bluuebunny/crossref_metadata_2025 huggingface dataset:
Iterating Bilinear Hardy Inequalities
Authors: Křepela Martin
Published: January 2017

An iteration technique for characterizing boundedness of certain types of multilinear operators is presented, reducing the problem to a corresponding linear-operator case. The method gives a simple proof of a characterization of validity of the weighted bilinear Hardy inequality

for all non-negative f, g on (a, b), for 1 < p1, p2, q < ∞. More equivalent characterizing conditions are presented.

The same technique is applied to various further problems, in particular those involving multilinear integral operators of Hardy type.
A revised and improved age model for the middle Miocene part of IODP Site U1318 (Porcupine Basin, offshore southwestern Ireland)
Authors: QUAIJTAAL WILLEMIJN , TESSEUR STEVEN , DONDERS TIMME H. , CLAEYS PHILIPPE , LOUWYE STEPHEN
Published: January 2017

Integrated Ocean Drilling Program Leg 307 Site U1318 is one of the few relatively complete middle Miocene drillcores from the North Atlantic (Porcupine Basin, offshore southwestern Ireland). Using benthic foraminiferal stable carbon and oxygen isotopes, the existing age model for Site U1318 was improved. The stable isotope record displays globally recognized isotope events, used to revise the existing magnetostratigraphy-based age model. Two intervals contained misidentified magnetochrons which were corrected. The sampled interval now has a refined age of 12.75–16.60 Ma with a temporal resolution of c. 29 ka.
HOBBES'S CONVENTIONALIST THEOLOGY, THE TRINITY, AND GOD AS AN ARTIFICIAL PERSON BY FICTION
Authors: ABIZADEH ARASH
Published: January 2017

By the time Hobbes wrote Leviathan, he was a theist, but not in the sense presumed by either side of the present-day debate concerning the sincerity of his professed theism. On the one hand, Hobbes's expressed theology was neither merely deistic, nor confined to natural theology: the Hobbesian God is not merely a first mover, but a person who counsels, commands, and threatens. On the other hand, the Hobbesian God's existence depends on being constructed artificially by human convention. The Hobbesian God is not a natural person; he exists as a person only insofar as he is by fiction represented. Like the state and pagan gods, he is an artificial person by fiction. The upshot is that Hobbes was a sincere theist and that his seventeenth-century critics were right to think that, in their sense, he was an atheist: he did not steadfastly believe in an independently existing deity who precedes human convention. Hobbes was agnostic on this question. He nevertheless believed that God is brought into being as an artificial person. This ‘personal theology’ not only involved a heretical interpretation of the Trinity, it also came to play a significant role in his moral and political philosophy.
‘IRELAND AS A WEAPON OF WARFARE’: WHIGS, TORIES, AND THE PROBLEM OF IRISH OUTRAGES, 1835 TO 1839
Authors: ROSZMAN JAY R.
Published: January 2017

This article contends that the Irish policy of both the Whig and Tory parties has received rather short shrift in the historiography surrounding Britain's decade of reform. In an attempt to rectify this gap, the article traces the emergence of the Whig policy of ‘justice to Ireland’ between 1835 and 1839; a policy championed by an emerging activist leadership within the party that promoted Catholics in Irish administration and attempted to pass substantial legislative reform. This ambitious Whig agenda upended a thirty-five-year consensus that relied on coercion to rule Ireland's recalcitrant population. Tories vehemently opposed this change, and used Irish agrarian violence – so-called ‘outrages’ – to undermine the success of the Whigs’ novel approach to governing Ireland through remedial legislation. This confrontation over Irish policy led to an 1839 House of Lords committee on Irish crime that passed a vote of censure on the Whigs’ Irish policy and nearly toppled Melbourne's government. However, the article demonstrates how the Whigs’ Irish policy was the one question that held together their big tent coalition of Whigs, English radicals, and O'Connellites, thus extending their administration for another two years.
“Anything Can Be Used to Stimulate Child Development”: Early Childhood Education and Development in Indonesia as a Durable Assemblage
Authors: Newberry Jan
Published: January 2017

An explosion of early childhood programs in Yogyakarta, Indonesia, has followed on disaster, democratization, growth of the middle class, and global neoliberal reform at the beginning of the twenty-first century. New forms of professional expertise have emerged as a part of this global assemblage to deal with the expanded notions of development advocated by the World Bank and other intergovernmental organizations. Yet, what has remained relatively unremarked is the continued reliance on older New Order forms of social welfare linked to the community form and women's labor. Here, trauma healing programs aimed at the young after the 2006 earthquake, new preschools and playgroups in the era of democratization, and the proliferation of international curricula and pedagogy illustrate how the restless contingency associated with global assemblages is rooted in durable forms of community organization.
Copro-PCR prevalence of Echinococcus granulosus infection in dogs in Kerman, south-eastern Iran
Authors: Mirbadie S.R. , Kamyabi H. , Mohammadi M.A. , Shamsaddini S. , Harandi M.F.
Published: January 2017

