bluuebunny/crossref_metadata_2025 huggingface dataset:
Proliferation of adult human bronchial epithelial cells without a telomere maintenance mechanism for over 200 population doublings
Authors: Peters‐Hall Jennifer R. , Min Jaewon , Tedone Enzo , Sho Sei , Siteni Silvia , Mender Ilgen , Shay Jerry W.
Published: November 2019

To date, there is no direct evidence of telomerase activity in adult lung epithelial cells, but typical culture conditions only support cell proliferation for 30‐40 population doublings (PD), a point at which telomeres remain relatively long. Here we report that in in vitro low stress culture conditions consisting of a fibroblast feeder layer, rho‐associated coiled coil protein kinase inhibitor (ROCKi), and low oxygen (2%), normal human bronchial epithelial basal progenitor cells (HBECs) divide for over 200 PD without engaging a telomere maintenance mechanism (almost four times the “Hayflick limit”). HBECs exhibit critically short telomeres at 200 PD and the population of cells start to undergo replicative senescence. Subcloning these late passage cells to clonal density, to mimic lung injury in vivo, selects for rare subsets of HBECs that activate low levels of telomerase activity to maintain short telomeres. CRISPR/Cas9 knockout of human telomerase reverse transcriptase or treatment with the telomerase‐mediated telomere targeting agent 6‐thio‐2′deoxyguanosine abrogates colony growth in these late passage cultures (>200 PD) but not in early passage cultures (<200 PD). To our knowledge, this is the first study to report such long‐term growth of HBECs without a telomere maintenance mechanism. This report also provides direct evidence of telomerase activation in HBECs near senescence when telomeres are critically short. This novel cell culture system provides an experimental model to understand how telomerase is regulated in normal adult tissues.
Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting
Authors: Viola Domenico , Dona Ada , Caserta Enrico , Troadec Estelle , Gunes Emine Gulsen , Besi Francesca , McDonald Tinisha , Ghoda Lucy , Sanchez James F , Khalife Jihane , Martella Marianna , Karanes Chatchada , Htut Myo , Wang Xiuli , Rosenzweig Michael , Chowdhury Arnab , Sborov Douglas , Miles Rodney R , Yazaki Paul J. , Forman Stephen J , Shively John , Marcucci Guido , Rosen Steven T , Keats Jonathan J , Krishnan Amrita , Pichiorri Flavia
Published: November 2019

Daratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex-vivo and in vivo. In support of Dara’s immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.
The Statistical Foundation of Colour Space
Authors: Wilkins Lucas
Published: November 2019

The idea of a colour space where distance corresponds to discriminability has been fundamental to colour vision research since the 19th century. Despite their long-standing success there is a contradiction between the geometric framework that is typically used in these spaces (a particular application of Riemannian geometry) and a view of the transduction of sensory information as the result of a stochastic process. When this is made explicit, a subtly different approach is suggested which turns out to provide a general, and more complete framework for colour space. It is argued further that not only is a contradiction avoided, but that this framework is both intuitive and of real practical value, in particular for researchers interested in the visual behaviour and ecology of animals.
Chain caesium borophosphates with B:P ratio 1:2: synthesis, structure relationships and low-temperature thermodynamic properties
Authors: Shvanskaya Larisa , Yakubovich Olga , Krikunova Polina , Ovchenkov Evgeny , Vasiliev Alexander
Published: November 2019

Three caesium-bearing borophosphates, Cs[BP2O6(OH)2] (I), Cs0.51Mn1.17(H2O)2[BP2O8]·0.45H2O (II) and CsMn[BP2O8(OH)] (III), were synthesized by a hydrothermal method at 473–523 K. Their crystal structures have been studied by means of single-crystal X-ray diffraction; all three structures comprise borophosphate chain anions with a B:P ratio of 1:2. The unique construction of (I) is based on four-membered-ring chains running parallel to the [010] direction. These protonated borophosphate chains are linked via hydrogen-bond interactions to form a 3D framework with caesium cations incorporated. (II) is the first Cs and Mn2+,Mn3+member of a known family characterized by [BP2O8]∞helical chains running along [001]. These chains are connected through MnO4(H2O)2octahedra to form a 3D framework. The caesium cations are disordered over two independent positions in the channels, which they occupy together with water molecules. An additional MnO2(H2O)3bipyramid statistically shares a common edge and two corners with three main Mn octahedra to form tetrameric clusters. The topological relation between the chain anionic fragments of (I) and (II) as well as the structural relation between (I) and previously studied boro- and berillophosphates are discussed. Compound (III) presents the first Mn member of theAIMIII[BP2O8(OH)] family and is characterized by a 3D framework built by open-branched borophosphate chains and MnO5semi-octahedra sharing vertices. The measurements of thermodynamic properties,i.e.magnetizationMand specific heatCp, to 2 K and 30 T, provide evidence that (II) orders antiferromagnetically at the Néel temperatureTN= 4.6 K and exhibits a plateau-like feature under the action of an external magnetic field accompanied by a pronounced magnetocaloric effect.
Structure and mechanism of piperideine-6-carboxylate dehydrogenase fromStreptomyces clavuligerus
Authors: Hasse Dirk , Hülsemann Janne , Carlsson Gunilla H. , Valegård Karin , Andersson Inger
Published: November 2019

