bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptional profiling of genes in tongue epithelial tissue from immature and adult rats by the RNA‐Seq technique
Authors: Ke Xiumei , Lin Junzhi , Li Pan , Wu Zhenfeng , Xu Runchun , Ci Zhimin , Yang Ming , Han Li , Zhang Dingkun
Published: September 2019

Children are more sensitive than adults to bitterness and thus dislike bitter tastes more than adults do. However, why children are more sensitive to bitterness has never been revealed. To elucidate the effects of age on taste perception, a double‐bottle preference test was first performed with immature and adult rats. Then, RNA‐Seq analysis was performed on tongues obtained from rats of the same ages as those in the double‐bottle test. The immature rats exhibited a lower consumption rate of bitter solution than the adult rats. Bioinformatics analysis yielded 1,347 differentially expressed genes (DEGs) between male adult rats (MARs, 80 days old) and male immature rats (MIRs, 20 days old) and 380 DEGs between female adult rats (FARs, 80 days old) and female immature rats (FIRs, 20 days old). These DEGs were mainly associated with growth, development, differentiation, and extracellular processes, among other mechanisms. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, the DEGs were enriched for bitter taste transduction. Specifically, the Gnb3 and TRPM5 genes were downregulated in FARs compared with FIRs and in MARs compared with MIRs, and the protein expression of TRPM5 was significantly downregulated in MARs compared with MIRs. The data presented herein suggest that transcriptional regulation of taste‐associated signal transduction occurs differently in tongue epithelial tissue of rats at different ages, although additional analyses are needed to confirm this conclusion.
LncRNA NEAT1 promotes autophagy via regulating miR‐204/ATG3 and enhanced cell resistance to sorafenib in hepatocellular carcinoma
Authors: Li Xinyu , Zhou Yong , Yang Liang , Ma Yingbo , Peng Xueqiang , Yang Shuo , Li Hangyu , Liu Jingang
Published: September 2019

Long noncoding RNAs (lncRNAs) has been acknowledged in tumorigenesis gradually because of the great importance in different cancers. LncRNA nuclear enriched abundant transcript 1 (NEAT1) is a novel lncRNA and has been reported to promote multiple cancer progression. However, the biological roles of NEAT1 in hepatocellular carcinoma (HCC) is not cleared nowadays. In the present research, the level of NEAT1 was found to be upregulated in HCC by The Cancer Genome Atlas. In addition, NEAT1 expression is negatively correlated with the survival rate in HCC. Further investigation revealed that NEAT1 upregulation inhibited sorafenib efficacy and promoted autophagy. We found that NEAT1 could be a sponge for microRNA‐204 (miR‐204) and inhibits its level to upregulate ATG3 expression. In addition to the above, we demonstrated that miR‐204 mimics also attenuated tumor autophagy. And rescue assays demonstrated that NEAT1 promotes HCC autophagy through modulating miR‐204/ATG3 pathway. Collectively, this study first demonstrated that a novel NEAT1/miR‐204/ATG3 signaling regulates HCC progression.
Home and away: Why do consumers shy away from reporting negative experiences in the peer‐to‐peer realms?
Authors: Osman Hanaa , D'Acunto David , Johns Nick
Published: September 2019

This study investigates how customers use their construct of “home” in evaluating their experience in peer‐to‐peer rented accommodation, as opposed to traditional hotels. The literature has paid considerable attention to people's perceptions of destinations, but almost none to their perceptions of “home” and its complexities whilst visiting a destination. We examine the relationships between the concepts of “home” or “here” represented in peer‐to‐peer accommodation and the construct of “away” or “there” represented in traditional hotels. A mixed‐method approach determines the existence of bias in reporting behavior. Our findings indicate that there is a consistent review gap between institutional actors and peer‐to‐peer actors. Also, consumers of peer‐to‐peer accommodation prefer not to engage in negative reporting if a bond with the host is developed. This perception of a home shapes consumers' relationship with the host and leads to reporting bias. This study provides clear theoretical insights to advance our knowledge about the underlying motives behind reporting behavior of negative experiences. Furthermore, it offers practical implications for both institutional and peer‐to‐peer contexts.
Modeling the Effect of Income Segregation on Communicable Disease Transmission
Authors: Pham Anh
Published: September 2019

Income segregation has been on the rise in developing countries, where many communicable diseases are still prevalent. This study investigates how income segregation affects communicable disease transmission through the development of a novel model that includes income segregation and individuals’ health‐seeking behavior. The general model proposed here assumes that health of an individual is affected by (i) the health‐seeking behavior of individuals (e.g., going to the hospital, taking medicine); (ii) the communal health stock; and (iii) exposure to the communal health stock. The communal health stock is comprised of the amenities that make people healthier in a given community (e.g., the number of health‐care facilities). Income segregation is defined here as a combination of income inequality and residential segregation, which exists when some people have higher exposure to the communal health stock than other people. In this model, income segregation exists when poor people disproportionately live in neighborhoods with lower exposure to the communal health stock than rich people. A decrease in income segregation means the income of the poor increases along with their exposure to the communal health stock. The general model applied here predicts that an increase in the poor's income will increase their health by enabling them to afford more health‐seeking behavior and finds that higher exposure to the communal health stock directly increases the health of the poor. Higher exposure to the communal health stock, however, is found to decrease the poor's health‐seeking behavior, which reduces their health. The general model finds, therefore, that a decrease in income segregation will have an ambiguous effect on the health of individuals and the overall community. Probing further, the analysis replaces the general model with a more specific model, which predicts that overall, a decrease in income segregation increases individual health. Furthermore, in the more specific model, it is possible that the poor get stuck in a low‐health equilibrium while the rich stay in a high‐health equilibrium.
Process models: plans, predictions, proclamations or prophecies?
Authors: Stacey Martin , Eckert Claudia , Hillerbrand Rafaela
Published: September 2019

