bluuebunny/crossref_metadata_2025 huggingface dataset:
The Ephrin receptor A2 and Roundabout Guidance Receptor 1 heterodimer: A potential theranostic for squamous cell carcinomas
Authors: Pang Ka M. , Srivastava Saumya , Iida Mari , Nelson Michael , Liu Jiayi , Nam Arin , Wang Jiale , Mambetsariev Isa , Mohanty Atish , McDaniel Nellie , Behal Amita , Kulkarni Prakash , Wheeler Deric L. , Salgia Ravi
Published: April 2020

Squamous cell carcinomas (SCC) of the lung (LSCC) and head and neck (HNSCC) are very prevalent with poor prognosis and limited treatment options. In both cancer types, Ephrin receptor A2 (EPHA2) is known to be overexpressed and exhibit opposing effects via two distinct signaling mechanisms. While it can inhibit cancer cell survival and migration by ligand-dependent signaling through tyrosine kinase phosphorylation at Y588 and Y772, it can promote tumor progression and cell migration in a ligand-independent manner via phosphorylation at S897. Variable ABnormal morphology (VAB-1) is theC. elegansortholog of the human ephrin receptor (EPHR) that interacts genetically and biochemically in a dose-dependent manner with the axon guidance receptor, SAX3, the worm ortholog of ROBO. Double mutants ofvab-1(EPHR)/sαx-3(ROBO) are synthetic lethal, underscoring the interaction between the two signaling pathways which prompted us to investigate their role in SCC. Using biochemical and biophysical techniques, we show that EPHA2 and ROBO1 reside in the same complex and interact physically to form a functional heterodimer in LSCC and HNSCC. Furthermore, we show that treating squamous cells with the SLIT2, ligand of ROBO1, hinders phosphorylation of EPHA2 at S897, and thereby, attenuates cell proliferation. Interestingly, SLIT2 can interact with EPHA2 and attenuate the proliferation of cells that have low ROBO1 expression. Additionally, SLIT2 can act synergistically with the EPHA2 inhibitor, Ensartinib to attenuate cell growth in LSCC and HNSCC cells. Taken together, the data suggest that SLIT2 may serve as a novel therapeutic for LSCC and HNSCC. Here, we propose to stratify patients for treatment with SLIT2 and/or Ensartinib, based on their EPHA2 and ROBO1 expression levels in the diseased tissue. Thus 85% of LSCC cases can be treated with combination of SLIT2+Ensartinib and 55% of HNSCC cases can be treated with either SLIT2 or Ensartinib. Furthermore, EPHA2 and ROBO1 may represent novel theranostics in these two diseases.

One sentence summary

Heterodimerization of EPHA2 and ROBO1 receptors attenuates growth of squamous cell carcinomas of the lung and head and neck.
A role for the autophagic receptor, SQSTM1/p62, in trafficking NF-κB/RelA to nucleolar aggresomes
Authors: Lobb Ian T , Morin Pierre , Martin Kirsty , Lieshi Xhordi , Olsen Karl , Duncan Rory R , Stark Lesley A
Published: April 2020

Elevated NF-κB activity is a contributory factor in many haematological and solid malignancies. Nucleolar sequestration of NF-κB/RelA represses this elevated activity and mediates apoptosis of cancer cells. Here we set out to understand the mechanisms that control the nuclear/nucleolar distribution of RelA and other regulatory proteins, so that agents can be developed that specifically target these proteins to the organelle. We demonstrate that RelA accumulates in intra-nucleolar aggresomes in response to specific stresses. We also demonstrate that the autophagy receptor, SQSTM1/p62, accumulates alongside RelA in these nucleolar aggresomes. This accumulation is not a consequence of inhibited autophagy. Indeed, our data suggest nucleolar and autophagosomal accumulation of p62 are in active competition. We identify a conserved motif at the N-terminus of p62 that is essential for nucleoplasmic-to nucleolar transport of the protein. Furthermore, using a dominant negative mutant deleted for this nucleolar localisation signal (NoLS), we demonstrate a role for p62 in trafficking RelA and other aggresome-related proteins to nucleoli. Together, these data identify a novel role for p62 in trafficking nuclear proteins to nucleolar aggresomes under conditions of cell stress, thus maintaining nuclear proteostasis. They also provide invaluable information on the mechanisms that regulate the nuclear/nucleolar distribution of RelA that could be exploited for therapeutic purpose.

Significance

Aberrant NF-κB activity drives many of the hallmarks of cancer and plays a key role in cancer progression. Nucleolar sequestration of NF-κB/RelA is one mechanism that switches off this activity and induces the death of cancer cells. Here we define a novel role for the autophagy receptor, SQSTM1/p62 in transport of nucleoplasmic NF-κB/RelA to nucleoli. Identification of this new trafficking mechanism opens up avenues for the development of a unique class of therapeutic agents that transport RelA and other cancer regulatory proteins to this organelle.
MgrA regulates interaction ofStaphylococcus aureuswith mucin
Authors: Parker Connor P. , Akil Nour , Shanrock Cullen R. , Allen Patrick D. , Chaly Anna L. , Crosby Heidi A. , Kwiecinski Jakub , Horswill Alexander R. , Fischer Anthony J.
Published: April 2020

Background

To defend the lungs, mucus adheres to bacterial cells and facilitates their removal by ciliary transport. Our goals were to measure the affinity of mucus for the respiratory pathogenStaphylococcus aureusand identify bacterial genes that regulate this interaction.

