bluuebunny/crossref_metadata_2025 huggingface dataset:
An Overview of Zoonotic Disease Outbreaks and its Forensic Management Over Time
Authors: Serrano Isa , Gomes Diana , Ramilo David , Rebelo Maria Teresa , da Fonseca Isabel Pereira , Moreira Anabela , Oliveira Manuela
Published: February 2019

Most emerging or re‐emerging infections are vector‐borne or zoonotic and can be disseminated worldwide by infected humans or animals. They are a major public health problem and cause a great impact on economy. Zoonotic outbreaks began to be characterized in the 90s, after the creation of Europol and the FBI. Such investigations are carried by forensic pathologists and other specialists to determine whether an outbreak is natural or deliberate. This review will discuss ten zoonotic outbreaks nonrelated to wars focusing on forensic management. In conclusion, some points should be highlighted in the management of a zoonotic outbreak: (i) its diagnosis and detection by forensic pathologists and the coordination of efforts between other specialists are key factors; (ii) communication guidelines and an efficient healthcare system are crucial for any emergency response; (iii) biosafety of all specialists involved must be guaranteed.
Effect of Hydrocolloids on the Retrogradation of Lotus Seed Starch Undergoing an Autoclaving–Cooling Treatment
Authors: Zheng Mingjing , Su Han , Luo Menglin , Shen Jinye , Zeng Shaoxiao , Zheng Baodong , Zeng Hongliang , Zhang Yi
Published: February 2019

The retrogradation properties of lotus seed starch (LS) blended with the hydrocolloids arabic gum (AG), carrageenan (CG), guar gum (GG), and xanthan (XN) were investigated undergoing an autoclaving–cooling treatment, a model for starch retrogradation acceleration. Compared with LS alone, LS–AG showed the increases in syneresis, tan δ (more solid‐like behavior), bound water content and immobile water content, molecular weight, the intensity at 480 cm−1 in Raman spectra and the ratio of absorbance 1047 cm–1/1022 cm–1 (R1047/1022) in FT–IR spectra. The results suggested that the addition of AG tended to promote the starch retrogradation, which was related to the increased molecular migration of free water, interactions of molecular starch chains, and the formation of ordered structures. The addition of CG, GG, or XN significantly decreased the syneresis, tan δ, the intensity at 480 cm−1, and R1047/1022 values of LS, indicating the prevention of LS retrogradation. The effects of CG and XN on starch retrogradation mainly resulted from competition for water and the increased viscosity, as well as the coating effect on starch. The dominant viscosity of GG was the main factor that influenced starch retrogradation. These results showed not all hydrocolloids would retard starch retrogradation under autoclaving–cooling treatment, for which fine structures altered by different hydrocolloids were the key factors.

Practical Application

Effects of hydrocolloids on the retrogradation of lotus seed starch were investigated undergoing an autoclaving–cooling treatment. The results will help guide the production and development of starchy foods having desirable properties by specific hydrocolloids during autoclaving–cooling process, especially to control starch retrogradation.
Observed Inflation‐target Adjustments in an Estimated DSGE Model for Indonesia: Do They Matter for Aggregate Fluctuations?
Authors: Lie Denny
Published: February 2019

This paper investigates the role of observed official inflation‐target adjustments in aggregate macroeconomic fluctuations in Indonesia, using an estimated Dynamic Stochastic General Equilibrium model. The paper finds that these adjustments or shocks play a non‐trivial role in the fluctuations of inflation and nominal interest rate in Indonesia. Output fluctuations, however, are virtually unaffected. A counterfactual exercise shows that a faster disinflation policy, through an immediate decrease in Bank Indonesia's inflation target, may have resulted in a lower average inflation and nominal interest rate, with virtually no output loss. The paper also provides additional insights on the contribution of various shocks in driving aggregate fluctuations in Indonesia. Technology and monetary‐policy shocks are found to be the main driving factor for both output and inflation fluctuations. Movements in the nominal interest rate are mostly driven by preference and risk‐premium shocks, with inflation‐target shocks playing a larger role in the longer run.
Metabolic geneNR4A1as a potential therapeutic target for non‐smoking female non‐small cell lung cancer patients
Authors: Sun Rong , Bao Min‐Yue , Long Xin , Yuan Yuan , Wu Miao‐Miao , Li Xin , Bao Jin‐Ku
Published: February 2019

Background

Although cigarette smoking is considered one of the key risk factors for lung cancer, 15% of male patients and 53% of female patients with lung cancer are non‐smokers. Metabolic changes are critical features of cancer. Therapeutic target identification from a metabolic perspective in non‐small cell lung cancer (NSCLC) tissue of female non‐smokers has long been ignored.

Results

Based on microarray data retrieved from Affymetrix expression arrays E‐GEOD‐19804, we found that the downregulated genes in non‐smoking female NSCLC patients tended to participate in protein/amino acid and lipid metabolism, while upregulated genes were more involved in protein/amino acid and carbohydrate metabolism. Combining nutrient metabolic co‐expression, protein–protein interaction network construction and overall survival assessment, we identifiedNR4A1andTIE1as potential therapeutic targets for NSCLC in female non‐smokers. To accelerate the drug development for non‐smoking female NSCLC patients, we identified nilotinib as a potential agonist targetingNR4A1encoded protein by molecular docking and molecular dynamic stimulation. We also show that nilotinib inhibited proliferation and induced senescence of cells in non‐smoking female NSCLC patients in vitro.