Design process models have a complex and changing relationship to the processes they model, and mean different things to different people in different situations. Participants in design processes need to understand each other’s perspectives and agree on what the models mean. The paper draws on philosophy of science to argue that understanding a design process model can be seen as an imagination game governed by agreed rules, to envisage what would be true about the world if the model were correct. The rules depend on the syntax and content of the model, on the task the model is used for, and on what the users see the model asbeing. The paper outlines twelve alternative conceptualizations of design process models—frames,pathways,positions,proclamations,projections,predictions,propositions,prophecies,requests,demands,proposals,promises—and discusses when they fit situations that stakeholders in design processes can be in. Articulating how process models are conceptualised can both help to understand how process management works and help to resolve communication problems in industrial practice.
Spiking a Silty-Sand Reference Soil with Bacterial DNA: Limits and Pitfalls in the Discrimination of Live and Dead Cells When Applying Ethidium Monoazide (EMA) Treatment
Authors: Wagner Andreas O. , Praeg Nadine , Illmer Paul
Published: September 2019

In the present study, EMA (ethidium monoazide) treatment was applied to a silty-sand reference soil prior to DNA extraction to enable a differentiation between dead and living cells. For this purpose, a reference soil was spiked with Listeria monocytogenes cells or cell equivalents, respectively. With the purpose of evaluating optimum treatment conditions, different EMA concentrations have been tested. However, the results remained largely inconclusive. Furthermore, varied dark incubation periods allowing EMA to penetrate dead cells did not allow the selective removal of DNA from membrane-compromised cells in downstream analyses. In contrast to undiluted soil, an effect of EMA treatment during DNA extraction could be observed when using a 1:10 dilution of the reference soil; however, the effect has not been sufficiently selective to act on heat-treated cells only. Although the application of EMA to soil requires further evaluation, the procedure harbors future potential for improving DNA-based approaches in microbial ecology studies.
Belastung des Neusiedler Sees mit anthropogenen Spurenstoffen: Überlegungen zu Herkunft und Verhalten
Authors: Zessner Matthias , Zoboli Ottavia , Reif Daniela , Amann Arabel , Sigmund Elisabeth , Kum Georg , Saracevic Zdravka , Saracevic Ernis , Kittlaus Steffen , Krampe Jörg , Wolfram Georg
Published: September 2019

Im vorliegenden Artikel wird auf Basis unterschiedlicher Datenquellen in einem ersten Schritt die Belastung des Neusiedler Sees mit national oder gemeinschaftlich geregelten anthropogenen Spurenstoffen dargestellt. Darüber hinaus werden für ausgewählte Stoffe Eintragspfade in Wulka und Neusiedler See identifiziert und für weitere Stoffe wird ein mögliches Umweltverhalten im See dargestellt. Auch wenn derzeit ein umfassendes Monitoring von allen national oder gemeinschaftlich geregelten Spurenstoffen im Neusiedler See fehlt, kann für den überwiegenden Teil dieser Stoffe auf Basis von Untersuchungen in der Wulka bzw. Fischuntersuchungen im See eine Einhaltung der UQN angenommen werden. Für einzelne Stoffe ist eine Zielverfehlung geben oder anzunehmen. Für andere Stoffe ist zurzeit aufgrund analytischer Schwierigkeiten ein eindeutiger Befund nicht möglich. In Abhängigkeit vom Stoff und der Betrachtungsebene können sowohl Kläranlagenabläufe, landwirtschaftliche Erosion als auch die atmosphärische Deposition auf die Oberfläche des Sees die Einträge dominieren. Mit Bedachtnahme auf die große Zahl der in die aquatische Umwelt emittierten anthropogenen Spurenstoffe muss unabhängig von der Betrachtung von Einzelstoffen für den Neusiedler See eine ganz besondere Vulnerabilität für diese Form der Belastung diagnostiziert werden. Dies liegt vor allem an der Funktion des Sees als Stoffsenke. Persistente Spurenstoffe, die in den See gelangen, werden im Freiwasser aufkonzentriert oder in den Sedimentbereichen des Schilfs gespeichert, von wo sie allenfalls wieder mobilisiert werden können. Selbst wenn eine Vielzahl von schwer abbaubaren Spurenstoffen durch Ab- oder Umbau aus dem Freiwasser des Sees eliminiert wird, ist über die Endprodukte eines solchen Umbaus noch wenig bekannt bzw. sind diese aufgrund der Vielzahl möglicher Stoffe nicht gänzlich zu überwachen. Als Grundlage zur Entwicklung von Strategien für ein langfristiges und effizientes Management des Sees wäre ein regelmäßiges Monitoring von Spurenstoffen in See und Schilfgürtel deutlich zu verstärken, um Fehlentwicklungen im See frühzeitig erkennen zu können.
Do Locus of Control, Self-esteem, Hope and Shame Mediate the Relationship Between Financial Hardship and Mental Health?
Authors: Frankham Charlotte , Richardson Thomas , Maguire Nick
Published: September 2019