Methods

S. aureuswas added to pig tracheas to determine whether it binds mucus or epithelial cells. To quantify its affinity for mucus, we developed a competition assay in microtiter plates. Mucin was added over a dose range as an inhibitor of bacterial attachment. We then examined how transcriptional regulator MgrA and cell wall transpeptidase sortase (SrtA) affect bacterial interaction with mucin.

Results

In pig tracheas,S. aureusbound mucus strands from submucosal glands more than epithelial cells. In microtiter plate assays, ΔsrtAfailed to attach even in the absence of mucin. Mucin blocked wild typeS. aureusattachment in a dose-dependent manner. Higher concentrations were needed to inhibit binding of ΔmgrA. Co-deletion ofebhandsraP, which encode surface proteins repressed by MgrA, suppressed the ΔmgrAbinding phenotype. No differences between ΔmgrAand wild type were observed when methylcellulose or heparin sulfate were substituted for mucin, indicating specificity.

Conclusions

Mucin decreases attachment ofS. aureusto plastic, consistent with its physiologic role in host defense.S. aureusdeficient in MgrA has decreased affinity for mucin. Ebh and SraP, which are normally repressed by MgrA, may function as inhibitors of attachment to mucin. These data show that specific bacterial factors may regulate the interaction ofS. aureuswith mucus.
Crystal Structure of INTS3/INTS6 complex reveals Functional Importance of INTS3 dimerization in DSB Repair
Authors: Jia Yu , Cheng Zixiu , Bharath Sakshibeedu R , Sun Qiangzu , Su Nannan , Huang Jun , Song Haiwei
Published: April 2020

SOSS1 is a single-stranded DNA (ssDNA)-binding protein complex that plays a critical role in double-strand DNA break (DSB) repair. SOSS1 consists of three subunits: INTS3, SOSSC, and hSSB1 with INTS3 serving as a scaffold to stabilize this complex. Moreover, the integrator complex subunit 6 (INTS6) participates in the DNA damage response through direct binding to INTS3 but how INTS3 interacts with INTS6 thereby, impacting DBS repair is not clear. Here, we determined the crystal structure of the C-terminus of INTS3 (INTS3c) in complex with the C-terminus of INTS6 (INTS6c) at a resolution of 2.4 Å. Structure analysis revealed that two INTS3c subunits dimerize and interact with INTS6c via conserved residues. Subsequent biochemical analyses confirmed that INTS3c forms a stable dimer and INTS3 dimerization is important for recognizing the longer ssDNA. Perturbation of INTS3c dimerization and disruption of the INTS3c/INTS6c interaction, impair the DSB repair process. Altogether, these results unravel the underappreciated role of INTS3 dimerization and the molecular basis of INTS3/INTS6 interaction in DSB repair.
Replication of Equine arteritis virus is efficiently suppressed by purine and pyrimidine biosynthesis inhibitors
Authors: Valle-Casuso José Carlos , Gaudaire Delphine , Martin-Faivre Lydie , Madeline Anthony , Dallemagne Patrick , Pronost Stéphane , Munier-Lehmann Hélène , Zientara Stephan , Vidalain Pierre-Olivier , Hans Aymeric
Published: April 2020

RNA viruses are responsible for a large variety of animal infections. Equine Arteritis Virus (EAV) is a positive single-stranded RNA virus member of the familyArteriviridaefrom the orderNidoviraleslike theCoronaviridae.EAV causes respiratory and reproductive diseases in equids. Although two vaccines are available, the vaccination coverage of the equine population is largely insufficient to prevent new EAV outbreaks around the world. In this study, we present a high-throughputin vitroassay suitable for testing candidate antiviral molecules on equine dermal cells infected by EAV. Using this assay, we identified three molecules that impair EAV infection in equine cells: the broad-spectrum antiviral and nucleoside analog ribavirin, and two compounds previously described as inhibitors of dihydroorotate dehydrogenase (DHODH), the fourth enzyme of the pyrimidine biosynthesis pathway. These molecules effectively suppressed cytopathic effects associated to EAV infection, and strongly inhibited viral replication and production of infectious particles. Since ribavirin is already approved in human and small animal, and that several DHODH inhibitors are in advanced clinical trials, our results open new perspectives for the management of EAV outbreaks.
Bacterial DNAemia is associated with serum zonulin levels in older subjects
Authors: Gargari Giorgio , Taverniti Valentina , Del Bo’ Cristian , Bernardi Stefano , Andres-Lacueva Cristina , González-Domínguez Raul , Kroon Paul A. , Winterbone Mark S. , Cherubini Antonio , Riso Patrizia , Guglielmetti Simone
Published: April 2020