The main objective of this study was to determine the prevalence of taeniid parasites and the specific detection of Echinococcus granulosus using copro-DNA polymerase chain reaction (PCR) analysis in the stray dogs of Kerman, south-eastern Iran. From September 2013 to May 2014, faecal samples of stray dogs were collected from different parts of the city of Kerman and its suburbs. Faecal samples from dogs were collected randomly within 24 h of defecation. All samples were transferred to the research lab and coprological examinations were conducted by the formalin–ether concentration method. In the microscopically positive samples, mitochondrial cytochrome c oxidase subunit 1 (cox1) specific primers were used to determine the taeniid identity of the infection. In addition, another set of primers was used for the specific diagnosis of E. granulosus sensu lato. In total, 307 faecal samples from stray dogs were examined for the presence of the parasites. Taeniidae eggs were detected in 34 dogs (11.07%). All 34 taeniid-positive specimens were PCR positive for cox1 (444 bp). Of all taeniid-positive specimens, 21 samples (6.8% of all dog specimens) were positive according to primers specific for E. granulosus. The findings of the present study revealed that canine echinococcosis is prevalent in the stray dogs in Kerman. The findings of the present study have important implications for hydatid control programmes in the area.
Effect of host diversity and species assemblage composition on bovine tuberculosis (bTB) risk in Ethiopian cattle
Authors: SINTAYEHU DEJENE W. , HEITKÖNIG IGNAS M. A. , PRINS HERBERT H. T. , TESSEMA ZEWDU K. , DE BOER WILLEM F.
Published: January 2017

Current theories on diversity–disease relationships describe host species diversity and species identity as important factors influencing disease risk, either diluting or amplifying disease prevalence in a community. Whereas the simple term ‘diversity’ embodies a set of animal community characteristics, it is not clear how different measures of species diversity are correlated with disease risk. We therefore tested the effects of species richness, Pielou's evenness and Shannon's diversity on bovine tuberculosis (bTB) risk in cattle in the Afar Region and Awash National Park between November 2013 and April 2015. We also analysed the identity effect of a particular species and the effect of host habitat use overlap on bTB risk. We used the comparative intradermal tuberculin test to assess the number of bTB-infected cattle. Our results suggested a dilution effect through species evenness. We found that the identity effect of greater kudu – a maintenance host – confounded the dilution effect of species diversity on bTB risk. bTB infection was positively correlated with habitat use overlap between greater kudu and cattle. Different diversity indices have to be considered together for assessing diversity–disease relationships, for understanding the underlying causal mechanisms. We posit that unpacking diversity metrics is also relevant for formulating disease control strategies to manage cattle in ecosystems characterized by seasonally limited resources and intense wildlife–livestock interactions.
Nonsteroidal anti-inflammatory is more effective than anti-oxidant therapy in counteracting oxidative/nitrosative stress and heart disease inT. cruzi-infected mice
Authors: NOVAES RÔMULO D. , SANTOS ELIZIÁRIA C. , FIALHO MARIA DO CARMO Q. , GONÇALVES WAGNER G. , SEQUETTO PRISCILA L. , TALVANI ANDRÉ , GONÇALVES REGGIANI V.
Published: January 2017

We compared the relevance of ibuprofen, vitamins C and E to control oxidative/nitrosative stress and heart disease in mice infected byTrypanosoma cruzi. Swiss mice were randomized into five groups: control, uninfected; infected without treatment; and infected treated with vitamins C, E or ibuprofen. Animals were inoculated with 2000 trypomastigote forms ofT. cruzi. After 20 days, infected mice presented reduced vitamin C and E tissue levels, high cytokines (interferon gamma, tumour necrosis factor-α, interleukin 10 and chemokine ligand 2), prostaglandin F2α(PGF2α) and nitric oxide (NO) cardiac production, intense myocarditis and reactive tissue damage, which was directly correlated with the intensity of the inflammatory infiltrate and the degree of pathological cardiac remodelling. Vitamins C and E supplementation were irrelevant to counteract reactive tissue damage and myocarditis in infected animals. Conversely, ibuprofen reduced tissue levels of cytokines, PGF2αand NO, as well as lipid and protein oxidation, antioxidant enzyme activity and the cardiac damage, without interfering with heart parasitism. Our results do not support the applicability of vitamin C and E supplementation in the management of acute Chagas cardiomyopathy. By controlling the inflammatory infiltrate, anti-inflammatory-based therapy proved to be a more rational strategy than a direct antioxidant therapy in attenuating oxidative/nitrosative stress and cardiac damage.
Developing best practice guidelines for designing living environments for people with dementia and sight loss
Authors: BOWES ALISON , DAWSON ALISON , GREASLEY-ADAMS CORINNE , MCCABE LOUISE
Published: January 2017

The paper considers a process of developing evidence-based design guidelines to be used in environments where people with dementia and sight loss are living. The research involved a systematically conducted literature review and a series of consultations with people affected by dementia and/or sight loss who lived or worked in care homes or in domestic settings. Findings from the literature and the consultations were used in an iterative process to develop the guidelines. The process is outlined, providing examples from the guidelines about lighting and colour and contrast. In discussing the research findings and the development process, the authors consider implications of the work including the weakness of the evidence base, the challenges of improving this and the need for innovative approaches to understanding the complexities of design for people with dementia and sight loss. They highlight the emphasis in the literature on independence for people with sight loss and the focus on control of people with dementia, arguing that this falls short of a genuinely person-centred approach, which recognises the active participation of people with dementia and sight loss.
Living with Parkinson's disease – perceptions of invisibility in a photovoice study
Authors: ROGER KERSTIN , WETZEL MONIKA , PENNER LESLIE
Published: January 2017