In a longitudinal study of 104 participants, the psychological factors of economic locus of control, self-esteem, hope and shame were explored for their impact on the relationship between financial hardship and mental health. Participants completed measures of financial hardship, the psychological factors and measures of mental health three times at three-monthly intervals. A hierarchical regression analyses indicated that subjective financial hardship, hope and shame significantly predicted mental health outcomes. Mediation analyses demonstrated that hope mediated the relationship between subjective financial hardship and depression, stress and wellbeing; that shame mediated the relationship between subjective financial hardship and anxiety; and that neither shame nor hope mediated the relationship between subjective financial hardship and suicide ideation.
Optical polarization shift in beams emitted by quantum cascade lasers
Authors: Pruszyńska-Karbownik Emilia , Gutowski Piotr , Karbownik Piotr
Published: September 2019

In this paper, we present experimental results of current-induced polarization change and transverse mode change in mid-infrared quantum cascade lasers. The polarization of laser beam was determined by measuring of far-field distributions of polarization projection on the linear polarization basis. The measured amount of TE-polarized light is associated with transversal mode structure, which was determined based on the far-field power distributions. The TE polarized light contribution in the beams varies from 6 to 19%. This quantity is anti-correlated to the fundamental transverse mode contribution.
Oxidation of cycloalkanes catalysed by N-hydroxyimides in supercritical carbon dioxide
Authors: Lisicki Dawid , Orlińska Beata
Published: September 2019

This paper reports cyclopentane, cyclohexane and cyclooctane oxidation in the presence of N-hydroxyphthalimide or 4-dodecyloxycarbonyl-N-hydroxyphthalimide in combination with Co(II) and Fe(II) salts using O2/CO2 mixture (0.5 MPa O2, 9.5 MPa CO2). The studies demonstrated that the application of scCO2 in cyclohexane and cyclooctane oxidation processes results in higher conversion and yield of respective ketone and alcohol in comparison to processes performed using air under pressure (0.7 MPa).
Addressing the Vepris verdoorniana complex (Rutaceae) in West Africa, with two new species
Authors: Cheek Martin , Onana Jean-Michel , Yasuda Shigeo , Lawrence Poppy , Ameka Gabriel , Buinovskaja Greta
Published: September 2019

Vepris verdoorniana(Rutaceae) has long been regarded as a widespread and variable species occurring from Guinea to Gabon. Recent evidence has shown that the original material from the type locality in Cameroon consists of two different species,V. verdoornianain the strict sense, endemic to Lower Guinea (Cameroon, Gabon and C.A.R. in W-C Africa) andV. letouzeyiOnana, which was thought to occur from Guinea to Cameroon. In this paper we show that the West African (Upper Guinea) material previously referred to asV. letouzeyi/V. verdoornianais separate morphologically from that in Cameroon (Lower Guinea). In fact the West African material referred to comprises two distinct species, here described asV. occidentalisCheek & Onana (Guinea to Ghana, but probably extending to Benin) a tree of lowland marginal dry evergreen and semi-deciduous forest, andV. ferCheek, a species restricted to four mainly lower submontane forest locations on iron substrates in Liberia and Sierra Leone (also Upper Guinea).Vepris occidentalisis here assessed as Least Concern due to its wide range and high frequency, whilstV. feris assessed as Endangered due to the low number of locations and threats from iron ore mining projects. Both new species are illustrated and mapped.
Cyber security and the brand
Authors: Chikada Akino
Published: September 2019

A brand is an organisation's most valuable asset. It gives out strong messages, both explicit and implicit, to anyone who encounters it – customers, employees, advocates, investors and even competitors. It will leave a clear understanding of what the product or organisation is all about and if it is something which they may want to get more involved with. Many top brands such as Apple and Coca-Cola are valued in the tens of billions of pounds. 1, 2

Brand protection has become more of a priority in recent years and a key element of this for many organisations is keeping their customers safe. Incorporating cyber security best practices into brand-protection strategies as well as working with the right registrar are good places to start, explains Akino Chikada of MarkMonitor.
Two components is too simple: an example of oscillatory Fisher–KPP system with three components
Authors: Girardin Léo
Published: September 2019

In a recent paper by Cantrell et al. [9], two-component KPP systems with competition of Lotka–Volterra type were analyzed and their long-time behaviour largely settled. In particular, the authors established that any constant positive steady state, if unique, is necessarily globally attractive. In the present paper, we give an explicit and biologically very natural example of oscillatory three-component system. Using elementary techniques or pre-established theorems, we show that it has a unique constant positive steady state with two-dimensional unstable manifold, a stable limit cycle, a predator–prey structure near the steady state, periodic wave trains and point-to-periodic rapid travelling waves. Numerically, we also show the existence of pulsating fronts and propagating terraces.
Moving toward community based telehealth services using mhealth for hypertensive patients
Authors: Zare Sahar , Rezaee Rita , Aslani Azam , Shirdeli Mohammad , Kojuri Javad
Published: September 2019

Background

Although self-care can control and prevent complications in hypertensive patients, self-care adherence is relatively low among these patients. Community-based telehealth services through mhealth can be an effective solution.