The increased presence of bacteria in blood is a plausible contributing factor in the development and progression of aging-associated diseases. In this context, we performed the quantification and the taxonomic profiling of the bacterial DNA in blood samples collected from a group of forty-three older subjects enrolled in a nursing home. Quantitative PCR targeting the 16S rRNA gene revealed that all the older volunteers contained detectable amounts of bacterial DNA in their blood. The total amount of 16S rRNA gene copies varied considerably between subjects. Correlation analyses revealed that the bacterial DNAemia (expressed as concentration of 16S rRNA gene copies in blood) significantly correlated with the serum levels of zonulin, an emerging marker of intestinal permeability. This result was confirmed by the analysis of a second set of blood samples collected after approximately four months from the same subjects. Analyses of 16S rRNA gene profiling revealed that most of the bacterial DNA detected in blood was ascribable to the phylum Proteobacteria with a predominance of Pseudomonadaceae and Enterobacteriaceae. Several control samples were also analyzed to assess the influence exerted by contaminant bacterial DNA potentially originating from reagents and materials. The date reported here suggest that para-cellular permeability of epithelial (and potentially also endothelial) cell layers may play an important role in bacterial migration into the bloodstream. Bacterial DNAemia is likely to impact on several aspects of host physiology and could underpin the development and prognosis of various diseases in older subjects.
Zoned deformation prediction model for super high arch dams using hierarchical clustering and panel data
Authors: Hu Jiang , Ma Fuheng
Published: April 2020

Purpose

The purpose of this study is to develop and verify a methodology for a zoned deformation prediction model for super high arch dams, which is indeed a panel data-based regression model with the hierarchical clustering on principal components.

Design/methodology/approach

The hierarchical clustering method is used to highlight the main features of the time series. This method is used to select the typical points of the measured ambient and concrete temperatures as predictors and divide the deformation observation points into groups. Based on this, the panel data of each zone can be established, and its type can be judged using F and Hausman tests successively. Then hydrostatic–temperature–time–season models for zones can be constructed. Through the comparative analyses of the distributions and the fitted coefficients of these zones, the spatial deformation mechanism of a dam can be identified. A super high arch dam is taken as a case study.

Findings

According to the measured radial displacements during the initial operation period, the investigated pendulums are divided into four zones. After tests, fixed-effect regression models are established. The comparative analyses show that the dam deformation conforms to the natural condition. The factors such as the unstable temperature field and the nonlinear time-dependent effect have obvious effects on the dam deformation. The results show the efficiency of the proposed methodology in zoning and prediction modeling for deformation of super high arch dams and the potential to mining dam deformation mechanism.

Originality/value

A zoned deformation prediction model for super high arch dams is proposed where hierarchical clustering on principal component method and panel data model are combined.
Comprehending customer satisfaction with hotels
Authors: Li Hongxiu , Liu Yong , Tan Chee-Wee , Hu Feng
Published: April 2020

Purpose

Building on the three-factor theory, this study aims to unravel how the role of hotel attributes such as basic, excitement and performance factors could differ in accordance with different hotel star ratings and distinct customer segments.

Design/methodology/approach

This study explores the asymmetric effects of hotel attributes on customer satisfaction by extracting 412,784 consumer-generated reviews from TripAdvisor across different cities in China.

Findings

By taking into account the origins of customers and hotel star ratings, the study uncovers that guests’ expectations of hotel performance differ with respect to their origins (domestic and international guests) and the star ratings of the hotels being reviewed, thereby moderating the asymmetric impact of hotel attributes on customer satisfaction.

Research limitations/implications

The study compares and contrasts the determinants of customer satisfaction for domestic and international guests in the context of Chinese hotels. Care should still be exercised when generalizing the insights gleaned from this study to other contexts.

Practical implications

The findings from this study translate into actionable guidelines for hotel operators to make informed decisions regarding service improvement.

Originality/value

The study extends previous work by offering a deeper understanding of the asymmetric impact of hotel attributes on customer satisfaction. Specifically, this study provides a deep understanding of the different hotel attributes such as basic, performance and excitement factors in explaining customer satisfaction among different hotel customer segments. Findings from this study can not only inform hotel operators on the significance of various hotel attributes in determining customer satisfaction but also guide the formulation of business strategies to retain customers by inducing delight and not frustration.
Conflicts between business and government in bike sharing system
Authors: Yang Hong , Hu Yimei , Qiao Han , Wang Shouyang , Jiang Feng
Published: April 2020

Purpose

The purpose of this paper is to elaborate on the interactive conflicts between business and governmental authorities in the regulatory process of an emerging business model: sharing economy. Focusing on bike sharing system, the study also investigates the conflict-handling strategy of bike sharing companies and government regulation.

Design/methodology/approach

An evolutionary game model is introduced to illustrate the interactive conflict between bike sharing companies and government regulation, combined with system dynamics (SD) to simulate the evolutionary conflict-handling strategies between the two players.

Findings

The dynamic strategies of the two players are observed, and under five conditions the conflict outcomes are evolutionary stable states. Simulations show that each party sacrifices part of its interest and adjust its strategy according to that of the other, indicating the conflict-handling strategy as a compromising mode. Furthermore, the strategies of bike sharing companies are sensitive to additional operation and maintenance costs for producing low-quality bicycles and costs of positive regulation, which provides theoretical guidance for regulatory authorities.

Originality/value

The station-less bike sharing come up in China recently, and it is an important research field of entrepreneurship. Owing to the uniqueness and novelty of the phenomenon, conflicts and challenges exist during the regulation process. Thus, the study practically contributes to the conflict-handling strategies of businesses and government under the context of sharing economy. Methodologically, as a novel issue with less available data to carry out empirical research, this study combines evolutionary game theory with SD to shed light on the complex interactions between businesses and government. The research method can be applied to other entrepreneurial studies.
Career commitment and subjective career success: the moderating role of career-enhancing strategies
Authors: Ekmekcioglu Emre Burak , Erdogan Mahmure Yelda , Sokmen Alptekin
Published: April 2020

Purpose

The purpose of this study is to test the moderating role of career-enhancing strategies (CESs) in the relationship between career commitment (CC) and subjective career success (CS).

