bluuebunny/crossref_metadata_2025 huggingface dataset:
Brilliance or steadiness? A suggestion of an alternative model to Hardy's model concerning golf (1945)
Authors: Kang Jeehoon
Published: June 2017

There have been numerous attempts to model the governing dynamics between the two ostensibly competing concepts of brilliance and mechanical steadiness. One interesting study is given by the English mathematician G. H. Hardy in his model [1] describing two characteristically different golfers playing a match against each other. The model challenges the apparently accepted doctrine of the ‘Brilliant player’ having the advantage over the ‘Steady player’ in a long series of golf matches by holes. Hardy defines ‘brilliance’ as the capacity to produce ingenious results as well as the capacity to make mistakes, compared to ‘steadiness’ being completely mechanical producing the same average result all the time. The two players in his model are equal in performance on average, only the brilliant player has a higher standard deviation whereas the consistent player has a standard deviation of 0.
Integration based on the parametrisation of conics
Authors: Hoseana Jonathan
Published: June 2017

Integration is an important topic discussed in first year calculus. Many subsequent topics, such as solving first-order or second-order differential equations, requires the evaluation of at least one integral, and sometimes several.

The most challenging material in integration is arguably the techniques of integration. Unfortunately, due to time constraints, only basic techniques are commonly taught, while in reality, many integrals having special forms are solvable only by using more sophisticated techniques.
'Don't just listen: Tell me what to do!'
Authors: Hawke Philippa
Published: June 2017

Counselling is not a well-understood concept. Many people who haven’t undergone counselling believe a counsellor’s role is to listen to a person tell their problem and then ‘help’ them by giving advice about what they should do. Children and young people struggle with the idea that a counsellor is not a human form of Google. It is not easy for them to hear that their problem is complex and that sometimes working out an action plan themselves, with guidance from a trained counsellor, offers better value to their lives in the long run. Kids Helpline is an Australian child and youth-focused telephone and online counselling service with a long-term view of what ‘helping’ looks like. The free-call 24/7 counselling line challenges young clients to see beyond the immediate gratification of receiving instantaneous ‘answers’ to problems, and to value more highly the process of learning problem-solving and decision-making skills, transferable from issue to issue over the course of a lifetime. This article seeks to highlight the early intervention and prevention role that child helplines play in young people’s lives, encouraging and strengthening children and young people’s early forays into exploring consequential thinking. The article describes the processes used by Kids Helpline counsellors to encourage children and young people to become action planners, and demonstrates young people’s capacity to appreciate complexity and personal development.
Alana Piper (ed.), 'Brisbane Diseased: Contagions, Cures and Controversies', Brisbane: Boolarong Press, 2016, ISBN 9 7819 2523 6316, 349 pp., $32.99
Authors: Diamond Marion
Published: June 2017

Alana Piper (ed.), Brisbane Diseased: Contagions, Cures and Controversies, Brisbane: Boolarong Press, 2016, ISBN 9 7819 2523 6316, 349 pp., $32.99
Dropping out/dropping back in
Authors: Lund Anna , Trondman Mats
Published: June 2017

Nearly one in three students living in the segregated, multicultural city of Malmo, Sweden, fails to finish school with a completed diploma. To remedy this situation, students can attend introductory programs, but only some students who do so end up with a diploma. The aim of this article is to understand why young people from a migration background drop out of secondary school and why some of them drop back in and become school achievers. We explore what makes learning matter among youth who drop back into schooling. In seeking possible answers to this question, we listened to and learned from the students themselves. We hope readers will learn about the elementary forms of an enabling opportunity structure for school achievement, about the significance of relational capital, and about the deeply associated meanings of family and friendship and their importance to school success. The article is framed by the interdependencies of two conditioned temporalities: the temporality of the past — that is, the dropping-out process — and the temporality of the present, that is, the dropping-back-in process. We argue that school failure is not an inevitable phenomenon, and show that young people who are supported to drop back into schooling can discover that they are capable of learning with passion and perseverance.
Coffee berry borer in conilon coffee in the Brazilian Cerrado: an ancient pest in a new environment
Authors: Oliveira C.M. , Santos M.J. , Amabile R.F. , Frizzas M.R. , Bartholo G.F.
Published: June 2017

The aim of this study was to verify the occurrence of the coffee berry borer,Hypothenemus hampei(Ferrari), and to evaluate the population fluctuation of the pest in the Brazilian Cerrado (Federal District). The study was conducted, between November 2014 and October 2015, at Embrapa Cerrados (Planaltina/DF, Brazil) in an irrigated conilon coffee production area. In November 2014, 120 samples (ten berries/sample) were collected from berries that had fallen on the ground from the previous harvest. Between November 2014 and October 2015, insects were collected weekly, using traps (polyethylene terephthalate bottles) baited with ethyl alcohol (98 GL), ethyl alcohol (98 GL) with coffee powder, or molasses. Between January and July 2015, samples were collected fortnightly from 92 plants (12 berries per plant). All samples were evaluated for the presence of adult coffee berry borers. Samples from the previous harvest had an attack incidence of 72.4%. The baited traps captured 4062H. hampeiadults, and showed no statistical difference in capture efficiency among the baits. Pest population peaked in the dry season, with the largest percentage of captured adults occurring in July (31.0%). An average of 18.6% of the collected berries was attacked by the borer and the highest percentage incidence was recorded in July (33.2%). Our results suggest that the coffee berry borer, if not properly managed, could constitute a limiting factor for conilon coffee production in the Brazilian Cerrado.
Association between intestinal helminth infections and mid-upper-arm circumference among children in Sri Lanka: A cross-sectional study
Authors: Galgamuwa L.S. , Iddawela D. , Dharmaratne S.D.
Published: June 2017

