bluuebunny/crossref_metadata_2025 huggingface dataset:
Reelin Mediates Hippocampal Cajal-Retzius Cell Positioning and Infrapyramidal Blade Morphogenesis
Authors: Ha Seungshin R , Tripathi Prem , Daza Ray , Hevner Robert , Beier David R
Published: February 2019

We have previously described hypomorphic reelin (Reln) mutant mice, RelnCTRdel, in which the morphology of the dentate gyrus is distinct from that seen in reeler mice. In the RelnCTRdel mutant the infrapyramidal blade of the dentate gyrus fails to extend, while the suprapyramidal blade forms with a relatively compact granule neuron layer. The distribution of Cajal-Retzius cells in the dentate gyrus was aberrant; Cajal-Retzius neurons were increased in the suprapyramidal blade, but were greatly reduced along the subpial surface of the prospective infrapyramidal blade. We also observed multiple abnormalities of the fimbriodentate junction. Firstly, progenitor cells were distributed abnormally; the neurogenic cluster at the fimbriodentate junction was absent, lacking the normal accumulation of Tbr2-positive intermediate progenitors. However, the number of dividing cells in the dentate gyrus was not generally decreased. Secondly, a defect of secondary glial scaffold formation, limited to the infrapyramidal blade, was observed. The densely radiating glial fibers characteristic of the normal fimbriodentate junction were absent in mutants. These fibers might be required for migration of progenitors, which may account for the failure of neurogenic cluster formation. These findings suggest the importance of the secondary scaffold and neurogenic cluster of the fimbriodentate junction in morphogenesis of the mammalian dentate gyrus. Our study provides direct genetic evidence showing that normal RELN function is required for Cajal-Retzius cell positioning in the dentate gyrus, and for formation of the fimbriodentate junction to promote infrapyramidal blade extension.
Capabilities, strategies and firm performance in the United Kingdom
Authors: Parnell John , Brady Malcolm
Published: February 2019

Purpose

The purpose of this paper is to investigate the influence of internal capabilities and environmental turbulence on market (e.g. cost leadership and differentiation) and nonmarket (e.g. political and social) strategies (NMS), and considers how these strategies impact financial and non-financial performance in firms in the United Kingdom.

Design/methodology/approach

A survey was administered online to 215 practicing managers in the UK. Measures for competitive strategy (i.e. cost leadership and differentiation), NMS, strategic capabilities, market turbulence and firm performance were adopted from or based on previous work. Hypotheses were tested via SmartPLS.

Findings

Findings underscore the impact of market turbulence across all market and nonmarket strategy dimensions. Multiple links between capabilities and strategies were identified. Both cost leadership and differentiation were significantly linked to non-financial performance, but only differentiation was significantly linked to financial performance. An increased emphasis on social NMS was linked to higher financial performance, but not non-financial performance. Political NMS was linked to neither financial nor non-financial performance.

Research limitations/implications

The sample included managers in multiple industries. Self-typing scales were utilized to measure market turbulence, emphasis on capabilities, strategic emphasis and firm performance.

Practical implications

Emphasis on social NMS can promote financial performance, but political NMS does not appear to drive either financial or non-financial performance.

Originality/value

This paper provides empirical support for a UK-based model linking market turbulence, strategic capabilities, market and nonmarket strategies, and both social and firm performance. It supports NMS as a key performance driver, but with caveats.
Designing and testing a network of passive seismic surveying and monitoring in Dehdasht (South Western Iran)
Authors: Salinas Victor , Ugalde Arantza , Kamayestani Ahmad , Jokar Mehrab , Gharibvand Mojtaba Moradi , Villaseñor Antonio , Heidari Ghasem
Published: February 2019

From August 2016 to July 2017, a passive seismic survey was conducted in South Western Iran as a part of a pilot project aimed to improve the imaging in geologically complex areas. Passive seismic methods have shown to be a useful tool to infer the physical properties of the underground geological structures where traditional hydrocarbon exploration methods are challenging. For this purpose, a dense passive seismic network consisting of 119 three‐component borehole seismic stations was deployed over an area of 400 km2 around the city of Dehdasht. This paper focuses on the details of the network design, which was devoted to high‐resolution seismological applications, including local earthquake tomography and seismic attenuation imaging. In this regard, we describe the instrument types and the station installation procedures used to obtain high‐quality data that were used to retrieve three‐dimensional models of P‐ and S‐wave velocity and P‐wave attenuation in the area using tomographic inversion techniques. We also assess the network performance in terms of the seismic ambient noise levels recorded at each station site, and we revise the horizontal orientation of the sensors using surface waves from teleseismic earthquakes.
Optimizing compaction calculation for improved probabilistic 2D mapping
Authors: Babak Olena , Liu Kun , Gallop Jeremy
Published: February 2019

Integration of all available data in reservoir characterization is critically important. 2D mapping is a reliable and robust technique that allows integration of multiple secondary data, including geological and geophysical surfaces and maps, to generate realistic summaries of reservoir quality at each location in an area of interest with an associated measure of uncertainty. This is achieved in 2D mapping with a more straightforward implementation, requiring significantly less time and fewer resources than three‐dimensional modelling. In this paper, we propose an approach for the empirical calculation and optimization of differential compaction maps by leveraging existing well control for the use in 2D mapping. Success of the proposal is demonstrated through tests of accuracy, precision and fairness of the local uncertainty distributions for 100 new stratigraphical wells drilled in the Christina Lake and Kirby East area.
A Fatal Case of Acute Arsenic Poisoning
Authors: Lu Ping , Ma Jin‐Qi , Li Fan , Xu Guo‐Hui , Guo Wan , Zhou Hai‐Mei
Published: February 2019