Conclusions

These results not only uncover nutrient metabolic characteristics in non‐smoking female NSCLC patients, but also provide a new paradigm for identifying new targets and drugs for novel therapy for such patients.
inlabru: an R package for Bayesian spatial modelling from ecological survey data
Authors: Bachl Fabian E. , Lindgren Finn , Borchers David L. , Illian Janine B.
Published: February 2019

Spatial processes are central to many ecological processes, but fitting models that incorporate spatial correlation to data from ecological surveys is computationally challenging. This is particularly true of point pattern data (in which the primary data are the locations at which target species are found), but also true of gridded data, and of georeferenced samples from continuous spatial fields.

We describe here the R package inlabru that builds on the widely used RINLA package to provide easier access to Bayesian inference from spatial point process, spatial count, gridded, and georeferenced data, using integrated nested Laplace approximation (INLA, Rue et al., 2009).

The package provides methods for fitting spatial density surfaces and estimating abundance, as well as for plotting and prediction. It accommodates data that are points, counts, georeferenced samples, or distance sampling data.

This paper describes the main features of the package, illustrated by fitting models to the gorilla nest data contained in the package spatstat (Baddeley, & Turner, 2005), a line transect survey dataset contained in the package dsm (Miller, Rexstad, Burt, Bravington, & Hedley, 2018), and to a georeferenced sample from a simulated continuous spatial field.
Winning and Losing in Investor–State Dispute Settlement
Authors: Samples Tim R
Published: February 2019

As tensions between investors’ rights and sovereign power escalate, investor–state dispute settlement (ISDS) has become a focal point of backlash and controversy. As a result, ISDS now embodies two opposing currents in international law: (1) the erosion of sovereignty that accompanied economic globalization, trade frameworks, and investment treaties following the Second World War and (2) more recently, reassertions of sovereignty prompted by recent backlashes against the global economic order. This article measures and evaluates outcomes of the ISDS system for sovereign participants. Using the best available data, this article contributes more detailed assessments of sovereign winners (home states of claimants) and sovereign losers (respondent states) in the ISDS system. This article also considers the distribution and the proportional impact of outcomes for sovereign participants, both of which are fundamental in the legitimacy debates surrounding the ISDS system.
Sampling Increases Music Sales: An Empirical Copyright Study
Authors: Schuster Mike , Mitchell David , Brown Kenneth
Published: February 2019

The Supreme Court instructs that the most important consideration in analyzing fair use is the effect on the market for the original. Employing music sales data, this article presents evidence of digital sampling's effect on the sales of sampled songs. Our results indicate that a reassessment of fair use in the area of music sampling is needed since sales of sampled songs increased after being repurposed within new songs. These results are robust and highly statistically significant. Findings of this nature favor a judicial determination that sampling constitutes a fair use, even when considering the influence that a new work has on extant licensing markets for sample clearance. This article argues that the current sample–licensing market is a product of aberrant antisampling case law arising from a lack of relevant empirical data and nonutilitarian judicial opinions. As set forth herein, the goal of encouraging creative activity without hindering copyright owners’ capacity to financially gain from their work is served by implementing a limited presumption of fair use for sampling. The findings are further applicable outside of the fair use analysis, as the study is important in the private law when viewed through a law and strategy lens. Forward thinking music firms should reframe their approach by encouraging sampling of their works to secure cost‐free advertising and achieve a competitive advantage.
Genetically heterogeneous mice exhibit a female survival advantage that is age‐ and site‐specific: Results from a large multi‐site study
Authors: Cheng Catherine J. , Gelfond Jonathan A. L. , Strong Randy , Nelson James F.
Published: February 2019

The female survival advantage is a robust characteristic of human longevity. However, underlying mechanisms are not understood, and rodent models exhibiting a female advantage are lacking. Here, we report that the genetically heterogeneous (UM‐HET3) mice used by the National Institute on Aging Interventions Testing Program (ITP) are such a model. Analysis of age‐specific survival of 3,690 control ITP mice revealed a female survival advantage paralleling that of humans. As in humans, the female advantage in mice was greatest in early adulthood, peaking around 350 days of age and diminishing progressively thereafter. This persistent finding was observed at three geographically distinct sites and in six separate cohorts over a 10‐year period. Because males weigh more than females and bodyweight is often inversely related to lifespan, we examined sex differences in the relationship between bodyweight and survival. Although present in both sexes, the inverse relationship between bodyweight and longevity was much stronger in males, indicating that male mortality is more influenced by bodyweight than is female mortality. In addition, male survival varied more across site and cohort than female survival, suggesting greater resistance of females to environmental modulators of survival. Notably, at 24 months the relationship between bodyweight and longevity shifted from negative to positive in both sexes, similar to the human condition in advanced age. These results indicate that the UM‐HET3 mouse models the human female survival advantage and provide evidence for greater resilience of females to modulators of survival.
The value of ongoing venture capital investment to newly listed firms
Authors: Hsu Wei‐Huei , Owen Sian , Suchard Jo‐Ann
Published: February 2019

