.05, p – 0.03) as independent risk factors for predicting the risk of neurological deficit. Conclusion: Kyphosis > 30°, cord oedema, and canal encroachment (>50%) significantly predicted neurological deficit in patients with spine TB. Early surgery should be considered with all these risk factors to prevent a neurological deficit.
On the study of hydrodynamic instabilities in the presence of background magnetic fields in high-energy-density plasmas
Authors: Manuel M. J.-E. , Khiar B. , Rigon G. , Albertazzi B. , Klein S. R. , Kroll F. , Brack F. -E. , Michel T. , Mabey P. , Pikuz S. , Williams J. C. , Koenig M. , Casner A. , Kuranz C. C.
Published: March 2021

Blast-wave-driven hydrodynamic instabilities are studied in the presence of a background B-field through experiments and simulations in the high-energy-density (HED) physics regime. In experiments conducted at the Laboratoire pour l’utilisation des lasers intenses (LULI), a laser-driven shock-tube platform was used to generate a hydrodynamically unstable interface with a prescribed sinusoidal surface perturbation, and short-pulse x-ray radiography was used to characterize the instability growth with and without a 10-T B-field. The LULI experiments were modeled in FLASH using resistive and ideal magnetohydrodynamics (MHD), and comparing the experiments and simulations suggests that the Spitzer model implemented in FLASH is necessary and sufficient for modeling these planar systems. These results suggest insufficient amplification of the seed B-field, due to resistive diffusion, to alter the hydrodynamic behavior. Although the ideal-MHD simulations did not represent the experiments accurately, they suggest that similar HED systems with dynamic plasma-β (=2μ0ρv2/B2) values of less than ∼100 can reduce the growth of blast-wave-driven Rayleigh–Taylor instabilities. These findings validate the resistive-MHD FLASH modeling that is being used to design future experiments for studying B-field effects in HED plasmas.
Brain-inspired ferroelectric Si nanowire synaptic device
Authors: Lee M. , Park W. , Son H. , Seo J. , Kwon O. , Oh S. , Hahm M. G. , Kim U. J. , Cho B.
Published: March 2021

We herein demonstrate a brain-inspired synaptic device using a poly(vinylidene fluoride) and trifluoroethylene (PVDF-TrFE)/silicon nanowire (Si NW) based ferroelectric field effect transistor (FeFET). The PVDF-TrFE/Si NW FeFET structure achieves reliable synaptic plasticity such as symmetrical potentiation and depression, thanks to the reversible dynamics of the PVDF-TrFE permanent dipole moment. The calculated asymmetric ratio of potentiation and depression is as low as 0.41 at the optimized bias condition, indicating a symmetrical synaptic plasticity behavior. Pattern recognition accuracy based on the actual synaptic plasticity data of the synaptic device can be estimated via the CrossSim simulation software. Our simulation result reveals a high pattern recognition accuracy of 85.1%, showing a potential feasibility for neuromorphic systems. Furthermore, the inverter-in-synapse transistor consisting of the Si NW FeFET synapse and resistor connected in series is able to provide energy-efficient logic circuits. A total noise margin [(NMH + NML)/VDD] of 41.6% is achieved, and the power consumption [Ps = VDD(ID,L + ID,H)/2] of the logic-in-synapse transistor is evaluated to be 0.6 µW per logic gate. This study would shed light on the way toward a brain-inspired neuromorphic computing system based on the FeFET synapse device.
On the validity of ion selective membrane simplification in concentration polarization
Authors: Jiang Jiafei , Tang Jing , Al-Anzi Bader , Han Jongyoon , Li Zirui
Published: March 2021

Ion selective membrane (ISM) is widely used in electrochemical engineering and micro-fluidic processes, yet accurate modeling of the ISM is still challenging due to many scientific issues. So far, assumptions on the “ideal ISM” have been used in most simulation studies involving ion transport and electrokinetic flow in ion concentration polarization systems, but the validity or accuracy of those assumptions has never been investigated. In this paper, using a two-dimensional nanochannel system with practical significance, we verify the validity of the ideal ISM model by making comparisons between the idealized ISM system and a more realistic permselective nanochannel system in terms of simplifications over the electrical potential, counter-ion concentration, and zero co-ion flux. Our results show that the simplifications of fixed voltage and fixed counter-ion concentration in the ideal ISM model are largely accurate in most situations, especially under high applied voltage and/or with high charge density inside the ISM. However, zero co-ion flux simplification is not exactly accurate in most occasions. Significant errors may be incurred by the zero co-ion flux assumption when steady state solutions are sought using the ISM model. Some discussions over the influences of structures of the nanochannel system are also added. The obtained results will help in obtaining detailed understanding of the transport features inside the nanoporous ISM, especially when the comparison between simulation and experimental data is necessary.
Design and simulation of waveguide-integrated Ge/SiGe quantum-confined Stark effect optical modulator based on adiabatic coupling with SiGe waveguide
Authors: Traiwattanapong Worawat , Chaisakul Papichaya , Frigerio Jacopo , Chrastina Daniel , Isella Giovanni , Vivien Laurent , Marris-Morini Delphine
Published: March 2021