Intestinal helminth infections constitute a major health problem in low socio-economic communities worldwide. A cross-sectional study was conducted in children aged between 12 and 60 months. A structured questionnaire was used to collect socio-demographic data and stool samples were subjected to direct smear, stained with Lugol's iodine, and formaldehyde–ether concentration techniques to determine the prevalence of intestinal helminth infections. The circumference of each child's left mid upper arm (MUAC) was measured using standard procedures. Two hundred and six children with a mean MUAC of 14.7 cm (SD ± 1.1) were assessed from September to December 2014. The prevalence of acute energy undernutrition was 6.3% (13/206). All of them had moderate acute undernutrition and no cases of severe acute undernutrition. Paternal occupation was significantly associated with MUAC. Intestinal helminth infections were detected in 12.6% of children. Four species of parasites were identified; Ascaris lumbricoides (9.7%) followed by Enterobius vermicularis (1.5%), Trichuris trichiura (1.0%) and hookworms (1.0%). Uninfected children aged between 1 and 2 years showed significantly higher MUAC than infected children. No statistically significant association was detected between the severity of intestinal helminth infections and MUAC. Although intestinal helminth infections are a major public health problem in this community, they are not related to MUAC. Future research, providing more insight into the nutritional impact of intestinal helminth infections, is required to determine the association between parasitic infections and physical growth in this community.
Challenges and opportunities of a landscape governance approach to the REDD+ programme: a conservation outlook
Authors: Mbatu Richard
Published: June 2017

Implementing the Reducing Emissions from Deforestation and forest Degradation (REDD+) programme has the potential to significantly reduce greenhouse gases whilst also helping to maintain biodiversity. However, a proposed landscape governance approach to the REDD+ programme, encompassing all land-use activities, could alter these desirable outcomes. Under the proposed approach, governments and private entities could encourage types of land use that have the potential to threaten biodiversity and disrupt ecosystems. Yet a landscape governance approach could also stimulate governments to develop land-use management policies to facilitate adaptation to climate change. I organized focus group discussions with members of conservation groups, REDD+ scholars, and members of the REDD+ agroforestry research community at the Association of American Geographers 2016 Annual Meeting, to identify potential conservation challenges and opportunities associated with carbon-farming in grasslands and plantations under the proposed landscape governance approach to REDD+. I evaluate and synthesize this information, making recommendations for strategies to maximize the conservation opportunities and minimize the challenges. Understanding the challenges and opportunities will enable policy makers and other stakeholders to improve the presentation of their arguments in their efforts to shape the course of the REDD+ programme in the post-Paris Agreement era.
They ‘don't cure old age’: older Ugandans’ delays to health-care access
Authors: SCHATZ ENID , SEELEY JANET , NEGIN JOEL , MUGISHA JOSEPH
Published: June 2017

Uganda's population is ageing, which comes with increased and varied burdens of disease and health-care needs. At the same time, gerontological care in Uganda remains neglected. This paper examines the factors that cause older Ugandans to delay health-care access. We conduct a thematic analysis of data drawn from nine focus groups held with rural Ugandans aged 60-plus. Our analysis highlights the factors that delay older persons’ access to health care and how these align with the Three-Delay Model, which was originally developed to assess and improve obstetric care in low-resource settings. Our participants report delays in deciding to seek care related to mobility and financial limitations, disease aetiology, severity and stigma (Delay I); reaching care because of poor roads and limited transportation options (Delay II); and receiving appropriate care because of ageism among health-care workers, and poorly staffed and under-supplied facilities (Delay III). We find these delays to care are interrelated and impacted by factors at the individual, community and health-system levels. We conclude by arguing for multi-pronged interventions that will address these delays, improve access to care and ultimately enhance older Ugandans’ health and wellbeing.
Legitimacy and institutional change in international organisations: a cognitive approach
Authors: Lenz Tobias , Viola Lora Anne
Published: June 2017

Why are some institutional designs perceived as more legitimate than others, and why is the same institutional design sometimes perceived as legitimacy-enhancing in one setting and not in another? In a world in which most international organisations (IOs) do not fully embody societal values and norms, such as democratic participation and equal treatment, why do legitimacy deficits in some organisations lead to pressure for institutional change while in others they are tolerated? These are important questions given that many analysts have diagnosed a ‘legitimacy crisis’ of IOs, but we argue that existing approaches are ill equipped to answer them. We show that the existing legitimacy literature has an implicit model of institutional change – the congruence model – but that this model has difficulty accounting for important patterns of change and non-change because it lacks microfoundations. We argue that attributions of legitimacy rest on perceptions and this implies the need to investigate the cognitive bases of legitimacy. We introduce a cognitive model of legitimacy and deduce a set of testable propositions to explain the conditions under which legitimacy judgments change and, in turn, produce pressures for institutional change in IOs.
SENTIMENTS, CONDUCT, AND TRUST IN THE LABORATORY
Authors: Smith Vernon L. , Wilson Bart J.
Published: June 2017