The core of β-lactam antibiotics originates from amino acids of primary metabolism in certain microorganisms. β-Lactam-producing bacteria, includingStreptomyces clavuligerus, synthesize the precursor of the amino acid α-aminoadipic acid by the catabolism of lysine in two steps. The second reaction, the oxidation of piperideine-6-carboxylate (or its open-chain form α-aminoadipate semialdehyde) to α-aminoadipic acid, is catalysed by the NAD+-dependent enzyme piperideine-6-carboxylate dehydrogenase (P6CDH). This structural study, focused on ligand binding and catalysis, presents structures of P6CDH fromS. clavuligerusin its apo form and in complexes with the cofactor NAD+, the product α-aminoadipic acid and a substrate analogue, picolinic acid. P6CDH adopts the common aldehyde dehydrogenase fold, consisting of NAD-binding, catalytic and oligomerization domains. The product binds in the oxyanion hole, close to the catalytic residue Cys299. Clear density is observed for the entire cofactor, including the nicotinamide riboside, in the binary complex. NAD+binds in an extended conformation with its nicotinamide ring overlapping with the binding site of the carboxylate group of the product, implying that the conformation of the cofactor may change during catalysis. The binding site of the substrate analogue overlaps with that of the product, suggesting that the cyclic form of the substrate, piperideine-6-carboxylate, may be accepted as a substrate by the enzyme. The catalytic mechanism and the roles of individual residues are discussed in light of these results.
Foresight for stock market volatility – a study in the Indian perspective
Authors: Dixit Jitendra Kumar , Agrawal Vivek
Published: November 2019

Purpose

Volatility is a permanent behavior of the stock market around the globe. The presence of the volatility in the stock price makes it possible to earn abnormal profits by risk seeking investors and creates hesitancy among risk averse investors as high volatility means high return with high risk. Investors always consider market volatility before making any investment decisions. Random fluctuations are termed as volatility of stock market. Volatility in financial markets is reflected because of uncertainty in the price and return, unexpected events and non-constant variance that can be measured through the generalized autoregressive conditional heteroscedasticity family models and that will give an insight for investment decision-making.

Design/methodology/approach

Daily data of the closing value of Bombay Stock Exchange (BSE) (Sensex) and National Stock Exchange (NSE) (Nifty) from April 1, 2011 to March 31, 2017 is collected through the web-portal of BSE (www.bseindia.com) and NSE (www.nseindia.com) for the analysis purpose.

Findings

The outcome of the study suggested that P-GARCH model is most suitable to predict and forecast the stock market volatility for both the markets.

Research limitations/implications

Future research can be extended to other stock market segments and sectoral indices to explore and forecast the volatility to establish a trade-off between risk and return.

Originality/value

The results of previous studies available are not conducive to this research, and very limited scholarly work is available in the Indian context, so required to be re-explored to identify the appropriate model to predict market volatility.
The promise and limit of freedom: South Africa and the pursuit of racial justice
Authors: Ngqulunga Bongani
Published: November 2019

Purpose

The purpose of this paper is to discuss South Africa’s trajectory of socio-economic development since the advent of democracy a quarter century ago. This is done through a critical discussion and review of major policy interventions that have been implemented to achieve the goal of racial justice. The author argues that while the advent of democracy brought about significant opportunities for social justice, socio-economic development in South Africa has been characterised by increasing wealth and income inequality, which has undermined the cause of racial justice. The key argument the author advances in the paper is that the decline in the power resources of the working class and the poor accounts for the neoliberal turn in economic policy in South Africa.

Design/methodology/approach

The paper relies on primary policy documents of the government and on primary political and policy documents of the African National Congress and its political allies such as the Congress of South African Trade Unions and the South African Communist Party. The author also reviews the extensive literature on the subject of development policymaking in the new South Africa.

Findings

The main finding is that the advent of democracy a quarter century ago and the policy interventions by the government have brought about social progress in some areas. However, the colonial and apartheid domination still shapes access to social-economic opportunities in South Africa. In anything, income and wealth inequality has increased since 1994. The goal of racial justice appears far from being achieved.

Research limitations/implications

The key implication arising from the research is that strengthening political organisations of the working class and the poor is critical to attaining the goal of social equity. This is particularly true in a context where elite interests in the state and the corporate sector have been ascendant for the past two decades.

Originality/value

What is original about the paper is that it is one of the first papers that assess the progress that has made in bringing about racial justice 25 years after the advent of democracy in South Africa. Furthermore, the paper uses the power resources theory to explain the dearth of pro-poor social reform in South Africa. This is a departure from the dominant approach, which explains the adoption of neoliberalism in South Africa as either inevitable due to poor economic performance or an outcome of the sell-out by the ANC political elite.
Tax compliance behaviour of small business enterprises in Uganda
Authors: Kiconco Rebecca Isabella , Gwokyalya Waliya , Sserwanga Arthur , Balunywa Waswa
Published: November 2019

Purpose

This study aims to investigate the extent to which the theory of reasoned action (TRA) can be used to explain tax compliance among small business enterprises (SBEs) in Uganda and extends the application and relevance of the theory to a new area of tax compliance. It contributes the TRA, as a predictor of tax compliance in a developing country context.

