bluuebunny/crossref_metadata_2025 huggingface dataset:
Progressing through mathematics
Authors: Imrie Jane
Published: June 2016

I could not resist combining the theme of BCME7 (Mathematical Progressions) with some thoughts on my personal journey and a focus on how mathematics can enable people to progress in so many areas. I like the double meaning tied up in the conference theme. It not only relates to some very interesting mathematics but also shows how mathematics enables progression in many areas. I am going to indulge myself on the way with some glimpses into my own journey through mathematics and the influences on the choices I made. I will also explore such influences more widely, as well as possible implications for teaching, learning and professional development.
Reflections on the Woolwich Ferry
Authors: Colman W.J. A.
Published: June 2016

A ferry starting on one side of a river is to cross to the adjacent point on the opposite bank travelling at a constant speed f but moving against a variable river sneed We will ignore starting and stonninc difficulties which only operate for a short interval of time. The ferry moves so that it is always aiming at the target position T. The river is assumed to be straight and the speed of the river is given by the function r(x) which is non-negative, continuous and differentiable for 0 ≤ x ≤ a, where a is the width of the river. We shall show that the solution reduces to two integrations and the condition which determines whetIer the derry can reach its destination will be given.
Relations on Sets
Authors: MacHale Des , MacHale Peter
Published: June 2016

This paper is dedicated to the memory of George Boole FRS (1815-1864), first Professor of Mathematics at University College Cork.

A relation on a non-empty set K is any subset W of the cartesian product K × K. If (x, x) ∈ W for every x ∈ K, W is said to be reflexive on K. If for x, y, z ∈ K, (x, y) ∈ W implies that (y, x) ∈ W, W is said to be symmetric on K. If for x, y, z ∈ K (x, y) ∈ W and (y, z) ∈ W together imply that (x, z) ∈ W, W is said to be transitive on K. Finally, if the relation W is reflexive, symmetric and transitive on K, W is said to be an equivalence relation on K. We contend that equivalence relations are of central importance in many areas of mathematics. Many texts on algebra (for example Topics in Algebra [1]) contain as an exercise the following fallacious argument which the reader is challenged to refute.
Pascal-like triangles and Fibonacci-like sequences
Authors: Matsui H. , Minematsu D. , Yamauchi T. , Miy Adera R.
Published: June 2016

In [1] and [2] we demonstrated how Pascal-like triangles arose from the probabilities associated with the various outcomes of a particular game (see Definition 1 below). It was also shown that they could be considered as generalisations of Pascal's triangle. In this article we show how Fibonacci-like sequences arise from our Pascal-like triangles, and demonstrate the existence of simple relationships between these Fibonacci-like sequences and the Fibonacci sequence itself. In addition we will investigate a generalisation of the binomial coefficients that appears when considering an extended version of the game. We start by describing this game.
The polarisation ellipse and associated properties
Authors: Mahony John
Published: June 2016

The ellipse is well known to students of mathematics at an advanced high school level and at an undergraduate level through its associations with, say, conic sections and their deployment as hardware in dual reflector antenna systems. Perhaps less well known is its appearance on the software side, so to speak, for example in RF (Radio Frequency) engineering in the context of polarisation, where it is known as the polarisation ellipse. It is the purpose here to discuss this manifestation and dwell particularly on the concept of a circumscribing rectangle for this ellipse because such aspects are of interest to the RF engineer who may be involved with measurements to determine its properties. This exercise affords an interesting insight into a very practical application of tertiary level mathematics and whilst it is of course helpful to appreciate the physical concepts involved, a lack of such knowledge does not detract from an appreciation of the underlying sums, which should be within the grasp of the above, interested student.
Central European parasitic flatworms of the family Renicolidae Dollfus, 1939 (Trematoda: Plagiorchiida): molecular and comparative morphological analysis rejects the synonymization ofRenicola pinguiscomplex suggested by Odening
Authors: HENEBERG PETR , SITKO JILJÍ , BIZOS JIŘÍ , HORNE ELIZABETH C.
Published: June 2016