Design/methodology/approach

Data were collected from 217 full-time employees working for three different sectors in Ankara, Turkey. The participants were asked to respond to a self-reported survey. The hypotheses were tested using a hierarchical regression analysis.

Findings

The results indicated that CC had a significant and positive effect on subjective CS. Furthermore, the positive relationship between CC and subjective CS was stronger for employees with a high level of self-nomination and for employees with a high level of networking. However, creating career opportunities did not moderate the effects of CC on subjective CS.

Research limitations/implications

Because this study had a cross-sectional research design, causality cannot be established among the study variables.

Practical implications

The findings suggest a better understanding of the way CC is able to affect subjective CS through the networking and self-nomination CESs.

Originality/value

This study is original, in that no previous studies have investigated the moderating role of CESs in the relationship between CC and subjective CS.
Effect of cage-pocket wear on the dynamic characteristics of ball bearing
Authors: Li Hui , Liu Heng , Li Hao , Qi Shemiao , Liu Yi , Wang Fengtao
Published: April 2020

Purpose

The purpose of this paper is to investigate the effect of the cage-pocket wear on the dynamic behavior of the ball bearing.

Design/methodology/approach

Through analyzing the complicated relationship and interactions among the ball bearing elements, the dynamic modeling of the ball bearing was established considering the gravity, drag force from the oil, hydrodynamic effect on the cage and the dynamic simulations with different amounts of the cage-pocket wear loss of the ball bearing (BPWL) were obtained by solving the ball bearing dynamic equations using Runge–Kutta method.

Findings

The results show that the trajectory of the cage’s centroid presents two vibration modes with different amplitudes. In addition, those two different forms of trajectory of different amplitudes emerge alternatively with BPWL increase moreover the diameter of the trajectory decrease significantly with the BPWL increasing, which is consistent with the experimental result and last BPWL has lightly effect on the average skidding ratio of the cage, however, the BPWL would produce significant effects on the fluctuation of the skidding ratio, which can directly reflect the stability of motion to a certain extent.

Originality/value

Practice shows that the bearing failure resulting from the cage accounts for 25 per cent of the total failure of the rolling bearings. However, few discussions about how the wear of the cage-pocket would influence the dynamic characteristics of the cage. This study can provide important ideas for the design of bearing cage-pocket size and the fault identification of the ball bearing to decrease the failure rate caused by the cage.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/ILT-12-2019-0535/
POLAR QUESTION PARTICLES AND THEIR SOURCES: A SEMANTIC APPROACH TO GRAMMATICALISATION1
Authors: Aigro Mari
Published: April 2020

Abstract

This study investigates the semantic systematicity in the pathways through which various functional markers become polar question particles (PQPs). This research proposes that the high degree of semantic cohesion between sources and targets suggests that a pre‐existing semantic component radically increases the likelihood of some markers becoming PQPs. It observes that all functional classes which have been noted to become PQPs in various languages share semantic similarities, meaning that they can all be analysed as markers of polarity (negation, affirmation or open polarity). It tests this pattern by means of an in‐depth corpus analysis, examining the modern and historical PQP pathways in Estonian – a language unusually rich in PQPs. The results show that the sources for all six analysed PQPs, as well as elements which they themselves have given rise to, confirm the proposed pattern of PQPs arising from polarity markers. The semantic map summarising these patterns illustrates the space of polarity between two axis – mood (interrogative and non‐interrogative) and bias (negative, affirmative, open polarity). These results highlight the importance of semantic factors in grammaticalisation.
External validation of a simple risk score based on the ASPRE trial algorithm for preterm pre‐eclampsia considering maternal characteristics in nulliparous pregnant women: a multicentre retrospective cohort study
Authors: Brunelli E , Seidenari A , Germano C , Prefumo F , Cavoretto P , Di Martino D , Masturzo B , Morano D , Rizzo N , Farina A
Published: April 2020

Objective

To validate the performance of a first‐trimester simple risk score based on the ASPRE trial algorithm for pre‐eclampsia.

Design

Multicentre retrospective cohort analysis.

Setting

Four Italian hospitals.

Population

Unselected nulliparous women at 11–13 weeks of gestation from January 2014 through to January 2018.

Methods

Model performance was evaluated based on discrimination and calibration.

Main outcome measures

Delivery before 37 weeks of gestation with a diagnosis of pre‐eclampsia.

Results

Based on 73 preterm pre‐eclampsia cases and 7546 controls (including 101 cases of late pre‐eclampsia), the area under the receiver operating characteristics curve was 0.659 (95% CI 0.579–0.726). The sensitivity was 32.9% (95% CI 22.1–43.7) at a false‐positive rate of 8.8%. The positive likelihood ratio was 3.74 (95% CI 2.67–5.23), the positive predictive value was 3.49% (95% CI 2.12–4.86%) and the negative predictive value was 99.3% (95% CI 99.1–99.5%). The sensitivity and positive likelihood ratio were approximately 40% lower than in the original study. The calibration analysis showed a good agreement between observed and expected risks (P = 0.037). Comparison with the Fetal Medicine Foundation (FMF) algorithm yielded a difference in the area under the curve of 0.084 (P = 0.007).

