bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of dynamic balance between vesicle transport and microtubule growth in neurite outgrowth enables formation of dystrophic bulbs
Authors: Yadaw Arjun Singh , Siddiq Mustafa M. , Rabinovich Vera , Tolentino Rosa , Iyengar Ravi , Hansen Jens
Published: June 2017

Whole cell responses involve multiple subcellular processes (SCPs). To understand how balance between SCPs controls the dynamics of whole cell responses we studied neurite outgrowth in rat primary cortical neurons in culture. We used a combination of dynamical models and experiments to understand the conditions that permitted growth at a specified velocity and when aberrant growth could lead to the formation of dystrophic bulbs. We hypothesized that dystrophic bulb formation is due to quantitative imbalances between SCPs. Simulations predict redundancies between lower level sibling SCPs within each type of high level SCP. In contrast, higher level SCPs, such as vesicle transport and exocytosis or microtubule growth characteristic of each type need to be strictly coordinated with each other and imbalances result in stalling of neurite outgrowth. From these simulations, we predicted the effect of changing the activities of SCPs involved in vesicle exocytosis or microtubule growth could lead to formation of dystrophic bulbs. siRNA ablation experiments verified these predictions. We conclude that whole cell dynamics requires balance between the higher-level SCPs involved and imbalances can terminate whole cell responses such as neurite outgrowth.
Alpha EEG power reflects the suppression of Pavlovian bias during social reinforcement learning
Authors: Thompson James C , Westwater Margaret L
Published: June 2017

Socially appropriate behavior involves learning actions that are valued by others and those that have a social cost. Facial expressions are one way that others can signal the social value of our actions. The rewarding or aversive properties of signals such as smiles or frowns also evoke automatic approach or avoidance behaviors in receivers, and a Pavlovian system learns cues that predict rewarding or aversive outcomes. In this study, we examined the computational and neural mechanisms underlying interactions between Pavlovian and Instrumental systems during social reinforcement learning. We found that Pavlovian biases to approach cues predicting social reward and avoid cues predicting social punishment interfered with Instrumental learning from social feedback. While the computations underlying Pavlovian and Instrumental interactions remained the same as when learning from monetary feedback, Pavlovian biases from social outcomes to approach or withdraw were not significantly correlated with biases from money. Trial-by-trial measures of alpha (8-14Hz) EEG power was associated with suppression of Pavlovian bias to social outcomes, while suppression of bias from money was associated with theta (4-7Hz) EEG power. Our findings demonstrate how emotional reactions to feedback from others are balanced with the instrumental value of that feedback to guide social behavior.

Significance statement

A smile from another can be a signal to continue what we are doing, while an angry scowl is a sure sign to stop. Feedback from others such as this plays an important role in shapeing social behavior. The rewarding nature of a smile (or the aversive nature of a scowl) can also lead to automatic tendencies to approach (or avoid), and we can learn situations that predict positive or negative social outcomes. In this study, we examined the brain mechanisms that come into play when the instrumental demands of a situation are in conflict with our automatic biases to approach or withdraw, such as when we have to approach someone who is scowling at us or withdraw from someone who is smiling.
Analysis of RAS as a tumor suppressor
Authors: Kenney Chelsey , Stites Edward C.
Published: June 2017

The RAS GTPases are among the best-understood oncogenes that promote human cancer. Many have argued that non-mutated, wild-type, RAS also functions as a tumor suppressor. The arguments for RAS tumor suppressor activity often involve data that are claimed to be inconsistent with known principles of RAS biology. RAS tumor suppressor activity is invoked to explain these observations. Here, we consider an alternative hypothesis: these data are actually consistent with RAS biology. We investigate by using our previously developed mathematical model of RAS regulation. We find that three of five arguments for RAS having tumor suppressor activity are based upon data that the model demonstrates are actually consistent with known RAS biology. We also find that the other two types of data interpreted to indicate a tumor suppressor effect can be explained by our model with the additional assumption that RAS protein expression does not vary proportionally with gene dosage. Measurements of RAS protein expression as a function of gene dosage could help resolve whether or not RAS has tumor suppressor activity. Overall, we conclude that the evidence for RAS having tumor suppressor activity is much less strong that it has appeared.
A computational panel of pathological RAS mutants with implications for personalized medicine and genetic medicine
Authors: Kenney Chelsey , Stites Edward C.
Published: June 2017