The Renicolidae are digenean parasites of piscivorous and molluscivorous birds. Although they exhibit few morphological autapomorphies and are highly variable, the numerous suggested re-classifications within the family have never been supported by any molecular analyses. We address the possible synonymization of species within theRenicola pinguiscomplex suggested previously by Odening. We provide and analyse sequences of two nuclear (ITS2, 28S rDNA) and two mitochondrial (CO1, ND1) DNA loci of central European species of the Renicolidae, namelyRenicola lari, Renicola pinguisandRenicola sternaesp. n., and we also provide first sequences ofRenicola sloanei. The combined molecular and comparative morphological analysis confirms the previously questioned validity of the threeRenicolaspp. of highly similar morphology, which display strict niche separation in terms of host specificity and selectivity. We identify two previously unreported clades within the genusRenicola; however, only one of them is supported by the analysis of adult worms. We also provide comparative measurements of the three examined closely related central European renicolids, and describe the newly proposed tern-specialized speciesRenicola sternaesp. n., which was previously repeatedly misidentified asRenicola paraquinta. Based on the extensive dataset collected in 1962–2015, we update the host spectrum of Renicolidae parasitizing central European birds (Renicola bretensis, R. lari, Renicola mediovitellata, R. pinguis, Renicola secundaandR. sternaesp. n.) and discuss their host-specific prevalence and intensity of infections.
Reification and Modern Drama: an Analysis, a Critique, and a Manifesto
Authors: Urban Eva
Published: June 2016

Drawing on a close reading of Theodor Adorno's essay, ‘Education after Auschwitz’, in this article Eva Urban develops the argument that an analysis of the reification that reduces human relationships to mere business interactions has been a central concern of modern drama. The article offers an analysis of some of the ways in which this theme continues to be represented, interrogated, and challenged internationally in contemporary political plays and theatre performances across a range of genres and grounded in a variety of dramaturgical principles. It asks how drama, theatre-making, theatre-spectating, and theatre-participating can create dynamics necessary to enable a move from reified consciousness towards the development of critical autonomy and solidarity. A negotiation of the principles of critical consciousness and solidarity is problematic within economic structures that cause social, ethnic, and religious atomization and divisions. Her argument concludes with an outline for a manifesto for political drama and theatre practice to work against reification. Eva Urban is a lecturer and researcher in the English Department and an Associate of the Irish Studies Research Centre, CEI/CRBC, at the University of Rennes 2, France. She recently completed a British Academy Postdoctoral Fellowship at the University of Cambridge and is a Life Member of Clare Hall, Cambridge. The author of Community Politics and the Peace Process in Contemporary Northern Irish Drama (Peter Lang, 2011), she has also published articles in New Theatre Quarterly, Etudes Irlandaises, Caleidoscopio, and edited book collections.
Cutting, Interruption, and the End of Hamlet
Authors: Dobson Michael
Published: June 2016

In this essay Michael Dobson considers the evolution of certain habitual cuts to the text of Hamlet between the seventeenth and early twentieth centuries, identifying in particular a tendency to increase the abruptness with which the play's last act interrupts its otherwise digressive movement. Looking in particular at the fate of Fortinbras, he examines changes to the ways in which these cuts have been indicated to readers, arguing that a decisive separation between the play as read and as acted makes itself felt at the turn of the nineteenth century. He concludes with a discussion of when and why it became desirable to advertise not manageably edited stage versions, but ‘uncut’ marathons. Michael Dobson is Director of the Shakespeare Institute in Stratford-upon-Avon and Professor of Shakespeare Studies at the University of Birmingham. His publications include the co-editorship of The Oxford Companion to Shakespeare, Shakespeare and Amateur Performance, Performing Shakespeare's Tragedies Today, and The Making of the National Poet.
The slope conjecture for graph knots
Authors: MOTEGI KIMIHIKO , TAKATA TOSHIE
Published: June 2016