This manuscript reported a case of fatal arsenic poisoning. A woman with schizophrenia took arsenic‐containing “pills,” which consisted of arsenic trioxide and realgar (arsenic (II) sulfide) and wrapped with gauze. The victim consumed 1.09 and 0.819 g arsenic on two occasions, respectively, with the interval between the two doses of 3 days. The woman died on the sixth day after the first dose without any treatment. In this case, pathological examination revealed fat degeneration of the liver rather than hepatomegaly, a rare finding in acute arsenic poisoning. Arsenic in tissue samples was measured, the total arsenic and inorganic arsenic in blood, liver, and gastric wall was 10.2 μg/mL (9.61 μg/mL), 23.1 μg/g (20.7 μg/g), and 32.3 μg/g (28.6 μg/g), respectively.
Predictive Model for Growth of Bacillus cereus at Temperatures Applicable to Cooling of Cooked Pasta
Authors: Juneja Vijay K. , Golden Chase E. , Mishra Abhinav , Harrison Mark A. , Mohr Tim B.
Published: February 2019

A model was developed to predict the growth of Bacillus cereus from spores during cooling of cooked pasta. Cooked pasta was inoculated with a cocktail of four strains of heat‐shocked (80 °C/10 min) B. cereus spores to obtain a final spore concentration of approximately 2 log CFU/g. Thereafter, growth was determined at isothermal temperatures starting at 10 °C and every three degrees up to 49 °C. Samples were removed periodically and plated on mannitol egg yolk polymyxin agar. The plates were incubated for 24 hr at 30 °C. Baranyi, Huang, and modified Gompertz primary growth models were used to fit growth data. The modified Ratkowsky secondary model was used to fit growth rates determined by the primary growth models with respect to temperature. All three primary models fitted the growth data well. The modified Ratkowsky secondary model adequately fit growth rates generated by the three primary models (R2 values ranging from 0.96 to 0.98). After acceptable prediction zone (APZ) validation and goodness of fit statistical analyses, it was determined that the Baranyi primary growth model was best suited for these data. For both single‐rate exponential cooling and biphasic linear cooling model validation, all Baranyi model predictions (n = 24 and 28, respectively) fell within the APZ (−1.0 to 0.5 log CFU/g). The model will assist institutional food service settings to determine the safety of cooked pasta subjected to longer cooling times or stored at improper temperatures.

Practical Application

Predictive model can be used to estimate extent of microbial growth during cooling of cooked pasta and in designing HACCP program and setting of critical control levels. Retail food industry would need fewer challenge studies to validate the safety of their products. The model will provide regulatory agencies and food industry with an objective means of assessing the microbial risk and ensuring that the public is not at risk of acquiring food poisoning.
Clinical significance of positive anti‐neutrophil cytoplasmic antibodies without evidence of anti‐neutrophil cytoplasmic antibodies‐associated vasculitis
Authors: Bornstein Gil , Ben‐Zvi Ilan , Furie Nadav , Grossman Chagai
Published: February 2019

Aim

Anti‐neutrophil cytoplasmic antibodies (ANCA) have a role in the diagnostic workup of ANCA‐associated vasculitis. However, the clinical significance of positive ANCA in the absence of vasculitis is yet to be determined. Therefore, we sought to investigate the clinical spectrum and rate of patients with a positive ANCA without evidence of vasculitis.

Methods

Retrospective analysis of patients positive for cytoplasmic ANCA (C‐ANCA) and proteinase 3 (PR3) or P‐ANCA and myeloperoxidase (MPO) between 2007 and 2016 in the Chaim Sheba Medical Center, Israel. The proportion of patients who had no evidence of vasculitis among all patients with a positive C‐ANCA/PR3 or P‐ANCA/MPO was calculated according to tertiles of enzyme‐linked immunosorbent assay (ELISA) antibody levels.

Results

Among 113 patients who tested positive for C‐ANCA/PR3 or P‐ANCA/MPO, 68 (60.1%) had no evidence of vasculitis. ELISA antibody titers were significantly higher among patients with vasculitis than those without (6.2 vs 3.2, for C‐ANCA/PR3 and 5.4 vs 2.6 for P‐ANCA/MPO, P < 0.05). The proportion of patients without vasculitis among all patients with a positive C‐ANCA/PR3 and among all patients with a positive P‐ANCA/MPO declined in parallel to the increases in ELISA antibody level tertiles (96%, 57% and 22% in the 1st, 2nd and highest tertiles, respectively, for patients with C‐ANCA/PR3 patients and 100%, 66% and 20% in the 1st, 2nd and highest tertiles, respectively, for patients with P‐ANCA/MPO).

Conclusion

A significant proportion of patients with a positive C‐ANCA/PR3 or P‐ANCA/MPO do not have evidence of vasculitis, particularly those with low‐medium ELISA antibody titers. Using a higher threshold of ANCA titers may be required to improve specificity.
Mitochondrial NDUFA4L2 protein promotes the vitality of lung cancer cells by repressing oxidative stress
Authors: Meng Lifei , Yang Xuhui , Xie Xiao , Wang Mingsong
Published: February 2019

Background

Non‐small cell lung cancer (NSCLC) accounts for a significant proportion of cancer‐related deaths and lacks an effective treatment strategy. NSCLC tissues are generally found in a low oxygen environment. The NDUFA4L2 protein, located in the mitochondria, is encoded by the nucleus genome and is considered a crucial mediator that regulates cell survival. A better understanding of the mechanism of NDUFA4L2 in NSCLC survival in hypoxic environments is essential to design new therapeutic methods.