We report on the design and simulation of a waveguide-integrated Ge/SiGe quantum-confined Stark effect (QCSE) optical modulator based on the use of a Ge-rich SiGe relaxed buffer on a graded buffer as an optical waveguide. Despite the promising potential of this waveguide platform, efficient and wideband optical integration with a Ge-based active device has not been properly addressed so far. In this paper, via 3D finite-difference time domain simulation, we demonstrate that a simple 2D taper is sufficient to enable adiabatic optical coupling from the fundamental mode of the input SiGe waveguide to the fundamental mode of the Ge/SiGe multiple quantum well (MQW) modulator without the excitation of higher-order modes in Ge/SiGe MQWs. The 2D taper shows good fabrication tolerance considering critical variations in its dimensions. Significantly, wideband optical modulation performance in terms of extinction ratio and insertion loss is presented over the whole low-loss spectral range of the Ge/SiGe MQWs at different electrical bias values, device lengths, and numbers of quantum wells in order to comprehensively report its potential for Si-based optical modulators.
Recent advances in flexible alternating current electroluminescent
devices
Authors: Zhang Xin , Wang Feng
Published: March 2021

Since its first discovery by Destriau in oil dispersion of ZnS:Cu phosphors, alternating current electroluminescence (ACEL) has found enormous applications in lighting, full-color displays, and optoelectronics. ACEL materials are particularly useful for constructing flexible light-emitting devices owing to their low cost and easy integration with flexible electrodes and polymer substrates. ACEL devices utilizing the phosphor-elastomer composite as the emissive layer are intrinsically stretchable/deformable, in contrast to direct current light-emitting diodes that are often built on rigid panels. In this Research Update, we summarize recent advances in the design and preparation of various flexible-panel ACEL devices. Emerging applications enabled by these flexible ACEL devices are also highlighted.
Free vibration analysis of elastically connected composite laminated double-plate system with arbitrary boundary conditions by using meshfree method
Authors: Kim Kwanghun , Kwak Songhun , Jang Paeksan , Sok Myongkuk , Jon Sunjong , Ri Kumchol
Published: March 2021

In this paper, the meshfree method is adopted for the first time to study the free vibration of a composite laminated double-plate system (CLDPS). The first order shear deformation theory is used to analyze the free vibration of the CLDPS, and the artificial elastic spring technique is utilized to generalize its boundary conditions. All of the displacement functions including the boundary conditions are approximated by a meshfree shape function. The reliability and accuracy of the proposed technique are verified through the comparison with the results in the previous literature and by the finite element method. The effects of various boundary conditions, material properties, and geometries of the CLDPS on its natural frequencies are considered in detail.
Spin injection into vanadium dioxide films from a typical ferromagnetic metal, across the metal–insulator transition of the vanadium dioxide films
Authors: Tamura Kazuma , Kanki Teruo , Shirai Shun , Tanaka Hidekazu , Teki Yoshio , Shikoh Eiji
Published: March 2021

A vanadium dioxide VO2 film shows metal-insulator transition (MIT) induced by changing environmental temperature. We report the temperature dependence of electromotive force properties generated in VO2/Ni80Fe20 bilayer junctions under the ferromagnetic resonance (FMR) of the Ni80Fe20 layer. An electromotive force generated in a VO2/Ni80Fe20 bilayer junction under the FMR showed a small change across the MIT temperature of the VO2 film, while the VO2 film resistance drastically changed. This behavior was not only explained with the temperature dependence of the electromotive force property generated in the Ni80Fe20 film itself under the FMR, but also with the generated electromotive forces due to the inverse spin-Hall effect (ISHE) in the VO2 film under the FMR of the Ni80Fe20 film. That is, we successfully demonstrated the spin injection from a Ni80Fe20 film into a VO2 film across the MIT temperature of the VO2 film.
Collagen’s enigmatic, highly conserved
N
-glycan has an essential proteostatic function
Authors: Li Rasia C. , Wong Madeline Y. , DiChiara Andrew S. , Hosseini Azade S. , Shoulders Matthew D.
Published: March 2021