Design/methodology/approach

A cross-sectional survey targeting different categories of SBEs was carried out using interviewer-administered questionnaires. A sample of 384 SBEs was used in the study.

Findings

The TRA contributes critical insights on the tax compliance behaviour of small businesses in developing economies. It influences tax compliance behaviour. The study illustrates evidence about the negative attitudes SBEs have on intentions to comply with tax regulations and the extent to which these attitudes influence their compliance behaviour. Subjective norms positively influence tax compliance intentions in a positive manner. Overall, the appearance of these intentions shows a negative effect on tax compliance behaviour. These findings also imply that Uganda Revenue Authority needs to understand the social psychology of taxpayers and tailor these in their policies and efforts to increase compliance.

Research limitations/implications

The TRA has been used to explain behaviour in numerous situations in psychology. The study used this theory in a new geographical, economic and administrative environment; Uganda. This theory has proved relevant in explaining psychological, sociological and economic behaviour; specifically tax compliance. The TRA was revised to include a new construct of perceived behavioural control, which turned into the theory of planned behaviour. This could not be studied due to time and logistic constraints. Therefore, there is a need to investigate if this revised theory can explain tax compliance behaviour better.

Practical implications

The paper suggests that tax administration efforts and policies should consider the social-psychology aspects of the taxpayers to improve tax compliance.

Originality/value

This study adds a new arena of explaining tax compliance from a theory commonly used in psychology to a new setting in finance.
Methods of bribery in multinational corporations
Authors: Teichmann Fabian Maximilian Johannes
Published: November 2019

Purpose

This paper aims to investigate how bribery is conducted in multinational corporations. In particular, sources of funding and methods of transferring bribes are investigated.

Design/methodology/approach

In all, 100 interviews were conducted with criminals and white-collar crime prevention experts, and responses were subjected to qualitative content analysis.

Findings

The interviews and survey revealed concrete techniques for creating funds for bribery and transferring bribes to counterparties. The results indicate that the compliance mechanisms aimed at preventing bribery in multinational corporations can be easily circumvented.

Research limitations/implications

This study’s findings were limited to the perspectives of 100 interviewees. Hence, it is possible that a study with a larger sample conducted in different countries or at a different time could have yielded different results.

Practical implications

Identifying the concrete methods of funding and transferring bribes should provide both compliance officers and legislators with valuable insights into criminal activity. By better understanding the specific steps taken by criminals, compliance officers should be able to more effectively combat bribery.

Originality/value

Whereas the prior literature has focused on the organizations and mechanisms involved in combating bribery, this paper instead explores how criminals avoid detection by taking into account existing compliance mechanisms and criminal perspectives.
Sources of criminal law in the area of responsibility for economic crimes in Russia and Italy
Authors: Rusanov Georgy
Published: November 2019

Purpose

The purpose of this study is to investigate the sources of criminal law in the area of responsibility for economic crimes in Russia and Italy.

Design/methodology/approach

This study is based on the study of five types of sources of criminal law: criminal legislation, legislation of other branches of law in the sphere of regulation of economic relations, legislation of other branches of law in the sphere of protection of economic relations, judicial practice and customs.

Findings

Based on the study of Russian and Italian legislation were revealed: in general, that systems of sources of criminal law in Italy and Russia are similar and based on the legislation.

Originality/value

This is explained by the fact that both countries are close to the Roman-Germanic legal system. It is also an important legislation of other branches of law. It consists of regulatory and protective norms of other branches of law. Court decisions, including decisions of the Constitutional Court and some legal positions of other vessels, are also considered as sources of criminal law.
Japan’s Yakuza – still alive, and yes, they do matter
Authors: Newsham Grant Frederick
Published: November 2019

Purpose

This paper aims to inform the reader of the nature of Japanese organize crime (“the Yakuza”) and the extent to which it has penetrated and is a powerful force in nearly all facets of Japanese society – with particular focus on the “legitimate” business and financial worlds. The paper also describes in detail the actual harmful effects of Yakuza influence and also provides a cautionary note for foreign business ventures in Japan.

Design/methodology/approach

The paper offers an in-depth narrative description based on the author’s over 20 years’ experience researching the topic along with practical experience gained while working in the business risk mitigation field in Japan and assisting private entities in avoiding underworld entanglements.

Findings

The paper demonstrates how the Yakuza remains a potent force with widespread influence in Japan, despite the government’s enactment of specific regulations designed to pressure underworld organizations.

Research limitations/implications

The paper offers insights into an aspect of Japanese society that receives limited examination, and the information contained in the article is potentially useful to other scholars and the foreign business community as well. The Yakuza are a broad topic, and the author’s perspectives are necessarily focused on cases of Yakuza involvement in the legitimate economy and political world rather than the entire panoply of underworld activity.

Practical implications

The insights and descriptions of underworld involvement in “legitimate” parts of Japanese society might encourage Japanese authorities to assess why the Yakuza remain entrenched and take appropriate counter measures.

Social implications

The paper is potentially of use to foreign business and governmental organizations in better understanding and countering risks and threats posed by the Japanese underworld, both in Japan and beyond its borders.