We examine whether the market values continuing venture capital (VC) investor involvement in firms post‐IPO. Compared to the US, Australian VC investors exit their investments post‐IPO by on‐market sales rather than distribution of holdings to their investors. Lockup periods tend to be longer and ownership thresholds for reporting trades lower. We find that the market responds positively to buy transactions, negatively to sell transactions of VC investors and negatively to the resignation of VC directors. These results are consistent with VC investors in the firm having a positive influence and creating value from which the VCs and other shareholders benefit.
Factors affecting the success of artificial pack formation in an endangered, social carnivore: the African wild dog
Authors: Marneweck C. , Becker P. A. , Beverley G. , Davies‐Mostert H. T. , du Plessis C. , Forssman K. , Graf J. , Gusset M. , Hofmeyr M. , Kelly C. , Kilian P. J. , Marchal A. F. J. , Marneweck D. G. , Marnewick K. , Owen C. , Postiglione G. , Slotow R. , Somers M. J. , Szykman Gunther M. , van Dyk G. , Whittington‐Jones B. , Parker D. M.
Published: February 2019

Social integration is an important factor when reintroducing group‐living species, but examples of the formation of social groups before reintroduction are largely lacking. African wild dogs Lycaon pictus are endangered, and reintroductions have become a routine part of range expansion in South Africa. Wild dogs form packs that are essential to their reproduction and survival, and artificial pack formation is often required before reintroduction. We examined the proximate (i.e. social integration) and ultimate (i.e. reproduction) success of 43 artificial pack formation attempts in the South African managed metapopulation, between 1995 and 2018. The top (and dominant) model for proximate success included an interaction between total group size and an initial separation fence. Larger groups took longer to integrate, irrespective of initial separation, whereas smaller groups brought together immediately integrated faster than those that were initially separated. The top models for ultimate success included an interaction between the proportion of males and number of days spent in the pre‐release enclosure, the total number of days in the enclosure and an interaction between the proportion of captive‐sourced individuals and the total number of days in the enclosure. Ultimate success increased when packs spent less time in the enclosure, especially if those packs had a low proportion of males (i.e. female biased) or included >25% captive‐sourced individuals. Neither the size of the artificially created pack nor the season in which the pack was released affected ultimate success. The success of social integration and reproductive success of artificially formed packs in this study was higher than for natural pack formations. We provide guidelines for optimizing future artificial pack formation in wild dogs for reintroduction success. Our results serve as an example of the practical importance of social behavior in successfully implementing conservation measures for group‐living species.
Underestimated mitochondrial diversity in gypsy moth Lymantria dispar from Asia
Authors: Zhao Jie , Wu Yunke , Kurenshchikov Dmitry K. , Ilyinykh Alexandr V. , Shi Juan
Published: February 2019

The gypsy moth Lymantria dispar (L.) (Erebidae) is one of the most important agricultural and forest insect pests. It currently includes three subspecies: Lymantria dispar dispar (L.), Lymantria dispar asiatica Vnukovskij and Lymantria dispar japonica (Motschulsky). The first subspecies is known as the European gypsy moth (EGM), whereas the latter two are collectively referred to as the Asian gypsy moth (AGM).

Asian gypsy moth possesses traits that include a strong female flight capability and broader larval host range, which make it a more threatening pest than EGM when invading new areas.

To better understand the genetic structure within AGM and in particular among Chinese populations, we reconstructed a mitochondrial gene tree based on four mitochondrial protein‐coding genes (ND2, ND6, ATP6 and ATP8) from 17 Chinese locations and 21 locations from other countries.

None of the three subspecies of gypsy moth is recovered as monophyletic on the mitochondrial gene tree, likely as a result of human‐mediated transportation and a high level of cryptic genetic diversity.

Chinese populations are split into four mitochondrial clusters. Surprisingly, China I is nested within EGM and China II is the sister group of sampled EGM. China III grouped with samples from South Korea and the Russian Far East to represent the typical L. d. asiatica. China IV formed a sister relationship with the former group.

The results of the present study confirm that the recently discovered genotype from the Black Sea‐Caspian region consists of an independent mitochondrial genetic lineage from other subspecies.
Population genetic structure of Zeugodacus tau species complex in Thailand
Authors: Kitthawee Sangvorn , Julsirikul Duangta
Published: February 2019

The tephritid fruit fly Zeugodacus tau is a serious agriculture pest, especially of cucurbits in Thailand, where it is classified as a complex species of nine siblings (Z. tau A, B, C, D, E, F, G, I and J).

Based on single‐strand conformation polymorphism (SSCP) analysis, 33 distinct mitochondrial cytochrome c oxidase subunit I (mtCOI) haplotypes were found in three sibling species, Z. tau A, C and J, in Thailand. Genetic structure analysis of the population revealed relatively large genetic differences among these sibling species, reflecting a tendency toward speciation.

The maximum likelihood tree and median‐joining network reconstructed from the mtCOI sequences of 33 haplotypes supported the separation of these three sibling species within the Z. tau complex.

The three‐level hierarchical analysis of molecular variance based on geographical regions and the Mantel test for isolation‐by‐distance showed significant genetic structuring of the Z. tau complex in Thailand.

However, the genetic differentiation among geographical groups was rather low, which may be reasonably explained by natural and human mediated dispersal, as well as host associated differentiation.