In this essay we provide a brief account and interpretation of The Theory of Moral Sentiments showing that it departs fundamentally from contemporary patterns of thought in economics that are believed to govern individual behavior in small groups, and contains strong testable propositions governing the expression of that behavior. We also state a formal representation of the model for individual choice of action, apply the propositions to the prediction of actions in trust games, report two experiments testing these predictions, and interpret the results in terms directly related to the model. In short, we argue that the system of sociability developed by Adam Smith provides a coherent non-utilitarian model that is consistent with the pattern of results in trust games, and leads to testable new predictions, some of which we test.
WHAT ECONOMICS CAN AND CANNOT SAY ABOUT EGALITARIAN REDISTRIBUTION
Authors: White Lawrence H.
Published: June 2017

I critically consider four purported economic-efficiency arguments for egalitarian redistribution of income or wealth. (1) Jeremy Bentham’s “greatest aggregate happiness” criterion has been used (by Bentham, John Stuart Mill, Alfred Marshall, A. C. Pigou, Abba Lerner, and more recently Richard Layard) to argue for wealth transfers toward the poor based on the supposition that they register higher happiness from a marginal dollar. Drawing from Vilfredo Pareto and Lionel Robbins, however, I argue that modern economic theory is not about individual happiness, let alone aggregate happiness, and therefore does not support (nor refute) any happiness-based case for wealth redistribution. (2) Theories based on a “social welfare function” misapply the economic way of thinking in a different way. (3) Other writers have framed redistribution as a public good, and public goods provision by the state as a voluntary collective means of satisfying individual preferences, thereby using modern economic theory to formulate a rationale for redistributive policies based on Pareto-efficiency. I criticize this rationale for resting on suppositions about actual preferences that are self-immunized against falsification. (4) James Buchanan made a related case for taxing inheritances based on the supposition that in constitutional deliberation behind a veil of ignorance we would agree to such a policy based on our preference for a certain kind of fairness. I find this argument non-economic, equally unfalsifiable, and no more plausible than alternative suppositions about our common preferences. The economic way of thinking does speak clearly, however, about how taxes on income or wealth discourage its production, the more so the higher the marginal tax rate.
BOYCOTTS AND THE SOCIAL ENFORCEMENT OF JUSTICE
Authors: Radzik Linda
Published: June 2017

This essay examines the ethics of boycotting as a social response to injustice or wrongdoing. The boycotts in question are collective actions in which private citizens withdraw from or avoid consumer or cultural interaction with parties perceived to be responsible for some transgression. Whether a particular boycott is justified depends, not only on the reasonableness of the underlying moral critique, but also on what the boycotters are doing in boycotting. The essay considers four possible interpretations of the kind of act in which boycotting consists: the avoidance of complicity, protest speech, social punishment, or social coercion. Each interpretation provides a plausible account of at least some cases of boycotting, yet each raises distinct challenges to justifying boycotting activities.
FORMS OF DIFFERENTIAL SOCIAL INCLUSION
Authors: Wolff Jonathan
Published: June 2017

Advocates of social equality need to develop an account of the society they favor. I have argued elsewhere that social equality should be conceived negatively: in terms of opposition to asymmetric and alienating relations such as hierarchy, domination and social exclusion, rather than in terms of a positive model of equality. This essay looks in detail at social exclusion, or rather “differential social inclusion,” and especially at the mechanisms that create exclusion and bind excluded groups together, and the consequent effects these mechanisms have on the reinforcement of inequality of opportunity and failure of social solidarity. Possible policies, such as improved social mobility, assertive self-affirmation, validation of subcultures, integration, and the creation of a large public sector are considered as possible responses to differential social inclusion in order to move closer to the idea of a society of equals.
PRACTICING PPE: THE CASE OF ADAM SMITH
Authors: Hanley Ryan Patrick
Published: June 2017

Adam Smith has long been celebrated as a polymath, and his wide interests in and contributions to each of the discrete component fields of PPE have long been appreciated. Yet Smith deserves the attention of practitioners of PPE today not simply for his substantive insights, but for the ways in which his inquiries into these different fields were connected. Smith’s inquiry was distinguished by a synthetic approach to knowledge generation, and specifically to generating knowledge with applications exportable to other fields. Further, Smith’s investigations of various areas of study led him to recognize patterns in and across these fields, and his sensitivity to such patterns helped guide his inquiry and render it a connected enterprise. This paper examines several of Smith’s discrete inquiries in the history of astronomy, language, moral philosophy, and political economy, to show how he employed the techniques of pattern detection that he practiced in each of these inquiries to the task of generating new insights into new fields of inquiry. In so doing, Smith not only distinguished himself as an early practitioner of what we today identify with PPE, but he also provides a useful point of reference for those doing PPE today.
MOST IMPORTANT BARRIERS AND FACILITATORS REGARDING THE USE OF HEALTH TECHNOLOGY ASSESSMENT
Authors: Cheung Kei Long , Evers Silvia M.A.A. , de Vries Hein , Hiligsmann Mickaël
Published: June 2017

Objectives: Several studies have reported multiple barriers to and facilitators for the uptake of health technology assessment (HTA) information by policy makers. This study elicited, using best-worst scaling (BWS), the most important barriers and facilitators and their relative weight in the use of HTA by policy makers.