Methods

Twenty NSCLC and corresponding paired non‐tumorous lung tissue samples were collected. NSCLC cell lines were cultured in hypoxic conditions to investigate the mechanism of NDUFA4L2 in NSCLC. The role of NDUFA4L2 was confirmed by using Western blotting, reactive oxygen species measurement, flow cytometry, immunofluorescence analysis, and wound healing and colony formation assays.

Results

The expression of HIF‐1α and mitochondrial NDUFA4L2 increased in NSCLC cell lines cultured in hypoxic conditions (1% O2). NDUFA4L2 was drastically overexpressed in human NSCLC tissues and cell lines cultured in hypoxic conditions. HIF‐1α regulated the expression of NDUFA4L2. Knockdown of NDUFA4L2 notably increased mitochondrial reactive oxygen species production, which suppressed the viability of NSCLC.

Conclusion

In conclusion, overexpression of NDUFA4L2 is a key factor for maintaining NSCLC growth, suggesting that mitochondrial NDUFA4L2 may be a potential target for the treatment of lung cancer.
respR—An R package for the manipulation and analysis of respirometry data
Authors: Harianto Januar , Carey Nicholas , Byrne Maria
Published: February 2019

Respirometry is a ubiquitous practice in experimental biology, but there is a lack of standard practices when analysing the resulting data, limiting transparency and reproducibility. As respirometry datasets become increasingly large and analytical approaches more complex, manipulating the data remains a challenge and often intractable with existing tools.

Here we describe therespRRpackage, a collection of functions that implement a workflow‐based approach to automate the analysis and visualisation of respirometry data. The package can be used for closed, intermittent flow, flow‐through and open‐tank respirometry and uses well‐defined sets of rules to reliably and rapidly generate reproducible results.

We demonstrate howrespRuses novel computing methods such as rolling regressions and kernel density estimates to reliably detect maximum, minimum and most linear sections of the data, and critical oxygen tension,.

Although designed specifically with aquatic respirometry in mind, the object‐oriented approach of the package and the unit‐less nature of its analytical functions mean that parts of the package can easily be used to estimate linear relationships from a range of applications in many research disciplines.
Rules about smoking and vaping in the home: findings from the 2016 International Tobacco Control Four Country Smoking and Vaping Survey
Authors: Nahhas Georges J. , Braak David , Cummings K. Michael , Heckman Bryan W. , Alberg Anthony J. , Yong Hua‐Hie , Fong Geoffrey T. , Boudreau Christian , Hitchman Sara C. , McNeill Ann
Published: February 2019

Aims

To examine rules about smoking and vaping in the home in relation to beliefs about the relative harm of second‐hand vapor (SHV) compared with second‐hand smoke (SHS) in four countries: Canada, United States, England and Australia.

Design

Data were available from 12 294 adults (18+) who participated in the 2016 (wave 1) International Tobacco Control Four Country Smoking and Vaping (ITC 4CV1) Survey.

Participants

All participants were current or recent former adult smokers.

Measurements

Data were analyzed by weighted logistic regression on rules about smoking and vaping in the home; odds ratios and 95% confidence intervals were reported, adjusted for demographic and behavioral variables.

Findings

Of all respondents, 37.4% allowed smoking inside their home. Among a subset who were current vapers (n = 6135), 60.4% allowed vaping in their homes. After controlling for demographic and behavioral characteristics, beliefs about the harm of SHV compared with SHS was not associated with allowing smoking in the home, but was associated with allowing vaping in the home [odds ratio (OR) = 2.86 in Canada, OR = 1.82 in the United States and OR = 1.68 in England]. Characteristics that were associated with rules about vaping inside the home included daily vaping (OR = 2.95, 2.04–4.26; OR = 7.00, 4.12–11.87; OR = 5.50, 3.40–8.88; OR = 7.78, 1.90–31.80), living with a spouse who vapes (OR = 2.48, 1.54–3.98; OR = 2.69, 1.42–5.11; OR = 4.67, 2.74–7.95; OR = 21.82, 2.16–220.9) and living with children aged under 18 years (OR = 0.50, 0.37–0.68; OR = 0.89, 0.48–1.65; OR = 0.76, 0.53–1.09; OR = 0.26, = 0.11–0.61) in Canada, the United States, England and Australia, respectively. Similar characteristics were associated with rules about smoking inside the home.

