bluuebunny/crossref_metadata_2025 huggingface dataset:
Aberrant brain response after auditory deviance in PTSD compared to trauma controls: An EEG study
Authors: Bangel Katrin A. , van Buschbach Susanne , Smit Dirk J.A. , Mazaheri Ali , Olff Miranda
Published: September 2017

Part of the symptomatology of post-traumatic stress disorder (PTSD) are alterations in arousal and reactivity which could be related to a maladaptive increase in the automated sensory change detection system of the brain. In the current EEG study we investigated whether the brain’s response to a simple auditory sensory change was altered in patients with PTSD relative to trauma-exposed matched controls who did not develop the disorder. Thirteen male PTSD patients and trauma-exposed controls matched for age and educational level were presented regular auditory pure tones (1000 Hz, 200 ms duration), with 11% of the tones deviating in both duration (50 ms) and frequency (1200 Hz) while watching a silent movie. Relative to the controls, patients who had developed PTSD showed enhanced mismatch negativity (MMN), increased theta power (5-7 Hz), and stronger suppression of upper alpha activity (13-15 Hz) after deviant vs. standard tones. Behaviourally, the alpha suppression in PTSD correlated with decreased spatial working memory performance suggesting it might reflect enhanced stimulus-feature representations in auditory memory. These results taken together suggest that PTSD patients and trauma-exposed controls can be distinguished by enhanced involuntary attention to changes in sensory patterns.
Increased Activity of Tyrosine Hydroxylase Leads to Elevated Amphetamine Response and Markers of Oxidative Stress in Transgenic Mice
Authors: Vecchio Laura M. , Bermejo M. Kristel , Dunn Amy , Milenkovic Marija , Urs Nikhil , Ramsey Amy , Miller Gary W. , Salahpour Ali
Published: September 2017

In Parkinson’s disease, noradrenergic cells of the locus coeruleus and dopamine cells within the nigrostriatal pathway undergo profound degeneration. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the production of all catecholamines, including dopamine and noradrenaline, and is selectively expressed in the cells that produce these neurotransmitters.In vitrostudies have previously shown that the TH-synthetic system can contribute to the formation of reactive oxygen species. In addition, animal models of dopamine mishandling demonstrated that free dopamine is neurotoxic. To examine how increased TH activity might influence catecholamine systemsin vivo, we generated TH-overexpressing mice (TH-HI) with six total copies of theTHmurine gene. A commensurate increase inTHmRNA produced a threefold increase in both total TH protein and phosphorylated TH levels. We found an increased rate of dopamine synthesis in both young and adult mice, reflected by the accumulation of L-DOPA following NSD-1015 administration, as well as elevated dopamine tissue content in young mice and an increased presence of dopamine metabolites at both ages. Adult mice show no difference in baseline locomotor behaviour compared to wildtype littermates, but a have potentiated response to amphetamine. In addition to elevated dopamine turnover in the striatum, TH-HI mice show reduced levels of glutathione and increased levels of cysteinylated catechols. These results indicate that a heightened level of active TH can produce oxidative stress, and may represent a source of toxicity that is specific to catecholamine cells, which are most vulnerable to degeneration in Parkinson’s disease.
A potential link between tuberculosis and lung cancer through non-coding RNAs
Authors: Barh Debmalya , Tiwari Sandeep , Kumavath Ranjith N. , Azevedo Vasco
Published: September 2017

Pulmonary tuberculosis caused byMycobacteriumand lung cancer are two major causes of deaths worldwide and the former increases the risk of developing lung cancer. However, the precise molecular mechanism ofMycobacteriumassociated increased risk of lung cancer is not entirely understood. Here, usingin silicoapproaches, we show that hsa-mir-21 andM. tuberculosissRNA_1096 and sRNA_1414 could play important roles in the pathogenesis of both these diseases. Further, we postulated a “Genetic remittance” hypothesis where these sRNAs may play important roles. The sRNA_1096 could be involved in tuberculosis through multiple infectious processes, and if transferred to the host, it may activate the TLR8 mediated pro-metastatic inflammatory pathway by acting as a ligand to TLR8 similar to the mir-21 leading to lung tumorigenesis and chemo-resistance. Analogous to SH3GL1, it may also regulate cell cycle. On the other hand, sRNA_1414 is probably involved in survivability and drug response of the pathogen. However, it may be a metastatic factor for lung cancer providing EPS8L1 and SORBS1 like functions upon remittance. Further, all these three non-coding RNAs are predicted to act in rifampicin resistance inMycobacterium.Currently, we are applying robust bioinformatics strategies and conducting experimental validations to confirm ourin-silicofindings and hypothesis.
Characterization ofAzotobacter vinelandiiand Kits for Its Synthetic Biology Applications
Authors: Leung King Pong , Loo Jacky Fong Chuen , Seak Leo Chi U , Lai Tung Faat , Yip Kevin Yuk Lap , Kong Siu Kai , Chan Ting Fung , Chan King Ming
Published: September 2017