The SSCP analysis on the population genetic structure of Z. tau species complex in the present study should benefit pest management.
Primates create seedling growth hotspots through pattern of dung deposition
Authors: Kalbitzer Urs , McInnis Victoria , Chapman Colin A.
Published: February 2019

Primates play important roles in tropical forests through seed dispersal and herbivory. They comprise a large part of the biomass of forest communities and tend to have clumped patterns of defecations (i.e. at favoured food trees or sleeping sites). Therefore, they may also play important roles in accelerating ecosystem nutrient cycling. Here we conduct a controlled growth experiment to quantify the effect of the addition of primate dung on the growth of both light‐demanding and shade‐tolerant seedlings over 1 year in Kibale National Park, Uganda. A mixed model analysis revealed that light‐demanding species were affected by the natural dung treatment and plants with small initial size had accelerated growth, whereas there was no effect on plant growth for shade‐tolerant species. The long‐term implications of increased dung deposition on the local tree community are unclear as shade‐tolerant species may only show an effect over the long‐term and light‐demanding species may only be able to take advantage of the increased growth if subsequently exposed to high light conditions, such as a treefall gap.
Beyond the Local Trap: New Municipalism and the Rise of the Fearless Cities
Authors: Russell Bertie
Published: February 2019

The Fearless Cities summit, coordinated by Barcelona en Comú in June 2017, marked the first global gathering of the nascent “new municipalist” movement. Responding to the “imperative that geographers engage critically and creatively with the way localism is being articulated”, this paper argues that the new municipalist initiatives are developing urban political strategies that successfully avoid the Local Trap. Rather than essentialising cities as inherently progressive or democratic, the municipal is instead becoming framed as a “strategic front” for developing a transformative politics of scale. Given this critical awareness, this nascent movement demonstrates how local loyalties can be mobilised as part of a progressive scalar strategy without falling into the trap of a “particular localism”. What remains to be seen is whether these initiatives are able to develop a variegated scalar strategy of transformation that retains the democratic essence that underpins them.
Translational research in retinal vascular disease. An approach
Authors: Bek Toke
Published: February 2019

The clinical presentation of the most frequent vision threatening retinal diseases is dominated by lesions indicating that disturbances in retinal blood flow are involved in the pathogenesis of these diseases. The present review describes the experience from a translational strategy pursued to investigate retinal vascular diseases with diabetic retinopathy as the main object. The normal regulation of retinal blood flow is investigated in porcine retinal vessels in vitro and ex vivo. Subsequently, the in vitro findings are translated to clinical studies in normal persons in vivo, and it is investigated whether the mechanisms are disturbed in retinal vascular disease. This is followed by clinical intervention studies on these diseases. The approach has been used to investigate pressure autoregulation, metabolic autoregulation and vasomotion in retinal vessels. The investigations have shown that retinal vascular tone can be regulated by receptor‐specific agonists and antagonists to vasoactive compounds such as purines, prostaglandins and nitric oxide synthesis and that the vasoactive effects can be modulated by the concentration and the mode of administration of these compounds. Additionally, it has been shown that retinal precapillary arterioles and capillaries not visible by ophthalmoscopy may play an important role for the pathophysiology of retinal vascular disease and its treatment. Future studies should focus on investigating normal and pathological regulation of retinal blood flow in these smaller vessels.
Postural effects on spontaneous retinal venous pulsations in healthy individuals
Authors: Georgevsky Dana , Gangoda Sumudu V. S. , Golzan Seyyed Mojtaba
Published: February 2019

Purpose

To assess amplitudes of spontaneous retinal venous pulsations (SVP) in three various postures (sitting, supine and lateral decubitus) in healthy individuals.

Methods

Thirty participants (28 ± 8 years, 25 females) were included in the study. Intraocular pressure (IOP), blood pressure (BP) and SVP's were measured at three different postures using a calibrated Tono‐Pen applanation tonometer, a digital sphygmomanometer, and a custom‐built handheld video ophthalmoscope, respectively. Retinal venous pulsations (SVP) amplitudes were extracted from the retinal videos using a custom written MATLAB algorithm. Mean arterial pressure (MAP = (systolic + 2diastolic)/3) and mean ocular perfusion pressure (MOPP = (2/3 MAP)‐IOP) were also calculated at each posture. A one‐way ANOVA was applied to each parameter to determine any significant difference for the various postural changes.

Results

Mean IOP increased (p < 0.0001) and mean SVP decreased (p < 0.0001) from sitting to supine. The mean IOP (mmHg) and SVP (MU; measuring units) in sitting, supine and lateral decubitus were 16.2 ± 2, 19.4 ± 4, 19.8 ± 2 mmHg and 5.8 ± 2, 4.5 ± 2, and 4.7 ± 2 MU, respectively. Mean arterial pressure (MAP) and MOPP also decreased significantly from sitting to supine (p < 0.001, p < 0.001) and sitting to lateral decubitus (p < 0.05, p < 0.01). There were no significant differences between IOP, SVP, MAP or MOPP during a postural modification from supine to lateral decubitus.