The RAS proteins (KRAS, NRAS, and HRAS) play important roles in multiple diseases. This includes many types of cancer and the developmental syndromes collectively referred to as the RASopathies. There are many different RAS mutants that are found to drive these diseases. Mutant-to-mutant differences pose a challenge for personalized medicine. To investigate this problem, we extend our previously developed model of oncogenic RAS mutants to a total of 16 oncogenic mutants. We also extend our model to RASopathy associated mutants using data for 14 such RAS mutants. The model finds that the known biochemical defects of these mutants are typically sufficient to explain their elevated levels of RAS signaling. In general, our analysis finds that the oncogenic mutants are stronger than the RASopathy mutants. However, the model suggests that RAS signal intensities are spanned by the pathological variants; there does not appear to be a perfect separation between cancer promoting and developmental syndrome promoting mutants. Analysis of the panel also finds that the relative strengths of pathological RAS mutants is not absolute, but rather can vary depending on context. We discuss implications of this finding for personalized cancer medicine and for medical genetics. As genomics permeates clinical medicine, computational models that can resolve mutant specific differences, like the one presented here, may be useful for augmenting clinical thinking with their ability to logically translate biochemical knowledge into system level outputs of perceived clinical relevance.
Global Efficiency of Retinal Networks shows Robustness and Degenerate States
Authors: Signorelli Camilo Miguel
Published: June 2017

This exploratory project report provides a study of the retina in response to spontaneous and evoked pattern of flashes for different time cycles. These patterns induce changes at individual neural level and network level, while global efficiency, a topological network measure, presents robustness and degenerate states across time. This report also discusses some alternatives to explain changes observed and how it could be related to oscillatory plasticity mechanism.
The dynamics between entrepreneurial orientation, transformational leadership, and intrapreneurial intention in Iranian R&D sector
Authors: Razavi Seyed Hadi , Ab Aziz Kamarulzaman
Published: June 2017

Purpose

The purpose of this paper is to examine the relationship between entrepreneurial orientation (EO) and intrapreneurial intentions among knowledge workers in the Iranian R&D sector using transformational leadership (TL) as a moderator and to also investigate the extent of the knowledge workers’ intrapreneurial intentions.

Design/methodology/approach

The research was tested as a cross-sectional survey of knowledge workers involved in the R&D centers in Iran under the Society of the Centers for Research. The sampling method in this study was based on simple random sampling. Finally, 380 valid questionnaires were collected from 48 R&D centers of different industries.

Findings

The findings of this study reveal that except for the “need for achievement (NFA),” other variables such as “innovativeness,” “proactiveness,” “risk taking,” and “networking” had a significant and positive relationship toward “intrapreneurial intention.” Moreover, it was found that “TL” had a moderating role in the relations between innovativeness, proactiveness, and risk taking with intrapreneurial intention; however, TL did not have a moderating role in the relations between NFA and networking with intrapreneurial intention.

Research limitations/implications

Reliance on cross-sectional questionnaires instead of an experimental design imposes caution about the relationships between the predictors and intrapreneurial intention.

Originality/value

This paper is one of the few studies on the EO at the individual level with new dimensions on the intrapreneurial intention, which examined moderating role of TL at this relationship, which took place in Iranian R&D sector.
E-portfolios and personal development: a higher educational perspective
Authors: McKenna Gary , Baxter Gavin , Hainey Thomas
Published: June 2017

Purpose

The purpose of this paper is to investigate the attitudes of staff and students towards adopting the use of e-portfolios for the purposes of supporting the concept of personal development planning (PDP). The study compares and contrasts the views and opinions of staff and students at one UK Higher Education Institution (HEI) about whether e-portfolios can support PDP.

Design/methodology/approach

Adopting a case study approach, this study presents empirical data gathered from two surveys involving 460 students and 182 lecturers from one UK HEI, collected from four different campuses across the West of Scotland.

Findings

The results of the surveys showed that the framework the authors used in the research to collect information about students and staffs attitudes was effective and that further research is merited for a more extensive investigation into PDP e-portfolio usage within HEI.

Research limitations/implications

The research was conducted at only one UK HEI so at this stage of the research, it is difficult to assess how generalisable the findings are.

Practical implications

This study provides useful empirical evidence to educators who may be considering employing e-portfolios within an educational context. For example, the views of students and staff identified in this paper can aid towards informing educators about some of the issues that might impact on using e-portfolios for supporting PDP in higher education.

Originality/value

To the best of the authors’ knowledge, this is the first work that presents survey data on both students’ and lecturers’ attitudes towards e-portfolio use to support and facilitate PDP.
Emotional reframing as a mediator of the relationships between transformational school leadership and teachers’ motivation and commitment
Authors: Berkovich Izhak , Eyal Ori
Published: June 2017

Purpose

Empirical evidence links transformational school leadership to teachers’ autonomous motivation and affective organizational commitment. Little empirical research, however, has focused on the emotional mechanisms behind these relations. Following the argument in the literature that transformational leadership can transform followers’ emotions, the purpose of this paper is to examine whether teacher’s experience of emotional reframing by principal mediates the relationships between transformational school leadership and these work-related outcomes (i.e. teachers’ motivation and commitment).

Design/methodology/approach

Questionnaires were used to collect information from 639 primary school teachers nested in 69 randomly sampled schools. The data were analyzed using multilevel path analysis software.