Conclusions

Among current and former smokers in 2016 in Canada, the United States, England and Australia, 37.4% allowed smoking in the home; 60.4% of current vapers allowed vaping. Both concurrent users and exclusive vapers were more likely to allow vaping than smoking inside the home. Allowing vaping inside the home was correlated with the belief that second‐hand vapor is less harmful than second‐hand smoke.
Predation of fruit and seed of Aloe pretoriensis – A little known effect on reproductive output in aloes
Authors: van den Bosch Kaylee , van Noort Simon , Cron Glynis V.
Published: February 2019

The effect of seed predation by phytophagous/parasitoid wasps on the reproductive output of aloes is relatively unknown. In this study, conducted at a nature reserve in Pretoria East, South Africa, the range of insects utilising Aloe pretoriensis (Asphodelaceae) fruits and/or seeds and the impact of this usage on its reproductive output were investigated. Using a GLMM, we explored the effects of morphological features (e.g. floral display size) and selected ecological factors (viz. distance between the aloes and conspecifics and other surrounding vegetation) on fruit utilisation and seed predation. A variety of insect visitors to A. pretoriensis (mainly bees and wasps) were identified including a number of seed predators and parasitoids. Evidence of phytophagy in dissected flowers showed increasing evidence of fruit utilisation and seed predation over an 8‐week period. Emergence boxes with infructescences revealed a range of insect phytophages (and their associated parasitoids) in the aloe fruits and seeds: the drosophilid fly, Apenthecia and six species of wasp – five of them associated with ultilisation of aloe fruits/seeds for the first time: Eurytoma aloineae (Chalcididae), Mesopolobus sp., Pteromalus sp., and c.f. Chlorocytus in the Pteromalidae, Bracon sp. (Braconidae) and Pediobius (Eulophidae). Fruit set ranged between 48% and 93%, with an average of 76%, while average percentage utilisation of fruits was 29%, ranging between 7% and 68%. Average seed set was 23 seeds per fruit and average percentage seed predation 21% (range: 0–51%). Fruit utilisation was found to be significantly negatively correlated with distance to the nearest flowering bush (usually Helichrysum kraussii), but display size did not significantly affect fruit utilisation, nor did distance to conspecifics. Aloe pretoriensis thus serves as host to a variety of phytophagous insects and their associated parasitoids, which impacts considerably on its reproductive output with possible implications for the future conservation of this aloe species.
Violence, Nonviolence, and the Effects of International Human Rights Law
Authors: Lupu Yonatan , Wallace Geoffrey P. R.
Published: February 2019

Under what conditions are individuals more likely to approve of human rights abuses by their governments? While various theoretical expectations have been offered about public approval of repression, many of them have not been directly tested. We analyze the effects of differing opposition tactics, differing government tactics, and legal constraints on approval of repression through a series of survey experiments in India, Israel, and Argentina. Our results indicate that violent action by opposition groups consistently increases support for government repression. In the context of contentious politics, we find that the effects of international law vary by national context. While our respondents in India were less likely to approve of their government when told the government violated international law, the same information likely increased approval of the government in our Israel experiment. The findings provide insights into the microfoundations of existing theories and suggest areas for theory refinement.
Treatment and management of adrenal cancer in a specialized Australian endocrine surgical unit: approaches, outcomes and lessons learnt
Authors: Kwok Grace T. Y. , Zhao Jing‐Ting , Glover Anthony R. , Ip Julian C. Y. , Sywak Mark , Clifton‐Bligh Roderick , Clarke Stephen , Robinson Bruce , Sidhu Stan B.
Published: February 2019

Background

Adrenocortical carcinoma is a rare and heterogeneous malignancy with poor outcomes. Recent research has suggested that outcomes may be improved by centralization of care in specialist centres. We review our evolving 21‐year experience in managing adrenocortical carcinoma with a view towards outcomes and lessons learnt.

Methods

A retrospective study of patients treated in our specialist endocrine surgical unit over 21 years was undertaken.

Results

Thirty‐five patients were treated from diagnosis, 29 forming a primary study cohort. Additionally, seven patients were referred to us for quaternary care, forming a secondary study cohort. The European Network for the Study of Adrenal Tumours (ENSAT) stage and immunohistochemical marker Ki‐67 index were strong prognostic indicators for survival.

Conclusions

Early stage, complete resection and Ki‐67 <10% are the best prognosticators for survival. Aggressive surgical resection at index operation and of recurrent oligometastatic disease along with multimodal adjuvant treatment has led to long‐term survivors of patients with Stage 4 disease in our aggregate cohort.
Pharmacokinetics of ticarcillin–clavulanate in premature infants
Authors: Watt Kevin M. , Hornik Christoph P. , Balevic Stephen J. , Mundakel Gratias , Cotten C. Michael , Harper Barrie , Benjamin Daniel K. , Anand Ravinder , Laughon Matthew , Smith P. Brian , Cohen‐Wolkowiez Michael ,   on behalf of the Best Pharmaceuticals for Children Act — Pediatric Trials Network Steering Committee
Published: February 2019

Ticarcillin–clavulanate covers a broad spectrum of pathogens that are common in premature infants. In infants <30 weeks gestational age, pharmacokinetic data to guide ticarcillin–clavulanate dosing are lacking. We enrolled 15 premature infants <30 weeks gestational age, determined pharmacokinetic parameters, and performed dosing simulations to determine optimal dosing for ticarcillin–clavulanate. The infants had a median (range) postnatal age (PNA) of 18 days (6–44 days) and gestational age of 25 weeks (23–28 weeks). Clearance was lower in infants with a PNA <14 days (0.050 L/kg/h [range 0.043–0.075]) compared with a PNA ≥14–45 days (0.078 L/kg/h [0.047–0.100]), consistent with maturation of renal function. Dosing simulations determined that ticarcillin 75 mg/kg q12h (PNA <14 days) or q8h (PNA ≥ 14–45 days) achieved the target exposure for organisms with a minimum inhibitory concentration ≤16 μ/mL in >90% of simulated infants. For highly resistant organisms (minimum inhibitory concentration 32 μg/mL), increased dosing frequency or extended infusion are necessary.
Central nervous system effects of the histamine‐3 receptor antagonist CEP‐26401, in comparison with modafinil and donepezil, after a single dose in a cross‐over study in healthy volunteers
Authors: Baakman Anne C. , Zuiker Rob , van Gerven Joop M.A. , Gross Nicholas , Yang Ronghua , Fetell Michael , Gershon Ari , Gilgun‐Sherki Yossi , Hellriegel Edward , Spiegelstein Ofer
Published: February 2019

Aims

In previous studies, the histamine‐3 receptor antagonist CEP‐26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 μg), and a dose‐dependent disruption of sleep. In the current study, 3 low‐dose levels of CEP‐26401 were compared with modafinil and donepezil.