Azotobacter vinelandii, a Gram-negative aerobic bacterium with an intracellular anaerobic environment that maintains the oxygen-sensitive enzymatic cascades for nitrogen fixation, could be used to express oxygen-sensitive proteins. However, little is known about the properties ofA. vinelandiifor synthetic biology applications. We therefore first characterized and optimized the conditions for growing and screening BioBrick constructs inA. vinelandiiin the presence of 2 antibiotics, ampicillin and chloramphenicol, and then developed two sets of BioBricks for regulated protein expression. The first kit used T7 RNA polymerase, whose expression is under the control of a nitrogen-repressiblenifHpromoter. The commonly used T7-dependent system inEscherichia colican then be used inA. vinelandii. Because its intracellular anaerobic environment is favorable for processes such as magnetosome biogenesis, we attempted to migrate the biogenesis machineries from the magnetotactic bacteriumMagnetospirillum gryphiswaldensetoA. vinelandii. During this undertaking, another insertion kit construct was developed to allow protein conjugation onto magnetosomes. The kit consists ofmamC, a gene encoding a transmembrane protein on magnetosomes, and multiple restriction sites downstream ofmamCfor fusing a gene of interest. This insertion kit allows the attachment of any desired protein onto the magnetosome membrane by fusing with the mamC protein. We demonstrated the function of this kit by fusing mamC to a GFP nanobody. This kit will facilitate the conjugation of any target protein onto magnetosomes for downstream applications in the future.

Financial Disclosure

We received sponsorship from the 2012–15 Teaching Development Grants Triennium, Faculty of Engineering and Biochemistry Program, School of Life Sciences, The Chinese University of Hong Kong. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests

The authors declare that no competing interests exist.

Ethics Statement

N/A.

Data Availability

All data are fully available without restriction.
CscoreTool: Fast Hi-C Compartment Analysis at High Resolution
Authors: Zheng Xiaobin , Zheng Yixian
Published: September 2017

The chromosome conformation capture (Hi-C) has revealed that the eukaryotic genome can be partitioned into A and B compartments that have distinctive chromatin and transcription features. Current Principle Component Analyses (PCA)-based method for the prediction of A/B compartment prediction from Hi-C data requires substantial CPU time and memory. We report the development of a method, CscoreTool, that enables fast and memory-efficient determination of A/B compartments at high resolution even in dataset with low sequencing depth.

Availability

github.com/scoutzxb/CscoreTool

Contact

xzheng@carnegiescience.edu
Motif signatures of transcribed enhancers
Authors: Kleftogiannis Dimitrios , Ashoor Haitham , Zarokanellos Nikolaos , Bajic Vladimir B.
Published: September 2017

In mammalian cells, transcribed enhancers (TrEn) play important roles in the initiation of gene expression and maintenance of gene expression levels in spatiotemporal manner. One of the most challenging questions in biology today is how the genomic characteristics of enhancers relate to enhancer activities. This is particularly critical, as several recent studies have linked enhancer sequence motifs to specific functional roles. To date, only a limited number of enhancer sequence characteristics have been investigated, leaving space for exploring the enhancers genomic code in a more systematic way. To address this problem, we developed a novel computational method, TELS, aimed at identifying predictive cell type/tissue specific motif signatures. We used TELS to compile a comprehensive catalog of motif signatures for all known TrEn identified by the FANTOM5 consortium across 112 human primary cells and tissues. Our results confirm that distinct cell type/tissue specific motif signatures characterize TrEn. These signatures allow discriminating successfully a) TrEn from random controls, proxy of non-enhancer activity, and b) cell type/tissue specific TrEn from enhancers expressed and transcribed in different cell types/tissues. TELS codes and datasets are publicly available athttp://www.cbrc.kaust.edu.sa/TELS.
Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity
Authors: Andrysik Zdenek , Galbraith Matthew D. , Guarnieri Anna L. , Zaccara Sara , Sullivan Kelly D. , Pandey Ahwan , MacBeth Morgan , Inga Alberto , Espinosa Joaquín M.
Published: September 2017

The tumor suppressor TP53 is the most frequently mutated gene product in human cancer. Close to half of all solid tumors carry inactivating mutations in the TP53 gene, while in the remaining cases, TP53 activity is abrogated by other oncogenic events, such as hyperactivation of its endogenous repressors MDM2 or MDM4. Despite identification of hundreds of genes regulated by this transcription factor, it remains unclear which direct target genes and downstream pathways are essential for the tumor suppressive function of TP53. We set out to address this problem by generating multiple genomic data sets for three different cancer cell lines, allowing the identification of distinct sets of TP53-regulated genes, from early transcriptional targets through to late targets controlled at the translational level. We found that although TP53 elicits vastly divergent signaling cascades across cell lines, it directly activates a core transcriptional program of ∼100 genes with diverse biological functions, regardless of cell type or cellular response to TP53 activation. This core program is associated with high-occupancy TP53 enhancers, high levels of paused RNA polymerases, and accessible chromatin. Interestingly, two different shRNA screens failed to identify a single TP53 target gene required for the anti-proliferative effects of TP53 during pharmacological activation in vitro. Furthermore, bioinformatics analysis of thousands of cancer genomes revealed that none of these core target genes are frequently inactivated in tumors expressing wild-type TP53. These results support the hypothesis that TP53 activates a genetically robust transcriptional program with highly distributed tumor suppressive functions acting in diverse cellular contexts.
Calibrating SANS data for instrument geometry and pixel sensitivity effects: access to an extendedQrange
Authors: Karge Lukas , Gilles Ralph , Busch Sebastian
Published: September 2017