Based on previous community research, we prioritise the need to understand better how experiences and feelings of invisibility could be shaped by relational dynamics, interfacing with service provision, and social forces, with the overarching view of understanding better the experiences of participants living with Parkinson's disease. A photovoice methodology was employed. A discussion of one case study of Bindy and Volta leads to a better understanding of how strong spousal support can significantly alter how one individual experiences and defines living with Parkinson's.
The SESAME materials science beamline for XRD applications
Authors: Abdellatief M. , Rebuffi L. , Khosroabadi H. , Najdawi M. , Abu-Hanieh T. , Attal M. , Paolucci G.
Published: January 2017

We present a detailed description of the SESAME Materials Science (MS) beamline for X-ray diffraction (XRD) applications, presently under construction in Allan, Jordan. The beamline is based on components previously installed at the Swiss Light Source, but modifications in the beamline design have been introduced to match the characteristics of the SESAME storage ring. The SESAME MS beamline will accommodate XRD experiments in the energy range between 5 and 25 keV. The beamline ray tracing analysis at 10 keV estimates the flux at the sample to be of the order of 1013 (photons s−1), the energy resolution is about 2 eV and the effective beam size at the sample of 300 × 2800 µm2. Investigations of microstruture will be possible as the instrumental broadening, resulted from simulating the diffraction pattern for a standard material, is of the order of 0.01° at 15 keV. A wide range of applications will be possible at the beamline, such as powder diffraction studies, single crystals and in situ XRD. The commisioning of the beamline is expected to be in the second half of 2017.
Challenges in the industrial implementation of generative design systems: An exploratory study
Authors: Nordin Axel
Published: January 2017

The aim of this paper is to investigate the challenges associated with the industrial implementation of generative design systems. Though many studies have been aimed at validating either the technical feasibility or the usefulness of generative design systems, there is, however, a lack of research on the practical implementation and adaptation in industry. To that end, this paper presents two case studies conducted while developing design systems for industrial uses. The first case study focuses on an engineering design application and the other on an industrial design application. In both cases, the focus is on detail-oriented performance-driven generative design systems based on currently available computer-assisted design tools. The development time and communications with the companies were analyzed to identify challenges in the two projects. Overall, the results show that the challenges are not related to whether the design tools are intended for artistic or technical problems, but rather in how to make the design process systematic. The challenges include aspects such as how to fully utilize the potential of generative design tools in a traditional product development process, how to enable designers not familiar with programming to provide design generation logic, and what should be automated and what is better left as a manual task. The paper suggests several strategies for dealing with the identified challenges.
Characterizing innovative processes in design spaces through measuring the information entropy of empirical data from protocol studies
Authors: Kan Jeff W.T. , Gero John S.
Published: January 2017

This paper reports on a study characterizing design processes and the potential of design spaces through measuring the information entropy of empirical data derived from protocol studies. The sequential segments in a protocol analysis can be related to each other by examining their semantic content producing a design session's linkograph, which defines the design space for a design session. From a linkograph, it is possible to compute the probabilities of the connectivity of each segment for its forelinks and its backlinks, together with the probabilities of distance among links. A linkograph's entropy is a measure of the information in the design session. It is claimed that the entropy of the linkograph measures the potential of the design space being generated as the design proceeds chronologically. We present an approach to the automated construction of linkographs by connecting segments using the lexical database WordNet and measure its entropy. A case study of two design sessions with different characteristics was conducted, one considered more productive and creative, the other more pragmatic. Those segments with high entropy and those associated with high rates of change of entropy are analyzed. The creative session has a higher linkograph entropy. This result indicates the potential of using entropy to characterize a design process.
Assessing the impact of mowing on Common RedshanksTringa totanusbreeding on saltmarshes: lessons for conservation management
Authors: EXO KLAUS-MICHAEL , WELLBROCK ARNDT H. J. , SONDERMANN JULIA , MAIER MARTIN
Published: January 2017