Originality/value

This topic is infrequently covered in any depth in English language sources and seldom if ever by someone with over two decades of practical experience identifying and helping private entities navigate around Yakuza dangers.
Consumer perception of tourist experience through online reviews
Authors: Oliveira Cristina , Brochado Ana , Moro Sérgio , Rita Paulo
Published: November 2019

Purpose

Overall, there is a lack of research using online reviews as a proxy of customer experience when addressing the study of tourism in island destinations.

Design/methodology/approach

The current investigation aims to fill this gap by focussing on an African small island developing states, i.e. Cape Verde. This paper reports of tourist reviews extracted from TripAdvisor from “two islands of the senses” as coined by this archipelago’s national tourism organization, specifically Santo Antão and Fogo islands. The data analysis was performed through Leximancer software to generate concepts out of words, followed by themes.

Findings

The present research focussed on experiences in island tourism to identify their main dimensions based on visitors’ narratives in online reviews. The obtained results are of potential value to the literature by contributing to a better understanding of tourist experience in the context of tourism in islands in an understudied country, Cape Verde.

Originality/value

Results are presented and object of discussion vis-à-vis scientific literature and conclusions put forward in this journal paper.
Genome analysis of sponge symbiont ‘Candidatus Halichondribacter symbioticus’ shows genomic adaptation to a host‐dependent lifestyle
Authors: Knobloch Stephen , Jóhannsson Ragnar , Marteinsson Viggó Þór
Published: November 2019

The marine sponge Halichondria panicea inhabits coastal areas around the globe and is a widely studied sponge species in terms of its biology, yet the ecological functions of its dominant bacterial symbiont ‘Candidatus Halichondribacter symbioticus’ remain unknown. Here, we present the draft genome of ‘Ca. H. symbioticus’ HS1 (2.8 Mbp, ca. 87.6% genome coverage) recovered from the sponge metagenome of H. panicea in order to study functions and symbiotic interactions at the genome level. Functional genome comparison of HS1 against closely related free‐living seawater bacteria revealed a reduction of genes associated with carbohydrate transport and transcription regulation, pointing towards a limited carbohydrate metabolism, and static transcriptional dynamics reminiscent of other bacterial symbionts. In addition, HS1 was enriched in sponge symbiont specific gene families related to host–symbiont interactions and defence. Similarity in the functional gene repertoire between HS1 and a phylogenetically more distant symbiont in the marine sponge Aplysina aerophoba, based on COG category distribution, suggest a convergent evolution of symbiont specific traits and general metabolic features. This warrants further investigation into convergent genomic evolution of symbionts across different sponge species and habitats.
Managing ethical uncertainty: implicit normativity and the sociology of ethics
Authors: Cribb Alan
Published: November 2019

This article illustrates and discusses the idea of ‘implicit normativity’, and specifically its relevance to the management of ethical uncertainty. In particular I consider (i) the role implicit normativity plays in masking and containing potential ethical uncertainty and (ii) the contrast and boundary between implicit normativity and ‘overt ethics’ where ethical contestation – as well as particular processes and agents – are highlighted as salient. Using examples I show how the idea of implicit normativity can be applied not only to specific practices but also to whole fields of practice. The notion of ‘moral settlements’ – along with the explanatory role of the threat of ‘chaos’ – is introduced and elucidated to develop these points. I argue that attention to the management of ethical uncertainty shows the critically important contribution that an ambitious sociology of ethics can make to clinical ethics, including by helping to formulate and drive home questions about the ‘ethics of ethics’. The account presented here has resonances with work that seeks to use sociological lenses to move beyond conventional bioethics, including Petersen's (2013) call for a ‘normative sociology’.
Relation Between Gut Microbiota Composition and Traditional Spontaneous Fermented Dairy Foods Among Kazakh Nomads in Xinjiang, China
Authors: Li Ruiyao , Zheng Xiaowei , Yang Jie , Shen Xuemei , Jiao Lin , Yan Zheng , Chen Bo , Han Beizhong
Published: November 2019

The human gastrointestinal tract represents one of the most densely populated microbial ecosystems studied to date. Although this microbial consortium has been recognized to have a crucial impact on human health, its precise composition is still subject to intense investigation, as people from different regions have different gut microbiota structures. The Kazakh nomads in Xinjiang, China still retain their nomadic lifestyle and traditional diet. Their specific diet style and ancient genetic background shaped their gut microbiota to contain unique characteristics. In present study, the compositions of the gut microbiota and fermented dairy foods were assessed by high‐throughput sequencing of the 16S rRNA gene. Twenty‐nine Kazakh nomads were recruited, and 33 traditional fermented dairy foods were collected from five pasturing areas (Buerjin, Zhaosu, Nilka, Tekes, and Fuhai) in northern Xinjiang, China. The correlation of the physical index with the gut microbiota was also analyzed. The unique diet style of Kazakh may be a critical factor in keeping their gut microbiota in a balanced state and help them to remain in good health.

Practical Application

This research shows that the consumption of spontaneous fermented dairy food plays an important role in increasing gut microbial diversity. Some probiotics in fermented dairy food, such as Bifidobacterium and Lactobacillus, have positive correlation with human body health index such as body mass index and blood glucose. These may provide some theoretical supports to adjuvant therapy of obesity and diabetes through scientific dietary intervention.
The role of a transparent cap in the endoscopic removal of foreign bodies in the esophagus: A propensity score‐matched analysis
Authors: Fang Rui , Cao Bin , Zhang Qian , Li Peng , Zhang Shu Tian
Published: November 2019

Objective

To investigate the effectiveness and safety of transparent cap‐assisted endoscopy in removing foreign bodies in the esophagus.