An improved data-reduction procedure is proposed and demonstrated for small-angle neutron scattering (SANS) measurements. Its main feature is the correction of geometry- and wavelength-dependent intensity variations on the detector in a separate step from the different pixel sensitivities: the geometric and wavelength effects can be corrected analytically, while pixel sensitivities have to be calibrated to a reference measurement. The geometric effects are treated for position-sensitive3He proportional counter tubes, where they are anisotropic owing to the cylindrical geometry of the gas tubes. For the calibration of pixel sensitivities, a procedure is developed that is valid for isotropic and anisotropic signals. The proposed procedure can save a significant amount of beamtime which has hitherto been used for calibration measurements.
In situlaser irradiation setup for a Bruker three-circle goniometer
Authors: Yufit Dmitry S.
Published: September 2017

A new design of a setup forin situlaser irradiation of single crystals during an X-ray diffraction experiment is presented. The system is designed for use with a Bruker three-circle goniometer in combination with a Helix ultra-low-temperature cryostat and consists of a laser mount and a set of three adjustable mirrors. The main advantages of the presented system include a stationary laser mount, the ability to irradiate a sample inside the Be nozzle and no impediments to the goniometer movements.
Web mining for the mayoral election prediction in Taiwan
Authors: Huang Jia-Yen
Published: September 2017

Purpose

The prediction of pre-election polls is an issue of concern for both politicians and voters. The Taiwan nine-in-one election held in 2014 ended with jaw-dropping results; apparently, traditional polls did not work well. As a remedy to this problem, the purpose of this paper is to utilize the comments posted on social media to analyze civilians’ views on the two candidates for mayor of Taichung City, Chih-chiang Hu, and Chia-Lung Lin.

Design/methodology/approach

After conducting word segmentation and part-of-speech tagging for the collected reviews, this study constructs the opinion phrase extraction rules for identifying the opinion words associated with the attribute words. Next, this study classifies the attribute words into six municipal governance-related topics and calculates the opinion scores for each candidate. Finally, this study uses correspondence analysis to transform opinion information on the candidates into a graphical display to facilitate the interpretation of voters’ views.

Findings

The results show that the topics of candidates’ backgrounds and transport infrastructure were the two most critical factors for the election prediction. Based on the predication, Lin outscores Hu by 17.74 percent which is close to the real election results.

Research limitations/implications

This study proposes new rules for the extraction of Chinese opinion words associated with attribute words.

Practical implications

This study applies Chinese semantic analysis to assist in predicting election results and investigating the topics of concern to voters.

Originality/value

The proposed opinion phrase extraction rules for Chinese social media, as well as the election forecast process, can provide valuable references for political parties and candidates to plan better nomination and election strategies.
What makes a competent change manager? The importance of developing the “right” attitudes
Authors: Hoe Siu Loon
Published: September 2017

Purpose

The purpose of this paper is to highlight the importance of developing the “right” attitudes toward change.

Design/methodology/approach

The viewpoint is based on more than 20 years of experience gained and insights developed through consulting projects and training conducted for numerous multinational companies and public sector organizations across Asia. An overview of international and national competency frameworks that include change management from Australia, United Kingdom, and Singapore is also presented.

Findings

A competent change manager requires a combination of knowledge, skills, and attitude to effect change. While knowledge and skills have traditionally been emphasized, there is a need to develop the “right” attitude as well.

Research limitations

This article is based on the author's personal viewpoint which may be subjective.

Practical limitations

The paper provides researchers with an insight on the importance of attitudes as a key contributing factor to change management competency. For the practitioners, it provides another perspective for designing more effective education programs to train change managers with an emphasis on attitudes.

Originality/value

This paper contributes to the existing change management literature by providing insights on the importance of competency, in particular, the “right” attitude required of a change manager.
A set of constitutive functions for dried body to predict entire deformation process of ceramic products during firing
Authors: Matsubara Seishiro , Tarada Kenjiro , Kobayashi Takaya , Saitou Toshiyuki , Umeda Manabu , Mihara Yasuko , Oide Kai , Shin Hiroto , Katsuda Yasuhiro
Published: September 2017

Purpose

The purpose of this paper is to propose a set of constitutive functions for dried bodies for accurate prediction of the entire deformation process of ceramic products during firing and to present relevant methods for determining their coefficients from a series of respective thermo-mechanical analysis (TMA) tests.

Design/methodology/approach

The function forms of the sintering-induced strain rate, viscoplastic multiplier and elastic modulus are formulated in order with reference to empirical data of relative densities. Separate TMA tests are conducted to identify their coefficients, while a stairway thermal cycle test is carried out to identify the parameters in the densification rate. Then, various finite element analyses (FEA) are performed for accuracy confirmation.

Findings

The performances of the present constitutive functions along with the identified material parameters were validated in comparison with the relevant test results. It has then been confirmed that these functions enable us to some extent to accurately estimate the non-mechanical and mechanical deformations of dried bodies during firing. Also, by performing FEA of an actual sanitary ware product, the applicability and capability of the proposed set of constitutive functions could be demonstrated.

Practical implications

The present methodology with the proposed constitutive functions is a simple, but reliable and practical approach for simulating the deformation process of arbitrary ceramic products subjected to firing and applicable for practical applications in various engineering fields.