Informed application of habitat management measures is crucial, especially in saltmarshes that function as last refuges for breeding waders in Europe. Despite a reduction in agricultural use of saltmarshes since the establishment of the Wadden Sea National Parks at the end of the 1980s, there remains controversy regarding management measures such as the timing of mowing. We modelled the proportion of nests and chicks that would be jeopardised by mowing at different dates, using long-term breeding data of the Common RedshankTringa totanus– an endangered and widespread indicator species of saltmarshes – from four study sites in the German Wadden Sea. At two study sites in the western Jadebusen, the proportion of broods that were at risk of being killed when mowing began on 1 July ranged between 78% in early, to 96% in late, breeding years, averaging 87%. Although Common Redshanks in the eastern Jadebusen started breeding one week earlier, the model still predicted a loss of 73% of chicks; while 97% of broods were at risk on the island of Wangerooge. Postponement of mowing to 1 August reduced these proportions to 21%, 11% and 32%, respectively. This study is the first to model the positive effects of delayed mowing of saltmarshes on ground-nesting birds. By implementing adjusted mowing dates in addition to previously suggested reductions in artificial drainage, direct and indirect adverse effects caused by mowing and drainage, such as an increased predation risk, are likely to be reduced, such that a ’favourable conservation status’ according to the EC Habitats Directive may be achieved.
The Use of Emergency Lights and Sirens by Ambulances and Their Effect on Patient Outcomes and Public Safety: A Comprehensive Review of the Literature
Authors: Murray Brett , Kue Ricky
Published: January 2017

The benefits of emergency lights and sirens (L&S) use as warning devices by ambulances continue to be a debated topic in Emergency Medical Services (EMS). While the most widely studied aspect of L&S use has been related to their effect on ambulance response and transport times, the literature suggests minimal time savings with more questionable impact on actual patient outcomes. As L&S use has been shown to increase the risk for vehicle crashes, the secondary concern of ambulance design and safety also becomes an important aspect on potential design recommendations that could mitigate the effects of a crash on patients, EMS providers, and the general public. The least studied aspect of L&S use (and probably the most important) is their effect on patient outcomes and quality of medical care during transport. The current evidence suggests no significant improvement on patient outcomes and potential worsening to certain aspects of patient care during transport. The purpose of this review was to examine the current literature regarding ambulance L&S use and the risks they pose to EMS providers, patients, and the general public. In doing so, it will provide sound background for EMS leaders to better develop policies governing the use of L&S by ambulances and promote better research in the patient outcomes effect associated with their use. This review offers some strategies in mitigating the risks associated with L&S use, such as ways to reduce their overall use and modifying other related factors to emergency medical vehicle collisions (EMVCs).

MurrayB, KueR. The use of emergency lights and sirens by ambulances and their effect on patient outcomes and public safety: a comprehensive review of the literature. Prehosp Disaster Med. 2017;32(2):209–216.
Laser-Assisted Atom Probe Tomography of Deformed Minerals: A Zircon Case Study
Authors: La Fontaine Alexandre , Piazolo Sandra , Trimby Patrick , Yang Limei , Cairney Julie M.
Published: January 2017

The application of atom probe tomography to the study of minerals is a rapidly growing area. Picosecond-pulsed, ultraviolet laser (UV-355 nm) assisted atom probe tomography has been used to analyze trace element mobility within dislocations and low-angle boundaries in plastically deformed specimens of the nonconductive mineral zircon (ZrSiO4), a key material to date the earth’s geological events. Here we discuss important experimental aspects inherent in the atom probe tomography investigation of this important mineral, providing insights into the challenges in atom probe tomography characterization of minerals as a whole. We studied the influence of atom probe tomography analysis parameters on features of the mass spectra, such as the thermal tail, as well as the overall data quality. Three zircon samples with different uranium and lead content were analyzed, and particular attention was paid to ion identification in the mass spectra and detection limits of the key trace elements, lead and uranium. We also discuss the correlative use of electron backscattered diffraction in a scanning electron microscope to map the deformation in the zircon grains, and the combined use of transmission Kikuchi diffraction and focused ion beam sample preparation to assist preparation of the final atom probe tip.
Peirce’s semeiotics: a methodology for bridging the material–ideational divide in IR scholarship
Authors: Drieschova Alena
Published: January 2017

The New Materialisms in IR scholarship seek to transcend the divide between matter and ideas, with among others such concepts as practices, or artifacts. This paper makes a start in developing a systematic methodology for the New Materialisms. It proposes Peirce’s semeiotics as one way to unpack how practices and artifacts are ideational and simultaneously material. Peircean semeiotics is a semeiotics of materialism, which creates room for material constitution and analyses practices and artifacts as signs. Peircean semeiotics acknowledges that many signs are objects and practices in the material world, and therefore underlie material constraints, while they also limit and enable the possibilities for action upon the world. Simultaneously though, as signs they convey a particular meaning to the people who surround them, not always by intent. Just as language, material things can signify by arbitrary social convention, but they can also signify by resembling the object they represent, or by being causally related to it. The linguistic model is thus incomplete to study the significative role of material reality. I will illustrate the use of Peircean semeiotics on an analysis of GDP as an inscription device and a complex sign.
Bidirectional Associations Between Self-Perceptions of Aging and Processing Speed Across 3 Years
Authors: Seidler Anna L. , Wolff Julia K.
Published: January 2017