The slope conjecture proposed by Garoufalidis asserts that the Jones slopes given by the sequence of degrees of the coloured Jones polynomials are boundary slopes. We verify the slope conjecture for graph knots, i.e. knots whose Gromov volume vanish.
Debates on Constitutionalism and the Legacies of the Cultural Revolution
Authors: Changchang Wu
Published: June 2016

This article focuses on the debate surrounding constitutionalism that has been driven by a constitutionalist alliance of media reporters, intellectuals and lawyers since 2010, and follows its historical trajectory. It argues that this debate forms a discourse with a structuring absence, the roots of which can be traced back to the taboos surrounding the Cultural Revolution, the 1975 Constitution, and everything associated with them. The absence manifests itself in the silence on workers' right to strike, a right which was deleted from the 1982 Constitution in an attempt to correct the ultra-leftist anarchy of the Cultural Revolution. Previous and in contrast to that, there was a Maoist constitutional movement in the Cultural Revolution, represented by the 1975 Constitution, that aimed to protect the constituent power of the workers by legalizing their right to strike. Today, we are witnessing the rise of migrant workers as they struggle for trade union reform and collective bargaining with little support from the party-state or local trade unions. In this context, a third constitutional transformation should be considered that is not a return to the 1975 Constitution but which instead adds some elements which protect labour's right to strike to the 1982 Constitution.
High and novel genetic diversity ofFrancisella tularensisin Germany and indication of environmental persistence
Authors: SCHULZE C. , HEUNER K. , MYRTENNÄS K. , KARLSSON E. , JACOB D. , KUTZER P. , GROßE K. , FORSMAN M. , GRUNOW R.
Published: June 2016

In Germany tularemia is a re-emerging zoonotic disease. Therefore, we investigated wild animals and environmental water samples for the presence and phylogenetic diversity ofFrancisella tularensisin the poorly studied Berlin/Brandenburg region. The phylogenomic analysis of three isolates from wild animals revealed three new subclades within the phylogenetic tree ofF. tularensis[B.71 from a raccoon dog (Nyctereutes procyonoides); B.74 from a red fox (Vulpes vulpes), and B.75 from a Eurasian beaver (Castor fiber albicus)]. The results from histological, PCR, and genomic investigations on the dead beaver showed that the animal suffered from a systemic infection. Indications were found that the bacteria were released from the beaver carcass into the surrounding environment. We demonstrated unexpectedly high and novel phylogenetic diversity ofF. tularensisin Germany and the fact that the bacteria persist in the environment for at least one climatic season. These findings support a broader host species diversity than previously known regarding Germany. Our data further support the assumption derived from previous serological studies of an underestimated frequency of occurrence of the pathogen in the environment and in wild animals.F. tularensiswas isolated from animal species not previously reported as natural hosts in Germany.
Twenty years of Hendra virus: laboratory submission trends and risk factors for infection in horses
Authors: SMITH C. S. , McLAUGHLIN A. , FIELD H. E. , EDSON D. , MAYER D. , OSSEDRYVER S. , BARRETT J. , WALTISBUHL D.
Published: June 2016

Hendra virus (HeV) was first described in 1994 in an outbreak of acute and highly lethal disease in horses and humans in Australia. Equine cases continue to be diagnosed periodically, yet the predisposing factors for infection remain unclear. We undertook an analysis of equine submissions tested for HeV by the Queensland government veterinary reference laboratory over a 20-year period to identify and investigate any patterns. We found a marked increase in testing from July 2008, primarily reflecting a broadening of the HeV clinical case definition. Peaks in submissions for testing, and visitations to the Government HeV website, were associated with reported equine incidents. Significantly differing between-year HeV detection rates in north and south Queensland suggest a fundamental difference in risk exposure between the two regions. The statistical association between HeV detection and stockhorse type may suggest that husbandry is a more important risk determinant than breedper se. The detection of HeV in horses with neither neurological nor respiratory signs poses a risk management challenge for attending veterinarians and laboratory staff, reinforcing animal health authority recommendations that appropriate risk management strategies be employed for all sick horses, and by anyone handling sick horses or associated biological samples.
Post-Acousmatic Practice: Re-evaluating Schaeffer’s heritage
Authors: Adkins Monty , Scott Richard , Tremblay Pierre Alexandre
Published: June 2016