Significance

Development and repair of connective tissues require the rapid biosynthesis of large quantities of collagen, the most abundant protein in the human body. The functional importance of collagen has motivated extensive efforts to uncover molecular mechanisms responsible for matching collagen production to physiological needs. While many roles for collagen chaperones and modifying enzymes are well established, the function of the highly conserved
N
-glycosylation site within collagen’s C-terminal globular domain has remained elusive for decades. By assaying
N
-glycan function under conditions of impaired collagen folding, we show that, although the
N
-glycan is dispensable under normal conditions, it is essential for collagen folding and secretion under conditions that challenge proteostasis. Such environments are commonly encountered during development, tissue repair, and disease.
Now what?
Authors: Corpas Pastor Gloria , Sánchez Rodas Fernando
Published: March 2021

This chapter provides a brief outline of language technologies applied to translation and interpreting with a view to identifying challenges and research opportunities. Section 1 covers new trends within the automation of processes, the integration of language technologies in translators and interpreters’ workflows and industry demands. Section 2 moves on to other relevant technology-based resources for oral and written mediation, including new types of corpora for interpreting, computer-assisted interpreting tools (CAI) or cloud interpreting, among others. Section 3 delves into the concept of ‘tech-savviness’ and adoption of technology among language service providers (LSPs). Final thoughts are presented as a conclusion in Section 4.
ZHEN
Authors: Gu Yi , Frankenberg-Garcia Ana
Published: March 2021

Most Chinese-English parallel corpora consist of English source texts translated into Chinese. This chapter discusses the need for corpora representative of the under-resourced Chinese into English translation direction. After a brief overview of the current Chinese-English translation scenario and an analysis of existing parallel corpora for this language pair, we discuss problems in mining contemporary Chinese to English translations and issues in Chinese to English parallel text alignment. We then introduce ZHEN, a corpus of circa one-million characters of contemporary simplified Chinese source texts from a range of text types aligned with authentic translations into English. Its aim is to contribute to our understanding of Chinese to English translation norms and of features of English translated from Chinese.
Temporary Employment and Family Formation: An Income or Insecurity Effect?
Authors: van Wijk Daniël C , de Valk Helga A G , Liefbroer Aart C
Published: March 2021

Recent studies show that temporary workers postpone family formation transitions, but it remains unclear whether this effect is due to the lower income or the stronger perceptions of job insecurity that go with a temporary contract. To address this question, we link data from a large-scale survey among Dutch employees to longitudinal population register data on marriage and first births. Logistic regression models estimate the effects of temporary employment on marriage and first birth, and mediation analyses assess to what extent these effects are explained by income and perceptions of job insecurity. Results show that temporarily employed women delay first birth. There is also some evidence that temporarily employed men postpone marriage and first birth. These effects are partly explained by income, which increases marriage and first birth rates among men and women alike. Perceptions of job insecurity generally had little effect on family formation, although higher marriage rates were found among women who experienced affective job insecurity. Overall, this shows that it is their low income rather than their feelings of insecurity about future employment that explains why temporary employees postpone family formation.
Exploratory comparison of Healthcare costs and benefits of the UK’s Covid-19 response with four European countries
Authors: Thom Howard , Walker Josephine , Vickerman Peter , Hollingworth Will
Published: March 2021

Background

In responding to Covid-19, governments have tried to balance protecting health while minimizing gross domestic product (GDP) losses. We compare health-related net benefit (HRNB) and GDP losses associated with government responses of the UK, Ireland, Germany, Spain and Sweden from UK healthcare payer perspective.

Methods

We compared observed cases, hospitalizations and deaths under ‘mitigation’ to modelled events under ‘no mitigation’ to 20 July 2020. We thus calculated healthcare costs, quality adjusted life years (QALYs), and HRNB at £20,000/QALY saved by each country. On per population (i.e. per capita) basis, we compared HRNB with forecast reductions in 2020 GDP growth (overall or compared with Sweden as minimal mitigation country) and qualitatively and quantitatively described government responses.

Results

The UK saved 3.17 (0.32–3.65) million QALYs, £33 (8–38) billion healthcare costs and £1416 (220–1637) HRNB per capita at £20,000/QALY. Per capita, this is comparable to £1455 GDP loss using Sweden as comparator and offsets 46.1 (7.1–53.2)% of total £3075 GDP loss. Germany, Spain, and Sweden had greater HRNB per capita. These also offset a greater percentage of total GDP losses per capita. Ireland fared worst on both measures. Countries with more mask wearing, testing, and population susceptibility had better outcomes. Highest stringency responses did not appear to have best outcomes.