Abstract. Background: Previous studies point to a potential relationship between self-perceptions of aging (SPA) and cognitive performance. However, most of these studies are limited by their experimental design. Previous longitudinal studies looked solely at memory as an outcome variable without examining the directionality of effects. The present study examines the direction of effects between two domains of SPA (personal growth and physical losses) and processing speed (PS). Methods: The sample consists of 8,198 participants of the German Ageing Survey (DEAS), aged between 40 and 93 years. A cross-lagged path model was estimated to examine directions of relationships across 3 years via chi-squared difference tests for each domain of SPA. Results: In the unconstrained models, the effect of SPA domain personal growth in 2008 on PS in 2011 and vice versa were marginally significant. For SPA domain physical losses, the effect of SPA on PS was significant, whereas the other direction of the effect did not reach significance. However, the cross-lagged paths of both domains of SPA on PS and vice versa could be set equal without a significant loss of model fit. The resulting associations indicate a significant bidirectional relationship between both domains of SPA and PS. Discussion and conclusion: This study provides initial evidence that SPA can influence trajectories of cognitive decline and vice versa. The results emphasize the detrimental and beneficial effects that stereotypes can have on individuals and add further evidence to the theory of stereotype embodiment.
Music Therapy for Epilepsy
Authors: Maguire Melissa
Published: January 2017

Abstract. Researchers are increasingly looking toward nondrug therapeutic interventions in controlling seizures in epilepsy. Music therapy has shown potential therapeutic benefit in cognitive science. Here we focus on the evidence base for its utility as a therapy in epilepsy.
Kunsttherapie bei Alzheimer-Patienten
Authors: Komzáková Martina
Published: January 2017

Zusammenfassung. Der Beitrag beschreibt kunsttherapeutische Prozesse mit polymorbiden, älteren Alzheimer-Patienten in einer offenen Therapiegruppe an der Langzeiteinrichtung Privamed in Pilsen. Therapieziel ist es, durch künstlerische Aktivitäten den emotionalen Fluss, Selbstvertrauen und geistige wie soziale Mobilität zu verbessern, psychomotorische Fähigkeiten und Raumorientierung zu fördern und sozialkommunikative Kooperation zu intensivieren. Technisch-funktionale sowie kreativ-darstellende Momente spielen in der Kunsttherapie naturgemäß zusammen und führen zur Steigerung des künstlerischen wie des ich-expressiven Anspruchs. Soziale Interaktivität und fein abgestimmte therapeutische Unterstützung im Sinne von Winnicotts „ausreichend guter Mutter“ ( Fornagy & Target, 2005 ) beeinflussen entscheidend die therapeutische Effizienz.
A Rab5 endosomal pathway mediates Parkin-dependent mitochondrial clearance
Authors: Hammerling Babette C. , Najor Rita H. , Cortez Melissa Q. , Shires Sarah E. , Leon Leonardo J. , Gonzalez Eileen R. , Boassa Daniela , Phan Sébastien , Thor Andrea , Jimenez Rebecca E. , Li Hong , Kitsis Richard N. , Dorn Gerald W. , Sadoshima Junichi , Ellisman Mark H. , Gustafsson Åsa B.
Published: January 2017

Damaged mitochondria pose a lethal threat to cells that necessitates their prompt removal. The currently recognized mechanism for disposal of mitochondria is autophagy, where damaged organelles are marked for disposal via ubiquitylation by Parkin. Here we report a novel pathway for mitochondrial elimination, in which these organelles undergo Parkin-dependent sequestration into Rab5-positive early endosomes via the ESCRT machinery. Following maturation, these endosomes deliver mitochondria to lysosomes for degradation. Although this endosomal pathway is activated by stressors that also activate mitochondrial autophagy, endosomal-mediated mitochondrial clearance is initiated before autophagy. The autophagy protein Beclin1 regulates activation of Rab5 and endosomal-mediated degradation of mitochondria, suggesting cross-talk between these two pathways. Abrogation of Rab5 function and the endosomal pathway results in the accumulation of stressed mitochondria and increases susceptibility to cell death in embryonic fibroblasts and cardiac myocytes. These data reveal a new mechanism for mitochondrial quality control mediated by Rab5 and early endosomes.
Structural basis for ELL2 and AFF4 activation of HIV-1 proviral transcription
Authors: Qi Shiqian , Li Zichong , Schulze-Gahmen Ursula , Stjepanovic Goran , Zhou Qiang , Hurley James H.
Published: January 2017

The intrinsically disordered scaffold proteins AFF1/4 and the transcription elongation factors ELL1/2 are core components of the super elongation complex required for HIV-1 proviral transcription. Here we report the 2.0-Å resolution crystal structure of the human ELL2 C-terminal domain bound to its 50-residue binding site on AFF4, the ELLBow. The ELL2 domain has the same arch-shaped fold as the tight junction protein occludin. The ELLBow consists of an N-terminal helix followed by an extended hairpin that we refer to as the elbow joint, and occupies most of the concave surface of ELL2. This surface is important for the ability of ELL2 to promote HIV-1 Tat-mediated proviral transcription. The AFF4–ELL2 interface is imperfectly packed, leaving a cavity suggestive of a potential binding site for transcription-promoting small molecules.
KIF13B establishes a CAV1-enriched microdomain at the ciliary transition zone to promote Sonic hedgehog signalling
Authors: Schou Kenneth B. , Mogensen Johanne B. , Morthorst Stine K. , Nielsen Brian S. , Aleliunaite Aiste , Serra-Marques Andrea , Fürstenberg Nicoline , Saunier Sophie , Bizet Albane A. , Veland Iben R. , Akhmanova Anna , Christensen Søren T. , Pedersen Lotte B.
Published: January 2017