Conclusions

In this study, we showed a significant reduction in SVP amplitudes and a significant increase in IOP from sitting to supine position in a healthy young cohort. This supports the rationale to further study such phenomenon in ocular conditions such as glaucoma to determine whether relative SVP change, for a similar postural change, can reveal early signs of vascular dysfunction.
Antitumor activity and apoptotic action of coelomic fluid from the earthworm Dendrobaena veneta against A549 human lung cancer cells
Authors: Fiołka Marta J. , Rzymowska Jolanta , Bilska Sylwia , Lewtak Kinga , Dmoszyńska‐Graniczka Magdalena , Grzywnowicz Krzysztof , Kaźmierski Wojciech , Urbanik‐Sypniewska Teresa
Published: February 2019

It is known that earthworm coelomic fluid (CF) can affect not only cancer but also normal cells. The study demonstrated that the CF of the earthworm Dendrobaena veneta exhibited cytotoxicity against A549 lung cancer cells but did not toward the bronchial epithelial cell line BEAS‐2B. The selective effect on the tumor cells was achieved after a short‐term CF heat pre‐treatment at 70 °C. The cytotoxic effect of the CF was time‐ and concentration‐dependent. The CF noticeably decreased the viability and affected the morphology of the A549 cells. Scanning electron microscopy revealed a different degree of destruction of the nucleus and cytoplasm of A549 cells. As determined by atomic force microscopy, the cell surface roughness increased while the cell stiffness was reduced upon the CF treatment. A twofold increase in the caspase 3, 4, 5, and 10 levels was observed in the A549 cells after the incubation with the CF. The results obtained by flow cytometry using Annexin V confirmed the proapoptotic effect of the earthworm CF on A549 lung cancer cells. The D. veneta CF and active fraction obtained with cytotoxicity toward A549 lung cancer is an interesting and promising preparation for further biological, chemical, and biomedical research.
Methadone dosing strategies in preterm neonates can be simplified
Authors: van Donge Tamara , Samiee‐Zafarghandy Samira , Pfister Marc , Koch Gilbert , Kalani Majid , Bordbar Arash , van den Anker John
Published: February 2019

Aims

A dramatic increase in newborn infants with neonatal abstinence syndrome has been observed and these neonates are frequently treated with complex methadone dosing schemes to control their withdrawal symptoms. Despite its abundant use, hardly any data on the pharmacokinetics (PK) of methadone is available in preterm neonates. Therefore we investigated developmental PK of methadone and evaluated current dosing strategies and possible simplification in this vulnerable population.

Methods

A single‐centre open‐label prospective study was performed to collect PK data after a single oral dose of methadone in preterm neonates. A population PK model was built to characterize developmental PK of (R)‐ and (S)‐methadone. Model‐based simulations were performed to identify a simplified dosing strategy to reach and maintain target methadone exposure.

Results

A total of 121 methadone concentrations were collected from 31 preterm neonates. A one‐compartment model with first order absorption and elimination kinetics best described PK data for (R)‐ and (S)‐methadone. Clearance increases with advancing gestational age and differs between R‐ and S‐enantiomer, being slightly higher for the former (0.244 vs 0.167 L/h). Preterm neonates reached target exposure after 48 hours with currently used dosing schedules. Output from simulations revealed that target exposures can be achieved with a simplified dosing strategy during the first 4 days of treatment.

Conclusion

Methadone clearance in preterm neonates increases with advancing gestational age and its disposition is influenced by its chirality. Simulations that account for developmental PK changes indicate a shorter methadone dosing strategy can maintain target exposure to control withdrawal symptoms.
The carcinogenic potential of non‐ionizing radiations: The cases of S‐50 Hz MF and 1.8 GHz GSM radiofrequency radiation
Authors: Soffritti Morando , Giuliani Livio
Published: February 2019

Epidemiological studies have suggested that human exposure to extremely low‐frequency electromagnetic fields from the electric power and to mobile phone radiofrequency electromagnetic fields induce an increased risk of developing malignant tumours. However, no adequate laboratory data, in particular long‐term carcinogenicity bioassays to support the epidemiological evidence, have yet been available. This motivated the Ramazzini Institute to embark on a first project of four large life‐span carcinogenic bioassays conducted on over 7000 Sprague Dawley rats exposed from prenatal life until natural death to S‐50 Hz MF alone or combined with gamma radiation or formaldehyde or aflatoxin B1. Results now available from these studies, which started concurrently, have shown that exposure to Sinusoidal‐50 Hz Magnetic Field (S‐50 Hz MF) combined with acute exposure to gamma radiation or to chronic administration of formaldehyde in drinking water induces a significantly increased incidence of malignant tumours in males and females. A second project of two large life‐span carcinogenic bioassays was conducted on over 3000 Sprague Dawley rats exposed from prenatal life until natural death to 1.8 GHz GSM of mobile phone radio base station, alone or combined with acute exposure to gamma radiation. Early results from the experiment on 1.8 GHz GSM alone show a statistically significant increase in the incidence of heart malignant schwannoma among males exposed at the highest dose.
How new technology is addressed by researchers in Educational Studies: Approaches from high‐performing universities in China and the UK
Authors: Crook Charles , Gu Xiaoqing
Published: February 2019