Conclusions

Our exploratory analysis indicates the benefit of government Covid-19 responses may outweigh their economic costs. The extent that HRNB offset economic losses appears to relate to population characteristics, testing levels, and mask wearing, rather than response stringency.
Large Genetic Diversity and Strong Positive Selection in F-Box and GPCR Genes among the Wild Isolates of Caenorhabditis elegans
Authors: Ma Fuqiang , Lau Chun Yin , Zheng Chaogu
Published: March 2021

The F-box and chemosensory GPCR (csGPCR) gene families are greatly expanded in nematodes, including the model organism Caenorhabditis elegans, compared with insects and vertebrates. However, the intraspecific evolution of these two gene families in nematodes remain unexamined. In this study, we analyzed the genomic sequences of 330 recently sequenced wild isolates of C. elegans using a range of population genetics approaches. We found that F-box and csGPCR genes, especially the Srw family csGPCRs, showed much more diversity than other gene families. Population structure analysis and phylogenetic analysis divided the wild strains into eight non-Hawaiian and three Hawaiian subpopulations. Some Hawaiian strains appeared to be more ancestral than all other strains. F-box and csGPCR genes maintained a great amount of the ancestral variants in the Hawaiian subpopulation and their divergence among the non-Hawaiian subpopulations contributed significantly to population structure. F-box genes are mostly located at the chromosomal arms and high recombination rate correlates with their large polymorphism. Moreover, using both neutrality tests and extended haplotype homozygosity analysis, we identified signatures of strong positive selection in the F-box and csGPCR genes among the wild isolates, especially in the non-Hawaiian population. Accumulation of high-frequency-derived alleles in these genes was found in non-Hawaiian population, leading to divergence from the ancestral genotype. In summary, we found that F-box and csGPCR genes harbor a large pool of natural variants, which may be subjected to positive selection. These variants are mostly mapped to the substrate-recognition domains of F-box proteins and the extracellular and intracellular regions of csGPCRs, possibly resulting in advantages during adaptation by affecting protein degradation and the sensing of environmental cues, respectively.
Fifteen years later: moving forward Heller’s heritage on fiscal space for health
Authors: Barroy Hélène , Gupta Sanjeev
Published: March 2021

Economist Peter Heller, writing a seminal paper published in Health, Policy and Planning in 2006, identified five opportunities for expanding fiscal space for health: raising revenue, reprioritizing expenditure, borrowing, using seigniorage and mobilizing external grants. The development of the initial framework marked a significant conceptual advancement in health financing, by situating health reforms within a broader macro-fiscal context. Fifteen years later, fiscal space for health is not viewed simply as a question of finding additional revenues but also as a matter of improving public financial management (PFM) in the health sector, specifically for publicly funded health systems. This paper advances the concept of budgetary space for health, which explores available resources generated through greater overall public expenditure, prioritized budget allocations, and improved PFM. The paper adds a critical component, unpacking the ways through which PFM improvements can maximize budgetary space for health. The approach fits the realities of public finances in the era of the Sustainable Development Goals. The key implication is that PFM aspects should be systematically included in assessments of budgetary space to inform more effective country dialogues between the finance and health sectors.
Humanization of a tandem repeat in IG-DMR causes stochastic restoration of paternal imprinting at mouseDlk1-Dio3domain
Authors: Hara Satoshi , Terao Miho , Tsuji-Hosokawa Atsumi , Ogawa Yuya , Takada Shuji
Published: March 2021

The Dlk1-Dio3 imprinted domain, regulated by an intergenic differentially methylated region (IG-DMR), is important for mammalian embryonic development. Although previous studies have reported that DNA methylation of a tandem repeated array sequence in paternal IG-DMR (IG-DMR-Rep) plays an essential role in the maintenance of DNA methylation in mice, the function of a tandem repeated array sequence in human IG-DMR (hRep) is unknown. Here, we generated mice with a human tandem repeated sequence, which replaced the mouse IG-DMR-Rep. Mice that transmitted the humanized allele paternally exhibited variable methylation status at the IG-DMR and were stochastically rescued from the lethality of IG-DMR-Rep deficiency, suggesting that hRep plays a role in human IG-DMR for the regulation of imprinted expression. Moreover, chromatin immunoprecipitation analysis showed that TRIM28 was enriched in hypermethylated paternal hRep without ZFP57. Our results suggest that hRep contributes to the maintenance of human IG-DMR methylation imprints via the recruitment of TRIM28.
Assessment of a Polygenic Risk Score for Colorectal Cancer to Predict Risk of Lynch Syndrome Colorectal Cancer
Authors: Jenkins Mark A , Buchanan Daniel D , Lai John , Makalic Enes , Dite Gillian S , Win Aung K , Clendenning Mark , Winship Ingrid M , Hayes Richard B , Huyghe Jeroen R , Peters Ulrike , Gallinger Steven , Marchand Loïc Le , Figueiredo Jane C , Pai Rish K , Newcomb Polly A , Church James M , Casey Graham , Hopper John L
Published: March 2021