Findings

The results indicated that the effect of transformational school leadership behaviors on teachers’ autonomous motivation was fully mediated by emotional reframing, and that the effect of transformational school leadership on affective organizational commitment was partially mediated by it. The authors further found an indirect relationship of transformational school leadership with affective organizational commitment through emotional reframing and autonomous motivation.

Originality/value

The present study makes a unique contribution to the literature by confirming that teachers’ sense of emotional reframing is a key affective mechanism by which school leaders influence teachers’ motivation and commitment.
Financial performance and operating strategies of Malaysian property development companies during the global financial crisis
Authors: Chan Toong Khuan , Abdul-Aziz Abdul-Rashid
Published: June 2017

Purpose

The purpose of this paper is to characterise the financial performance and to identify the operating strategies of property development companies in Malaysia during the 2008 global financial crisis (GFC).

Design/methodology/approach

The research approach includes a comprehensive analysis of the financial statements and annual reports of 35 property development companies listed on the Kuala Lumpur stock exchange. The financial statements were analysed to evaluate the financial performance of these companies and to assess the severity of the impact of the GFC on revenues and profits. The operating strategies were determined from a content analysis of the statement to shareholders.

Findings

An aggregated analysis of the financial performance indicates a 23 per cent decline in net profit in 2008. Classifying these companies into two separate sets of distressed and non-distressed companies showed that poor financial performance and a high debt-to-equity ratio pre-GFC led to continuing poor performance during the GFC period and beyond. Survival strategies adopted by distressed companies include the disposal of assets to improve cash flow, refinancing loans, delaying the launch of new projects and reducing their workforce. Non-distressed companies adopted growth strategies such as purchasing land for development, focusing their offerings towards high-end products, vertically integrating and diversification.

Practical implications

The increased understanding of the financial performance and operational strategies will allow managers of property development companies to improve financial management and adopt appropriate strategies in response to the impact of future financial distress.

Originality/value

The study presented in this paper is the first to analyse the financial performance of Malaysian public-listed property development companies during the period of the 2008 GFC and to link their financial performance to operational strategies.
Simulation of charring depth of timber structures when exposed to non-standard fire curves
Authors: Mindeguia Jean-Christophe , Cueff Guillaume , Dréan Virginie , Auguin Gildas
Published: June 2017

Purpose

The fire resistance of wooden structures is commonly based on the calculation or measurement of the char layer. Designers usually estimate the char layer at the surface of a structural element by using analytical models. Some of these charring models can be found in regulations, as Eurocode 5. These analytical models, quite simple to use, are only reliable for the standard fire curve. In that case, the design of the structure is qualified as “prescriptive-based design” and can lead to oversizing the structure. Optimization of a structure can be achieved by using a “Performance-based design”, where realistic fire scenarios are taken into account by means of more or less complex models [parametric fires, two-zones models, computational fluid dynamics (CFD)]. For these so-called “natural fires”, no model for charring is available. The purpose of this paper is to present a novel methodology for applying a performance-based design to a simple timber structure.

Design/methodology/approach

This paper presents the development of a numerical model aiming to simulate the thermal transfer and charring in wood, under any type of thermal exposure, including non-standard fire curves. After presenting the physical background, the model is calibrated and compared to existing experimental studies on wood samples exposed to different fire curves. The model is then used as a tool for assessing the fire resistance of a common wooden structure exposed to standard and non-standard fire curves.

Findings

The results show that the fire resistance is obviously dependent on the choice of the thermal exposure. The reliability of the model is also discussed and the importance of taking into account particular reactions in wood during heating is underlined.

Originality/value

One aim of this paper is to show the opportunity to apply a performance-based approach when designing a wooden structure. It shows that more knowledge of the material behaviour under non-standard fires is still needed, especially during the decay phase.
Advanced analyses of the membrane action of composite slabs under natural fire scenarios
Authors: Lelli Lorenzo , Loutan Jonas
Published: June 2017

Purpose

This paper aims to detail the advanced natural fire simulations that were carried out for the composite steel-reinforced concrete structure of the JTI Building in Geneva, Switzerland. The results of these analyses led to a significant reduction of in the fireproofing of the steel floor framing.

Design/methodology/approach

Several scenarios were studied considering different thermal behaviours of the peripheral cladding. Despite the small thickness of the resisting slabs, the analyses performed with SAFIR software showed that the typical wide storey bay (12 × 15.86 m) can resist to the design’s fire temperatures without the protection of the main and secondary beams while the spandrels remain protected. For study completeness, the composite frame-membrane model was also simulated with Hasemi-localized fire routines on SAFIR.

Findings

The analyses have showed that the membrane behaviour of composite slabs under fire allows a significant reduction of the fire protection, even in case of small thickness of the concrete topping. The increase of the reinforcement ratio to sustain the membrane forces is widely compensated by the savings related to the fireproofing of the steel framing.