Originality/value

The constitutive functions of the viscoplastic multiplier and elastic modulus, which enable us to properly characterize the mechanical behavior of dried bodies subjected to firing, are originally formulated in analogy with that of the sintering-induced strain.
Mental Wellbeing Impact Assessment (MWIA) in the workplace
Authors: Burford Charlotte , Davey Silvia , Knight Alec , King Sadie , Cooke Anthea , Coggins Tony
Published: September 2017

Purpose

The Mental Wellbeing Impact Assessment (MWIA) is an evidence-based tool that guides decision makers, such as policy makers and service managers, about the potential impacts of a new programme or policy change. It was initially used in urban regeneration but has subsequently been used in housing, children’s centres and education. The purpose of this paper is to report, for the first time, on the strengths and weaknesses of using the MWIA in the workplace.

Design/methodology/approach

Feedback was collected from staff who participated in stakeholder workshops as part of the MWIA process at two different public sector organisations.

Findings

The MWIA can be used as an effective workplace assessment tool and is valuable as both a diagnostic tool and as an intervention in its own right. The MWIA generates tailored action plans focussed on addressing the organisation or team-specific issues. The weaknesses of the MWIA in the workplace are mainly focussed around management cooperation and commitment to the process which should be screened for prior to engaging in the full stakeholder workshop.

Originality/value

This is the first report of MWIA’s use in the workplace but suggests that it is a useful tool which can be used to support workplace wellbeing, especially in relation to a policy or organisational change. Further studies should be carried out to fully understand the impact of the MWIA in the workplace.
A multi-level test for social regulatory focus and team member creativity
Authors: Lin Chen-Ju
Published: September 2017

Purpose

In this study, self-leadership strategy serves as a self-regulatory mediating mechanism of individual differences in predicting individual creativity because it is related to actions intended to lead their own goal-directed activities. The purpose of this paper is to explore the boundary conditions of the effect of regulatory focus on employee self-leadership behaviors.

Design/methodology/approach

Considering the contextual influence, cross-level moderating effect of empowering leadership on the relationship between the promotion (prevention) focus and self-leadership has been examined. The research data were collected from 441 employees of 65 work teams from three software companies located in Northern Taiwan. A time-lagged design by implementing three time surveys was applied to minimize potential problems of cross-sectional design. At Time 1, employees completed the measures of promotion focus, prevention focus, empowering leadership, and individual-level control variables. At Time 2, employees reported the extent of their self-leadership at work. In the final survey, team leaders assessed the individual employee creativity.

Findings

This study concludes several findings. When self-leading behavior-focused strategies are considered as mediators, the indirect relationships that promotion focus and prevention focus had with individual creativity were confirmed. As an influential team-level indicator, empowering leadership could moderate the relatedness between employees promotion-focused strategies and behavior-focused strategies that positively influenced on individual creativity.

Originality/value

In this study, responding to the call by De Stobbeleiret al.(2011) to examine how employees actively manage their creative performance, the author zoomed in on self-leadership strategies and how these strategies relate to actual creative performance.
Separation and purification of hypocholesterolaemic peptides from whey protein and their stability under simulated gastrointestinal digestion
Authors: Jiang Chen , Liu Lu , Li Xiaodong , Ma Liyuan , Du Lingling , Zhao Yongbo , Li Donghua , Zhao Weili
Published: September 2017

In this study, hypocholesterolaemic peptides were separated from whey protein trypsin hydrolysates (WPTHs) and the inhibition of cholesterol micellar solubility (ICMS) and the stability of hypocholesterolaemic peptides after exposure to simulated gastrointestinal conditions were evaluated. Whey protein trypsin hydrolysates were concentrated by ultrafiltration and then desalted through macroporous adsorption resin DA201‐C. Sephadex G‐50 gel filtration chromatography was used to separate the hypocholesterolaemic peptides from the fraction eluted with 75% ethanol. The results suggested that the fraction obtained by gel filtration with a molecular weight (MW) ranging from 1900 Da to 3100 Da exhibited the highest hypocholesterolaemic activity. This fraction was further separated by reversed‐phase high‐performance liquid chromatography into 14 fractions; the peptides with the highest activities were obtained from the fifth peak with a MW of 2454 Da and 58.77% ICMS. The hypocholesterolaemic peptides were relatively stable when exposed to simulated gastrointestinal digestion.
FGF19 genetic amplification as a potential therapeutic target in lung squamous cell carcinomas
Authors: Zhang Xiaochen , Kong Mei , Zhang Zhen , Xu Suzhen , Yan Feifei , Wei Liyuan , Zhou Jianying
Published: September 2017

Background

Although FGF19 gene aberrations are associated with carcinogenesis and progression in human cancers, the roles of FGF19 genetic amplification and expression in Chinese patients with lung squamous cell carcinoma (LSCC) and FGF19 amplification as a potential therapeutic target for LSCC are not well understood.

Methods

Fluorescence in situ hybridization analysis and quantitative real‐time‐PCR was used to detect FGF19 genetic amplification and FGF19 messenger RNA expression in LSCC tumor and paired adjacent samples. Small interfering RNA and short hairpin RNA were used to knockdown FGF19 in vitro and in vivo.

Results

FGF19 amplification was identified in a subset of LSCC patients (37.5%, 15/40), and upregulation of FGF19 expression was found in 60% (24/40) of tumor tissues compared to adjacent non‐tumorous tissues. Correlation analysis with clinicopathologic parameters showed that FGF19 upregulation was significantly associated with heavy smoking. Small interfering RNA knockdown of FGF19 led to the significant inhibition of cell growth and induced apoptosis in LSCC cells carrying the amplified FGF19 gene, but these effects was not observed in non‐amplified LSCC cells. Interfering FGF19 expression with short hairpin RNA also resulted in tumor growth inhibition and induced apoptosis in LSCC xenografts with amplified FGF19 in tumor cells.