Methods

Patients with foreign body lodged in the esophagus who received a transparent cap‐assisted or conventional endoscopy between October 2004 and July 2018 were retrospectively enrolled. Propensity score matching was performed. The success rate of the endoscopic procedure, procedure time, clearness of endoscopic view and adverse event rate were compared between the two groups.

Results

Of the 838 patients who had a foreign body lodged in the esophagus, 728 (86.9%) underwent endoscopic intervention. After matched by prospensity score, 224 patients each received either transparent cap‐assisted endoscopy or conventional endoscopy. No difference was noted between the two groups in terms of the success rate (100% vs 99.1%, P = 0.499). Transparent cap‐assisted endoscopy was associated with shorter procedure time for removing jujube pits ([4.24 ± 2.81] min vs [7.62 ± 8.15] min, P = 0.001), fish bones ([2.99 ± 2.15] min vs [6.49 ± 6.54] min, P < 0.001) and other sharp objects ([4.29 ± 3.36] min vs [10.60 ± 19.79 min], P = 0.027) and higher rates of clear endoscopic views in extracting jujube pits, fish bones, poultry bones and other sharp objects (98% vs 43.4%, 97.5% vs 74.1%, 100% vs 81.3% and 100% vs 82.7%; all P < 0.05). No significant differences in the rates of adverse event were observed between the groups (P = 1.000).

Conclusion

Transparent cap‐assisted endoscopic technique is effective and safe for removing sharp foreign bodies in the esophagus.
A new temple platform at Tell F6 on Failaka Island, Kuwait
Authors: Højlund Flemming , Hagelquist Christoffer P.
Published: November 2019

In the first half of the second millennium, Tell F6 on Failaka Island was the location of two large public buildings (a temple and a production/storage facility) belonging to the Early Dilmun Culture. During excavation in 2018, an elevation in the north‐eastern margin of the tell proved to contain the remains of a 11.5 × 11.5 m platform. The nature of the building and its position in relation to the main temple indicate that it served as the platform for yet another—now razed—temple. Radiocarbon analysis dates its construction to the early second millennium BC and suggests that it was constructed contemporary with the adjacent main temple. The discovery further substantiates the general impression of a dramatic increase in investments in public buildings in this period of the Early Dilmun Culture.
Parents Allowing Drinking Is Associated With Adolescents’ Heavy Alcohol Use
Authors: Staff Jeremy , Maggs Jennifer L.
Published: November 2019

Background

Using intergenerational prospective data from the Millennium Cohort Study (MCS), we examine whether parents allowing 14‐year‐olds to drink alcohol is associated with greater likelihood of early adolescents’ heavy episodic drinking (i.e., lifetime, rapid escalation from first drink, and frequent past year), beyond shared risk factors for parental alcohol permissiveness and adolescent alcohol use.

Methods

The MCS is a unique, contemporary, nationally representative study with mother, father, and child data from infancy through age 14 years (n = 11,485 children and their parents). In a series of multivariate logistic regressions, we estimated whether teenagers whose parents allowed them to drink alcohol (16% of parents said “yes”) faced an elevated likelihood of heavy alcohol use at age 14, controlling for a large host of likely child and parent confounders measured when children were age 11. To further assess plausible intergenerational associations of parental alcohol permissiveness and offspring heavy alcohol use, coarsened exact matching (CEM) was used to match 14‐year‐olds whose parents allowed them to drink alcohol with teens whose parents did not allow them to drink on these childhood antecedent variables.

Results

Adolescents whose parents allowed them to drink had higher odds of heavy drinking (odds ratio [OR] = 2.40; 95% confidence interval [CI] = 1.96 to 2.94), rapidly escalating from initiation to heavy drinking (OR = 1.94; CI = 1.52 to 2.49), and frequent heavy drinking (OR = 2.32; 1.73 to 3.09), beyond child and parent confounders and using CEM methods.

Conclusions

Adolescents who were allowed to drink were more likely to have transitioned quickly from their first drink to consuming 5 or more drinks at 1 time and to drinking heavily 3 or more times in the past year. Given well‐documented harms of adolescent heavy drinking, these results do not support the idea that parents allowing children to drink alcohol inoculates them against alcohol misuse.
25B‐NBOMe, a novel N‐2‐methoxybenzyl‐phenethylamine (NBOMe) derivative, may induce rewarding and reinforcing effects via a dopaminergic mechanism: Evidence of abuse potential
Authors: Custodio Raly James Perez , Sayson Leandro Val , Botanas Chrislean Jun , Abiero Arvie , You Kyung Yi , Kim Mikyung , Lee Hyun Jun , Yoo Sung Yeun , Lee Kun Won , Lee Yong Sup , Seo Joung‐Wook , Ryu In Soo , Kim Hee Jin , Cheong Jae Hoon
Published: November 2019