Practical/implications

A natural fire approach is particularly advisable in case of fully glazed buildings. In fact when the façade collapses, the entry of a large cold air quantity limits the increase of the gas temperature inside the compartment.

Originality/value

The analyses were carried out with recent SAFIR routines for localized fires (Hasemi fire model) and represent one of the first applications in practice. The issue of the rebar orientation in mesh is raised out. The latest SAFIR release allows the definition of a global orientation of the rebars and amends the issue.
Political Representation on the New Auckland Council – Has Amalgamation Led to Greater Diversity?
Authors: Webster Karen Lesley , Fa'apoi Emiliana
Published: June 2017

This paper explores the diversity of local government electoral candidates and elected members, in Auckland – one of the world's most diverse cities (Chen 2015: 56) – following the 2010 amalgamation. It responds to questions raised over the democratic gaps created by enlarged wards, a lack of diverse representation, and higher elected member ratios. The research asks the question – who stood and who was elected in the election following the Auckland 2010 reforms, and how does this compare with the city's diverse population. Pitkin's (1967) concept of descriptive representation provides the foundation for a comparison of the gender, age, and ethnicity of local population, local government candidates, and elected members, to ascertain descriptive representation. The human rights framework provides a theoretical foundation to examine the diversity of representation. Preliminary findings support the view that under the shared governance model, electoral candidates are becoming more ethnically and gender diverse at the local level; while at the regional level, the dominance of the archetypal councillor as European, middle‐aged and male, prevails.
A ‘movement for improvement’? A qualitative study of the adoption of social movement strategies in the implementation of a quality improvement campaign
Authors: Waring Justin , Crompton Amanda
Published: June 2017

Given the difficulties of implementing ‘top‐down’ quality improvements, health service leaders have turned to methods that empower clinicians to co‐produce ‘bottom‐up’ improvements. This has involved the adoption of strategies and activities associated with social movements, with clinicians encouraged to participate in collective action towards the shared goal of improvement. This paper examines the adoption of social movement methods by hospital managers as a strategy for implementing a quality improvement ‘campaign’. Our case study suggests that, despite the claim of empowering clinicians to develop ‘bottom‐up’ improvements, the use of social movement methods can be more narrowly concerned with engaging clinicians in pre‐determined programmes of ‘top‐down’ change. It finds a prominent role for ‘hybrid’ clinical leaders and other staff representatives in the mobilisation of the campaign, especially for enrolling clinicians in change activities. The work of these ‘hybrids’ suggests some degree of creative mediation between clinical and managerial interests, but more often alignment with the aspirations of management. The study raises questions about the translation of social movement's theories as a strategy for managing change and re‐inventing professionalism.
The Psychology of Billing
Authors: Hansen Victoria J. , Jackson Scott B. , Schaefer Tammie J. , Stewart Bryan W.
Published: June 2017

Contracting between tax entities and tax professionals occurs millions of times every year, yet little is known about the nature of these economic interactions. This study examines the effect of commonly occurring contextual factors on tax professionals’ billing decisions for tax research. These contextual factors are unrelated to the tax research itself and the time it takes to conduct the tax research, but we find that billing decisions are strongly influenced by the three non‐time‐related contextual factors that we manipulate. Initial client volume impacts amounts billed for tax research, with lower initial client volume resulting in higher per client fees. Further, we find that initial billing decisions serve as value billing benchmarks for unanticipated subsequent clients who benefit from research conducted for initial clients. As a result, subsequent clients are billed higher fees when they follow a smaller number of initial clients. We also find that client referrals are billed higher fees than nonclient referrals because professionals attempt to avoid making initial clients feel as though they have been treated unfairly relative to subsequent clients who would otherwise be billed lower fees. The results of this study are relevant beyond the traditional confines of accounting research—they are relevant to the millions of tax entities that contract with tax professionals each year.
EUROPEAN CENTRAL BANK FOOTPRINTS ON INFLATION FORECAST UNCERTAINTY
Authors: Makarova Svetlana
Published: June 2017

The finding of the paper shows the relative effectiveness of the “one size fits all” policy of the European Central Bank. The paper provides strong evidence in favor of this by testing whether the monetary policy effects (footprints) found in inflation uncertainty converge to a common level. These footprints are measured as the fraction of the estimated policy‐induced reduction in this uncertainty. The testing was conducted by applying a bootstrap‐type test in a regression of the rate of growth of these fractions on their initial values, computed for 16 euro area countries. (JEL C33, E52, E58)
Effects of plant quality and ant defence on herbivory rates in a neotropical ant‐plant
Authors: MENDES GISELE M. , CORNELISSEN TATIANA G.
Published: June 2017

1. Understanding the degree to which populations and communities are limited by both bottom‐up and top‐down effects is still a major challenge for ecologists, and manipulation of plant quality, for example, can alter herbivory rates in plants. In addition, biotic defence by ants can directly influence the populations of herbivores, as demonstrated by increased rates of herbivory or increased herbivore density after ant exclusion. The aim of this study was to evaluate bottom‐up and top‐down effects on herbivory rates in a mutualistic ant‐plant.