Conclusion

Our results suggested that FGF19 signaling activation is required for cell growth and survival of FGF19 amplified LSCC cells, both in vitro and in vivo. Intervention of FGF19 activation could be a potential therapeutic strategy for LSCC patients with FGF19 amplification.
Impact of shoulder dystocia, stratified by type of manoeuvre, on severe neonatal outcome and maternal morbidity
Authors: Michelotti Flurina , Flatley Christopher , Kumar Sailesh
Published: September 2017

Background

Shoulder dystocia is an uncommon and unpredictable obstetric emergency. It is associated with significant neonatal, maternal and medico‐legal consequences.

Aim

To ascertain the impact shoulder dystocia has on severe neonatal and maternal outcomes specific to the type of manoeuvre.

Materials and methods

This was a retrospective study of 48 021 term singleton vaginal deliveries the Mater Mothers' Hospital in Brisbane between 2007 and 2015. Maternal and neonatal outcomes were compared between deliveries complicated by shoulder dystocia and those uncomplicated.

Results

Deliveries complicated by shoulder dystocia are associated with low Apgar scores (≤3) at five minutes (odds ratio (OR) 5.25, 95% CI 3.23–8.56, P < 0.001), acidosis (OR 3.10, 95% CI 2.76–3.50, P < 0.001), postpartum haemorrhage (OR 2.28, 95% CI 1.90–2.75, P < 0.001) and perineal trauma (OR 1.92, 95% CI 1.54–2.39, P < 0.001). Compared to McRoberts' manoeuvre and suprapubic pressure alone, the odds of serious neonatal outcome are increased with internal rotational manoeuvres (OR 3.82, 95% CI 2.54–5.74, P < 0.001) and delivery of the posterior arm (OR 4.49, 95% CI 3.54–5.69, P < 0.001). The OR of maternal injury is 2.07 (95% CI 1.77–2.45, P < 0.001), 2.26 (95% CI 1.21–4.21, P < 0.001) and 2.29 (95% CI 1.58–3.32, P < 0.001) with McRoberts'/suprapubic pressure, internal rotation and posterior arm delivery, respectively. Brachial plexus injuries and fractures complicate 1.4 and 0.9% of deliveries, with the risk of injury increasing when greater than one manoeuvre is required.

Conclusion

The risk of neonatal and maternal trauma is strongly associated with the number and types of manoeuvres. Given the associated implications, adequate antenatal counselling, simulation training and enhanced labour surveillance are essential.
Nutritive value and fermentation quality of palisadegrass and stylo mixed silages
Authors: da Silva Juliana S. , Ribeiro Karina G. , Pereira Odilon G. , Mantovani Hilário C. , Cecon Paulo R. , Pereira Rosana C. , Silva Janaina de L.
Published: September 2017

The nutritive value and fermentation quality of palisadegrass (Brachiaria brizantha cv. Xaraes) and stylo (Stylosanthes capitata × S. macrocephala cv. Campo Grande) mixed silages were evaluated. The experiment was analyzed in a factorial scheme (5 × 2) in a completely randomized design using increasing levels of stylo (0, 25, 50, 75 and 100% on a fresh matter basis) on palisadegrass silages, with and without microbial inoculants (MI). With the increased ratio of stylo in mixed silages, dry matter (DM), crude protein (CP), acid detergent fiber (ADF), and lignin content increased in silages. The presence of MI promoted lower DM content, and higher neutral detergent fiber corrected for ash and protein, ADF and lignin content. The acid detergent insoluble nitrogen content and the lactic acid bacteria populations were not affected by treatments. The in vitroDM digestibility was affected by the interaction of levels of the stylo and MI. The pH, NH3‐N/total nitrogen and butyric acid concentrations decreased with increasing levels of stylo. Better nutritive value and quality of fermentation was found in the silage containing higher proportions of this stylo mixed with palisadegrass. The microbial inoculant evaluated did not alter the nutritive value or quality of the fermentation of the silages in this experiment.
PDE1A inhibition elicits cGMP‐dependent relaxation of rat mesenteric arteries
Authors: Khammy Makhala Michell , Dalsgaard Thomas , Larsen Peter Hjørringgaard , Christoffersen Claus Tornby , Clausen Dorte , Rasmussen Lars Kyhn , Folkersen Lasse , Grunnet Morten , Kehler Jan , Aalkjær Christian , Nielsen Jacob
Published: September 2017

Background and Purpose

PDE1, a subfamily of cyclic nucleotide PDEs consisting of three isoforms, PDE1A, PDE1B and PDE1C, has been implicated in the regulation of vascular tone. The PDE1 isoform(s) responsible for tone regulation is unknown. This study used isoform‐preferring PDE1 inhibitors, Lu AF58027, Lu AF64196, Lu AF66896 and Lu AF67897, to investigate the relative contribution of PDE1 isoforms to regulation of vascular tone.

Experimental Approach

In rat mesenteric arteries, expression and localization of Pde1 isoforms were determined by quantitative PCR and in situ hybridization, and physiological impact of PDE1 inhibition was evaluated by isometric tension recordings.