It was not known whether the polygenic risk scores (PRSs) that predict colorectal cancer could predict colorectal cancer for people with inherited pathogenic variants in DNA mismatch repair genes—people with Lynch syndrome. We tested a PRS comprising 107 established single-nucleotide polymorphisms associated with colorectal cancer in European populations for 826 European-descent carriers of pathogenic variants in DNA mismatch repair genes (293 MLH1, 314 MSH2, 126 MSH6, 71 PMS2, and 22 EPCAM) from the Colon Cancer Family Registry, of whom 504 had colorectal cancer. There was no evidence of an association between the PRS and colorectal cancer risk, irrespective of which DNA mismatch repair gene was mutated, or sex (all 2-sided P > .05). The hazard ratio per standard deviation of the PRS for colorectal cancer was 0.97 (95% confidence interval = 0.88 to 1.06; 2-sided P = .51). Whereas PRSs are predictive of colorectal cancer in the general population, they do not predict Lynch syndrome colorectal cancer.
Asthma and Physical Activity in Urban Children
Authors: Koinis-Mitchell Daphne , Kopel Sheryl J , Dunsiger Shira , McQuaid Elizabeth L , Miranda Luis Gonzalez , Mitchell Patricia , Vehse Nico , Jelalian Elissa
Published: March 2021

Objectives 

Asthma and obesity disproportionately affect urban minority children. Avoidance of physical activity contributes to obesity, and urban children with asthma are at risk for lower levels of physical activity. We examined associations between lung function and moderate to vigorous physical activity (MVPA) and moderators of this association in a diverse sample of children with asthma.

Methods 

Urban children (N = 142) ages 7–9 with persistent asthma and their caregivers completed a study of asthma and physical activity. Longitudinal mixed effects models examining daily-level asthma and physical activity evaluated the association between asthma and MVPA, and the moderating effect of weight, and cultural/contextual factors on this association.

Results 

Average daily MVPA was below recommended guidelines. Differences in MVPA were found by racial/ethnic group (p = .04) and weight (p = .001). Poorer asthma status was associated with lower MVPA in Latino and Black participants (p’s < .05), and in normal weight youth (p = .01). Body mass index (BMI) moderated the association between asthma and MVPA. Those with lower BMI had more optimal asthma status and higher MVPA levels, whereas associations attenuated for participants with higher BMI (p = .04). Caregivers’ perceptions of neighborhood safety and fear of asthma were marginally associated with children’s symptoms and MVPA: as perceptions of safety decreased and fear increased, associations between asthma and MVPA weakened (p’s = .09 and .07, respectively).

Conclusions 

Suboptimal asthma status is associated with less MVPA in urban children. Weight status and cultural/contextual factors play a role in the association and are worthy targets for future research and intervention.
Drug resistance via radixin-mediated increase of P-glycoprotein membrane expression during SNAI1-induced epithelial-mesenchymal transition in HepG2 cells
Authors: Kamioka Hiroki , Edaki Kazue , Kasahara Haruka , Tomono Takumi , Yano Kentaro , Ogihara Takuo
Published: March 2021

Objectives

Epithelial–mesenchymal transition (EMT) plays a role in cancer metastasis as well as in drug resistance through various mechanisms, including increased drug efflux mediated by P-glycoprotein (P-gp). In this study, we investigated the activation mechanism of P-gp, including its regulatory factors, during EMT in hepatoblastoma-derived HepG2 cells.

Methods

HepG2 cells were transfected with SNAI1 using human adenovirus serotype 5 vector. We quantified mRNA and protein expression levels using qRT-PCR and western blot analysis, respectively. P-gp activity was evaluated by uptake assay, and cell viability was assessed by an MTT assay.

Key findings

P-gp protein expression on plasma membrane was higher in SNAI1-transfected cells than in Mock cells, although there was no difference in P-gp protein level in whole cells. Among the scaffold proteins such as ezrin, radixin and moesin (ERM), only radixin was increased in SNAI1-transfected cells. Uptake of both Rho123 and paclitaxel was decreased in SNAI1-transfected cells, and this decrease was blocked by verapamil, a P-gp inhibitor. The reduced susceptibility of SNAI1-transfected cells to paclitaxel was reversed by elacridar, another P-gp inhibitor.