Conclusions

In our Italian population, the simple risk score had a lower performance than expected for the prediction of preterm pre‐eclampsia in nulliparous women. The FMF algorithm applied to the same data set resulted in a better prediction.

Tweetable abstract

Simple risk score predicts preterm pre‐eclampsia in Italy.
Clinical and ethical challenges for emergency departments during communicable disease outbreaks: Can lessons from Ebola Virus Disease be applied to the COVID‐19 pandemic?
Authors: Markwell Alexandra , Mitchell Rob , Wright April L , Brown Anthony FT
Published: April 2020

EDs fulfil a frontline function during public health emergencies (PHEs) and will play a pivotal role during the COVID‐19 pandemic. This perspective article draws on qualitative data from a longitudinal, ethnographic study of an Australian tertiary ED to illustrate the clinical and ethical challenges faced by EDs during PHEs. Interview data collected during the 2014 Ebola Virus Disease PHE of International Concern suggest that ED clinicians have a strong sense of professional responsibility, but this can be compromised by increased visibility of risk and sub‐optimal engagement from hospital managers and public health authorities. The study exposes the tension between a healthcare worker's right to protection and a duty to provide treatment. Given the narrow window of opportunity to prepare for a surge of COVID‐19 presentations, there is an immediate need to reflect and learn from previous experiences. To maintain the confidence of ED clinicians, and minimise the risk of moral injury, hospital and public health authorities must urgently develop processes to support ethical healthcare delivery and ensure adequate resourcing of EDs.
GLP‐1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes
Authors: Love Kaitlin M. , Liu Jia , Regensteiner Judith G. , Reusch Jane E.B. , Liu Zhenqi
Published: April 2020

Muscle microvasculature critically regulates skeletal and cardiac muscle health and function. It provides endothelial surface area for substrate exchange between the plasma compartment and the muscle interstitium. Insulin fine‐tunes muscle microvascular perfusion to regulate its own action in muscle and oxygen and nutrient supplies to muscle. Specifically, insulin increases muscle microvascular perfusion, which results in increased delivery of insulin to the capillaries that bathe the muscle cells and then facilitate its own transendothelial transport to reach the muscle interstitium. In type 2 diabetes, muscle microvascular responses to insulin are blunted and there is capillary rarefaction. Both loss of capillary density and decreased insulin‐mediated capillary recruitment contribute to a decreased endothelial surface area available for substrate exchange. Vasculature expresses abundant glucagon‐like peptide 1 (GLP‐1) receptors. GLP‐1, in addition to its well‐characterized glycemic actions, improves endothelial function, increases muscle microvascular perfusion, and stimulates angiogenesis. Importantly, these actions are preserved in the insulin resistant states. Thus, treatment of insulin resistant patients with GLP‐1 receptor agonists may improve skeletal and cardiac muscle microvascular perfusion and increase muscle capillarization, leading to improved delivery of oxygen, nutrients, and hormones such as insulin to the myocytes. These actions of GLP‐1 impact skeletal and cardiac muscle function and systems biology such as functional exercise capacity. Preclinical studies and clinical trials involving the use of GLP‐1 receptor agonists have shown salutary cardiovascular effects and improved cardiovascular outcomes in type 2 diabetes mellitus. Future studies should further examine the different roles of GLP‐1 in cardiac as well as skeletal muscle function.
Effects of consumer cohorts and age on meat expenditures in the United States
Authors: Lee Ji Yong , Qian Yiwei , Gustavsen Geir Wæhler , Nayga Rodolfo M. , Rickertsen Kyrre
Published: April 2020

Meat demand is likely influenced by the birth cohort and age of the individual. In this study, we examine the demand for beef, pork, poultry, and other meat in the United States using the 1984–2012 Consumer Expenditure Survey and the almost ideal demand system with the incorporation of age, period, and cohort (APC) effects. We find that the model with APC effects performs better than the models without APC effects. The results indicate that cohorts born in earlier time periods are expected to purchase significantly less poultry compared to cohorts born in later time periods, when they are measured at the same age. Over the life cycle, purchase of poultry is expected to increase with age while the opposite is true for red meat. We also find that the own‐price elasticity for beef is highest among the products examined, while the own‐price elasticity for other meat is lowest and the inclusion of APC effects increases the absolute value of the own‐price elasticities for beef, pork, and poultry, but reduces the own‐price elasticity for other meat. Our forecasts indicate that the aggregate poultry purchase will continue to increase until 2022, while the aggregate purchase of red meat will slightly increase until 2017, but will either decrease or stay at same level from year 2017 to 2022.
Point‐of‐care lung ultrasound in patients with COVID‐19 – a narrative review
Authors: Smith M. J. , Hayward S. A. , Innes S. M. , Miller A. S. C.
Published: April 2020