2. In this study, the role ofAzteca alfariants as biotic defence in individuals ofCecropia pachystachyawas investigated experimentally with a simultaneous manipulation of both bottom‐up (fertilisation) and top‐down (ant exclusion) factors. Four treatments were used in a fully factorial design, with 15 replicates for each treatment: (i) control plants, without manipulation; (ii) fertilised plants, ants not manipulated; (iii) unfertilised plants and excluded ants and (iv) fertilised plants and ants excluded.

3. Fertilisation increased the availability of foliar nitrogen inC. pachystachya, and herbivory rates by chewing insects were significantly higher in fertilised plants with ants excluded.

4. Herbivory, however, was more influenced by bottom‐up effects – such as the quality of the host plant – than by top‐down effects caused by ants as biotic defences, reinforcing the crucial role of leaf nutritional quality for herbivory levels experienced by plants. Conditionality in ant defence under increased nutritional quality of leaves through fertilisation might explain increased levels of herbivory in plants with higher leaf nitrogen.
Competition, student sorting and performance gains in local education markets: The Dutch secondary sector
Authors: Cabus Sofie , Cornelisz Ilja
Published: June 2017

This article empirically examines the implications of competition among Dutch secondary schools: (1) regarding the sorting of students by performance levels in schools at the begiining of secondary education; and (2) regarding performance gains in the secondary school career, controlling for the aforementioned sorting patterns. We used data from about 13,000 students enrolled at 102 school locations in The Netherlands. Using differences in the distribution of competition intensity across local education markets, we applied Kernel estimation techniques to match students from relatively high‐ to low‐competitive markets on the basis of student and household characteristics. Our results indicate that, with increasing competition, relatively more schools target the group of high‐achieving students. As a result, schools will arguably have to enrol more ‘students at the margin’ to ensure sufficient enrolment rates. To conclude, we observed that, accounting for sorting patterns, competition was related to small negligible improvements in academic achievement at the bottom of the distribution of student performance within the first three years of secondary education. Furthermore, a negative result for competition was found for categorical academic classrooms settings.
The distribution of skills among the European adult population and unemployment: A comparative approach
Authors: Calero Jorge , Choi Álvaro
Published: June 2017

The most painful effect of the Great Recession in European countries has been the surge in unemployment rates during a period that has been characterised by an increase in income inequality and the heterogeneous pattern of this inequality by educational level. Thus, workers with low levels of educational attainment were among the first to lose their jobs. This article addresses two main research questions: first, it estimates the importance of the level of skills and education on the probability of being unemployed, disentangling the extent of the effects of human capital and signalling theories of education; and, second, it provides evidence of the impact of inequalities in the previous socioeconomic and cultural background of individuals on the probability of being unemployed. These two objectives are assessed using data for 24 jurisdictions that participated in the first round of the OECD's Programme for the International Assessment of Adult Competencies (PIAAC). Skill levels play a central role in explaining unemployment in Europe and act as an indirect channel via which a family's sociocultural background has an impact on its labour market status. Combining the results of alternative models, we identify those European labour markets that are most sensitive to human capital.
Aligning pedagogy with physical learning spaces
Authors: van Merriënboer Jeroen J. G. , McKenney Susan , Cullinan Dominic , Heuer Jos
Published: June 2017

The quality of education suffers when pedagogies are not aligned with physical learning spaces. For example, the architecture of the triple‐decker Victorian schools across England fits the information transmission model that was dominant in the industrial age, but makes it more difficult to implement student‐centred pedagogies that better fit a modern knowledge society. Yet, very little is known about how to reach powerful alignment of pedagogies and physical learning spaces. This article aims to fill this gap by describing a participatory design process to help to realise physical spaces and school buildings that optimally support specific visions of learning and pedagogy. Three phases are distinguished in this design process: (1) specifying the pedagogy, (2) aligning the pedagogy with seating arrangements and physical learning spaces, and (3) realising the school building. Particular attention is given to the core tasks relating to pedagogy (phases one and two), and especially the second phase, in which school management, teachers and students on the one hand, and architects and interior designers on the other must collaborate in a participatory design process. Illustrations are given from two schools, UCL Academy in London, UK, and De Werkplaats Kindergemeenschap in Bilthoven, The Netherlands.
Chemical, nutritional and phenolic composition of wheatgrass and pulse shoots
Authors: Ghumman Atinder , Singh Narpinder , Kaur Amritpal
Published: June 2017