An increasing number of N‐2‐methoxybenzyl‐phenethylamine (NBOMe) derivatives are being misused worldwide, including the potent hallucinogen 2‐(4‐bromo‐2,5‐dimethoxyphenyl)‐N‐(2‐methoxybenzyl)ethanamine (25B‐NBOMe). However, the number of studies characterizing the abuse potential and psychopharmacological properties of 25B‐NBOMe is limited; thus, we examined its rewarding and reinforcing effects using conditioned place preference (CPP) and self‐administration (SA) tests. Pretreatment with SCH23390 (SCH), Haloperidol (HAL), and ketanserin (KS), antagonists of dopamine D1 (DRD1), dopamine D2 (DRD2), and serotonin 2A (5‐HT2A receptor) receptors, respectively, was utilized during a CPP test to investigate the involvement of the dopaminergic and serotonergic systems in 25B‐NBOMe‐mediated effects. We also examined the effects of 25B‐NBOMe on the expression of dopamine‐related proteins in the nucleus accumbens (NAcc) and ventral tegmental area (VTA). Then, we measured the dopamine level, phosphorylated CREB (p‐CREB), deltaFosB (ΔFosB), and brain‐derived neurotrophic factor (BDNF) in the NAcc. In addition, we explored the involvement of 5‐HT2A receptors in the 25B‐NBOMe‐induced head twitch response (HTR). We also examined the effects of 25B‐NBOMe on brain wave activity using electroencephalography. 25B‐NBOMe elicited CPP and SA. SCH and HAL blocked 25B‐NBOMe‐induced CPP, whereas KS did not. Moreover, 25B‐NBOMe altered the DRD1, DRD2, and dopamine transporter expression and increased dopamine levels. It also induced changes in p‐CREB, ΔFosB, and BDNF expression. 25B‐NBOMe induced HTR and increased 5‐HT2A receptor mRNA levels, effects inhibited by KS. Furthermore, 25B‐NBOMe altered delta and gamma wave activity, which was normalized by SCH and HAL. These findings show that 25B‐NBOMe may induce rewarding and reinforcing effects via a dopaminergic mechanism, suggesting its abuse potential.
Microbial risk factors for treatment failure of pivmecillinam in community‐acquired urinary tract infections caused by ESBL‐producing Escherichia coli
Authors: Syre Heidi , Hetland Marit Andrea Klokkhammer , Bernhoff Eva , Bollestad Marianne , Grude Nils , Simonsen Gunnar Skov , Löhr Iren Høyland
Published: November 2019

The aim of this study was to identify microbial risk factors for treatment failure of pivmecillinam in community‐acquired urinary tract infections (ca‐UTIs) caused by ESBL‐producing Escherichia coli. Eighty‐nine ESBL‐producing E. coli isolated from women suffering from ca‐UTIs were included. The susceptibilities to mecillinam were determined using MIC gradient strip. Whole genome sequencing was performed on a MiSeq platform, and genome assembly was performed using SPAdes v3.11.0. Neither mecillinam MICs nor ESBL genotypes were associated with treatment outcome of patients treated with pivmecillinam. Specific STs, however, showed significant differences in treatment outcome. Patients infected with ST131 were more likely to experience treatment failure compared to patients infected with non‐ST131 (p 0.02) when adjusted for pivmecillinam dose, mecillinam MIC and severity of infection. Patients infected with ST69 were more often successfully treated compared to patients infected with non‐ST69 (p 0.04). Patients infected with blaCTX‐M‐15 ST131 strains were more likely to experience treatment failure than those infected with non‐blaCTX‐M‐15 ST131 strains (p 0.02). The results suggest that specific STs are associated with the clinical efficacy of pivmecillinam. Further studies with a larger number of strains, including a larger number of mecillinam resistant strains, are needed to confirm these results.
Results of phase 2 trials exploring the safety and efficacy of omiganan in patients with human papillomavirus‐induced genital lesions
Authors: Rijsbergen Melanie , Rijneveld Rianne , Todd Marina , Feiss Gary L. , Kouwenhoven Stijn T.P. , Quint Koen D. , van Alewijk Dirk C.J.G. , de Koning Maurits N.C. , Klaassen Erica S. , Burggraaf Jacobus , Rissmann Robert , van Poelgeest Mariëtte I.E.
Published: November 2019

Aims

To assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high‐grade squamous intraepithelial lesions (HSIL).

Methods

Two randomized controlled trials in patients with external AGW and vulvar HSIL were conducted. Patients received topical omiganan 2.5% or placebo gel once daily for 12 weeks with a follow‐up of 12 weeks. Safety and tolerability were monitored and pharmacodynamics and clinical efficacy of omiganan were assessed by analysing lesion count, size and viral load. Self‐reported pain, itch and quality of life were assessed by an electronic diary and questionnaire.

Results

Twenty‐four AGW and 12 vulvar HSIL patients were enrolled. All patients had a high treatment adherence (99%). No serious adverse events occurred and all adverse events (n = 27) were mild, transient and self‐limiting. The treatment groups were not different in terms of safety and tolerability, lesion count and size, and patient‐reported outcomes pain, itch and quality of life. Human papillomavirus load significantly reduced after 12 weeks of treatment with omiganan compared to placebo (–96.6%; 95% confidence interval –99.9 to –7.4%; P = .045) in AGW patients only.