Ultrasound imaging of the lung and associated tissues may play an important role in the management of patients with COVID‐19–associated lung injury. Compared with other monitoring modalities, such as auscultation or radiographic imaging, we argue lung ultrasound has high diagnostic accuracy, is ergonomically favourable and has fewer infection control implications. By informing the initiation, escalation, titration and weaning of respiratory support, lung ultrasound can be integrated into COVID‐19 care pathways for patients with respiratory failure. Given the unprecedented pressure on healthcare services currently, supporting and educating clinicians is a key enabler of the wider implementation of lung ultrasound. This narrative review provides a summary of evidence and clinical guidance for the use and interpretation of lung ultrasound for patients with moderate, severe and critical COVID‐19–associated lung injury. Mechanisms by which the potential lung ultrasound workforce can be deployed are explored, including a pragmatic approach to training, governance, imaging, interpretation of images and implementation of lung ultrasound into routine clinical practice.
P‐wave indices as predictors of atrial fibrillation
Authors: Rasmussen Maria Uggen , Kumarathurai Preman , Fabricius‐Bjerre Andreas , Larsen Bjørn Strøier , Domínguez Helena , Davidsen Ulla , Gerds Thomas Alexander , Kanters Jørgen K. , Sajadieh Ahmad
Published: April 2020

Background

P‐wave duration (PDURATION) and P‐wave area (PAREA) have been linked to risk of atrial fibrillation (AF), but they do not improve the efficacy of Framingham AF risk score. We suggest the incorporation of both variables in one index, the P‐wave area/P‐wave duration (PAREA/DURATION) index, which may be considered an expression of the average amplitude of the P wave that reflects aspects of P‐wave morphology.

Objective

To assess the prognostic value of P‐wave area/P‐wave duration index (PAREA/DURATION index) in lead II together with other P‐wave indices (PWIs) in incidence of AF in the Copenhagen Holter Study.

Methods

The study included 632 men and women, between 55 and 75 years with no apparent heart disease or AF. Baseline standard 12‐lead Electrocardiography (ECGs) were analyzed manually.

Results

The median follow‐up time was 14.7 (14.5;14.9) years. A total of 68 cases of AF and 233 cases of death were recorded. The restricted cubic spline method showed a U‐shaped association between PAREA/DURATION and rate of AF. The lowest quintile of PAREA/DURATION index in lead II was associated with increased rate of AF, HR 2.80 (1.64–4.79). The addition of the new index to the Framingham model for AF improved the model in this population. The PAREA in lead II in its lowest quintile was also associated with increased rate of AF, HR 2.16 (1.25–3.75), but did not improve the Framingham model. PDURATION and P‐wave terminal force (PTF) were not significantly associated with AF.

Conclusion

A flat P wave as expressed by a small PAREA/DURATION index in lead II is associated with increased rate of incident AF beyond known AF risk factors.
Full‐field Electroretinography in Age‐related Macular Degeneration: can retinal electrophysiology predict the subjective visual outcome of cataract surgery?
Authors: Forshaw Thomas Richard Johansen , Ahmed Hassan Javed , Kjær Troels Wesenberg , Andréasson Sten , Sørensen Torben Lykke
Published: April 2020

Purpose

Predicting the visual gain from cataract surgery when the main cause of vision loss is age‐related macular degeneration may be difficult and warrants the need for an objective predictor of subjective outcome. Full‐field electroretinography is an objective measure of overall retinal function. We therefore wanted to study if full‐field electroretinography can predict subjective visual outcome using visual function questionnaire.

Methods

Thirty‐one patients with age‐related macular degeneration operated for bilateral cataract underwent full‐field electroretinography preoperatively. Full‐field electroretinography was performed according to International Society for the Clinical Electrophysiology of Vision standards using a Ganzfeld bowl (RETI‐port/scan 21, Roland, Berlin) and Dawson–Trick–Litzkow fibre electrodes. Vision‐related quality of life was measured using the National Eye Institute Visual Function Questionnaire‐39 before first‐eye surgery and 4.12 ± 2.11 months after second‐eye surgery.

Results

Mean change in composite visual function questionnaire score after cataract surgery was 9.2 ± 11.9. The patients were divided into three groups: visual function questionnaire composite score increase >10 (n = 17); no change (n = 8); and decrease (n = 6). In the dark‐adapted full‐field electroretinography responses, we found a significant difference between the three groups in the 0.01 b‐wave amplitude (p = 0.05), the 10.0 b‐wave amplitude (p = 0.04) and a near‐significant difference in 3.0 a‐wave amplitude (p = 0.09). Other dark‐adapted responses (the 3.0 b‐wave and 10.0 a‐wave) did not show any significant differences between the three groups, and neither did the light‐adapted responses.

Conclusion

Patients with low dark‐adapted responses on full‐field electroretinography preoperatively experience a decrease in subjective vision‐related quality of life, suggesting that maintained rod function before cataract surgery may be important.
Mechanobiology of antigen‐induced T cell arrest
Authors: Chabaud Mélanie , Paillon Noémie , Gaus Katharina , Hivroz Claire
Published: April 2020

To mount an immune response, T cells must first find rare antigens present at the surface of antigen‐presenting cells (APCs). They achieve this by migrating rapidly through the crowded space of tissues and constantly sampling the surface of APCs. Upon antigen recognition, T cells decelerate and polarise towards the APC, ultimately forming a specialised interface known as the immunological synapse. These conjugates form as the result of the interaction between pairs of receptors/ligands that are under mechanical stress due to the continuously reorganising cell cytoskeleton. In this review, we discuss the involvement of mechanical forces during antigen recognition by migrating T cells. We will explore this question from a conceptual and technical perspective, with the aim of providing new insights into the emerging field of mechanobiology.
Guidelines for endoscopic diagnosis of early gastric cancer
Authors: Yao Kenshi , Uedo Noriya , Kamada Tomoari , Hirasawa Toshiaki , Nagahama Takashi , Yoshinaga Shigetaka , Oka Masashi , Inoue Kazuhiko , Mabe Katsuhiro , Yao Takashi , Yoshida Masahiro , Miyashiro Isao , Fujimoto Kazuma , Tajiri Hisao
Published: April 2020