Conclusions

Increased expression of radixin during SNAI1-induced EMT leads to increased P-gp membrane expression in HepG2 cells, enhancing P-gp function and thereby increasing drug resistance.
State Aid Review in a Multi-level System
Authors: Kreuschitz Viktor , Nehl Hanns Peter
Published: March 2021

This introductory chapter discusses factors that motivate why aid is given by states in the first place. Highlighting the interplay between both the political and economic motivations that guide states and their sub-structures, it is possible to identify several related motivations for giving aid: the first consists of attaining political preferences of governments; a second, and often related reason is that political leaders may be guided by pure electoral pragmatism aimed to increase future votes; and third, State aid remains one of the few economic tools that Member States have at their disposal given increasing Europeanization. The necessity for control and review of State aid and subsidies could be linked to potential risks and disadvantages of aid. A key notion of analysing these risks of aid is the concept of inter-jurisdictional externalities: supporting economic development and activities in one jurisdiction may cause intended or unintended negative impacts on activities within other jurisdictions.
Criterion of State Origin
Authors: Kreuschitz Viktor , Nehl Hanns Peter
Published: March 2021

This chapter identifies the criterion for assessing State origin. Determining whether a measure originates from State sources is a decisive criterion to assess whether the measure is a State aid within the meaning of Article 107 of the Treaty on the Functioning of the European Union (TFEU). This criterion involves two separate and cumulative sub-criteria: the direct or indirect granting of State resources and the imputability of the measure to the State. Accordingly, advantages granted directly or indirectly through State resources constitute State aids within the meaning of Article 107(1) TFEU. Meanwhile, the State ‘imputability’ criterion is easily fulfilled when the aid is granted by a public authority or by a public or private body which is designated to administer the measure.
Aid Subject to a Discretionary Assessment under Article 107(3) TFEU
Authors: Kreuschitz Viktor , Nehl Hanns Peter
Published: March 2021

This chapter identifies aid subject to a discretionary assessment under Article 107(3) TFEU. In the evaluation of State aid under Article 107(3) TFEU the Commission must rely on ‘complex economic, social, regional and structural assessments’ and therefore, its decisions are covered by the notion of a broad discretion. Specifically, Article 107(3) TFEU addresses aids which may be compatible with the internal market, depending on the interpretation made by the Commission. Different categories are addressed, including aid promoting the economic development of areas where the standard of living is abnormally low or where there is serious underemployment; aid promoting the execution of an important project of common European interest or to remedy a serious disturbance in the economy of a Member State; aid facilitating the development of certain economic activities or of certain economic areas; and aid promoting culture and heritage conservation or any other categories specified by decision of the Council.
Article 4: Hardcore Restrictions
Authors: Wijckmans Frank , Tuytschaever Filip
Published: March 2021

This chapter addresses the hardcore restrictions which are included in Article 4 of Regulation 330/2010. Once it has been established that a vertical agreement falls within the scope of application of Regulation 330/2010, complies with the limitations included in Article 2(2)–(5), and does not exceed the market share limits, the next step is to check whether it contains any hardcore restrictions. This assessment constitutes the eleventh step of the analysis.The hardcore restrictions consist of RPM and certain territorial and customer restrictions. For the purposes of Regulation 330/2010, the list of hardcore restrictions in Article 4 is exhaustive. The inclusion of a hardcore restriction renders the block exemption inapplicable to the vertical agreement as a whole. In addition, the Vertical Guidelines provide for a rebuttable presumption that a hardcore restriction will fail to meet the conditions of Article 101(3) TFEU on an individual basis (self-assessment).
Promotion and Harmonization of Antitrust Damages Claims by Directive 2014/104/EU?
Authors: Rodger Barry , Ferro Miguel Sousa , Marcos Francisco
Published: March 2021

This chapter explains the contents and goals of the Antitrust Damages Directive (Directive 2014/104/EU), the corollary of the EU’s policy towards the promotion and facilitation of private enforcement of competition law. It first traces the evolution in EU competition law enforcement and policy that led to the adoption of the Directive before considering the goals of the Directive in more detail, namely to provide rules for the effective compensation of victims of antitrust infringements and to harmonize some rules concerning damages claims. It then examines the Directive’s legal basis under EU Law as well as substantive provisions, including those relating to compensatory principles, quantification of harm, and consensual dispute resolution. The chapter goes on to highlight neglected issues, limitations, and inherent biases regarding the scope and nature of the Directive’s rules and concludes with an analysis of issues arising from implementation of the Directive in Member States.
Poland
Authors: Bernatt Maciej , Gac Maciej
Published: March 2021

This chapter analyses the transposition of the Antitrust Damages Directive in Poland. It first provides an overview of the transposition procedure, focusing on the main stages of the implementation process that culminated in the adoption of the Act on actions for damages for infringements of the competition law provisions (ACD) that came into force on 27 June 2017. The chapter goes on to describe the scope of ACD before considering the novel aspects of Polish implementation with respect to disclosure of evidence, time-barring deadlines, the standing of business and consumer organizations to bring actions, and the possibility of bringing group actions. It also examines problematic issues relating to the effect of National Competition Authorities’ final infringement decisions, passing-on of overcharges, presumption of harm, the competency of courts handling actions for antitrust damages, leniency programmes, and settlement submissions. Finally, it reflects on future prospects for private enforcement of competition law in Poland.
Sweden
Authors: Henriksson Lars
Published: March 2021