Methods: Two BWS object case surveys (one for barriers, one for facilitators) were conducted among sixteen policy makers and thirty-three HTA experts in the Netherlands. A list of twenty-two barriers and nineteen facilitators was included. In each choice task, participants were asked to choose the most important and the least important barrier/facilitator from a set of five. We used Hierarchical Bayes modeling to generate the mean relative importance score (RIS) for each factor and a subgroup analysis was conducted to assess differences between policy makers and HTA experts.

Results: The five most important barriers (RIS > 6.00) were “no explicit framework for decision-making process,” “insufficient support by stakeholders,” “lack of support,” “limited generalizability,” and “absence of appropriate incentives.” The six most important facilitators were: “availability of explicit framework for decision making,” “sufficient support by stakeholders,” “appropriate incentives,” “sufficient quality,” “sufficient awareness,” and “sufficient support within the organization.” Overall, perceptions did not differ markedly between policy makers and HTA experts.

Conclusions: Our study suggests that barriers and facilitators related to “policy characteristics” and “organization and resources” were particularly important. It is important to stimulate a pulse at the national level to create an explicit framework for including HTA in the decision-making context.
On the origin and timing of Zika virus introduction in Brazil
Authors: MASSAD E. , BURATTINI M. NASCIMENTO , KHAN K. , STRUCHINER C. J. , COUTINHO F. A. B. , WILDER-SMITH A.
Published: June 2017

The timing and origin of Zika virus (ZIKV) introduction in Brazil has been the subject of controversy. Initially, it was assumed that the virus was introduced during the FIFA World Cup in June–July 2014. Then, it was speculated that ZIKV may have been introduced by athletes from French Polynesia (FP) who competed in a canoe race in Rio de Janeiro in August 2014. We attempted to apply mathematical models to determine the most likely time window of ZIKV introduction in Brazil. Given that the timing and origin of ZIKV introduction in Brazil may be a politically sensitive issue, its determination (or the provision of a plausible hypothesis) may help to prevent undeserved blame. We used a simple mathematical model to estimate the force of infection and the corresponding individual probability of being infected with ZIKV in FP. Taking into account the air travel volume from FP to Brazil between October 2013 and March 2014, we estimated the expected number of infected travellers arriving at Brazilian airports during that period. During the period between December 2013 and February 2014, 51 individuals travelled from FP airports to 11 Brazilian cities. Basing on the calculated force of ZIKV infection (the per capita rate of new infections per time unit) and risk of infection (probability of at least one new infection), we estimated that 18 (95% CI 12–22) individuals who arrived in seven of the evaluated cities were infected. When basic ZIKV reproduction numbers greater than one were assumed in the seven evaluated cities, ZIKV could have been introduced in any one of the cities. Based on the force of infection in FP, basic reproduction ZIKV number in selected Brazilian cities, and estimated travel volume, we concluded that ZIKV was most likely introduced and established in Brazil by infected travellers arriving from FP in the period between October 2013 and March 2014, which was prior to the two aforementioned sporting events.
Text-based negotiated interaction of NNS-NNS and NNS-NS dyads on Facebook
Authors: Liu Sarah Hsueh-Jui
Published: June 2017

This study sought to determine the difference in text-based negotiated interaction between non-native speakers of English (NNS-NNS) and between non-native and natives (NNS-NS) in terms of the frequency of negotiated instances, successfully resolved instances, and interactional strategy use when the dyads collaborated on Facebook. It involved 10 native English speakers and 30 learners of English as a foreign language (EFL). NNS-NNS dyads consisted of five H-H pairs and five L-L pairs (H and L representing high- and low-proficiency learners). Similarly, NNS-NS dyads comprised five H-N pairs and five L-N pairs (N being native speakers). All dyads were required to use text chats to complete the given reading tasks synchronously in chatrooms on Facebook. The results suggested that negotiated instances, successfully resolved instances, and interactional strategy use occurred more frequently in H-H pairs than in L-N, L-L, or H-N pairs. In terms of strategy use, H-H, H-N, and L-N dyads were likely to engage in negotiated interaction by employing strategies such as clarifying unclear expressions or checking their comprehension, while L-L used interactional mechanisms infrequently and tended to use strategies such as continuers and asking for assistance. The research concludes with the pedagogical implications of the results.
A Semi-automatic and low-cost method to learn patterns for named entity recognition
Authors: MARRERO M. , URBANO J.
Published: June 2017

Named Entity Recognition is a basic task in Information Extraction that aims at identifying entities of interest within full text documents. The patterns used to recognize entities can be rule based, as in the popular JAPE system. However, hand-crafting effective patterns is often difficult, and yet there is little research devoted to methods capable of learning human-readable patterns, possibly with arbitrary sets of features. In this paper, we present a semi-automatic method to generate both regular expressions and a subset of the JAPE language. It does not need a corpus annotated beforehand. Instead, it employs active learning and combines clustering with an algorithm that finds alignments between symbols present in the entities discovered during the learning process. The method currently supports a fixed set of character features and an arbitrary set of token features, but it can incorporate other kinds of features as well. Through several experiments with an English corpus, we show the ability of the method to generate effective patterns at a low annotation cost, and how it can successfully help in the annotation of brand new corpora.
The Amber Road: Cross-Border Trade and the Regulation of the Burmite Market in Tengchong, Yunnan
Authors: Rippa Alessandro , Yang Yi
Published: June 2017