Chemical, nutritional and antiradical properties of juice and shoot powder from wheatgrass and pulses were evaluated. Wheatgrass powder (WP) showed higher radical scavenging capacity, ash and chlorophyll content and lower protein content as compared to pulse powder (PP). Wheatgrass (WJP) juice powder had significantly higher K and Mg content as compared to pulse juice powder (PJP). Powders with relatively higher K and Mg content had higher radical scavenging capacity and chlorophyll content. Vanillic acid was present only in free form in both WP and PP. Luteolin was equally distributed in acid‐ and base‐bound form; sinapic acid was higher in base‐bound fraction; and protocatechuic acid was higher in acid‐bound form in both the sources. Positive correlations were found between radical scavenging capacity and ferulic acid and sinapic acid, whereas radical scavenging capacity was negatively correlated with gallic acid and p‐coumaric acid. WJP had higher glutamic acid, histidine, threonine, citrulline, arginine, gamma‐amino butyric acid (GABA) and leucine as compared to PJP. The present study highlights the nutritional benefits of wheatgrass juice.
Immunogenicity of protein aggregates of a monoclonal antibody generated by forced shaking stress with siliconized and nonsiliconized syringes in BALB/c mice
Authors: Uchino Tomonobu , Miyazaki Yasunori , Yamazaki Takuto , Kagawa Yoshiyuki
Published: June 2017

Objective

In this study, we aimed to investigate the immunogenicity of protein aggregates of monoclonal antibodies (mAbs), generated by forced shaking stress with siliconized and nonsiliconized syringes in a mouse model.

Methods

Samples were filled in siliconized and nonsiliconized syringes with shaking and headspace air. Characterization studies were performed using high-performance size-exclusion chromatography, nanoparticle tracking analysis, flow cytometry, micro-flow imaging and resonant mass measurement. The samples (10 or 100 μg) were subcutaneously injected into BALB/c mice for 21 days, and the anti-drug antibody (ADA) concentrations were monitored.

Key findings

In samples shaken with siliconized syringes [SO (+)], large amounts of submicron and subvisible protein aggregates were formed by interactions with silicone oil droplets. The characteristics of protein aggregates differed between the mAb solution and shaken samples, which strongly indicates that silicone oil accelerates protein aggregation. When administered at low doses, the ADA concentration in all samples increased with repeated injections, and SO (+) induced the highest immunogenicity. However, when administered at high doses, ADA concentration decreased following prolonged repeated administration for tolerance.

Conclusions

These results indicated that mAb protein aggregation induced immunogenicity in mice, and SO (+) induced higher immunogenicity than samples shaken with nonsiliconized syringe.
Hepatocellular carcinoma in South America: Evaluation of risk factors, demographics and therapy
Authors: Debes Jose D. , Chan Aaron J. , Balderramo Domingo , Kikuchi Luciana , Gonzalez Ballerga Esteban , Prieto Jhon E. , Tapias Monica , Idrovo Victor , Davalos Milagros B. , Cairo Fernando , Barreyro Fernando J. , Paredes Sebastian , Hernandez Nelia , Avendaño Karla , Diaz Ferrer Javier , Yang Ju Dong , Carrera Enrique , Garcia Jairo A. , Mattos Angelo Z. , Hirsch Bruno S. , Gonçalves Pablo T. , Carrilho Flair J. , Roberts Lewis R.
Published: June 2017

Background & Aims

Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related death worldwide. Most studies addressing the epidemiology of HCC originate from developed countries. This study reports the preliminary findings of a multinational approach to characterize HCC in South America.

Methods

We evaluated 1336 HCC patients seen at 14 centres in six South American countries using a retrospective study design with participating centres completing a template chart of patient characteristics. The diagnosis of HCC was made radiographically or histologically for all cases according to institutional standards. Methodology of surveillance for each centre was following AASLD or EASL recommendations.

Results

Sixty‐eight percent of individuals were male with a median age of 64 years at time of diagnosis. The most common risk factor for HCC was hepatitis C infection (HCV, 48%), followed by alcoholic cirrhosis (22%), Hepatitis B infection (HBV, 14%) and NAFLD (9%). We found that among individuals with HBV‐related HCC, 38% were diagnosed before age 50. The most commonly provided therapy was transarterial chemoembolization (35% of HCCs) with few individuals being considered for liver transplant (<20%). Only 47% of HCCs were diagnosed during surveillance, and there was no difference in age of diagnosis between those diagnosed incidentally vs by surveillance. Nonetheless, being diagnosed during surveillance was associated with improved overall survival (P = .01).