Objective

This study aimed to evaluate the effect and acceptance of an mhealth application as a community-based telehealth intervention on self-care behavior adherence.

Method

This clinical trial included sixty hypertensive patients and their matched controls from two heart clinics affiliated to Shiraz University of Medical Sciences (SUMS). Self-care behaviors were assessed using Hill-Bone questionnaire before and after the intervention. Acceptability was evaluated in the intervention group at the end of the study period. The data were analyzed via SPSS 18 software using descriptive and inferential statistics.

Result

The results showed a significant difference between the intervention and control groups regarding the mean score of self-care behaviors (4.13 ± 0.23 versus 3.18 ± 0.27, p < .001). Additionally, a significant difference was observed between the two groups concerning the mean scores of the two subscales of self-care behaviors, including “medication taking” and “proper diet”. However, no significant difference was observed between the two groups regarding the mean score of “appointment keeping” (p = .075). Overall, the intervention group participants were satisfied (4.27 ± 0.34) with this approach for managing hypertension.

Conclusion

Community-based telehealth services through mhealth had the potential to improve self-care behaviors in hypertensive patients and seemed to be accepted by the patients in the intervention group.
Epidemiology, molecular characterisation and antimicrobial susceptibility ofNeisseria gonorrhoeaeisolates in Madrid, Spain, in 2016
Authors: Guerrero-Torres M. D. , Menéndez M. B. , Guerras C. S. , Tello E. , Ballesteros J. , Clavo P. , Puerta T. , Vera M. , Ayerdi O. , Carrio J. C. , Mozo I. , Del Romero J. , Vázquez J. A. , Abad R.
Published: September 2019

With the aim to elucidate gonococcal antimicrobial resistance (AMR)–risk factors, we undertook a retrospective analysis of the molecular epidemiology and AMR of 104Neisseria gonorrhoeaeisolates from clinical samples (urethra, rectum, pharynx and cervix) of 94 individuals attending a sexually transmitted infection clinic in Madrid (Spain) from July to October 2016, and explored potential links with socio-demographic, behavioural and clinical factors of patients. Antimicrobial susceptibility was determined byE-tests, and isolates were characterised byN. gonorrhoeaemulti-antigen sequence typing. Penicillin resistance was recorded for 15.4% of isolates, and most were susceptible to tetracycline, cefixime and azithromycin; a high incidence of ciprofloxacin resistance (~40%) was found. Isolates were grouped into 51 different sequence types (STs) and 10 genogroups (G), with G2400, ST5441, ST2318, ST12547 and G2992 being the most prevalent. A significant association (P= 0.015) was evident between HIV-positive MSM individuals and having a ciprofloxacin-resistant strain. Likewise, a strong association (P= 0.047) was found between patient age of MSM and carriage of isolates expressing decreased susceptibility to azithromycin. A decrease in the incidence of AMR gonococcal strains and a change in the strain populations previously reported from other parts of Spain were observed. Of note, the prevalent multi-drug resistant genogroup G1407 was represented by only three strains in our study, while the pan-susceptible clones such as ST5441, and ST2318, associated with extragenital body sites were the most prevalent.
Particulate matter-induced senescence of skin keratinocytes involves oxidative stress-dependent epigenetic modifications
Authors: Ryu Yea Seong , Kang Kyoung Ah , Piao Mei Jing , Ahn Mee Jung , Yi Joo Mi , Bossis Guillaume , Hyun Young-Min , Park Chang Ook , Hyun Jin Won
Published: September 2019

Ambient air particulate matter (PM) induces senescence in human skin cells. However, the underlying mechanisms remain largely unknown. We investigated how epigenetic regulatory mechanisms participate in cellular senescence induced by PM with a diameter <2.5 (PM2.5) in human keratinocytes and mouse skin tissues. PM2.5-treated cells exhibited characteristics of cellular senescence. PM2.5 induced a decrease in DNA methyltransferase (DNMT) expression and an increase in DNA demethylase (ten–eleven translocation; TET) expression, leading to hypomethylation of the p16INK4A promoter region. In addition, PM2.5 led to a decrease in polycomb EZH2 histone methyltransferase expression, whereas the expression of the epigenetic transcriptional activator MLL1 increased. Furthermore, binding of DNMT1, DNMT3B, and EZH2 to the promoter region of p16INK4A decreased in PM2.5-treated keratinocytes, whereas TET1 and MLL1 binding increased, leading to decreased histone H3 lysine 27 trimethylation (H3K27Me3) and increased H3K4Me3 in the promoter of p16INK4A. PM2.5-induced senescence involved aryl hydrocarbon receptor (AhR)-induced reactive oxygen species (ROS) production. ROS scavenging dampened PM2.5-induced cellular senescence through regulation of DNA and histone methylation. Altogether, our work shows that skin senescence induced by environmental PM2.5 occurs through ROS-dependent the epigenetic modification of senescence-associated gene expression. Our findings provide information for the design of preventive and therapeutic strategies against skin senescence, particularly in light of the increasing problem of PM2.5 exposure due to air pollution.
Revisiting NTRKs as an emerging oncogene in hematological malignancies
Authors: Joshi Sunil K. , Davare Monika A. , Druker Brian J. , Tognon Cristina E.
Published: September 2019