This paper investigates the new and hitherto unstudied boom in cross-border Burmese amber (Burmite) trade between Myanmar and Tengchong, Yunnan province. Based on interviews with amber dealers and local officials, it describes how since 2012–13 the amber trade has become increasingly lucrative for Chinese and Myanmar traders, and has attracted a large number of people to Tengchong, which, within Yunnan, virtually monopolises the trade. After a brief historical introduction, the paper analyses the conditions that, in both countries, have made the Burmite trade boom possible. It further describes the current composition of the amber market in both Myanmar and China, before analysing recent attempts to monitor and regulate the amber trade through the institution of the Tengchong Amber Association by the city's main amber traders in collaboration with local authorities.
„Was misst eigentlich die Blockspanne?“ – Der Goldstandard im Fokus
Authors: Weicker Juliane , Hudl Nicole , Thöne-Otto Angelika
Published: June 2017

Zusammenfassung. Die Blockspanne ist eines der verbreitetsten Testverfahren in der klinischen Neuropsychologie, auch bekannt als Corsi- / Block-Tapping-Test. Das Verfahren gilt als Goldstandard zur Messung des räumlichen Kurzzeit- und Arbeitsgedächtnisses (Baddeley, 2003). Trotz der häufigen Anwendung im klinischen Alltag fand die Erforschung zugrunde liegender kognitiver Prozesse erstaunlich wenig Beachtung. Dieser Übersichtsartikel vermittelt den aktuellen Forschungsstand durch Beschreibung der wichtigsten Studien, die anhand von Befragungen, Blickbewegungen oder Parallelaufgaben untersuchten, was die Blockspannenaufgabe tatsächlich misst. Dabei wird deutlich, dass nicht nur nonverbale räumliche Aspekte erfasst werden, sondern, insbesondere unter hohen Anforderungen, zusätzlich verbale und exekutive Ressourcen rekrutiert werden. Es wird diskutiert, inwieweit Zahlen- und Blockspannen als Analoga gelten können und ob die Darbietung der Blockspanne rückwärts im Vergleich zur Vorwärtsvariante einen diagnostischen Mehrwert bietet.
Mapping Dengue Fever Hazard with Machine Learning
Authors: Hornyak Tim
Published: June 2017

Researchers develop a predictive software system to identify city-specific, dengue fever risk areas amid a global increase in cases.
Acquired cross-linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption
Authors: Meyer Stefan , Stevens Adam , Paredes Roberto , Schneider Marion , Walker Michael J , Williamson Andrew J K , Gonzalez-Sanchez Maria-Belen , Smetsers Stephanie , Dalal Vineet , Teng Hsiang Ying , White Daniel J , Taylor Sam , Muter Joanne , Pierce Andrew , de Leonibus Chiara , Rockx Davy A P , Rooimans Martin A , Spooncer Elaine , Stauffer Stacey , Biswas Kajal , Godthelp Barbara , Dorsman Josephine , Clayton Peter E , Sharan Shyam K , Whetton Anthony D
Published: June 2017

BRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse. We modeled acquired cross-linker resistance with an FA-derived BRCA2-mutated acute myeloid leukemia (AML) platform. Associated with acquired cross-linker resistance was the expression of a functional BRCA2 protein variant lacking exon 5 and exon 7 (BRCA2ΔE5+7), implying a role for BRCA2 splicing for acquired chemo-resistance. Integrated network analysis of transcriptomic and proteomic differences for phenotyping of BRCA2 disruption infers impact on transcription and chromatin remodeling in addition to the DNA damage response. The striking overlap with transcriptional profiles of FA patient hematopoiesis and BRCA mutation associated ovarian cancer helps define and explicate the ‘BRCAness’ profile.
Bilirubin neurotoxicity is associated with proteasome inhibition
Authors: Huang Hongbiao , Guo Mingxing , Liu Ningning , Zhao Chong , Chen Haoyu , Wang Xiaoli , Liao Siyan , Zhou Ping , Liao Yuning , Chen Xin , Lan Xiaoying , Chen Jinghong , Xu Dacai , Li Xiaofen , Shi Xianping , Yu Li , Nie Yuqiang , Wang Xuejun , Zhang Chang-E , Liu Jinbao
Published: June 2017