Methods

In this double‐blind, placebo‐ and positive‐controlled, randomized, partial 6‐way cross‐over study, 40 healthy subjects received single doses of placebo, CEP‐26401 (5, 25 or 125 μg) or modafinil 200 mg or donepezil 10 mg. Pharmacokinetic and pharmacodynamic measurements were performed predose and at designated time points postdose.

Results

The main endpoint between‐errors of the spatial working memory‐10‐boxes task only improved for the 125 μg dose of CEP‐26401 with a difference of 2.92 (confidence interval [CI] –1.21 to 7.05), 3.24 (CI –1.57 to 8.04) and 7.45 (CI 2.72 to 12.19) for respectively the 5, 25 and 125 μg dose of CEP‐26401, −1.65 (CI –0.572 to 1.96) for modafinil and − 3.55 (CI –7.13 to 0.03) for donepezil. CEP‐26401 induced an improvement of adaptive tracking, saccadic peak velocity and reaction time during N‐back, but a dose‐related inhibition of sleep and slight worsening of several cognitive parameters at the highest dose. CEP‐26401 significantly changed several subjective visual analogue scales, which was strongest at 25 μg, causing the same energizing and happy feeling as modafinil, but with a more relaxed undertone.

Discussion

Of the doses tested, the 25 μg dose of CEP‐26401 had the most optimal balance between favourable subjective effects and sleep inhibition. Whether CEP‐26401 can have beneficial effects in clinical practice remains to be studied.
Predictive modeling for response to lithium and quetiapine in bipolar disorder
Authors: Kim Thomas T. , Dufour Steven , Xu Colin , Cohen Zachary D. , Sylvia Louisa , Deckersbach Thilo , DeRubeis Robert J. , Nierenberg Andrew A.
Published: February 2019

Objectives

Lithium and quetiapine are known to be effective treatments for bipolar disorder. However, little information is available to inform prediction of response to these medications. Machine‐learning methods can identify predictors of response by examining variables simultaneously. Further evaluation of models on a test sample can estimate how well these models would generalize to other samples.

Methods

Data (N = 482) were drawn from a randomized clinical trial of outpatients with bipolar I or II disorder who received adjunctive personalized treatment plus either lithium or quetiapine. Elastic net regularization (ENR) was used to generate models for lithium and quetiapine; these models were evaluated on a test set.

Results

Predictions from the lithium model explained 17.4% of the variance in actual observed scores of patients who received lithium in the test set, while predictions from the quetiapine model explained 32.1% of the variance of patients that received quetiapine. Of the baseline variables selected, those with the largest parameter estimates were: severity of mania; attention‐deficit/hyperactivity disorder (ADHD) comorbidity; nonsuicidal self‐injurious behavior; employment; and comorbidity with each of two anxiety disorders (social phobia/society anxiety and agoraphobia). Predictive accuracy of the ENR model outperformed the simple and basic theoretical models.

Conclusion

ENR is an effective approach for building optimal and generalizable models. Variables identified through this methodology can inform future research on predictors of response to lithium and quetiapine, as well as future modeling efforts of treatment choice in bipolar disorder.
Potent effects of dioscin against hepatocellular carcinoma through regulating TP53‐induced glycolysis and apoptosis regulator (TIGAR)‐mediated apoptosis, autophagy, and DNA damage
Authors: Mao Zhang , Han Xu , Chen Dahong , Xu Youwei , Xu Lina , Yin Lianhong , Sun Huijun , Qi Yan , Fang Lingling , Liu Kexin , Peng Jinyong
Published: February 2019

Background and purpose

Dioscin shows potent effects against cancers. We aimed to elucidate its pharmacological effects and mechanisms of action on hepatocellular carcinoma (HCC) in vivo and in vitro.

Experimental approach

Effects of dioscin were investigated in SMMC7721 and HepG2 cells, diethylnitrosamine‐induced primary liver cancer in rats, and cell xenografts in nude mice. Isobaric tags for relative and absolution quantitation (iTRAQ)‐based proteomics was used to find dioscin's targets and investigate its mechanism.

Key results

In SMMC7721 and HepG2 cells dioscin markedly inhibited cell proliferation and migration, induced apoptosis, autophagy, and DNA damage. It inhibited DEN‐induced primary liver cancer in rats, markedly changed body weights and restored levels of α fetoprotein, alanine transaminase, aspartate transaminase, γ‐glutamyltransferase, alkaline phosphatase, and Ki67. It also inhibited growth of xenografts in mice. In SMMC7721 cells, 191 differentially expressed proteins were found after dioscin, based on iTRAQ‐based assay. TP53‐inducible glycolysis and apoptosis regulator (TIGAR) was identified as being significantly down‐regulated by dioscin. Dioscin induced cell apoptosis, autophagy, and DNA damage via increasing expression levels of p53, cleaved PARP, Bax, cleaved caspase‐3/9, Beclin‐1, and LC3 and suppressing those of Bcl‐2, p‐Akt, p‐mammalian target of rapamycin (mTOR), CDK5, p‐ataxia telangiectasia‐mutated gene (ATM). The transfection of TIGAR siRNA into SMMC7721 cells and xenografts in nude mice further confirmed that the potent activity of dioscin against HCC is evoked by adjusting TIGAR‐mediated inhibition of p53, Akt/mTOR, and CDK5/ATM pathways.