There is a crisis of expectation in relation to educational technology. This is sometimes interpreted as a failure of academic researchers to disseminate their work to educational practitioners. However, another interpretation dwells on the lack of vision characterising such research. Because teachers often encounter research most intensely during their own pre‐service and in‐service education, we review academic research here through a snapshot of output from 10 leading university Education departments sampled in the UK and China. Empirical papers with a central interest in new technology were scarce, representing only around 10% of the sample. Research was strongly situated in “classroom” contexts, although, as critics have suggested, with limited attention to the wider ecology of those places, and with teachers being the focal interest as much as students. A “learning outcomes” research orientation was less common than an interest in process and practice. Although this was approached with different methodologies in China and the UK. Discussion addresses the challenge of effective and authoritative dissemination and those constraints from the political economy of research practice.
Difficulty and self‐efficacy: An exploratory study
Authors: Power Jason , Lynch Raymond , McGarr Oliver
Published: February 2019

Serious games are becoming increasingly popular due to their association with increased learning outcomes when compared to traditional self‐regulated learning activities. However, the majority of research examining the outcomes of serious games has focused almost exclusively on learning outcomes. This has resulted in a lack of research examining why these types of games result in increased positive outcomes, such as engagement or performance. This study seeks to address this gap in existing research by examining the relationship between game difficulty and participants’ engagement, performance and self‐efficacy in a Pacman style maze navigation game. This required the use of hidden difficulty variations which participants were randomly assigned. Participants engaged with the game over a 5‐days practice period. Results from this study suggest that difficulty plays a considerable role in influencing participants’ self‐efficacy for the task. Self‐efficacy has been consistently linked to positive outcomes such as increased engagement and performance. This highlights the importance of difficulty as a game design factor as well as providing an insight into the manner in which serious games could be further refined in order to increase user’s self‐efficacy and associated positive outcomes. Implications for future serious games and self‐efficacy research are discussed.
Pathological downstaging as a novel endpoint for the development of neoadjuvant chemotherapy for upper tract urothelial carcinoma
Authors: Martini Alberto , Daza Jorge , Poltiyelova Elona , Gul Zeynep , Heard John R. , Ferket Bart S. , Waingankar Nikhil , Galsky Matthew D. , Sfakianos John P.
Published: February 2019

Objectives

To evaluate whether pathological downstaging (pDS) was more informative in predicting overall survival (OS) than pathological complete response (pCR) in patients treated with neoadjuvant chemotherapy (NAC) for upper tract urothelial carcinoma (UTUC).

Patients and Methods

The National Cancer Database was queried for patients with high‐grade cN0M0 disease who had received NAC. pDS was defined as a decrease of at least one stage from cT to pT stage along with pN0, including pCR. A multivariable Cox model predicting OS was generated by fitting alternatively either pDS or pCR, and adjusted for potential confounders. The discrimination of the Cox models for predicting OS was evaluated using Harrell's C‐index. The analyses were repeated in patients diagnosed as having cT2–4N0M0 disease.

Results

Among 264 patients meeting the inclusion criteria, 72 (27%) and 39 (15%) achieved pDS and pCR, respectively. On multivariable analysis, both pDS (hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.13, 0.45; P < 0.001) and pCR (HR 0.37, 95% CI 0.18, 0.79; P = 0.01) were associated with OS. The model including pDS achieved better discrimination with respect to the model including pCR: C‐index 76.4 vs 72.7, respectively.

In the 128 patients diagnosed with cT2–4 disease, both pDS (HR 0.19, 95% CI 0.09, 0.40; P < 0.001) and pCR (HR 0.31, 95% CI 0.11, 0.85; P = 0.023) were confirmed as predictors of OS. The model including pDS was confirmed to discriminate better than the model including pCR: C‐index 75 vs 68.9, respectively.

Conclusion

The study showed that pDS after NAC for UTUC was more informative than pCR when predicting OS. These findings, although requiring prospective validation, can aid in the design of clinical trials seeking to refine the use of chemotherapy and other systemic therapies in this setting.
The relationship between the morphological subtypes of microglia and Alzheimer’s disease neuropathology
Authors: Paasila Patrick Jarmo , Davies Danielle Suzanne , Kril Jillian June , Goldsbury Claire , Sutherland Greg Trevor
Published: February 2019

Microglial associations with both the major Alzheimer’s disease (AD) pathognomonic entities, β‐amyloid‐positive plaques and tau‐positive neurofibrillary tangles, have been noted in previous investigations of both human tissue and mouse models. However, the precise nature of their role in the pathogenesis of AD is debated; the major working hypothesis is that pro‐inflammatory activities of activated microglia contribute to disease progression. In contrast, others have proposed that microglial dystrophy with a loss of physiological and neuroprotective activities promotes neurodegeneration. This immunohistochemical study sought to gain clarity in this area by quantifying the morphological subtypes of microglia in the mildly‐affected primary visual cortex (PVC), the moderately affected superior frontal cortex (SFC) and the severely affected inferior temporal cortex (ITC) of 8 AD cases and 15 age and gender‐matched, non‐demented controls with ranging AD‐type pathology. AD cases had increased β‐amyloid and tau levels compared to controls in all regions. Neuronal loss was observed in the SFC and ITC, and was associated with atrophy in the latter. A major feature of the ITC in AD was a decrease in ramified (healthy) microglia with image analysis confirming reductions in arborized area and skeletal complexity. Activated microglia were not associated with AD but were increased in non‐demented controls with greater AD‐type pathology. Microglial clusters were occasionally associated with β‐amyloid‐ and tau‐positive plaques but represented less than 2% of the total microglial population. Dystrophic microglia were not associated with AD, but were inversely correlated with brain pH suggesting that agonal events were responsible for this morphological subtype. Overall these novel findings suggest that there is an early microglial reaction to AD‐type pathology but a loss of healthy microglia is the prominent feature in severely affected regions of the AD brain.
Adrenoceptors in white, brown, and brite adipocytes
Authors: Evans Bronwyn A. , Merlin Jon , Bengtsson Tore , Hutchinson Dana S.
Published: February 2019