Key Results

In rat mesenteric arteries, Pde1a mRNA expression was higher than Pde1b and Pde1c. In situ hybridization revealed localization of Pde1a to vascular smooth muscle cells (VSMCs) and only minor appearance of Pde1b and Pde1c. The potency of the PDE1 inhibitors at eliciting relaxation showed excellent correlation with their potency at inhibiting PDE1A. Thus, Lu AF58027 was the most potent at inhibiting PDE1A and was also the most potent at eliciting relaxation in mesenteric arteries. Inhibition of NOS with l‐NAME, soluble GC with ODQ or PKG with Rp‐8‐Br‐PET‐cGMP all attenuated the inhibitory effect of PDE1 on relaxation, whereas PKA inhibition with H89 had no effect.

Conclusions and Implications

Pde1a is the dominant PDE1 isoform present in VSMCs, and relaxation mediated by PDE1A inhibition is predominantly driven by enhanced cGMP signalling. These results imply that isoform‐selective PDE1 inhibitors are powerful investigative tools allowing examination of physiological and pathological roles of PDE1 isoforms.
p53‐mediated regulation of bile acid disposition attenuates cholic acid‐induced cholestasis in mice
Authors: Chen Pan , Li Dongshun , Chen Yixin , Sun Jiahong , Fu Kaili , Guan Lihuan , Zhang Huizhen , Jiang Yiming , Li Xi , Zeng Xuezhen , Chen Xiao , Huang Min , Bi Huichang
Published: September 2017

Background and Purpose

The tumour suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have demonstrated that it contributes to metabolic diseases. Here, we investigated the role of p53 in the regulation of bile acid disposition and cholestasis.

Experimental Approach

The bile acid disposition‐related gene expression profile affected by p53 activation was assessed in mouse primary hepatocytes with p53 depletion and in Trp53‐null mice. Dual luciferase reporter assay was used to detect the transcriptional activities of target genes. Anticholestatic effects of p53 activator doxorubicin were investigated in a 0.5% cholic acid‐fed mouse model of cholestasis. Changes in bile acids were evaluated using metabolomics analysis.

Key Results

Doxorubicin‐mediated p53 activation induced Cyp2b10, Sult2a1 and Abcc2/3/4 expression in mice in vitro and in vivo. ABCC3 and CYP2B6 (human orthologue of Cyp2b10) were identified as direct p53 target genes. Doxorubicin attenuated cholic acid‐induced cholestasis in mice, as demonstrated by shrunken gall bladder, decreased serum total bile acid and total bilirubin levels and alkaline phosphatase activity. Targeted metabolomics analysis revealed that doxorubicin enhanced the excretion of bile acid metabolites from serum and liver to intestine and faeces. Up‐regulation of Cyp2b10, Sult2a1 and Abcc2/3/4 expression was further confirmed in cholestatic mice. Cholic acid‐induced cholestatic injury was aggravated in p53‐deficient mice and levels of bile acid in intestine and faeces were decreased.

Conclusions and Implications

Our findings suggest a novel role of p53 in promoting bile acid disposition and alleviating cholestatic syndrome, which provides a potential therapeutic target for cholestasis.
Nucleoside/nucleotide reverse transcriptase inhibitors attenuate angiogenesis and lymphangiogenesis by impairing receptor tyrosine kinases signalling in endothelial cells
Authors: Song Lin , Ding Sha , Ge Zhen , Zhu Xiaolong , Qiu Cong , Wang Yuewen , Lai Enyin , Yang Weijun , Sun Yi , Chow Samson A , Yu Luyang
Published: September 2017

Background and Purpose

Cardiovascular disease associated with antiretroviral therapy (ART) has become a major clinical challenge for HIV‐positive patients. However, the role of ART in blood vessel growth is largely unknown. Here, we examined an integral component of ART, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and investigated their effects on key microvascular functions, including angiogenesis and lymphangiogenesis.

Experimental Approach

The angiogenesis/lymphangiogenesis capability of endothelial cells (ECs) was evaluated using migration, proliferation and tube formation assaysin vitro, and mouse ear and Matrigel plug assaysin vivo. Expressions of signalling molecules and mitochondrial antioxidant catalases were determined using Western blotting. Receptor tyrosine kinase (RTK) internalization and endocytosis were examined using flow cytometry and confocal immunofluorescence microscopy respectively. Mitochondrial DNA copy number and ROS were determined using quantitative real‐time PCR and MitoSOX staining respectively.

Key Results

Pharmaceutical doses of NRTIs [azidothymidine (AZT), tenofovir disoproxil fumarate (TDF) and lamivudine (3TC)] inhibited angiogenesis and lymphangiogenesis bothin vivoandin vitroby affecting the proliferation and migration of ECs. Correspondingly, NRTIs selectively attenuated the activation and transduction of endothelial RTK signals, VEGFR2 and FGFR1 pathways, in vascular ECs and the VEGFR3 pathway in lymphatic ECs. Both TDF and 3TC restrained RTKs’ endocytosis into early endosomes but not internalization, while AZT blocked the protein maturation of RTKs. Excessive ROS levels were detected in NRTI‐treated ECs, and the MnSOD mimic MnTMPyP alleviated the angiogenic/lymphangiogenic defects induced by NRTIs.

Conclusions and Implications

NRTIs negatively regulate angiogenesis and lymphangiogenesis by inducing mitochondrial oxidative stress and subsequently impairing RTK signalling in ECs.