NTRK fusions are dominant oncogenic drivers found in rare solid tumors. These fusions have also been identified in more common cancers, such as lung and colorectal carcinomas, albeit at low frequencies. Patients harboring these fusions demonstrate significant clinical response to inhibitors such as entrectinib and larotrectinib. Although current trials have focused entirely on solid tumors, there is evidence supporting the use of these drugs for patients with leukemia. To assess the broader applicability for Trk inhibitors in hematological malignancies, this review describes the current state of knowledge about alterations in the NTRK family in these disorders. We present these findings in relation to the discovery and therapeutic targeting of BCR–ABL1 in chronic myeloid leukemia. The advent of deep sequencing technologies has shown that NTRK fusions and somatic mutations are present in a variety of hematologic malignancies. Efficacy of Trk inhibitors has been demonstrated in NTRK-fusion positive human leukemia cell lines and patient-derived xenograft studies, highlighting the potential clinical utility of these inhibitors for a subset of leukemia patients.
Effect of diabetes-specific nutrition formulas on satiety and hunger hormones in patients with type 2 diabetes
Authors: Mottalib Adham , Abrahamson Martin J. , Pober David M. , Polak Rani , Eldib Ahmed H. , Tomah Shaheen , Ashrafzadeh Sahar , Hamdy Osama
Published: September 2019

Objectives

Diabetes-specific nutritional formulas (DSNFs) are frequently used by patients with type 2 diabetes (T2D) as part of nutrition therapy to improve glycemic control and reduce body weight. However, their effects on hunger and satiety hormones when compared to an isocaloric standardized breakfast are not fully understood. This study aims to evaluate the postprandial effects of two DSNFs—Glucerna (GL) and Ultra Glucose Control (UGC)—versus oatmeal on selected satiety and hunger hormones.

Method

After an overnight fast, 22 patients with T2D (mean age 62.3 ± 6.8 years, A1C 6.8 ± 0.7%, body weight 97.4 ± 21.3 kg, and BMI 33.2 ± 5.9 kg/m²) were given 200 kcal of each meal on three separate days. Blood samples for amylin, cholecystokinin (CCK), ghrelin, glucagon, leptin, and peptide-YY (PYY) were collected at baseline and 30, 60, 90, 120, 180, and 240 min after the start of each meal. Incremental area under the curve (iAUC0-240) for each hormone was calculated.

Results

iAUC0-240 for glucagon and PYY were significantly higher after GL and UGC than after oatmeal (p < 0.001 for both). No difference was observed between the three meals on postprandial amylin, CCK, ghrelin, and leptin hormones.

Conclusions

Intake of DSNFs significantly increases secretion of PYY and glucagon, two important satiety hormones. While subjective satiety was not directly evaluated, the increased effect on satiety hormones may partially explain the mechanism of body weight loss associated with DSNF use.
Type 2 diabetes mellitus, blood cholesterol, triglyceride and colorectal cancer risk in Lynch syndrome
Authors: Dashti S. Ghazaleh , Li Wing Yan , Buchanan Daniel D. , Clendenning Mark , Rosty Christophe , Winship Ingrid M. , Macrae Finlay A. , Giles Graham G. , Hardikar Sheetal , Hua Xinwei , Thibodeau Stephen N. , Figueiredo Jane C. , Casey Graham , Haile Robert W. , Gallinger Steven , Le Marchand Loïc , Newcomb Polly A. , Potter John D. , Lindor Noralane M. , Hopper John L. , Jenkins Mark A. , Win Aung Ko
Published: September 2019

Background

Type 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population. These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer.

Methods

This study included 2023 (56.4% female) carriers with a mismatch repair gene mutation (737 in MLH1, 928 in MSH2, 230 in MSH6, 106 in PMS2, 22 in EPCAM) recruited by the Colon Cancer Family Registry between 1998 and 2012. Weighted Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between self-reported type 2 diabetes, high cholesterol, triglyceride and colorectal cancer risk.

Results

 Overall, 802 carriers were diagnosed with colorectal cancer at a median age of 42 years. A higher risk of colorectal cancer was observed in those with self-reported type-2 diabetes (HR 1.92; 95% CI, 1.03–3.58) and high cholesterol (HR 1.76; CI 1.23–2.52) compared with those without these conditions. There was no evidence of high triglyceride being associated with colorectal cancer risk.

Conclusion

For people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk.
Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells
Authors: Maugeri Marco , Nawaz Muhammad , Papadimitriou Alexandros , Angerfors Annelie , Camponeschi Alessandro , Na Manli , Hölttä Mikko , Skantze Pia , Johansson Svante , Sundqvist Martina , Lindquist Johnny , Kjellman Tomas , Mårtensson Inga-Lill , Jin Tao , Sunnerhagen Per , Östman Sofia , Lindfors Lennart , Valadi Hadi
Published: September 2019