Adrenoceptors play an important role in adipose tissue biology and physiology that includes regulating the synthesis and storage of triglycerides (lipogenesis), the breakdown of stored triglycerides (lipolysis), thermogenesis (heat production), glucose metabolism, and the secretion of adipocyte‐derived hormones that can control whole‐body energy homeostasis. These processes are regulated by the sympathetic nervous system through actions at different adrenoceptor subtypes expressed in adipose tissue depots. In this review, we have highlighted the role of adrenoceptor subtypes in white, brown, and brite adipocytes in both rodents and humans and have included detailed analysis of adrenoceptor expression in human adipose tissue and clonally derived adipocytes. We discuss important considerations when investigating adrenoceptor function in adipose tissue or adipocytes.

Linked Articles

This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc
Progress in understanding mitochondrial calcium uniporter complex‐mediated calcium signalling: A potential target for cancer treatment
Authors: Cui Chaochu , Yang Jianbo , Fu Liwu , Wang Mingyong , Wang Xianwei
Published: February 2019

Due to its Ca2+buffering capacity, the mitochondrion is one of the most important intracellular organelles in regulating Ca2+dynamic oscillation. Mitochondrial calcium uniporter (MCU) is the primary mediator of Ca2+influx into mitochondria, manipulating cell energy metabolism, ROS production, and programmed cell death, all of which are critical for carcinogenesis. The understanding of the uniporter complex was significantly boosted by recent groundbreaking discoveries that identified the uniporter pore‐forming subunit MCU and its regulatory molecules, including MCU‐dominant negative β subunit (MCUb), essential MCU regulator (EMRE), MCU regulator 1 (MCUR1), mitochondrial calcium uptake (MICU) 1, MICU2, and MICU3. These provide the means and molecular platform to investigate MCU complex (uniplex)‐mediated impaired Ca2+signalling in physiology and pathology. This review aims to summarize the progress of the understanding regulatory mechanisms of uniplex, roles of uniplex‐mediated Ca2+signalling in cancer, and potential pharmacological inhibitors of MCU.
Signalling in response to sub‐picomolar concentrations of active compounds: Pushing the boundaries of GPCR sensitivity
Authors: Civciristov Srgjan , Halls Michelle L.
Published: February 2019

There is evidence for ultra‐sensitive responses to active compounds at concentrations below picomolar levels by proteins and receptors found in species ranging from bacteria to mammals. We have recently shown that such ultra‐sensitivity is also demonstrated by a wide range of prototypical GPCRs, and we have determined the molecular mechanisms behind these responses for three family A GPCRs: the relaxin receptor, RXFP1; the β2‐adrenoceptor; and the M3 muscarinic ACh receptor. Interestingly, there are reports of similar ultra‐sensitivity by more than 15 human GPCR families, in addition to other human receptors and channels. These occur through a diverse range of signalling pathways and produce modulation of important physiological processes, including neuronal transmission, chemotaxis, gene transcription, protein/ion uptake and secretion, muscle contraction and relaxation, and phagocytosis. Here, we summarise the accumulating evidence of ultra‐sensitive receptor signalling to show that this is a common, though currently underappreciated, property of GPCRs.

Linked Articles

This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc
Evidence for metabotropic function of epithelial nicotinic cholinergic receptors in rat colon
Authors: Lottig Lena , Bader Sandra , Jimenez Marcel , Diener Martin
Published: February 2019

Background and Purpose

ACh exerts its actions via nicotinic (nAChR) and muscarinic receptors. In the peripheral nervous system, ionotropic nAChR mediate responses in excitable cells. However, recent studies demonstrate the expression of nAChR in the colonic epithelium, which are coupled to an induction of Cl− secretion via activation of the Na+‐K+‐pump.

Experimental Approach

In order to find out whether these epithelial nAChR function as ionotropic receptors, intracellular microelectrode and imaging experiments were performed in isolated crypts from rat colon. Apically permeabilized epithelia were used to measure pump current across the basolateral membrane.

Key Results

Imaging experiments with the Na+‐sensitive dye SBFI revealed that nicotine induced a decrease in the cytosolic Na+ concentration concomitant with a fall in the cytosolic Ca2+ concentration in about 50% of the cells. as shown in fura‐2 experiments. Nicotine hyperpolarized the membrane by 6.4 ± 2.1 mV. These observations contradict the assumption that epithelial nAChR function as ligand‐gated non‐selective cation channels. The decrease in the cytosolic Na+ concentration was strongly delayed, when the Na+‐K+‐pump was inhibited by scilliroside. Ussing chamber experiments revealed a strong dependence of the nicotine‐induced pump current on the presence of Ca2+, and chelation of cytosolic Ca2+ with BAPTA prevented the fall in the cytosolic Na+ concentration in SBFI‐loaded crypts. Inhibition of PKC with GF 109203X or Goe 6983 significantly reduced the nicotine‐induced pump current.