This chapter examines the transposition of the Antitrust Damages Directive in Sweden. It begins with an overview of the transposition process, focusing on the implementing law called the Antitrust Damages Act (ADA) that was enacted on 3 November 2016 and entered into force on 27 December 2016, as well as the general requirements considered by the Swedish Government for implementing EU law. It then describes the scope of the implementation process for ADA before analysing the main issues concerning implementation of the Directive, such as those relating to preconditions for liability in Swedish law, joint and several liability, limitation period for bringing damages claims, right to full compensation, interest in arrears on damages awarded, quantification of harm, passing on of overcharges in Swedish law, right to recover damages from other infringers, procedural rules for cases involving antitrust damages, disclosure of evidence, and incorrect or incomplete transposition.
Part I Normative Foundations, 3 The Design of the Optimal Abuse Tests
Authors: Renato Nazzini
Published: March 2021

This chapter examines the possible abuse tests applicable to exclusionary, exploitative, and discriminatory abuses. No single test for abuse of dominance is conceivable in theory and as a matter of enforcement policy. This does not mean, however, that the law is left without clear guiding principles so that competition law is in reality a set of ad hoc solutions perhaps suited to the facts of individual cases but devoid of any underpinning rationale. Exclusionary abuses may be assessed under tests of intent, the as efficient competitor test, and the consumer harm test. Meanwhile, exploitative abuses are clearly assessed under the consumer harm test. Beyond exclusionary and exploitative conduct, there may be a case for prohibiting discrimination on intermediate markets that distorts the competitive relationship between downstream buyers of the dominant firm. The hallmark of abusive discrimination is the impairment of the ability to compete of firms.
Introduction
Authors: Geradin Damien , Layne-Farrar Anne , Petit Nicolas
Published: March 2021

This introductory chapter provides an overview of EU competition law. Because it was first formally enacted in 1957, EU competition law is generally perceived as a relatively recent legal discipline. Its real, substantive, origins are however much older, and can be traced back to the history of ancient civilization. Today, the constraints imposed by EU competition law have become a major area of concern for decision-makers both in public and private sectors. Yet, beyond the cosmetics of press releases and business reports, the significance of EU competition law can be measured by its profound and lasting effects in economic activity. There are four possible objectives to the EU competition rules: the protection of fairness in competition; the promotion of economic freedom, plurality, and consumer choice; the promotion of economic efficiency; and the promotion of consumer welfare.
Enforcement, Institutions, and Procedure
Authors: Geradin Damien , Layne-Farrar Anne , Petit Nicolas
Published: March 2021

This chapter discusses the enforcement of EU competition law. EU competition law is primarily enforced through a system of ‘public enforcement’, where specialized administrative institutions initiate, decide, and terminate cases. Articles 101 and 102 TFEU are enforced by competition authorities at both the European—by the Commission—and national levels—by national competition authorities (NCAs). Since the adoption of Regulation 1/2003, the Commission and the NCAs form a ‘network’ of competition authorities called the European Competition Network (ECN). A set of specific legal mechanisms have been adopted to ensure a harmonious and effective enforcement of EU competition rules amongst the ECN. In addition, national courts also offer a remedial avenue for plaintiffs seeking to invoke EU competition rules. The chapter then looks at how the Commission and NCAs process competition cases. In general, a competition case goes through four stages: detection, investigation, evaluation, and decision.
Third Party Intervention
Authors: Brealey Mark , George Kyla
Published: March 2021

This chapter focuses on the rights of third parties to intervene in competition proceedings in the High Court (and appellate courts) and in the Competition Appeal Tribunal (CAT). It first considers intervention by third parties in the High Court under Rule 19.2 of the Civil Procedure Rules 1998 (CPR), intervention in judicial review proceedings, and intervention in appeal proceedings. It then discusses intervention in CAT, placing emphasis on appeals and reviews (applying for permission to intervene, the time limit for making an application to intervene, the role played by intervener at the hearing). It also explains how compensation claims are made under CAT rule 16 before concluding with an analysis of intervention by competition authorities, namely the Competition and Markets Authority (CMA) and the European Union Commission.
References
Authors: Brealey Mark , George Kyla
Published: March 2021

This chapter examines the key legal issues arising from the preliminary reference procedure in competition law. It first considers references to the Court of Justice of the European Union (CJEU), focusing on Article 267 of the Treaty on the Functioning of the European Union (TFEU) giving the Court jurisdiction to render preliminary rulings concerning the interpretation of the Treaty, and the validity and interpretation of acts of the institutions, bodies, offices, or agencies of the European Union. It then explains the role of a ‘court or tribunal’ in making a reference, as well as the issue of inadmissible references and mandatory references. Finally, it discusses the preliminary reference procedure, including the procedure before the referring court, and the order for reference, special requests, interventions, submission of written and oral observations, and the effect of a ruling.
Hearings
Authors: Brealey Mark , George Kyla
Published: March 2021