Linked Articles

This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visithttp://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc
Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding
Authors: Mariotti Laura , Pollock Katie , Guettler Sebastian
Published: September 2017

The Wnt/β‐catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration‐limited pathway components and a wide range of post‐translational modifications, including phosphorylation, ubiquitylation, sumoylation, poly(ADP‐ribosyl)ation (PARylation) and acetylation. Regulation of Wnt/β‐catenin signalling by PARylation was discovered relatively recently. The PARP tankyrase PARylates AXIN1/2, an essential central scaffolding protein in the β‐catenin destruction complex, and targets it for degradation, thereby fine‐tuning the responsiveness of cells to the Wnt signal. The past few years have not only seen much progress in our understanding of the molecular mechanisms by which PARylation controls the pathway but also witnessed the successful development of tankyrase inhibitors as tool compounds and promising agents for the therapy of Wnt‐dependent dysfunctions, including colorectal cancer. Recent work has hinted at more complex roles of tankyrase in Wnt/β‐catenin signalling as well as challenges and opportunities in the development of tankyrase inhibitors. Here we review some of the latest advances in our understanding of tankyrase function in the pathway and efforts to modulate tankyrase activity to re‐tune Wnt/β‐catenin signalling in colorectal cancer cells.

Linked Articles

This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc
How Children Construct Views of Themselves: A Social‐Developmental Perspective
Authors: Brummelman Eddie , Thomaes Sander
Published: September 2017

As they grow up, children construct views of themselves and their place in the world, known as their self‐concept. This topic has often been addressed by social psychologists (studying how the self‐concept is influenced by social contexts) and developmental psychologists (studying how the self‐concept changes over time). Yet, relatively little is known about the origins of the self‐concept. This article calls for research that bridges social and developmental psychology to illuminate this important issue. Adopting such a social‐developmental approach, the current special section shows that children construct their self‐concept based on the social relationships they have, the feedback they receive, the social comparisons they make, and the cultural values they endorse. These findings underline the deeply social nature of self‐development.
TSGA10 is a novel candidate gene associated with acephalic spermatozoa
Authors: Sha Y.‐W. , Sha Y.‐K. , Ji Z.‐Y. , Mei L.‐B. , Ding L. , Zhang Q. , Qiu P.‐P. , Lin S.‐B. , Wang X. , Li P. , Xu X. , Li L.
Published: September 2017

Acephalic spermatozoa is a rare teratozoospermia associated with male infertility. However, the pathogenesis of this disorder remains unclear. Here, we report a 27 years old infertile male from a consanguineous family, who presented with 99% headless sperm in his ejaculate. Electron microscopic and immunofluorescence analysis suggested breakage at the midpiece of the patient's sperm cells. Subsequent whole‐exome sequencing analysis identified a homozygous deletion within TSGA10 (c.211delG; p.A71Hfs*12), which resulted in the production of truncated TSGA10 protein. TSGA10 is a testis‐specific protein that localized to the midpiece in the spermatozoa of a normal control; however, immunostaining failed to detect TSGA10 protein in the patient's sperm. Western blot analysis also showed complete absence of TSGA10 protein in the patient. One cycle of in vitro fertilization‐assisted reproduction was conducted, but pregnancy was not achieved after embryo transfer, possibly due to poor embryo quality. Therefore, we speculate that the presence of rare sequence variants within TSGA10 may be associated with acephalic spermatozoa in humans.
Evaluation of volumetric dimensional changes in posterior extraction sites with and without ARP using a novel imaging device
Authors: Sbordone Carolina , Toti Paolo , Martuscelli Ranieri , Guidetti Franco , Porzio Massimo , Sbordone Ludovico
Published: September 2017

Background

Alveolar ridge volume loss may be minimized when postextraction sockets are filled by bone substitutes.

Purpose

The aim of the study was to measure the effect of alveolar ridge preservation (ARP) in maintaining the external contour of the ridge after fresh socket grafting with or without particulate anorganic bovine bone mineral (BBM) and resorbable barrier covering.

Materials and methods

In the present controlled study, patients subjected to single‐tooth extraction were allocated to 2 groups: postextraction sockets grafted with bovine bone mineral (bbm), and naturally healing sockets (nat). Before and at 5 months following tooth extraction, plaster cast contours of the sockets were acquired by means of an optical scanner; the 2 contours of each patient underwent voxelization and fusion using a matrix elaborator. Outcome variables at 5 months (volumetric, surface, and linear changes) were measured in digital fused plaster casts with a dental scan software analyzing a volume of interest ranging from residual papilla to 10 mm toward the apical point. Intra‐ and inter‐group pair‐wise variables' comparisons were conducted. Level of significance was set at 0.05.

Results

Twenty‐four sites were enrolled: 12 ARP and 12 naturally healed. Five‐month percentage of volume loss of the bbm‐group (21.7% ± 7.4%) was significantly lower (Ps < .0003) than that of the naturally healing group (38.8% ± 7.9%). When tooth position was investigated, volume loss in percentage registered a significantly better (P values ≤ .0485) behavior in molars (ΔV% = −19.1% ± 6.5% and ΔV% = −35.6% ± 7.6%, respectively, for bbm and nat) than that in premolars (ΔV% = −26.9% ± 7.2% and ΔV% = −45.1% ± 4.2%, respectively, for bbm and nat), in both the preserved and naturally healing groups.