The molecular mechanism underlying bilirubin neurotoxicity remains obscure. Ubiquitin–proteasome system-mediated proteolysis is pivotal to virtually all cellular processes and cell survival. Here we report for the first time that bilirubin at a clinically relevant elevated level impairs proteasomal function via inhibiting both the 19S proteasome-associated deubiquitinases (USP14 and UCHL5) and the chymotrypsin-like (CT-like) peptidase activity of 20S proteasomes, thereby contributing to bilirubin neurotoxicity. This is supported by multiple lines of evidence. First, sera from patients with hyperbilirubinemia were able to inhibit the peptidase activity of purified 20S proteasome in vitro in a bilirubin concentration-dependent manner; meanwhile, the blood cells of these patients showed significantly increased levels of ubiquitinated proteins (Ub-prs), consistent with proteasome inhibition. Second, intracerebroventricular injection to adult rats or intraperitoneal injections to neonatal rats of bilirubin-induced neural accumulation of Ub-prs, concurrent with other neural pathology; and brain malfunction and pathology induced by neonatal exposure to hyperbilirubinemia were detectable in the rats during their adulthood. Third, in primary cultures of hippocampal neurons, bilirubin strikingly induced Ub-pr accumulation before the activation of cell death pathway becomes discernible. Finally, bilirubin in vitro directly inhibited both the deubiquitination activity of proteasome-associated USP14 and UCHL5 and the CT-like peptidase activity of purified 20S proteasomes, in a dose-dependent manner. Hence, this study has discovered that increased bilirubin at a clinically achievable level can act as a proteasome inhibitor via targeting the 19S proteasome-associated deubiquitinases (DUBs) and, perhaps to a less extent, the 20S proteasome, identifying a novel mechanism for bilirubin neurotoxicity.
A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis
Authors: Dütting Sebastian , Gaits-Iacovoni Frederique , Stegner David , Popp Michael , Antkowiak Adrien , van Eeuwijk Judith M.M. , Nurden Paquita , Stritt Simon , Heib Tobias , Aurbach Katja , Angay Oguzhan , Cherpokova Deya , Heinz Niels , Baig Ayesha A. , Gorelashvili Maximilian G. , Gerner Frank , Heinze Katrin G. , Ware Jerry , Krohne Georg , Ruggeri Zaverio M. , Nurden Alan T. , Schulze Harald , Modlich Ute , Pleines Irina , Brakebusch Cord , Nieswandt Bernhard
Published: June 2017

Blood platelets are produced by large bone marrow (BM) precursor cells, megakaryocytes (MKs), which extend cytoplasmic protrusions (proplatelets) into BM sinusoids. The molecular cues that control MK polarization towards sinusoids and limit transendothelial crossing to proplatelets remain unknown. Here, we show that the small GTPases Cdc42 and RhoA act as a regulatory circuit downstream of the MK-specific mechanoreceptor GPIb to coordinate polarized transendothelial platelet biogenesis. Functional deficiency of either GPIb or Cdc42 impairs transendothelial proplatelet formation. In the absence of RhoA, increased Cdc42 activity and MK hyperpolarization triggers GPIb-dependent transmigration of entire MKs into BM sinusoids. These findings position Cdc42 (go-signal) and RhoA (stop-signal) at the centre of a molecular checkpoint downstream of GPIb that controls transendothelial platelet biogenesis. Our results may open new avenues for the treatment of platelet production disorders and help to explain the thrombocytopenia in patients with Bernard–Soulier syndrome, a bleeding disorder caused by defects in GPIb-IX-V.
Mitochondria localization induced self-assembly of peptide amphiphiles for cellular dysfunction
Authors: Jeena M. T. , Palanikumar L. , Go Eun Min , Kim Inhye , Kang Myoung Gyun , Lee Seonik , Park Sooham , Choi Huyeon , Kim Chaekyu , Jin Seon-Mi , Bae Sung Chul , Rhee Hyun Woo , Lee Eunji , Kwak Sang Kyu , Ryu Ja-Hyoung
Published: June 2017

Achieving spatiotemporal control of molecular self-assembly associated with actuation of biological functions inside living cells remains a challenge owing to the complexity of the cellular environments and the lack of characterization tools. We present, for the first time, the organelle-localized self-assembly of a peptide amphiphile as a powerful strategy for controlling cellular fate. A phenylalanine dipeptide (FF) with a mitochondria-targeting moiety, triphenyl phosphonium (Mito-FF), preferentially accumulates inside mitochondria and reaches the critical aggregation concentration to form a fibrous nanostructure, which is monitored by confocal laser scanning microscopy and transmission electron microscopy. The Mito-FF fibrils induce mitochondrial dysfunction via membrane disruption to cause apoptosis. The organelle-specific supramolecular system provides a new opportunity for therapeutics and in-depth investigations of cellular functions.
Factors related to good asthma control using different medical adherence scales in Latvian asthma patients: an observational study
Authors: Smits Dins , Brigis Girts , Pavare Jana , Maurina Baiba , Barengo Noël Christopher
Published: June 2017

One of the main challenges in asthma control is adherence to pharmaceutical treatment. The aim of this study was to test the association between adherence to asthma medication, control and medical beliefs, cognitive and emotional perceptions using three different validated questionnaires. Beliefs about asthma medicine, cognitive and emotional factors were determined in a cross-sectional survey of patients attending outpatient pulmonologist practices in Latvia (n = 352). The validated Beliefs about Medicines Questionnaire and the Brief Illness Perception Questionnaire were used. Adherence to asthma medication was assessed using the Morisky Medication Adherence Scale and two different versions of the Medication Adherence Reporting Scale. Several questions about necessity or concerns related to pharmaceutical treatment were able to predict poor adherence according to the Morisky scale. If the patient felt that without the asthma medication his life would be impossible, his risk to have poor treatment adherence was 46% reduced (odds ratio 0.54; 95% confidence interval 0.33–0.89). Furthermore, asthma patients who were convinced that their health depends on the asthma treatment were less likely to have poor treatment adherence (odds ratio 0.56: 95% confidence interval 0.32–0.97). In case the patient was concerned by the need to constantly use asthma medication or sometimes concerned by long-term effects of asthma medication the odds of poor treatment adherence were 1.96 (95% confidence interval 1.19–3.24) and 2.43 (95% confidence interval 1.45–4.08), respectively. In conclusion, medication beliefs, particularly concerns and necessity of asthma treatment were associated with poor treatment adherence when assessed with the Morisky or 5-item Medication Adherence Reporting Scale.
Genotoxicity and cytotoxicity of the plasma jet-treated medium on lymphoblastoid WIL2-NS cell line using the cytokinesis block micronucleus cytome assay
Authors: Hong Sung-Ha , Szili Endre J. , Fenech Michael , Gaur Nishtha , Short Robert D.
Published: June 2017