RNA-based therapeutics hold great promise for treating diseases and lipid nanoparticles (LNPs) represent the most advanced platform for RNA delivery. However, the fate of the LNP-mRNA after endosome-engulfing and escape from the autophagy-lysosomal pathway remains unclear. To investigate this, mRNA (encoding human erythropoietin) was delivered to cells using LNPs, which shows, for the first time, a link between LNP-mRNA endocytosis and its packaging into extracellular vesicles (endo-EVs: secreted after the endocytosis of LNP-mRNA). Endosomal escape of LNP-mRNA is dependent on the molar ratio between ionizable lipids and mRNA nucleotides. Our results show that fractions of ionizable lipids and mRNA (1:1 molar ratio of hEPO mRNA nucleotides:ionizable lipids) of endocytosed LNPs were detected in endo-EVs. Importantly, these EVs can protect the exogenous mRNA during in vivo delivery to produce human protein in mice, detected in plasma and organs. Compared to LNPs, endo-EVs cause lower expression of inflammatory cytokines.
The how’s and what’s of vaccine reactogenicity
Authors: Hervé Caroline , Laupèze Béatrice , Del Giudice Giuseppe , Didierlaurent Arnaud M. , Tavares Da Silva Fernanda
Published: September 2019

Reactogenicity represents the physical manifestation of the inflammatory response to vaccination, and can include injection-site pain, redness, swelling or induration at the injection site, as well as systemic symptoms, such as fever, myalgia, or headache. The experience of symptoms following vaccination can lead to needle fear, long-term negative attitudes and non-compliant behaviours, which undermine the public health impact of vaccination. This review presents current knowledge on the potential causes of reactogenicity, and how host characteristics, vaccine administration and composition factors can influence the development and perception of reactogenicity. The intent is to provide an overview of reactogenicity after vaccination to help the vaccine community, including healthcare professionals, in maintaining confidence in vaccines by promoting vaccination, setting expectations for vaccinees about what might occur after vaccination and reducing anxiety by managing the vaccination setting.
Label-free detection of transporter activity via GPCR signalling in living cells: A case for SLC29A1, the equilibrative nucleoside transporter 1
Authors: Vlachodimou Anna , IJzerman Adriaan P. , Heitman Laura H.
Published: September 2019

Transporters are important therapeutic but yet understudied targets due to lack of available assays. Here we describe a novel label-free, whole-cell method for the functional assessment of Solute Carrier (SLC) inhibitors. As many SLC substrates are also ligands for G protein-coupled receptors (GPCRs), transporter inhibition may affect GPCR signalling due to a change in extracellular concentration of the substrate/ligand, which can be monitored by an impedance-based label-free assay. For this study, a prototypical SLC/GPCR pair was selected, i.e. the equilibrative nucleoside transporter-1 (SLC29A1/ENT1) and an adenosine receptor (AR), for which adenosine is the substrate/ligand. ENT1 inhibition with three reference compounds was monitored sensitively via AR activation on human osteosarcoma cells. Firstly, the inhibitor addition resulted in an increased apparent potency of adenosine. Secondly, all inhibitors concentration-dependently increased the extracellular adenosine concentration, resulting in an indirect quantitative assessment of their potencies. Additionally, AR activation was abolished by AR antagonists, confirming that the monitored impedance was AR-mediated. In summary, we developed a novel assay as an in vitro model system that reliably assessed the potency of SLC29A1 inhibitors via AR signalling. As such, the method may be applied broadly as it has the potential to study a multitude of SLCs via concomitant GPCR signalling.
Species-energy relationships of indigenous and invasive species may arise in different ways – a demonstration using springtails
Authors: Treasure Anne M. , le Roux Peter C. , Mashau Mashudu H. , Chown Steven L.
Published: September 2019

Although the relationship between species richness and available energy is well established for a range of spatial scales, exploration of the plausible underlying explanations for this relationship is less common. Speciation, extinction, dispersal and environmental filters all play a role. Here we make use of replicated elevational transects and the insights offered by comparing indigenous and invasive species to test four proximal mechanisms that have been offered to explain relationships between energy availability, abundance and species richness: the sampling mechanism (a null expectation), and the more individuals, dynamic equilibrium and range limitation mechanisms. We also briefly consider the time for speciation mechanism. We do so for springtails on sub-Antarctic Marion Island. Relationships between energy availability and species richness are stronger for invasive than indigenous species, with geometric constraints and area variation playing minor roles. We reject the sampling and more individuals mechanisms, but show that dynamic equilibrium and range limitation are plausible mechanisms underlying these gradients, especially for invasive species. Time for speciation cannot be ruled out as contributing to richness variation in the indigenous species. Differences between the indigenous and invasive species highlight the ways in which deconstruction of richness gradients may usefully inform investigations of the mechanisms underlying them. They also point to the importance of population size-related mechanisms in accounting for such variation. In the context of the sub-Antarctic our findings suggest that warming climates may favour invasive over indigenous species in the context of changes to elevational distributions, a situation found for vascular plants, and predicted for springtails on the basis of smaller-scale manipulative field experiments.
Activation volume in superpressed glass-formers
Authors: Drozd-Rzoska Aleksandra
Published: September 2019