Ciliary membrane composition is controlled by transition zone (TZ) proteins such as RPGRIP1, RPGRIPL and NPHP4, which are vital for balanced coordination of diverse signalling systems like the Sonic hedgehog (Shh) pathway. Activation of this pathway involves Shh-induced ciliary accumulation of Smoothened (SMO), which is disrupted by disease-causing mutations in TZ components. Here we identify kinesin-3 motor protein KIF13B as a novel member of the RPGRIP1N-C2 domain-containing protein family and show that KIF13B regulates TZ membrane composition and ciliary SMO accumulation. KIF13B is upregulated during ciliogenesis and is recruited to the ciliary base by NPHP4, which binds to two distinct sites in the KIF13B tail region, including an RPGRIP1N-C2 domain. KIF13B and NPHP4 are both essential for establishment of a CAV1 membrane microdomain at the TZ, which in turn is required for Shh-induced ciliary SMO accumulation. Thus KIF13B is a novel regulator of ciliary TZ configuration, membrane composition and Shh signalling.
Single-step ambient-air synthesis of graphene from renewable precursors as electrochemical genosensor
Authors: Seo Dong Han , Pineda Shafique , Fang Jinghua , Gozukara Yesim , Yick Samuel , Bendavid Avi , Lam Simon Kwai Hung , Murdock Adrian T. , Murphy Anthony B. , Han Zhao Jun , Ostrikov Kostya
Published: January 2017

Thermal chemical vapour deposition techniques for graphene fabrication, while promising, are thus far limited by resource-consuming and energy-intensive principles. In particular, purified gases and extensive vacuum processing are necessary for creating a highly controlled environment, isolated from ambient air, to enable the growth of graphene films. Here we exploit the ambient-air environment to enable the growth of graphene films, without the need for compressed gases. A renewable natural precursor, soybean oil, is transformed into continuous graphene films, composed of single-to-few layers, in a single step. The enabling parameters for controlled synthesis and tailored properties of the graphene film are discussed, and a mechanism for the ambient-air growth is proposed. Furthermore, the functionality of the graphene is demonstrated through direct utilization as an electrode to realize an effective electrochemical genosensor. Our method is applicable to other types of renewable precursors and may open a new avenue for low-cost synthesis of graphene films.
The tumour suppressor APC promotes HIV-1 assembly via interaction with Gag precursor protein
Authors: Miyakawa Kei , Nishi Mayuko , Matsunaga Satoko , Okayama Akiko , Anraku Masaki , Kudoh Ayumi , Hirano Hisashi , Kimura Hirokazu , Morikawa Yuko , Yamamoto Naoki , Ono Akira , Ryo Akihide
Published: January 2017

Diverse cellular proteins and RNAs are tightly regulated in their subcellular localization to exert their local function. Here we report that the tumour suppressor adenomatous polyposis coli protein (APC) directs the localization and assembly of human immunodeficiency virus (HIV)-1 Gag polyprotein at distinct membrane components to enable the efficient production and spread of infectious viral particles. A proteomic analysis and subsequent biomolecular interaction assay reveals that the carboxyl terminus of APC interacts with the matrix region of Gag. Ectopic expression of APC, but not its familial adenomatous polyposis-related truncation mutant, prominently enhances HIV-1 production. Conversely, the depletion of APC leads to a significant decrease in membrane targeting of viral components, resulting in the severe loss of production of infectious virions. Furthermore, APC promotes the directional assembly of viral components at virological synapses, thereby facilitating cell-to-cell viral transmission. These findings reveal an unexpected role of APC in the directional spread of HIV-1.
Preserving π-conjugation in covalently functionalized carbon nanotubes for optoelectronic applications
Authors: Setaro Antonio , Adeli Mohsen , Glaeske Mareen , Przyrembel Daniel , Bisswanger Timo , Gordeev Georgy , Maschietto Federica , Faghani Abbas , Paulus Beate , Weinelt Martin , Arenal Raul , Haag Rainer , Reich Stephanie
Published: January 2017

Covalent functionalization tailors carbon nanotubes for a wide range of applications in varying environments. Its strength and stability of attachment come at the price of degrading the carbon nanotubes sp2 network and destroying the tubes electronic and optoelectronic features. Here we present a non-destructive, covalent, gram-scale functionalization of single-walled carbon nanotubes by a new [2+1] cycloaddition. The reaction rebuilds the extended π-network, thereby retaining the outstanding quantum optoelectronic properties of carbon nanotubes, including bright light emission at high degree of functionalization (1 group per 25 carbon atoms). The conjugation method described here opens the way for advanced tailoring nanotubes as demonstrated for light-triggered reversible doping through photochromic molecular switches and nanoplasmonic gold-nanotube hybrids with enhanced infrared light emission.
Orthogonal ubiquitin transfer identifies ubiquitination substrates under differential control by the two ubiquitin activating enzymes
Authors: Liu Xianpeng , Zhao Bo , Sun Limin , Bhuripanyo Karan , Wang Yiyang , Bi Yingtao , Davuluri Ramana V. , Duong Duc M. , Nanavati Dhaval , Yin Jun , Kiyokawa Hiroaki
Published: January 2017