Despite growing interest in the application of atmospheric plasma jets as medical treatment strategies, there has been comparatively little research on the potential genotoxic and cytotoxic effects of plasma jet treatment. In this study, we have employed the cytokinesis block micronucleus cytome (CBMN-Cyt) assay with WIL2-NS B lymphoblastoid cells to test the potential genotoxicity, as well as the cytotoxicity, of toxic species generated in cell culture media by an argon (Ar) plasma jet. Elevated levels of cell death (necrosis) and occurrence of chromosomal damage (micronuclei MN, nculeoplasmic bridge NPBs and nuclear bus, Nbuds) were observed when cells were exposed to plasma jet-treated media. These results provide a first insight into how we might measure the genotoxic and cytotoxic effect of plasma jet treatments (both indirect and direct) in dividing human cells.
Analysis of survival and hatching transcriptomes from potato cyst nematodes, Globodera rostochiensis and G. pallida
Authors: Duceppe Marc-Olivier , Lafond-Lapalme Joël , Palomares-Rius Juan Emilio , Sabeh Michaël , Blok Vivian , Moffett Peter , Mimee Benjamin
Published: June 2017

Potato cyst nematodes (PCNs), Globodera rostochiensis and G. pallida, cause important economic losses. They are hard to manage because of their ability to remain dormant in soil for many years. Although general knowledge about these plant parasitic nematodes has considerably increased over the past decades, very little is known about molecular events involved in cyst dormancy and hatching, two key steps of their development. Here, we have studied the progression of PCN transcriptomes from dry cysts to hatched juveniles using RNA-Seq. We found that several cell detoxification-related genes were highly active in the dry cysts. Many genes linked to an increase of calcium and water uptake were up-regulated during transition from dormancy to hydration. Exposure of hydrated cysts to host plant root exudates resulted in different transcriptional response between species. After 48 h of exposure, G. pallida cysts showed no significant modulation of gene expression while G. rostochiensis had 278 differentially expressed genes. The first G. rostochiensis significantly up-regulated gene was observed after 8 h and was coding for a transmembrane metalloprotease. This enzyme is able to activate/inactivate peptide hormones and could be involved in a cascade of events leading to hatching. Several known effector genes were also up-regulated during hatching.
Distinct arsenic metabolites following seaweed consumption in humans
Authors: Taylor Vivien F. , Li Zhigang , Sayarath Vicki , Palys Thomas J. , Morse Kevin R. , Scholz-Bright Rachel A. , Karagas Margaret R.
Published: June 2017

Seaweeds contain arsenic primarily in the form of arsenosugars, which can be metabolized to a wide range of arsenic compounds. To characterize human exposure to arsenic from seaweed consumption, we determined concentrations of arsenic species in locally available seaweeds, and assessed urinary arsenic compounds in an experimental feeding study. A total of 11 volunteers consumed 10 g per day of three types of seaweeds (nori, kombu, and wakame) for three days each, while abstaining from rice and seafood following a three-day washout period. Urinary arsenosugars and their metabolites (including dimethyl arsenate (DMA), thio-dimethylarsinoylethanol (thio-DMAE), thio-dimethylarsinoylacetate (thio-DMAA), and thio-DMA) were measured in spot urine samples prior to seaweed consumption, and in 24-hour urine samples while consuming seaweed. Commercial products made from whole seaweed had substantial concentrations of arsenic (12–84 µg/g), dominated by arsenosugars. Intact arsenosugars along with DMA, thio-DMAA, thio-DMAE all increased in urine after ingesting each type of seaweed, and varied between seaweed types and between individuals. Only trace levels of the known toxic metabolite, thio-DMA, were observed, across individuals. Thio-DMAE and thio-DMAA are unique products of arsenosugar breakdown, thus assessment of these compounds may help to identify dietary intake of arsenic from seaweed from other exposure pathways.
Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice
Authors: Rosario Fredrick J. , Nathanielsz Peter W. , Powell Theresa L. , Jansson Thomas
Published: June 2017