The Japan Gastroenterological Endoscopy Society developed the Guideline for Endoscopic Diagnosis of Early Gastric Cancer based on scientific methods. Endoscopy for the diagnosis of early gastric cancer has been acknowledged as a useful and highly precise examination, and its use has become increasingly more common in recent years. However, the level of evidence in this field is low, and it is often necessary to determine recommendations based on expert consensus only. This clinical practice guideline consists of the following sections to provide the current guideline: [I] Risk stratification of gastric cancer before endoscopic examination, [II] Detection of early gastric cancer, [III] Qualitative diagnosis of early gastric cancer, [IV] Diagnosis to choose the therapeutic strategy for gastric cancer, [V] Risk stratification after endoscopic examination, and [VI] Surveillance of early gastric cancer.
Influence of gastroesophageal flap valve on esophageal variceal bleeding in patients with liver cirrhosis
Authors: Koya Yudai , Shibata Michihiko , Watanabe Tatsuyuki , Kumei Shinsuke , Miyagawa Koichiro , Oe Shinji , Honma Yuichi , Kume Keiichiro , Yoshikawa Ichiro , Harada Masaru
Published: April 2020

Objectives

Esophageal variceal bleeding can be fatal in patients with liver cirrhosis. The aim of this study was to investigate the relationship between gastroesophageal flap valve (GEFV) and esophageal variceal bleeding.

Methods

Subjects were cirrhotic patients with endoscopically diagnosed esophageal varices treated at our hospital between 2005 and 2019, excluding those with F3 form and red color (RC) signs at first endoscopy. Sixty‐five patients with normal GEFV (Hill grade I or II) and 42 with abnormal GEFV (Hill grade III or IV) were enrolled. Propensity score matching eliminated the baseline differences, resulting in a sample size of 30 patients per cohort. The primary endpoint was esophageal variceal bleeding, and the secondary endpoint was variceal bleeding or appearance of RC sign. We analyzed the cumulative incidences and predictors of each endpoint.

Results

The 3‐, 5‐, and 10‐year cumulative incidences of the primary endpoints were all 3.4% in the normal GEFV group, and 19.0%, 24.6% and 34.0% in the abnormal GEFV group, respectively (log‐rank P = 0.011). Cumulative incidence of the secondary endpoint was 13.8%, 33.1% and 39.2% in the normal GEFV group, and 42.2%, 54.6% and 84.9% in the abnormal GEFV group, respectively (log‐rank P = 0.001). In multivariate Cox regression analyses, hazard ratios of abnormal GEFV of the primary and secondary endpoints were 12.79 (95% confidence interval 1.331–122.8) and 3.600 (1.653–7.840), respectively.

Conclusions

Abnormal GEFV was an independent risk factor for esophageal variceal bleeding and appearance of RC sign.
Endoscopic submucosal dissection is not for the interest of endoscopists but for the patients cure
Authors: Saito Yutaka , Ono Akiko
Published: April 2020

This Editorial refers to the article by McCarty et al., p 851–860 of this issue.
Point mutagenesis in mouse reveals contrasting pathogenetic effects between MEN2B‐ and Hirschsprung disease‐associated missense mutations of the RET gene
Authors: Nakatani Taichi , Iwasaki Mitsuhiro , Yamamichi Atsuhiro , Yoshioka Yuta , Uesaka Toshihiro , Bitoh Yuko , Maeda Kosaku , Fukumoto Takumi , Takemoto Tatsuya , Enomoto Hideki
Published: April 2020

Missense mutations of the RET gene have been identified in both multiple endocrine neoplasia (MEN) type 2A/B and Hirschsprung disease (HSCR: congenital absence of the enteric nervous system, ENS). Current consensus holds that MEN2A/B and HSCR are caused by activating and inactivating RET mutations, respectively. However, the biological significance of RET missense mutations in vivo has not been fully elucidated. In the present study, we introduced one MEN2B‐associated (M918T) and two HSCR‐associated (N394K and Y791F) RET missense mutations into the corresponding regions of the mouse Ret gene by genome editing (RetM919T, RetN396K and RetY792F) and performed histological examinations of Ret‐expressing tissues to understand the pathogenetic impact of each mutant in vivo. RetM919T/+ mice displayed MEN2B‐related phenotypes, including C‐cell hyperplasia and abnormal enlargement of the primary sympathetic ganglia. Similar sympathetic phenotype was observed in RetM919T/‐ mice, demonstrating a strong pathogenetic effect of the Ret M918T by a single‐allele expression. In contrast, no abnormality was found in the ENS of mice harboring the Ret N394K or Y791F mutation. Most surprisingly, single‐allele expression of RET N394K or Y791F was sufficient for normal ENS development, indicating that these RET mutants exert largely physiological function in vivo. This study reveals contrasting pathogenetic effects between MEN2B‐ and HSCR‐associated RET missense mutations, and suggests that some of HSCR‐associated RET missense mutations are by themselves neither inactivating nor pathogenetic and require involvement of other gene mutations for disease expressivity.
Association of glycaemic variables with trabecular bone score in post‐menopausal women with type 2 diabetes mellitus
Authors: Depczynski B. , Liew P. Y. , White C.
Published: April 2020

Aim

To determine the relationship between bone microarchitecture, as measured by trabecular bone score, and advanced glycation end‐product accumulation, as assessed by skin autofluorescence.