Protein ubiquitination is mediated sequentially by ubiquitin activating enzyme E1, ubiquitin conjugating enzyme E2 and ubiquitin ligase E3. Uba1 was thought to be the only E1 until the recent identification of Uba6. To differentiate the biological functions of Uba1 and Uba6, we applied an orthogonal ubiquitin transfer (OUT) technology to profile their ubiquitination targets in mammalian cells. By expressing pairs of an engineered ubiquitin and engineered Uba1 or Uba6 that were generated for exclusive interactions, we identified 697 potential Uba6 targets and 527 potential Uba1 targets with 258 overlaps. Bioinformatics analysis reveals substantial differences in pathways involving Uba1- and Uba6-specific targets. We demonstrate that polyubiquitination and proteasomal degradation of ezrin and CUGBP1 require Uba6, but not Uba1, and that Uba6 is involved in the control of ezrin localization and epithelial morphogenesis. These data suggest that distinctive substrate pools exist for Uba1 and Uba6 that reflect non-redundant biological roles for Uba6.
THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
Authors: Cayrol Florencia , Praditsuktavorn Pannee , Fernando Tharu M. , Kwiatkowski Nicholas , Marullo Rosella , Calvo-Vidal M. Nieves , Phillip Jude , Pera Benet , Yang Shao Ning , Takpradit Kaipol , Roman Lidia , Gaudiano Marcello , Crescenzo Ramona , Ruan Jia , Inghirami Giorgio , Zhang Tinghu , Cremaschi Graciela , Gray Nathanael S. , Cerchietti Leandro
Published: January 2017

Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients.
Portal protein functions akin to a DNA-sensor that couples genome-packaging to icosahedral capsid maturation
Authors: Lokareddy Ravi K. , Sankhala Rajeshwer S. , Roy Ankoor , Afonine Pavel V. , Motwani Tina , Teschke Carolyn M. , Parent Kristin N. , Cingolani Gino
Published: January 2017

Tailed bacteriophages and herpesviruses assemble infectious particles via an empty precursor capsid (or ‘procapsid’) built by multiple copies of coat and scaffolding protein and by one dodecameric portal protein. Genome packaging triggers rearrangement of the coat protein and release of scaffolding protein, resulting in dramatic procapsid lattice expansion. Here, we provide structural evidence that the portal protein of the bacteriophage P22 exists in two distinct dodecameric conformations: an asymmetric assembly in the procapsid (PC-portal) that is competent for high affinity binding to the large terminase packaging protein, and a symmetric ring in the mature virion (MV-portal) that has negligible affinity for the packaging motor. Modelling studies indicate the structure of PC-portal is incompatible with DNA coaxially spooled around the portal vertex, suggesting that newly packaged DNA triggers the switch from PC- to MV-conformation. Thus, we propose the signal for termination of ‘Headful Packaging’ is a DNA-dependent symmetrization of portal protein.
Bacillus subtilis biofilm extends Caenorhabditis elegans longevity through downregulation of the insulin-like signalling pathway
Authors: Donato Verónica , Ayala Facundo Rodríguez , Cogliati Sebastián , Bauman Carlos , Costa Juan Gabriel , Leñini Cecilia , Grau Roberto
Published: January 2017

Beneficial bacteria have been shown to affect host longevity, but the molecular mechanisms mediating such effects remain largely unclear. Here we show that formation of Bacillus subtilis biofilms increases Caenorhabditis elegans lifespan. Biofilm-proficient B. subtilis colonizes the C. elegans gut and extends worm lifespan more than biofilm-deficient isogenic strains. Two molecules produced by B. subtilis — the quorum-sensing pentapeptide CSF and nitric oxide (NO) — are sufficient to extend C. elegans longevity. When B. subtilis is cultured under biofilm-supporting conditions, the synthesis of NO and CSF is increased in comparison with their production under planktonic growth conditions. We further show that the prolongevity effect of B. subtilis biofilms depends on the DAF-2/DAF-16/HSF-1 signalling axis and the downregulation of the insulin-like signalling (ILS) pathway.
Inhibition of the integrin/FAK signaling axis and c-Myc synergistically disrupts ovarian cancer malignancy
Authors: Xu B , Lefringhouse J , Liu Z , West D , Baldwin L A , Ou C , Chen L , Napier D , Chaiswing L , Brewer L D , St. Clair D , Thibault O , van Nagell J R , Zhou B P , Drapkin R , Huang J-A , Lu M L , Ueland F R , Yang X H
Published: January 2017

Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 and JQ1 synergistically caused an arrest of tumor cells at the G2/M phase and a decrease in the XIAP-linked cell survival. Our subsequent mechanistic analyses indicate that this functional cooperation was strongly associated with the concomitant disruption of activation or expression of FAK and c-Myc as well as their downstream signaling through the PI3K/Akt pathway. In line with these observations, we detected a strong co-amplification or upregulation at genomic or protein level for FAK and c-Myc in a large portion of primary tumors in the TCGA or a local HGSOC patient cohort. Taken together, our results suggest that the integrin–FAK signaling axis and c-Myc synergistically drive cell proliferation, survival and oncogenic potential in HGSOC. As such, our study provides key genetic, functional and signaling bases for the small-molecule-based co-targeting of these two distinct oncogenic drivers as a new line of targeted therapy against human ovarian cancer.
Egr-1 regulates irradiation-induced autophagy through Atg4B to promote radioresistance in hepatocellular carcinoma cells
Authors: Peng W-x , Wan Y-y , Gong A-h , Ge L , Jin J , Xu M , Wu C-y
Published: January 2017

Although hepatocellular carcinoma (HCC) is usually response to radiation therapy, radioresistance is still the major obstacle that limits the efficacy of radiotherapy for HCC patients. Therefore, further investigation of underlying mechanisms in radioresistant HCC cells is warranted. In this study, we determined the effect of early growth response factor (Egr-1) on irradiation-induced autophagy and radioresistance in HCC cell lines SMMC-7721 and HepG2. We showed that autophagy-related gene 4B (Atg4B) is induced by Egr-1 upon ionizing radiation (IR) in HCC cells. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) revealed that Egr-1 binds to the Atg4B promoter to upregulate its expression in HCC cells. Suppression of Egr-1 function by dominant-negative Egr-1 dampens IR-induced autophagy, cell migration, and increases cell sensitivity to radiotherapy. Together, these results suggest that Egr-1 contributes to HCC radioresistance through directly upregulating target gene Atg4B, which may serve as a protective mechanism by preferential activation of the autophagy.
Elevated 5hmC levels characterize DNA of the cerebellum in Parkinson’s disease
Authors: Stöger Reinhard , Scaife Paula J. , Shephard Freya , Chakrabarti Lisa
Published: January 2017

5-methylcytosine and the oxidation product 5-hydroxymethylcytosine are two prominent epigenetic variants of the cytosine base in nuclear DNA of mammalian brains. We measured levels of 5-methylcytosine and 5-hydroxymethylcytosine by enzyme-linked immunosorbent assay in DNA from post-mortem cerebella of individuals with Parkinson’s disease and age-matched controls. 5-methylcytosine levels showed no significant differences between Parkinson’s disease and control DNA sample sets. In contrast, median 5-hydroxymethylcytosine levels were almost twice as high (p < 0.001) in both male and female Parkinson’s disease individuals compared with controls. The distinct epigenetic profile identified in cerebellar DNA of Parkinson’s disease patients raises the question whether elevated 5-hydroxymethylcytosine levels are a driver or a consequence of Parkinson’s disease.
Genetics and educational attainment
Authors: Cesarini David , Visscher Peter M.
Published: January 2017

We explore how advances in our understanding of the genetics of complex traits such as educational attainment could constructively be leveraged to advance research on education and learning. We discuss concepts and misconceptions about genetic findings with regard to causes, consequences, and policy. Our main thesis is that educational attainment as a measure that varies between individuals in a population can be subject to exactly the same experimental biological designs as other outcomes, for example, those studied in epidemiology and medical sciences, and the same caveats about interpretation and implication apply.
Low-dose acetaminophen induces early disruption of cell-cell tight junctions in human hepatic cells and mouse liver
Authors: Gamal Wesam , Treskes Philipp , Samuel Kay , Sullivan Gareth J. , Siller Richard , Srsen Vlastimil , Morgan Katie , Bryans Anna , Kozlowska Ada , Koulovasilopoulos Andreas , Underwood Ian , Smith Stewart , del-Pozo Jorge , Moss Sharon , Thompson Alexandra Inés , Henderson Neil C. , Hayes Peter C. , Plevris John N. , Bagnaninchi Pierre-Olivier , Nelson Leonard J.
Published: January 2017

Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis of various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming the blood-biliary barrier. In acetaminophen-hepatotoxicity, the mechanism by which tissue cohesion and polarity are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts the integrity of TJ and cell-matrix adhesions, with indicators of cellular stress with liver injury in the human hepatic HepaRG cell line, and primary hepatocytes. In mouse liver, at human-equivalence (therapeutic) doses, dose-dependent loss of intercellular hepatic TJ-associated ZO-1 protein expression was evident with progressive clinical signs of liver injury. Temporal, dose-dependent and specific disruption of the TJ-associated ZO-1 and cytoskeletal-F-actin proteins, correlated with modulation of hepatic ultrastructure. Real-time impedance biosensing verified in vitro early, dose-dependent quantitative decreases in TJ and cell-substrate adhesions. Whereas treatment with NAPQI, the reactive metabolite of acetaminophen, or the PKCα-activator and TJ-disruptor phorbol-12-myristate-13-acetate, similarly reduced TJ integrity, which may implicate oxidative stress and the PKC pathway in TJ destabilization. These findings are relevant to the clinical presentation of acetaminophen-hepatotoxicity and may inform future mechanistic studies to identify specific molecular targets and pathways that may be altered in acetaminophen-induced hepatic depolarization.