Maternal folate deficiency is linked to restricted fetal growth, however the underlying mechanisms remain to be established. Here we tested the hypothesis that mTOR functions as a folate sensor in vivo in mice and that maternal folate deficiency inhibits placental mTOR signaling and amino acid transporter activity and causes fetal growth restriction. Folate deficient mice had lower serum folate (−60%). In late pregnancy, fetal weight in the folate deficient group was decreased (−17%, p < 0.05), whereas placental weight, litter size and crown rump length were unaltered. Maternal folate deficiency inhibited placental mTORC1 and mTORC2 signaling and decreased trophoblast plasma membrane System A and L amino acid transporter activities and transporter isoform expression. Folate deficiency also caused a decrease in phosphorylation of specific functional readouts of mTORC1 and mTORC2 signaling in multiple maternal and fetal tissues. We have identified a novel specific molecular link between maternal folate availability and fetal growth, involving regulation of placental mTOR signaling by folate, resulting in changes in placental nutrient transport. mTOR folate sensing may have broad biological significance because of the critical role of folate in normal cell function and the wide range of disorders, including cancer, that have been linked to folate availability.
Generating conditional gene knockouts in Plasmodium – a toolkit to produce stable DiCre recombinase-expressing parasite lines using CRISPR/Cas9
Authors: Knuepfer Ellen , Napiorkowska Marta , van Ooij Christiaan , Holder Anthony A.
Published: June 2017

Successful establishment of CRISPR/Cas9 genome editing technology in Plasmodium spp. has provided a powerful tool to transform Plasmodium falciparum into a genetically more tractable organism. Conditional gene regulation approaches are required to study the function of gene products critical for growth and erythrocyte invasion of blood stage parasites. Here we employ CRISPR/Cas9 to facilitate use of the dimerisable Cre-recombinase (DiCre) that is frequently used to mediate the excision and loss of loxP-flanked DNA sequences in a rapamycin controlled manner. We describe novel CRISPR/Cas9 transfection plasmids and approaches for the speedy, stable and marker-free introduction of transgenes encoding the DiCre recombinase into genomic loci dispensable for blood stage development. Together these plasmids form a toolkit that will allow the rapid generation of transgenic DiCre-expressing P. falciparum lines in any genetic background. Furthermore, the newly developed 3D7-derived parasite lines, constitutively and stably expressing DiCre, generated using this toolkit will prove useful for the analysis of gene products. Lastly, we introduce an improved treatment protocol that uses a lower rapamycin concentration and shorter treatment times, leading to loxP-guided recombination with close to 100% efficiency within the same replication cycle.
Protective Efficacy of the Trivalent Pseudomonas aeruginosa Vaccine Candidate PcrV-OprI-Hcp1 in Murine Pneumonia and Burn Models
Authors: Yang Feng , Gu Jiang , Yang Liuyang , Gao Chen , Jing Haiming , Wang Ying , Zeng Hao , Zou Quanming , Lv Fenglin , Zhang Jinyong
Published: June 2017

Pseudomonas aeruginosa is a formidable pathogen that is responsible for a diverse spectrum of human infectious diseases, resulting in considerable annual mortality rates. Because of biofilm formation and its ability of rapidly acquires of resistance to many antibiotics, P. aeruginosa related infections are difficult to treat, and therefore, developing an effective vaccine is the most promising method for combating infection. In the present study, we designed a novel trivalent vaccine, PcrV28-294-OprI25-83-Hcp11-162 (POH), and evaluated its protective efficacy in murine pneumonia and burn models. POH existed as a dimer in solution, it induced better protection efficacy in P. aeruginosa lethal pneumonia and murine burn models than single components alone when formulated with Al(OH)3 adjuvant, and it showed broad immune protection against several clinical isolates of P. aeruginosa. Immunization with POH induced strong immune responses and resulted in reduced bacterial loads, decreased pathology, inflammatory cytokine expression and inflammatory cell infiltration. Furthermore, in vitro opsonophagocytic killing assay and passive immunization studies indicated that the protective efficacy mediated by POH vaccination was largely attributed to POH-specific antibodies. Taken together, these data provided evidence that POH is a potentially promising vaccine candidate for combating P. aeruginosa infection in pneumonia and burn infections.
Effective Synthesis of Highly Oxidized Graphene Oxide That Enables Wafer-scale Nanopatterning: Preformed Acidic Oxidizing Medium Approach
Authors: Chen Chun-Hu , Hu Shin , Shih Jyun-Fu , Yang Chang-Ying , Luo Yun-Wen , Jhang Ren-Huai , Chiang Chao-Ming , Hung Yung-Jr
Published: June 2017

Demand for rapid and massive-scale exfoliation of bulky graphite remains high in graphene commercialization and property manipulation. We report a procedure utilizing “preformed acidic oxidizing medium (PAOM)” as a modified version of the Hummers’ method for fast and reliable synthesis of graphene oxide. Pre-mixing of KMnO4 and concentrated H2SO4 prior to the addition of graphite flakes enables the formation of effectively and efficiently oxidized graphene oxide (EEGO) featured by its high yields and suspension homogeneity. PAOM expedites diffusion of the Mn-oxidants into the graphite galleries, resulting in the rapid graphite oxidation, capable of oxidizing bulky graphite flakes (~0.8 mm in diameter) that can not be realized by the Hummers’ method. In the scale-up tests, ten-time amount of graphite can be completely exfoliated by PAOM without need of extended reaction time. The remarkable suspension homogeneity of EEGO can be exploited to deposit ultra-flat coating for wafer-scale nanopatterning. We successfully fabricated GO optical gratings with well-defined periodicity (300 nm) and uniform thickness (variation <7 nm). The combination of the facile and potent PAOM approach with the wafer-scale patterning technique may realize the goal for massive throughput graphene nanoelectronics.