Conclusions and implications

The data suggest that dioscin has potential as a therapeutic, and TIGAR as a drug target for treating HCC.
The δ‐opioid receptor positive allosteric modulator BMS 986187 is a G‐protein‐biased allosteric agonist
Authors: Stanczyk M. Alexander , Livingston Kathryn E. , Chang Louise , Weinberg Zara Y. , Puthenveedu Manojkumar A. , Traynor John R.
Published: February 2019

Background and Purpose

The δ‐opioid receptor is an emerging target for the management of chronic pain and depression. Biased signalling, the preferential activation of one signalling pathway over another downstream of δ‐receptors, may generate better therapeutic profiles. BMS 986187 is a positive allosteric modulator of δ‐receptors. Here, we ask if BMS 986187 can directly activate the receptor from an allosteric site, without an orthosteric ligand, and if a signalling bias is generated.

Experimental Approach

We used several clonal cell lines expressing δ‐receptors, to assess effects of BMS 986187 on events downstream of δ‐receptors by measuring G‐protein activation, β‐arrestin 2 recruitment, receptor phosphorylation, loss of surface receptor expression, ERK1/ERK2 phosphorylation, and receptor desensitization.

Key Results

BMS 986187 is a G protein biased allosteric agonist, relative to β‐arrestin 2 recruitment. Despite showing direct and potent G protein activation, BMS 986187 has a low potency to recruit β‐arrestin 2. This appears to reflect the inability of BMS 986187 to elicit any significant receptor phosphorylation, consistent with low receptor internalization and a slower onset of desensitization, compared with the full agonist SNC80.

Conclusions and Implications

This is the first evidence of biased agonism mediated through direct binding to an allosteric site on an opioid receptor, without a ligand at the orthosteric site. Our data suggest that agonists targeting δ‐receptors, or indeed any GPCR, through allosteric sites may be a novel way to promote signalling bias and thereby potentially produce a more specific pharmacology than can be observed by activation via the orthosteric site.
A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension
Authors: Yang Peiran , Read Cai , Kuc Rhoda E. , Nyimanu Duuamene , Williams Thomas L. , Crosby Alexi , Buonincontri Guido , Southwood Mark , Sawiak Stephen J. , Glen Robert C. , Morrell Nicholas W. , Davenport Anthony P. , Maguire Janet J.
Published: February 2019

Background and Purpose

Apelin is an endogenous vasodilatory and inotropic peptide that is down‐regulated in human pulmonary arterial hypertension, although the density of the apelin receptor is not significantly attenuated. We hypothesised that a G protein‐biased apelin analogue MM07, which is more stable than the endogenous apelin peptide, may be beneficial in this condition with the advantage of reduced β‐arrestin‐mediated receptor internalisation with chronic use.

Experimental Approach

Male Sprague–Dawley rats received either monocrotaline to induce pulmonary arterial hypertension or saline and then daily i.p. injections of either MM07 or saline for 21 days. The extent of disease was assessed by right ventricular catheterisation, cardiac MRI, and histological analysis of the pulmonary vasculature. The effect of MM07 on signalling, proliferation, and apoptosis of human pulmonary artery endothelial cells was investigated.

Key Results

MM07 significantly reduced the elevation of right ventricular systolic pressure and hypertrophy induced by monocrotaline. Monocrotaline‐induced changes in cardiac structure and function, including right ventricular end‐systolic and end‐diastolic volumes, ejection fraction, and left ventricular end‐diastolic volume, were attenuated by MM07. MM07 also significantly reduced monocrotaline‐induced muscularisation of small pulmonary blood vessels. MM07 stimulated endothelial NOS phosphorylation and expression, promoted proliferation, and attenuated apoptosis of human pulmonary arterial endothelial cells in vitro.

Conclusion and Implications

Our findings suggest that chronic treatment with MM07 is beneficial in this animal model of pulmonary arterial hypertension by addressing disease aetiology. These data support the development of G protein‐biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.
Goblet cell hyperplasia as a feature of neutrophilic asthma
Authors: Alagha Khuder , Bourdin Arnaud , Vernisse Charlotte , Garulli Céline , Tummino Céline , Charriot Jérémy , Vachier Isabelle , Suehs Carey , Chanez Pascal , Gras Delphine
Published: February 2019

Background

Goblet cell hyperplasia (GCH) is a pathological finding classically reported across asthma severity levels and usually associated with smoking. Multiple biological mechanisms may contribute to excessive mucus production.

Objective

We aimed to decipher the clinical meanings and biological pathways related to GCH in non‐smokers with asthma.

Methods

Cough and sputum assessment questionnaire (CASA‐Q) responses at entry and 1 year later were compared to clinical and functional outcomes in 59 asthmatic patients. GCH was assessed through periodic‐acid shift (PAS) staining on endobronchial biopsies obtained at entry in a subset of 32 patients.