Conclusion

The dimensional loss in postextraction sockets grafted with anorganic bovine bone substitute and covered by a resorbable collagen barrier was lower than that of the naturally healing sites. However, ridge preservation was able to maintain almost 80% of the pristine bone.
First experience in colorectal surgery with a new robotic platform with haptic feedback
Authors: Spinelli A. , David G. , Gidaro S. , Carvello M. , Sacchi M. , Montorsi M. , Montroni I.
Published: September 2017

Aim

The use of robotic techniques in colorectal surgery is increasing. Recently, the Senhance™ surgical robotic system was introduced as a novel robotic platform designed to overcome some of the limits of standard laparoscopy. This study describes the initial, single‐center experience, evaluating feasibility and safety of the new robotic system in performing colorectal surgical procedures.

Methods

From June 2015 to November 2016, perioperative data of the first 45 patients who underwent robotic colorectal surgery with the Senhance™ surgical robotic system were collected and analysed. Indications for surgery included inflammatory bowel disease, colorectal cancer, endoscopically unresectable adenomas and complicated diverticular disease.

Results

The median age of patients was 57 (range: 18–92) years and the median body mass index (BMI) was 24 (range: 16–30) kg/m2. Surgical indications were colorectal cancer (66%), complicated inflammatory bowel disease (18%), diverticular disease (11%) and endoscopically unresectable adenoma (4.4%). The median operative time was 256 minutes, and the median docking time was 10.7 (range: 2–25) min. There were three conversions to standard laparoscopy and none to laparotomy. All patients operated on for malignancy (28 adenocarcinoma and 2 neuroendocrine tumours) underwent an appropriate oncological procedure. The median time to discharge was 5 (range: 3–19) days. The incidence of postoperative complications was 35.5% (Clavien–Dindo I/II, 14 patients; and Clavien–Dindo III, two patients). One patient was readmitted in the postoperative period. No patient required reoperation.

Conclusion

The results of this audit suggest that adoption of the Senhance™ surgical robotic system in colorectal surgery is feasible and safe. More clinical data are needed to determine whether this approach can offer any other benefits over other minimally invasive surgical techniques.
Exercise to preserve β‐cell function in recent‐onset Type 1 diabetes mellitus (EXTOD) – a randomized controlled pilot trial
Authors: Narendran P. , Jackson N. , Daley A. , Thompson D. , Stokes K. , Greenfield S. , Charlton M. , Curran M. , Solomon T. P. J. , Nouwen A. , Lee S. I. , Cooper A. R. , Mostazir M. , Taylor R. S. , Kennedy A. , Andrews R. C.
Published: September 2017

Aim

Residual β‐cell function is present at the time of diagnosis with Type 1 diabetes. Preserving this β‐cell function reduces complications. We hypothesized that exercise preserves β‐cell function in Type 1 diabetes and undertook a pilot trial to address the key uncertainties in designing a definitive trial to test this hypothesis.

Methods

A randomized controlled pilot trial in adults aged 16–60 years diagnosed with Type 1 diabetes within the previous 3 months was undertaken. Participants were assigned to control (usual care) or intervention (exercise consultation every month), in a 1 : 1 ratio for 12 months. The primary outcomes were recruitment rate, drop out, exercise adherence [weeks with ≥ 150 min of self‐reported moderate to vigorous physical activity (MVPA)], and exercise uptake in the control group. The secondary outcomes were differences in insulin sensitivity and rate of loss of β‐cell function between intervention and control at 6 and 12 months.

Results

Of 507 individuals who were approached, 58 (28 control, 30 intervention) entered the study and 41 completed it. Participants were largely white European males, BMI 24.8 ± 3.8 kg/m2, HbA1c 75 ± 25 mmol/mol (9 ± 2%). Mean level of objectively measured MVPA increased in the intervention group (mean 243 to 273 min/week) and 61% of intervention participants reached the target of ≥ 150 min/week of self‐reported MVPA on at least 42 weeks of the year. Physical activity levels fell slightly in the control group (mean 277 to 235 min of MVPA/week). There was exploratory evidence that intervention group became more insulin sensitive and required less insulin. However, the rate of loss of β‐cell function appeared similar between the groups, although the change in insulin sensitivity may have affected this.

Conclusion

We show that it is possible to recruit and randomize people with newly diagnosed Type 1 diabetes to a trial of an exercise intervention, and increase and maintain their exercise levels for 12 months. Future trials need to incorporate measures of greater adherence to exercise training targets, and include more appropriate measures of β‐cell function. (Clinical Trials Registry No; ISRCTN91388505)
First reported case of Hypoderma diana Brauer, 1985 (Diptera: Oestridae)‐associated myiasis in a horse in Germany
Authors: Borges F. , Sybrecht G. W. , von Samson‐Himmelstjerna G.
Published: September 2017

A massive infestation with warble fly larvae was observed in a mare in Lower Saxony, Germany. From a herd of 20 horses, only a single mare accidently escaped the routine treatment with macrocyclic lactone in autumn and showed the myiasis infestation next year in January. Eighteen subcutaneous nodules were found on the back (n = 2), ribs (n = 3), flank (n = 5) and croup (n = 8). Deer, the specific hosts of the warble fly Hypoderma diana, was abundant on this farm and some other risk factors for the hypodermiosis are discussed herein. This is the first report of myiasis caused by H. diana in horses in Germany. This massive warble fly infestation in a horse in Germany reported here is important to alert equine health professionals concerning the prevention of this disease in the routine parasite control programme.