Conclusion

Topical omiganan appears to be safe in patients with AGW and vulvar HSIL and reduced human papillomavirus load after 12 weeks of treatment in AGW patients.
Modelling pharmacokinetics and pharmacodynamics of the selective S1P1 receptor modulator cenerimod in healthy subjects and systemic lupus erythematosus patients
Authors: Lott Dominik , Juif Pierre‐Eric , Dingemanse Jasper , Krause Andreas
Published: November 2019

Aims

Assessment of time to attain steady state as well as drug accumulation following long‐term treatment with the selective sphingosine‐1‐phosphate 1 receptor modulator cenerimod and prediction of the incidence of low total lymphocyte (LY) counts. Differences in pharmacokinetics and pharmacodynamics based on demographic characteristics and between healthy subjects and systemic lupus erythematosus (SLE) patients were to be identified.

Methods

Data from 4 Phase I studies and 1 Phase II study were pooled to develop a population pharmacokinetic/pharmacodynamic model describing cenerimod concentration and its effect on LY count. Simulations addressed the objectives.

Results

Simulations of 365 days of treatment indicated a time to steady state of 49 days and changes in exposure of 15% beyond 35 days. For a dose of 2 mg, the predicted incidences of LY counts below 0.5 and 0.2 × 109 cells/L were 18.2 and 0.6% for healthy subjects and 25.9 and 1.0% for SLE patients, respectively. Incidence increased with higher dose and lower baseline LY counts. For body weights of 50 and 100 kg compared to 75 kg, exposure was predicted to change by +37% and −20%, respectively.

Conclusion

Long‐term cenerimod administration is not expected to result in exposure and LY count reduction substantially different from results of completed studies. Low LY counts are predicted to occur more frequently in SLE patients compared to healthy subjects. Dose individualization based on the model is not considered necessary. Model‐based simulations enable benefit–risk evaluations, supporting planning of late‐phase clinical studies and scientific exchange with health authorities.
Saying and doing: Social responsibility declared and applied
Authors: Sigurdsson Kjartan , Candi Marina
Published: November 2019

The purpose of this work is to examine the relationships between and among firms' commitment to social responsibility, their declarations—or reporting—on their social responsibility, the application of social responsibility in the form of social innovation, and customer acceptance. A research model drawing on the attributes of stakeholder theory is tested using data collected from 355 firms. The findings indicate that firms with commitments to social responsibility are likely to report on their social responsibility and are also likely to be engaged in social innovation. However, a negative relationship was found between reporting on social responsibility and social innovation. This highlights the importance of differentiating between saying and doing. Finally, social innovation was found to contribute to customer acceptance, while reporting on social responsibility was not. When it comes to social responsibility, it might be fair to say that “talk is cheap”, while social innovation “speaks louder than words”.
Eosinophil cytolysis on Immunoglobulin G is associated with microtubule formation and suppression of rho‐associated protein kinase signalling
Authors: Esnault Stephane , Leet Jonathan P. , Johansson Mats W. , Barretto Karina T. , Fichtinger Paul S. , Fogerty Frances J. , Bernau Ksenija , Mathur Sameer K. , Mosher Deane F. , Sandbo Nathan , Jarjour Nizar N.
Published: November 2019

Background

The presence of eosinophils in the airway is associated with asthma severity and risk of exacerbations. Cell‐free eosinophil granules are found in tissues in eosinophilic diseases, including asthma. This suggests that eosinophils have lysed and released cellular content, likely harming tissues.

Objective

The present study explores the mechanism of CD32‐ and αMß2 integrin‐dependent eosinophil cytolysis of IL3‐primed blood eosinophils seeded on heat‐aggregated immunoglobulin G (HA‐IgG).

Methods

Cytoskeletal events and signalling pathways potentially involved in cytolysis were assessed using inhibitors. The level of activation of the identified events and pathways involved in cytolysis was measured. In addition, the links between these identified pathways and changes in degranulation (exocytosis) and adhesion were analysed.

Results

Cytolysis of IL3‐primed eosinophils was dependent on the production of reactive oxygen species (ROS) and downstream phosphorylation of p‐38 MAPK. In addition, formation of microtubule (MT) arrays was necessary for cytolysis and was accompanied by changes in MT dynamics as measured by phosphorylation status of stathmin and microtubule‐associated protein 4 (MAP4), the latter of which was regulated by ROS production. Reduced ROCK signalling preceded cytolysis, which was associated with eosinophil adhesion and reduced migration.

Conclusion and Clinical Relevance

In this CD32‐ and αMß2 integrin‐dependent adhesion model, lysing eosinophils exhibit reduced migration and ROCK signalling, as well as both MT dynamic changes and p‐38 phosphorylation downstream of ROS production. We propose that interfering with these pathways would modulate eosinophil cytolysis and subsequent eosinophil‐driven tissue damage.
What do we know about the cytological features of pure intraductal carcinomas of the salivary glands?
Authors: Palicelli Andrea
Published: November 2019

Objective

Intraductal carcinomas (IDCs) are rare, poorly characterised salivary gland tumours. The cytological features of IDCs are even less known. In this paper, a systematic literature review of pure IDCs (without stromal invasion, not associated with other histotypes) of low‐grade (LG‐IDCs) and high‐grade (HG‐IDCs) was performed.

Methods

The bibliographic research included multiple databases (PubMed, Scopus, Web of Science). Mild‐moderate nuclear atypia favoured LG‐IDCs, severe atypia favoured HG‐IDCs.