Conclusions and Implications

These results suggest that epithelial nAChR activate the Na+‐K+‐pump via a PKC dependent on a sufficient cytosolic Ca2+ concentration.
Synthesis and biological activity of Ub2 derived peptides as potential host‐directed antitubercular therapy
Authors: Singh Shalini , Yabaji Shivraj M. , Ali Rafat , Srivastava Kishore K. , Haq Wahajul
Published: February 2019

The correlation of mycobactericidal property of macrophages with its potential to deliver bacteria to hydrolytic lysosomes, augmented with ubiquitin‐derived peptides (Ub2), activates the process of autophagy. This leads to the formation of phagolysosomes supported by factor involving increased cationic charges which regulate the acidic pH causing elimination of Mycobacterium. To better understand this interaction of cationic‐rich ubiquitin‐derived peptides with mycobacteria and to identify putative mycobacterial intrinsic resistance mechanisms for phagolysosome formation, we have synthesized a new series of Ub2 peptides, wherein the Gly residues are replaced with azaGly with the aim to improve metabolic stability. In addition to that a new methodology is reported for the synthesis of heteroaryl tethered peptides using azaGly as a linker. We have demonstrated that positive puncta (directly proportional to the acidification of lysosome) in cytosol was significantly increased after 6 hours on the treatment of macrophage with Ub2 peptide derivatives (1, 6, 10, and 11) causing the higher intensity of lysosome observed through LysoTracker Red Dye. The circular dichroism spectral studies are carried out in water and water:TFE mixture and demonstrated that the Ub2 peptides have helix‐forming tendency in the presence of TFE. The recognizable intracellular killing of Mycobacterium tuberculosis by Ub2 peptides provides a new approach for host‐directed therapy.
Synthesis of new bis‐pyrazole linked hydrazides and their in vitro evaluation as antimicrobial and anti‐biofilm agents: A mechanistic role on ergosterol biosynthesis inhibition in Candida albicans
Authors: Khan Irfan , Kanugala Sirisha , Shareef Mohd. Adil , Ganapathi Thipparapu , Shaik Anver Basha , Shekar Kunta Chandra , Kamal Ahmed , Kumar Chityal Ganesh
Published: February 2019

Literature reports suggest that pyrazoles and hydrazides are potential antimicrobial pharmocophores. Considering this fact, a series of nineteen conjugates containing hybrids of bis‐pyrazole scaffolds joined through a hydrazide linker were synthesized and further evaluated for their antimicrobial activity against a panel of Gram‐positive and Gram‐negative bacteria along with Candida albicansMTCC 3017 strain. Although the derivatives exhibited good antibacterial activity, some of the derivatives (13d, 13j, 13l, 13p, and 13r) showed excellent anti‐Candida activity with MICs values of 3.9 μg/ml, which was equipotent to that of the standard Miconazole (3.9 μg/ml), which has inspired us to further explore their anti‐Candida activity. The same compounds were also tested for anti‐biofilm studies against various Candida strains and among them, compounds 13l and 13r efficiently inhibited the formation of fungal biofilms. Field emission scanning electron micrographs revealed that one of the promising compound 13r showed cell damage and in turn cell death of the Candida strain. These potential conjugates (13l and 13r) also demonstrated promising ergosterol biosynthesis inhibition against some of the strains C. albicans, which were further validated through molecular docking studies. In silico computational studies were carried out to predict the binding modes and pharmacokinetic parameters of these conjugates.
Changes in alveolar process dimensions following extraction of molars with advanced periodontal disease: A clinical pilot study
Authors: Zhao Liping , Wei Yiping , Xu Tao , Zhang Bo , Hu Wenjie , Chung Kwok‐Hung
Published: February 2019

Objective

To use cone beam computed tomography (CBCT) to assess the alterations of socket dimensions after a 6‐month healing period following molar extraction.

Materials and methods

Seventeen molars were extracted due to advanced periodontitis. CBCT scans were taken immediately after extraction and once more 6 months later. Superimposition of CBCT images was used to measure the following: horizontal changes at extraction sites at three corono‐apical levels (−1, −3, and −5 mm) below the bone crest, three mesio‐distal levels (mesial, central, and distal), vertical changes at nine regions of the alveolar crest, and alveolar bone volume.

Results

The width of the central crests at −1 mm decreased by 0.59 and 0.72 mm in the buccal and 0.27 and 0.02 mm in the lingual, in the maxilla and mandible, respectively. No statistically significant decreases in the ridge height were observed except in the disto‐palatal region with a 1.11 mm decrease in the maxilla (p < 0.05). Heights of the buccal and lingual bone plates decreased significantly and ranged from 0.56 to 1.38 mm in the mandible after 6 months of healing (p < 0.05). Overall, ridge height changes were not significantly different between the maxilla and mandible (p > 0.05) and no significant volumetric bone loss occurred in either maxillary or mandibular sockets after 6 months of healing.

Conclusions

Socket dimensions of molars with advanced periodontal disease showed a significant increase at the middle‐central portion, although there were no significant changes of horizontal width 6 months following the procedures.