Conclusions

Our study represents the largest cohort to date reporting characteristics and outcomes of HCC across South America. We found an important number of HCCs diagnosed outside of surveillance programmes, with associated increased mortality in those patients.
Determination of metabolic resistance mechanisms in pyrethroid‐resistant and fipronil‐tolerant brown dog ticks
Authors: EIDEN A. L. , KAUFMAN P. E. , OI F. M. , DARK M. J. , BLOOMQUIST J. R. , MILLER R. J.
Published: June 2017

Rhipicephalus sanguineus (Latreille) (Ixodida: Ixodidae) is a three‐host dog tick found worldwide that is able to complete its' entire lifecycle indoors. Options for the management of R. sanguineus are limited and its' control relies largely on only a few acaricidal active ingredients. Previous studies have confirmed permethrin resistance and fipronil tolerance in R. sanguineus populations, commonly conferred by metabolic detoxification or target site mutations. Herein, five strains of permethrin‐resistant and three strains of fipronil‐tolerant ticks were evaluated for metabolic resistance using synergists to block metabolic enzymes. Synergist studies were completed with triphenyl phosphate (TPP) for esterase inhibition, piperonyl butoxide (PBO) for cytochrome P450 inhibition, and diethyl maleate (DEM) for glutathione‐S‐transferase inhibition. Additionally, increased esterase activity was confirmed using gel electrophoresis. The most important metabolic detoxification mechanism in permethrin‐resistant ticks was increased esterase activity, followed by increased cytochrome P450 activity. The inhibition of metabolic enzymes did not have a marked impact on fipronil‐tolerant tick strains.
Biodiversity collapse and early warning indicators in a spatial phase transition between neutral and niche communities
Authors: Saravia Leonardo A. , Momo Fernando R.
Published: June 2017

The dynamics of ecological communities have been described by neutral and niche theories that are now increasingly integrated into unified models. It is known that a critical transition exists between these two states, but the spatial aspect of this transition has not been studied. Our aim is to study the spatial aspect of the transition and propose early warning signals to detect it. We used a stochastic, spatially explicit model that spans a continuum from neutral to niche communities, and is driven by the intensity of hierarchical competition. The transition is indicated by the emergence of a large patch formed by one species that connects the whole area. The properties of this patch can be used as early warning indicators of a critical transition. If competition intensity increases beyond the critical point, our model shows a sudden decrease of the Shannon diversity index and a gentle decline in species richness. The critical point occurs at a very low value of competitive intensity, with the rate of migration from the metacommunity greatly influencing the position of this critical point. As an example, we apply our new method of early warning indicators to the Barro Colorado Tropical forest, which, as expected, appears to be far from a critical transition. Low values of competitive intensity were also reported by previous studies for different high‐diversity real communities, suggesting that these communities are located before the critical point. A small increase of competitive interactions could push them across the transition, however, to a state in which diversity is much lower. Thus this new early warnings indicator could be used to monitor high diversity ecosystems that are still undisturbed.
Targeted mutagenesis in tetraploid switchgrass (Panicum virgatum L.) using CRISPR/Cas9
Authors: Liu Yang , Merrick Paul , Zhang Zhengzhi , Ji Chonghui , Yang Bing , Fei Shui‐zhang
Published: June 2017

The CRISPR/Cas9 system has become a powerful tool for targeted mutagenesis. Switchgrass (Panicum virgatum L.) is a high yielding perennial grass species that has been designated as a model biomass crop by the U.S. Department of Energy. The self‐infertility and high ploidy level make it difficult to study gene function or improve germplasm. To overcome these constraints, we explored the feasibility of using CRISPR/Cas9 for targeted mutagenesis in a tetraploid cultivar ‘Alamo’ switchgrass. We first developed a transient assay by which a non‐functional green‐fluorescent protein gene containing a 1‐bp frameshift insertion in its 5′ coding region was successfully mutated by a Cas9/sgRNA complex resulting in its restored function. Agrobacterium‐mediated stable transformation of embryogenic calli derived from mature caryopses averaged a 3.0% transformation efficiency targeting the genes of teosinte branched 1(tb1)a and b and phosphoglycerate mutase (PGM). With a single construct containing two sgRNAs targeting different regions of tb1a and tb1b genes, primary transformants (T0) containing CRISPR/Cas9‐induced mutations were obtained at frequencies of 95.5% (tb1a) and 11% (tb1b), respectively, with T0 mutants exhibiting increased tiller production. Meanwhile, a mutation frequency of 13.7% was obtained for the PGM gene with a CRISPR/Cas9 construct containing a single sgRNA. Among the PGM T0 mutants, six are heterozygous and one is homozygous for a 1‐bp deletion in the target region with no apparent phenotypical alterations. We show that CRISPR/Cas9 system can generate targeted mutagenesis effectively and obtain targeted homozygous mutants in T0 generation in switchgrass, circumventing the need of inbreeding.
Epstein‐Barr viral loads do not predict post‐transplant lymphoproliferative disorder in pediatric lung transplant recipients: A multicenter prospective cohort study
Authors: Parrish Andrew , Fenchel Matthew , Storch Gregory A. , Buller Richard , Mason Sheila , Williams Nikki , Ikle David , Conrad Carol , Faro Albert , Goldfarb Samuel , Hayes Don , Melicoff‐Portillo Ernestina , Schecter Marc , Visner Gary , Sweet Stuart , Danziger‐Isakov Lara ,   the Clinical Trials in Organ Transplantation in Children (CTOTC‐03)
Published: June 2017