This chapter focuses on practice and procedure in hearings conducted in the High Court and in the Competition Appeal Tribunal (CAT). It first considers the preparation for hearings, taking into account the relevant rules, namely Civil Procedure Rules (CPR) and CAT Rules, as well as case management, location of proceedings, treatment of confidential information, skeleton arguments and their publication, preparation of bundles of documents, and site visits. The discussion then turns to how hearings are conducted, focusing on factors to consider such as the venue, witnesses, time limits, and transcripts. The chapter also examines matters consequent upon hearings, such as handing down and reporting of judgments, along with their publication and costs. Finally, it explains how applications for permission to appeal in the High Court and in the CAT are made.
Business and Legal Forms of Multinational
Enterprise
Authors: Muchlinski Peter T
Published: March 2021

This chapter discusses the relationship between the business organization and the legal form of multinational enterprises (MNEs). It seeks to answer a crucial question for MNE regulation: where does enterprise control reside, and do MNE legal forms adequately reflect the allocation of decision-making power in the firm? Legal forms may not coincide with the business organization of the firm. This can lead to a mismatch between the firm’s control structures and the legal structures through which the firm is regulated. The chapter then provides an overview of MNEs as business organizations, stressing the rise of new forms of organization based on advances in information technology (IT) and collaborative arrangements between firms. It also considers the main legal forms of the MNE, centred on contractual and equity-based structures, looking at the limitations of these traditional legal forms as regulatory devices. Finally, the chapter studies the interaction between business and legal forms and the issue of regulatory control.
Labour Relations
Authors: Muchlinski Peter T
Published: March 2021

This chapter examines labour relations. The main elements of corporate social responsibility (CSR) applicable to multinational enterprises (MNEs) revolve around labour relations, human rights and environmental sustainability, which form the core contents of international corporate social responsibility (ICSR) instruments. The extension of CSR to MNEs arises from the perceived risk that they have the power to act with impunity against the interests of stakeholders affected by their operations, giving rise to growing demands for rebalancing corporate responsibilities towards more social ends. Labour rights represent the oldest category of social rights under national and international law and are key to understanding the rise of ICSR and its legal responses. The chapter then explores the historical role of labour rights in ICSR. It considers how the operations of MNEs and global value chains (GVCs) have caused changes in labour practices. It also studies the consequences of these changes on the regulation of labour relations in MNEs and GVCs, including the shift in contemporary transnational labour standards to the notion of ‘decent work’. Finally, the chapter assesses how the ‘decent work’ idea can be put into practice through national laws, international labour rights and transnational labour practices.
The
Control of Investment Risks through International Investment
Agreements
Authors: Muchlinski Peter T
Published: March 2021

This chapter explores the control of host state investment risks through investor/investment protection standards under International Investment Agreements (IIAs). The United Nations Conference on Trade and Development (UNCTAD) divides IIAs into two types: bilateral investment treaties (BITs) and treaties with investment provisions (TIPs). Investor/investment protection standards in IIAs create issues of ‘regulatory space’, which, in international economic law, describes the regulatory freedom that states possess in the absence of international legal constraints. IIA protection standards affect the host state’s ‘right to regulate’ by placing certain legally binding requirements on domestic regulation so as to reduce investment risks arising from the potential disadvantages faced by foreign investors in the host state. The chapter then traces the development of international standards for the protection of foreign investors/investments and the development of ‘first-generation’ IIAs. It also describes the main instances of expansive arbitral interpretation that have led to recent calls for the reform of IIAs towards ‘new-generation’ agreements.
Introduction
Authors: Geiß Robin , Melzer Nils
Published: March 2021

This introductory chapter provides an overview of the twenty-first-century global security environment. Since the turn of the century, the global security environment has become increasingly dynamic, complex, and volatile; and the causes, mechanisms, and consequences of national and international (in-)security have become increasingly transnational and global in nature. Various powerful dynamics of a geopolitical, demographic, climatic, technological, social, and economic nature have been driving this trend, which has now been taken to entirely new levels by the recent outbreak of the COVID-19 pandemic. The convergence of so-called ‘old and new security challenges’, such as the return to power politics, the rise of asymmetric and hybrid warfare, and the emergence of novel threats posed by potent non-State actors, technological innovation, as well as dramatically increased economic, pandemic, and environmental risks, have entailed a veritable globalization of the security agenda. The chapter then outlines a number of overarching key dynamics, trends, and contestations that reflect the various intrinsic and extrinsic pressures and tensions international law is exposed to in the global security environment of the twenty-first century.