In pressurized glass-forming systems, the apparent (changeable) activation volume Va(P) is the key property governing the previtreous behavior of the structural relaxation time (τ) or viscosity (η), following the Super-Barus behavior: $${\boldsymbol{\tau }}{\boldsymbol{(}}{\boldsymbol{P}}{\boldsymbol{)}}{\boldsymbol{,}}{\boldsymbol{\eta }}{\boldsymbol{(}}{\boldsymbol{P}}{\boldsymbol{)}}{\boldsymbol{\propto }}{\bf{\exp }}{\boldsymbol{(}}{{\boldsymbol{V}}}_{{\boldsymbol{a}}}{\boldsymbol{(}}{\boldsymbol{P}}{\boldsymbol{)}}{\boldsymbol{/}}{\boldsymbol{R}}{\boldsymbol{T}}{\boldsymbol{)}}$$
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. This report shows that Va(P) ≪ V#(P) for P → Pg, where Pg denotes the glass pressure, and the magnitude V#(P) is coupled to the pressure steepness index (the apparent fragility). V#(P) and Va(P) coincides only for the basic Barus dynamics, where Va(P) = Va = const in the given pressure domain, or for P → 0. The simple and non-biased way of determining Va(P) and the relation for its parameterization are proposed. The derived relation resembles Murnaghan - O’Connel equation, applied in deep Earth studies. It also offers a possibility of estimating the pressure and volume at the absolute stability limit. The application of the methodology is shown for diisobutyl phthalate (DIIP, low-molecular-weight liquid), isooctyloxycyanobiphenyl (8*OCB, liquid crystal) and bisphenol A/epichlorohydrin (EPON 828, epoxy resin), respectively.
Human primary endothelial cells are impaired in nucleotide excision repair and sensitive to benzo[a]pyrene compared with smooth muscle cells and pericytes
Authors: Kress Joana M. , Dio Lorella Di , Heck Larissa , Pulliero Alessandra , Izzotti Alberto , Laarmann Kathrin , Fritz Gerhard , Kaina Bernd
Published: September 2019

The endothelium represents the inner cell layer of blood vessels and is supported by smooth muscle cells and pericytes, which form the vessel structure. The endothelium is involved in the pathogenesis of many diseases, including the development of atherosclerosis. Due to direct blood contact, the blood vessel endothelium is inevitably exposed to genotoxic substances that are systemically taken up by the body, including benzo[a]pyrene, which is a major genotoxic component in cigarette smoke and a common environmental mutagen and human carcinogen. Here, we evaluated the impact of benzo[a]pyrene diol epoxide (BPDE), which is the reactive metabolite of benzo[a]pyrene, on the three innermost vessel cell types. Primary human endothelial cells (HUVEC), primary human smooth muscle cells (HUASMC) and primary human pericytes (HPC) were treated with BPDE, and analyses of cytotoxicity, cellular senescence and genotoxic effects were then performed. The results showed that HUVEC were more sensitive to the cytotoxic activity of BPDE than HUASMC and HPC. We further show that HUVEC display a detraction in the repair of BPDE-induced adducts, as determined through the comet assay and the quantification of BPDE adducts in post-labelling experiments. A screening for DNA repair factors revealed that the nucleotide excision repair (NER) proteins ERCC1, XPF and ligase I were expressed at lower levels in HUVEC compared with HUASMC and HPC, which corresponds with the impaired NER-mediated removal of BPDE adducts from DNA. Taken together, the data revealed that HUVEC exhibit an unexpected DNA repair-impaired phenotype, which has implications on the response of the endothelium to genotoxicants that induce bulky DNA lesions, including the development of vascular diseases resulting from smoking and environmental pollution.
Semen miRNAs Contained in Exosomes as Non-Invasive Biomarkers for Prostate Cancer Diagnosis
Authors: Barceló Maria , Castells Manel , Bassas Lluís , Vigués Francesc , Larriba Sara
Published: September 2019

Although it is specific for prostatic tissue, serum prostate-specific antigen (PSA) screening has resulted in an over-diagnosis of prostate cancer (PCa) and many unnecessary biopsies of benign disease due to a well-documented low cancer specificity, thus improvement is required. We profiled the expression level of miRNAs contained in semen exosomes from men with moderately increased PSA levels to assess their usefulness, either alone or in addition to PSA marker, as non-invasive biomarkers, for the early efficient diagnosis and prognosis of PCa. An altered miRNA expression pattern was found by a high throughput profiling analysis in PCa when compared with healthy individuals (HCt) exosomal semen samples. The presence of vasectomy was taken into account for the interpretation of results. Fourteen miRNAs were selected for miRNA validation as PCa biomarkers in a subsequent set of semen samples. In this explorative study, we describe miRNA-based models, which included miRNA expression values together with PSA levels, that increased the classification function of the PSA screening test with diagnostic and/or prognostic potential: [PSA + miR-142-3p + miR-142-5p + miR-223-3p] model (AUC:0,821) to discriminate PCa from BPH (Sn:91,7% Sp:42,9% vs Sn:100% Sp:14,3%); and [PSA + miR-342-3p + miR-374b-5p] model (AUC: 0,891) to discriminate between GS ≥ 7 tumours and men presenting PSA ≥ 4 ng/ml with no cancer or GS6 tumours (Sn:81,8% Sp:95% vs Sn:54,5% Sp:90%). The pathway analysis of predicted miRNA target genes supports a role for these miRNAs in PCa aetiology and/or progression. Our study shows semen exosome miRNA-based models as molecular biomarkers with the potential to improve PCa diagnosis/prognosis efficiency. As the next step, further prospective studies on larger cohorts of patients are required to validate the diagnostic and/or prognostic role of the miRNA panel before it could be adopted into clinical practice.
Estimation of PM2.5 Concentrations in China Using a Spatial Back Propagation Neural Network
Authors: Wang Weilin , Zhao Suli , Jiao Limin , Taylor Michael , Zhang Boen , Xu Gang , Hou Haobo
Published: September 2019