Results

Periodic‐acid shift‐staining analysis revealed a double wave distribution discriminating patients with (>10% of the epithelial area) or without GCH. CASA‐Q scores were mostly driven by overall asthma severity (P < 0.0001). CASA‐Q scores remained stable at 1 year and were independently associated with BAL eosinophil content irrespective of the presence of GCH. GCH was unrelated to the presence of bronchiectasis at CT, GERD or chronic rhinosinusitis, but correlated well with neutrophilic inflammatory patterns observed upon BAL cellular analysis (P = 0.002 at multivariate analysis). BALF bacterial loads were unrelated to GCH or to CASA‐Q.

Conclusions and Clinical Relevance

Goblet cell hyperplasia is disconnected from chronic cough and sputum when assessed by a specific questionnaire. GCH is related to neutrophilic asthma whereas symptoms are related to airway eosinophilia. The clinical counterpart of GCH is unlikely assessed by the CASA‐Q.
Difference in cytokines, chemokines and growth factors produced by blood–brain barrier‐ and blood–nerve barrier‐composing cells
Authors: Oishi Mariko , Shimizu Fumitaka , Sano Yasuteru , Takeshita Yukio , Maeda Toshihiko , Fujikawa Susumu , Honda Masaya , Sato Ryota , Kanda Takashi
Published: February 2019

Objectives

The blood–brain barrier (BBB) and blood–nerve barrier (BNB) comprise the brain/peripheral nerve‐specific barrier system, formed by microvascular endothelial cells, pericytes and astrocytes in the BBB, and microvascular endothelial cells and pericytes in the BNB. The differences in the detailed cellular biology among these cells are still unclear. The purpose of the present study was to quantify and compare the cytokine/chemokine/growth factor levels in BBB‐ and BNB‐ composing cells.

Methods

We quantified the levels of 27 cytokines/chemokines/growth factors in human umbilical vein endothelial cells, human brain and peripheral nerve microvascular endothelial cells, pericytes, and astrocytes using a multiplexed fluorescent bead‐based immunoassay system.

Results

Basic fibroblast growth factor and regulated on activation, normal T cell expressed and secreted were mainly produced by both astrocytes and peripheral pericytes. Vascular endothelial growth factor and interferon‐inducible protein of 10 kDa were secreted by astrocytes. Interleukin‐1β, interleukin‐6, interleukin‐8 and macrophage chemoattractant protein‐1 were produced more abundantly by brain and peripheral nerve pericytes than by astrocytes. Larger amounts of basic fibroblast growth factor; interferon‐inducible protein of 10 kDa; regulated on activation, normal T cell expressed and secreted; and tumor necrosis factor‐α were secreted by brain microvascular endothelial cells than by peripheral nerve microvascular endothelial cells or human umbilical vein endothelial cells.

Conclusions

Similar to brain pericytes and astrocytes, peripheral nerve pericytes produce several cytokines, chemokines and growth factors. This suggests that these cells contribute to the barrier functions in the BNB, in the same manners as brain pericytes and astrocytes do in the BBB.
A global perspective on implant education: Cluster analysis of the “first dental implant experience” of dentists from 84 nationalities
Authors: Dragan Irina F. , Pirc Miha , Rizea Cristina , Yao Jie , Acharya Aneesha , Mattheos Nikos
Published: February 2019

Objectives

The aim of this cross‐sectional study was to explore the demographic and educational patterns related to the dentists’ first implant dental experience.

Material and methods

Participants of a Massive Open Online Course in implant dentistry who have placed and restored implants completed a 25‐item online questionnaire investigating their pathway of education and assessing their experience with the “first implant placement.” Exploratory analysis included hierarchical clustering using 9 demographic categorical factors.

Results

A total of 1015 respondents from 84 countries formed 5 distinct clusters. Age and work experience were dominant clustering traits, decreasing from Cluster 1 to Cluster 5. Clusters 1 and 3 represented “senior” and “younger” general dental practitioners, respectively, whilst Clusters 2 and 4 represented post‐graduate educated clinicians. Cluster 5 represented recent graduates. Asia, South America and Africa were over‐represented in “younger” clusters. Time in practice was a significant determinant of attitudes, followed by completion of post‐graduate education. There were significant differences in reported patterns of challenges and complications depending on dentists’ time in practice, age and post‐graduate education. Challenge in implant positioning was more frequently identified by “young post‐graduate” educated dentists. Recent graduates reported having the fewest complications of all clusters. Obtaining implant education in University settings was most frequently recommended by clusters of dentists with post‐graduate education.

Conclusions

Time in practice is a parameter to be considered when designing implant education. The absence of structured education and mentorship might lead to inability to properly assess treatment outcomes and identify complications. Quality‐assured and practice‐directed education is needed at a global level, to support in particular, recent graduates who now seem to engage with implant dentistry early in their career.
Four‐dimensional functional cortical maps of visual and auditory language: Intracranial recording
Authors: Nakai Yasuo , Sugiura Ayaka , Brown Erik C. , Sonoda Masaki , Jeong Jeong‐Won , Rothermel Robert , Luat Aimee F. , Sood Sandeep , Asano Eishi
Published: February 2019

Objective

The strength of presurgical language mapping using electrocorticography (ECoG) is its outstanding signal fidelity and temporal resolution, but the weakness includes limited spatial sampling at an individual patient level. By averaging naming‐related high‐gamma activity at nonepileptic regions across a large number of patients, we provided the functional cortical atlases animating the neural dynamics supporting visual‐object and auditory‐description naming at the whole brain level.