Prediction of PTLD after pediatric lung transplant remains difficult. Use of EBV VL in WB has been poorly predictive, while measurement of VL in BAL fluid has been suggested to have enhanced utility. The NIH‐sponsored Clinical Trials in Organ Transplantation in Children (CTOTC‐03) prospectively obtained serial quantitative measurements of EBV PCR in both WB and BAL fluid after pediatric lung transplantation. Descriptive statistics, contingency analyses, and Kaplan‐Meier analyses evaluated possible association between EBV and PTLD. Of 61 patients, 34 (56%) had an EBV+PCR (at least once in WB or BAL). EBV donor (D)+patients more often had a positive PCR (D+/recipient (R)−: 13/18; D+/R+: 14/23) compared to EBV D‐ patients (6/17). Several D−/R− (5/12) patients developed EBV, but none developed PTLD. All four PTLD patients were D+/R− with EBV+PCR. Neither the time to first EBV+PCR nor the CT for PCR positivity in BAL or WB was statistically different between those with and without PTLD. Having an EBV‐seropositive donor was associated with increased risk of EBV+PCR in WB. EBV load in BAL was not predictive of PTLD.
Causes As Difference‐Makers For Processes
Authors: Loew Christian
Published: June 2017

It is natural to think of causes as difference‐makers. What exact difference causes make, however, is an open question. In this paper, I argue that the right way of understanding difference‐making is in terms of causal processes: causes make a difference to a causal process that leads to the effect. I will show that this way of understanding difference‐making nicely captures the distinction between causing an outcome and helping determine how the outcome happens and, thus, explains why causation is not transitive. Moreover, the theory handles tricky cases that are problematic for competing accounts of difference‐making.
Impact of Macroeconomic Announcements on Foreign Exchange Volatility: Evidence from South Africa
Authors: Maserumule Tseke , Alagidede Paul
Published: June 2017

This study focuses on scheduled macroeconomic news announcements and evaluates their impact on the volatility of the South African rand (ZAR) and US dollar (USD) exchange rate using high frequency data. The following asymmetries are studied: news items by geographical location, no‐news vs. surprise news announcements and positive vs. negative news announcements. We make the following findings in our empirical study: (i) After the release of a news announcement, the level of foreign exchange volatility rises. This is independent of whether the news item surprised the market or not. (ii) Both South African and US news items significantly impact USD/ZAR volatility, suggesting that the news items are being used to formulate investor expectations regarding the future prospects of the currency pair. (iii) Negative news appears to have a greater impact on exchange rate volatility relative to positive news. This result is also state dependent, as investors tend to behave differently to news depending on the economic climate at that point in time. Investor cognitive biases give rise to the asymmetric news effects on exchange rate volatility. Finally, investors do not always act in rational manner, especially when faced with multiple news items that are contradictory to each other.
Changes in the inspiratory pattern contribute to modulate the sympathetic activity in sino‐aortic denervated rats
Authors: Amorim Mateus R. , Bonagamba Leni G. H. , Souza George M. P. R. , Moraes Davi J. A. , Machado Benedito H.
Published: June 2017

New Findings

What is the central question of this study?

Sino‐aortic denervated (SAD) rats present normal levels of sympathetic activity and mean arterial pressure. However, neural mechanisms regulating the sympathetic activity in the absence of arterial baroreceptors remain unclear. Considering that respiration modulates the sympathetic activity, we hypothesize that changes in the respiratory network contribute to keep the sympathetic outflow in the normal range after removal of arterial baroreceptors.

What is the main finding and its importance?

Despite longer inspiration observed in SAD rats, the respiratory–sympathetic coupling is working within a normal range of variation. These findings suggest that in the absence of arterial baroreceptors the respiratory modulation of sympathetic activity is maintained within the normal range.

The activity of presympathetic neurons is under respiratory modulation, and changes in the central respiratory network may impact on the baseline sympathetic activity and mean arterial pressure. It is well known that after removal of baroreceptor afferents [sino‐aortic denervation (SAD)], rats present an unexpected normal level of mean arterial pressure. We hypothesized that changes in the respiratory pattern and in the respiratory modulation of the sympathetic activity contribute to keep the sympathetic outflow within a normal range of variation in the absence of arterial baroreceptors in rats. To study these mechanisms, we recorded perfusion pressure and the activities of phrenic and thoracic sympathetic nerves in male juvenile rats using the working heart–brainstem preparation. The time of inspiration significantly increased in SAD rats, and this change was not dependent on the carotid bodies or on the vagal afferents. However, no changes were observed in the perfusion pressure or in the baseline thoracic sympathetic nerves in all phases of the respiratory cycle in SAD rats. Our data show that despite longer inspiratory activity, the baseline sympathetic activity is maintained at a normal level in SAD rats. These findings indicate that the respiratory–sympathetic coupling is normal after SAD and suggest that the respiratory modulation of sympathetic activity is maintained within the normal range after the removal of arterial baroreceptors.