Methods for estimating the spatial distribution of PM2.5 concentrations have been developed but have not yet been able to effectively include spatial correlation. We report on the development of a spatial back-propagation neural network (S-BPNN) model designed specifically to make such correlations implicit by incorporating a spatial lag variable (SLV) as a virtual input variable. The S-BPNN fits the nonlinear relationship between ground-based air quality monitoring station measurements of PM2.5, satellite observations of aerosol optical depth, meteorological synoptic conditions data and emissions data that include auxiliary geographical parameters such as land use, normalized difference vegetation index, elevation, and population density. We trained and validated the S-BPNN for both yearly and seasonal mean PM2.5 concentrations. In addition, principal components analysis was employed to reduce the dimensionality of the data and a grid of neural network models was run to optimize the model design. The S-BPNN was cross-validated against an analogous but SLV-free BPNN model using the coefficient of determination (R2) and root mean squared error (RMSE) as statistical measures of goodness of fit. The inclusion of the SLV led to demonstrably superior performance of the S-BPNN over the BPNN with R2 values increasing from 0.80 to 0.89 and with the RMSE decreasing from 8.1 to 5.8 μg/m3. The yearly mean PM2.5 concentration in China during the study period was found to be 41.8 μg/m3 and the model estimated spatial distribution was found to exceed Level 2 of the China Ambient Air Quality Standards (CAAQS) enacted in 2012 (>35 μg/m3) in more than 70% of the Chinese territory. The inclusion of spatial correlation upgrades the performance of conventional BPNN models and provides a more accurate estimation of PM2.5 concentrations for air quality monitoring.
Inhibition of casein kinase 1δ/εimproves cognitive-affective behavior and reduces amyloid load in the APP-PS1 mouse model of Alzheimer’s disease
Authors: Sundaram S. , Nagaraj S. , Mahoney H. , Portugues A. , Li W. , Millsaps K. , Faulkner J. , Yunus A. , Burns C. , Bloom C. , Said M. , Pinto L. , Azam S. , Flores M. , Henriksen A. , Gamsby J. , Gulick D.
Published: September 2019

Circadian rhythm disruption is one of the earliest biomarkers of Alzheimer’s disease (AD), and there exists a bidirectional relationship by which dysfunctions in the circadian clock drive AD pathology and AD pathology drives circadian dysfunction. Casein kinase 1 (CK1) isoforms ε and δ, key circadian regulators, are significantly upregulated in AD and may contribute to AD pathogenesis. In the current studies, we have examined how inhibition of CK1ε/δ with PF-670462 (at 10 mg/kg, δ isoform selective, or 30 mg/kg, δ and ε selective) impacts regional Aβ and circadian gene expression in 10–13 month old APP-PS1 mice and nontransgenic controls. We have also assessed circadian, cognitive, and affective behavioral correlates of these neural changes. At baseline, APP-PS1 mice showed a short period, as well as impaired cognitive performance in both prefrontal cortex and hippocampus-dependent tasks. Both doses of PF-670462 lengthened the period and improved affect, whereas only the higher dose improved cognition. Further, PF-670462 treatment produced a dose-dependent reduction in amyloid burden – overall Aβ signal decreased in all three areas; in the prefrontal cortex and hippocampus, PF-670462 also reduced plaque size. Together, these findings support chronotherapy as a potential tool to improve behavior in AD.
5-Dodecanolide interferes with biofilm formation and reduces the virulence of Methicillin-resistant Staphylococcus aureus (MRSA) through up regulation of agr system
Authors: Valliammai Alaguvel , Sethupathy Sivasamy , Priya Arumugam , Selvaraj Anthonymuthu , Bhaskar James Prabhanand , Krishnan Venkateswaran , Pandian Shunmugiah Karutha
Published: September 2019

Methicillin resistant Staphylococcus aureus (MRSA) is a predominant human pathogen with high morbidity that is listed in the WHO high priority pathogen list. Being a primary cause of persistent human infections, biofilm forming ability of S. aureus plays a pivotal role in the development of antibiotic resistance. Hence, targeting biofilm is an alternative strategy to fight bacterial infections. The present study for the first time demonstrates the non-antibacterial biofilm inhibitory efficacy of 5-Dodecanolide (DD) against ATCC strain and clinical isolates of S. aureus. In addition, DD is able to inhibit adherence of MRSA on human plasma coated Titanium surface. Further, treatment with DD significantly reduced the eDNA synthesis, autoaggregation, staphyloxanthin biosynthesis and ring biofilm formation. Reduction in staphyloxanthin in turn increased the susceptibility of MRSA to healthy human blood and H2O2 exposure. Quantitative PCR analysis revealed the induced expression of agrA and agrC upon DD treatment. This resulted down regulation of genes involved in biofilm formation such as fnbA and fnbB and up regulation of RNAIII, hld, psmα and genes involved in biofilm matrix degradation such as aur and nuc. Inefficacy of DD on the biofilm formation of agr mutant further validated the agr mediated antibiofilm potential of DD. Notably, DD was efficient in reducing the in vivo colonization of MRSA in Caenorhabditis elegans. Results of gene expression studies and physiological assays unveiled the agr mediated antibiofilm efficacy of DD.