Methods

This was a cross‐sectional study. Participants were 64 post‐menopausal women with type 2 diabetes and 175 post‐menopausal women without diabetes. Trabecular bone score and skin autofluorescence data were obtained at time of bone density measurement.

Results

Trabecular bone score and skin autofluorescence were inversely correlated in women with type 2 diabetes (r = –0.34, P = 0.006); no correlation was seen in post‐menopausal women without diabetes (r = –0.029, P = 0.707). After adjustment, neither skin autofluorescence nor a diagnosis of diabetes were associated with trabecular bone score, but HbA1c and waist circumference were independently associated with trabecular bone score.

Conclusion

Skin autofluorescence did not predict trabecular bone score. In contrast, glycaemia, as reflected by HbA1c, and visceral adiposity, as reflected by waist circumference, were independently associated with trabecular bone score.
Norepinephrine stabilizes translation‐dependent, homosynaptic long‐term potentiation through mechanisms requiring the cAMP sensor Epac, mTOR and MAPK
Authors: Maity Sabyasachi , Chandanathil Merin , Millis Richard M. , Connor Steven A.
Published: April 2020

Neuromodulators regulate higher‐order cognitive processes including learning and memory through modulation of synaptic transmission and plasticity. Norepinephrine is a neuromodulator that is secreted throughout the brain in response to novelty or increased arousal, which alters neural circuits by increasing the modifiability of CNS synapses. Norepinephrine activates metabotropic receptors, initiating complex intracellular signalling cascades that can promote enduring changes in synaptic strength including long‐term potentiation (LTP). In particular, activation of beta‐adrenergic receptors (β‐ARs) by norepinephrine enhances LTP through downstream engagement of signalling cascades which upregulate protein synthesis at synapses. Here, we sought to determine the select signalling pathways recruited by norepinephrine to promote homosynaptic LTP at hippocampal synapses in mice. Application of norepinephrine initiated a long‐lasting form of homosynaptic LTP that requires protein synthesis. Norepinephrine‐mediated enhancement of LTP was reduced by inhibition of mammalian target of rapamycin and exchange protein directly activated by cAMP (Epac) but not cAMP‐dependent protein kinase A, suggesting that the endogenous β‐AR ligand norepinephrine may preferentially recruit Epac signalling to promote enduring changes in synaptic strength. These findings advance our understanding of the mechanisms through which norepinephrine regulates synaptic plasticity associated with formation of new memories.
Integrating genetic and nongenetic drivers of somatic evolution during carcinogenesis: The biplane model
Authors: Gatenby Robert A. , Avdieiev Stanislav , Tsai Kenneth Y. , Brown Joel S.
Published: April 2020

The multistep transition from a normal to a malignant cellular phenotype is often termed “somatic evolution” caused by accumulating random mutations. Here, we propose an alternative model in which the initial genetic state of a cancer cell is the result of mutations that occurred throughout the lifetime of the host. However, these mutations are not carcinogenic because normal cells in multicellular organism cannot ordinarily evolve. That is, proliferation and death of normal cells are controlled by local tissue constraints typically governed by nongenomic information dynamics in the cell membrane. As a result, the cells of a multicellular organism have a fitness that is identical to the host, which is then the unit of natural selection. Somatic evolution of a cell can occur only when its fate becomes independent of host constraints. Now, survival, proliferation, and death of individual cells are dependent on Darwinian dynamics. This cellular transition from host‐defined fitness to self‐defined fitness may, consistent with the conventional view of carcinogenesis, result from mutations that render the cell insensitive to host controls. However, an identical state will result when surrounding tissue cannot exert control because of injury, inflammation, aging, or infection. Here, all surviving cells within the site of tissue damage default to self‐defined fitness functions allowing them to evolve so that the mutations accumulated over the lifetime of the host now serve as the genetic heritage of an evolutionary unit of selection. Furthermore, tissue injury generates a new ecology cytokines and growth factors that might promote proliferation in cells with prior receptor mutations. This model integrates genetic and nongenetic dynamics into cancer development and is consistent with both clinical observations and prior experiments that divided carcinogenesis to initiation, promotion, and progression steps.
Heuristics for the capacitated dispersion problem
Authors: Peiró Juanjo , Jiménez Iris , Laguardia José , Martí Rafael
Published: April 2020

In this paper, we investigate the adaptation of the greedy randomized adaptive search procedure (GRASP) and variable neighborhood descent (VND) methodologies to the capacitated dispersion problem. Dispersion and diversity problems arise in the placement of undesirable facilities, workforce management, and social media, among others. Maximizing diversity deals with selecting a subset of elements from a given set in such a way that the distance among the selected elements is maximized. We target here a realistic variant with capacity constraints for which a heuristic with a performance guarantee was previously introduced. In particular, we propose a hybridization of GRASP and VND implementing within the strategic oscillation framework. To evaluate the performance of our heuristic, we perform extensive experimentation to first set key search parameters, and then compare the final method with the previous heuristic. Additionally, we propose a mathematical model to obtain optimal solutions for small‐sized instances, and compare our solutions with the well‐known LocalSolver software.