Results

Preoperative fine‐needle aspiration cytology (FNAC) was performed in 13/94 published cases (14%): 10 parotid; two oral; one submandibular. All the cases were histologically LG‐IDCs, except two parotid IDCs. FNAC results included: negative for malignancy (three of 13 cases, 23%); tumour of uncertain malignant potential (seven of 13, 54%); malignancy (three of 13, 23%). The ductal component was identified in two cases; mucoepidermoid carcinoma was suggested in two additional cases. The grade was underestimated on FNAC evaluation in one HG‐IDC as focal high‐grade features were present on subsequent histological examination. The cases diagnosed as malignant tumours or describing intermediate atypia resulted in LG‐IDCs on subsequent histology. Occasional mitoses were described only in one HG‐IDC; this feature may have not been considered in the remaining published cases.

Conclusions

FNAC and clinico‐pathological correlation are important aids for clinicians and pathologists. FNAC could assist surgery even if an accurate diagnosis is sometimes impossible. Discrepancy in grading the nuclear atypia between the FNAC material and the resected specimen can occur, sometimes being unavoidable. Further studies are needed to better characterise this rare tumour.
KCNQ1OT1 promotes migration and inhibits apoptosis by modulating miR‐185‐5p/Rab14 axis in oral squamous cell carcinoma
Authors: Bao Qiyan , Liao Xiangling , Li Rongyin , Ding Nan
Published: November 2019

Long non‐coding RNAs (lncRNAs) play essential roles in the regulation of gene transcription in carcinogenesis and metastasis via interacting with microRNA. In this study, we explored the expressions and functions of lncRNA KCNQ1OT1 and miR‐185‐5p in oral squamous cell carcinoma (OSCC) cells. KCNQ1OT1 expression in OSCC tissues and cells was examined by qRT‐PCR. Small interfering RNAs against KCNQ1OT1 (si‐ KCNQ1OT1) were used to knockdown KCNQ1OT1 in OSCC cells. Cell function was assessed by wound healing assay, transwell assay, and apoptosis detection. The binding region between KCNQ1OT1 and miR‐185‐5p was confirmed by luciferase assays. MiR‐185‐5p expression was measured by qRT‐PCR. Rab14 was confirmed as a downstream target gene of miR‐185‐5p by measuring luciferase activities. The protein level of Rab14 in OSCC cells transfected with miR‐185‐5p or si‐KCNQ1OT1 was determined by Western blot. The OSCC cell function and Rab14 expression after co‐transfection of si‐KCNQ1OT1 and miR‐185‐5p inhibitor were also examined. KCNQ1OT1 was upregulated in OSCC tissues and cells. KCNQ1OT1 silencing suppressed OSCC cell malignancy and downregulated miR‐185‐5p level, which showed upregulated expression in OSCC samples. Rab14 as a target gene of miR‐185‐5p was highly expressed in OSCC. KCNQ1OT1 knockdown impaired the invasion capability of OSCC cells, promoted apoptosis, and suppressed Rab14 expression. The inhibition of miR‐185‐5p in KCNQ1OT1 silencing cells reversed the suppression of Rab14 and restored the cancerous growth of OSCC cells. These results indicated that KCNQ1OT1 promoted OSCC tumorigenesis via the modulation of miR‐185‐5p/Rab14 axis, which may serve as a therapeutic target for the treatment of OSCC.
The Brief 10‐Item Community Assessment of Psychic Experiences‐Positive Scale (Brief CAPE‐P10): Initial psychometric properties, gender measurement invariance and mean differences among Nigerian adolescents
Authors: Aloba Olutayo , Opakunle Tolulope
Published: November 2019

Aim

The aim of this study was to evaluate the Community Assessment of Psychic Experiences—Positive Scale (CAPE‐P) for its psychometric properties in terms of its reliability and validity, in addition to its factor structure and gender measurement invariance among Nigerian adolescents (n = 1336, Mage = 15.15).

Methods

The sample consisted of 606 (45.4%) males, who completed the 20‐items CAPE‐P in addition to the Positive and Negative Suicide Ideation Inventory (PANSI), the Hospital Anxiety and Depression Scale (HADS) and the Rosenberg Self‐Esteem Scale (RSES). We compared 11 a priori models of the CAPE‐P with the aim of identifying the one with the best fit indices applying Confirmatory Factor Analysis (CFA). Gender measurement invariance was examined with nested multiple‐group confirmatory factor analysis (MGCFA).

Results

All the 11 a priori models had poor fit indices. An examination of the scale's 20 items revealed that 10 items had poor correlation with the overall scale. The remaining 10 items which we labelled as the Brief CAPE—P10 were subjected to CFA which yielded a 3‐factor model (Bizarre Experiences‐5 items, Delusional Ideation‐3 items and Perceptual Anomalies‐2 items) with satisfactory fit indices (CFI = 0.961, SRMR = 0.0376, RMSEA = 0.062/90% CI = 0.052‐0.069).

The validity and reliability of the Brief CAPE—P10 and its subscales were modestly satisfactory. MGCFA affirmed the configural, metric and scalar gender invariance of the 3‐factor Brief CAPE‐P10.

Conclusions

The Brief CAPE—P10 is a promising instrument for the evaluation of PLEs among Nigerian adolescents.