Methods

We studied 79 patients who underwent extraoperative ECoG recording as epilepsy presurgical evaluation, and generated time‐frequency plots and animation videos delineating the dynamics of naming‐related high‐gamma activity at 70‐110 Hz.

Results

Naming task performance elicited high‐gamma augmentation in domain‐specific lower‐order sensory areas and inferior‐precentral gyri immediately after stimulus onset. High‐gamma augmentation subsequently involved widespread neocortical networks with left hemisphere dominance. Left posterior temporal high‐gamma augmentation at several hundred milliseconds before response onset exhibited a double dissociation; picture naming elicited high‐gamma augmentation preferentially in regions medial to the inferior‐temporal gyrus, whereas auditory naming elicited high‐gamma augmentation more laterally. The left lateral prefrontal regions including Broca's area initially exhibited high‐gamma suppression subsequently followed by high‐gamma augmentation at several hundred milliseconds before response onset during both naming tasks. Early high‐gamma suppression within Broca's area was more intense during picture compared to auditory naming. Subsequent lateral‐prefrontal high‐gamma augmentation was more intense during auditory compared to picture naming.

Significance

This study revealed contrasting characteristics in the spatiotemporal dynamics of naming‐related neural modulations between tasks. The dynamic atlases of visual and auditory language might be useful for planning of epilepsy surgery. Differential neural activation well explains some of the previously reported observations of domain‐specific language impairments following resective epilepsy surgery. Video materials might be beneficial for the education of lay people about how the brain functions differentially during visual and auditory naming.
Vertical integration as an input price hedge: The case of Delta Air Lines and trainer refinery
Authors: Almansur Abdullah Mohammed , Megginson William L. , Pugachev Leonid V.
Published: February 2019

In April 2012, Delta Air Lines (Delta) purchased a mothballed oil refinery. We use this case to illustrate when, how, and why vertical integration (VI) can hedge input price risk. First, we show that stockholders and creditors expected the move to create wealth. Consistent with their predictions, Delta's exposure to refining margins, cash flow volatility, cost of debt, and default probability all decreased, relative to peers, postacquisition. Our evidence is consistent with the refinery influencing Delta's operating strategies, especially in its most affected markets. The case demonstrates how asset specificity and financial hedging frictions can justify VI.
Clarifying the mechanisms and resources that enable the reciprocal involvement of seldom heard groups in health and social care research: A collaborative rapid realist review process
Authors: Ní Shé Éidín , Morton Sarah , Lambert Veronica , Ní Cheallaigh Cliona , Lacey Vanessa , Dunn Eleanor , Loughnane Cliona , O'Connor Joan , McCann Amanda , Adshead Maura , Kroll Thilo
Published: February 2019

Objective

Public and patient involvement is increasingly embedded as a core activity in research funding calls and best practice guidelines. However, there is recognition of the challenges that prevail to achieve genuine and equitable forms of engagement. Our objective was to identify the mechanisms and resources that enable the reciprocal involvement of seldom heard groups in health and social care research.

Methods

A rapid realist review of the literature that included: (a) a systematic search of CINAHL, PsycINFO, PubMed and Open Grey (2007‐2017); (b) documents provided by expert panel members of relevant journals and grey literature. Six reference panels were undertaken with homeless, women's, transgender, disability and Traveller and Roma organizations to capture local insights. Data were extracted into a theory‐based grid linking context to behaviour change policy categories.

Main results

From the review, 20 documents were identified and combined with the reference panel summaries. The expert panel reached consensus about 33 programme theories. These relate to environmental and social planning (7); service provision (6); guidelines (4); fiscal measures (6); communication and marketing (4); and regulation and legislation (6).

Conclusions

While there is growing evidence of the merits of undertaking PPI, this rarely extends to the meaningful involvement of seldom heard groups. The 33 programme theories agreed by the expert panel point to a variety of mechanisms and resources that need to be considered. Many of the programme theories identified point to the need for a radical shift in current practice to enable the reciprocal involvement of seldom heard groups.
Individual variation in feather corticosterone levels and its influence on haemosporidian infection in a Neotropical bird
Authors: Bosholn Mariane , Anciães Marina , Gil Diego , Weckstein Jason D. , Dispoto Janice H. , Fecchio Alan
Published: February 2019

Corticosterone (CORT) is the main glucocorticoid hormone of amphibians, reptiles, birds and some mammals. This hormone may have evolved as an adaptive metabolic mechanism, in part because increased concentrations ofCORTare essential for individuals to manage energy resources and thus cope with negative perturbations such as predation and storms. The benefits ofCORTare offset by costs, because elevated levels can suppress inflammatory responses of individuals, making them more susceptible to parasites and pathogens. In this study, we investigated the relationships between featherCORTlevels, infection status and diversity of haemosporidian parasites in the Blue‐crowned ManakinLepidothrix coronata, considering possible effects related to the sex and age of individuals. We predicted higher levels of featherCORTin infected individuals. We observed that featherCORTlevels were similar among individuals of different sexes and ages. Although haemosporidian infection status did not vary among sexes, occurrence probability was higher among younger individuals, which may indicate that the less developed immune system of these individuals makes them more susceptible to avian malaria. Contrary to expectations, we found that featherCORTlevels were not associated with the infection status and diversity of haemosporidian parasites. That haemosporidian occurrence probability does not increase with elevated featherCORTlevels suggests that individuals are not immunosuppressed by elevated levels of this hormone, at least to the extent that featherCORTtruly reflects individual differences in the level of this hormone.