This article posits the notion of the post-acousmatic. It considers the work of contemporary practitioners who are indebted to the Schaefferian heritage, but pursue alternative trajectories from the established canonical discourse of acousmatic music. It will outline the authors’ definition of the term and also outline a network of elements such as time, rhythm, pitch, dynamics, noise and performance to discuss work that the authors’ consider to be a critique, an augmentation and an outgrowth of acousmatic music and thinking.
Methodologies for Genre Hybridisation
Authors: Bentall Robert
Published: June 2016

This article attempts to explore working methods for developing hybrid tendencies within electroacoustic music compositions. These working methods, such as the novel concept of reconstructive sampling, are each explored with musical examples given. The article opens by giving definitions of genre, and then explores hybridisation as a concept through ideas developed by Duff (2000), Waters (2000) and Frow (2015). While the article focuses on the musical output of the author, personal compositions are placed in a broader context through the discussion of other artists within the wider field of electronic music composition.
MONETARY POLICY SWITCHING IN THE EURO AREA AND MULTIPLE STEADY STATES: AN EMPIRICAL INVESTIGATION
Authors: Dufrénot Gilles , Khayat Guillaume A.
Published: June 2016

This paper investigates, in the case of the euro area, the standard assumption that the liquidity trap steady state, which arises from the existence of the zero lower bound on the nominal interest rate, is locally unstable. We show that the policy function of the European Central Bank (ECB) is described by a nonlinear Taylor rule. Then, using our estimations, we show that around the liquidity trap steady state the equilibrium is locally determinate for most plausible parameter values. Finally, we find that an inflation shock is more efficient than a demand shock to escape the liquidity trap steady state.
Effect of Gas Pores on Mechanical Properties of High-Pressure Die-Casting AM50 Magnesium Alloy
Authors: Jiang Wei , Cao Zhanyi , Liu Liping , Jiang Bo
Published: June 2016

High-pressure die-casting (HPDC) AM50 tensile specimens were used to investigate characteristics of gas pores and its effect on mechanical properties of HPDC AM50 magnesium alloy. Combining microstructure morphology gained from optical microscopy, scanning electron microscopy (SEM), and three-dimensional (3D) reconstruction with the experimental data from uniaxial tensile testing, we pursued the relationship between gas pores and the mechanical properties of HPDC AM50 Mg alloy. Results indicate that comparing with 3D reconstruction models, 2D images like optical metallography images and SEM images have one-sidedness. Furthermore, the size and maximum areal fraction of gas pores have negative effects on the mechanical properties of HPDC AM50 Mg alloy. With increase of the maximum size of gas pores in the specimen, the ultimate tensile strength (UTS) and elongation decrease. In addition, with the maximum areal fraction becoming larger, both the UTS and elongation decrease linearly.
ADJOINT FUNCTORS BETWEEN CATEGORIES OF HILBERT -MODULES
Authors: Clare Pierre , Crisp Tyrone , Higson Nigel
Published: June 2016

Let$E$be a (right) Hilbert module over a$C^{\ast }$-algebra$A$. If$E$is equipped with a left action of a second$C^{\ast }$-algebra$B$, then tensor product with$E$gives rise to a functor from the category of Hilbert$B$-modules to the category of Hilbert$A$-modules. The purpose of this paper is to study adjunctions between functors of this sort. We shall introduce a new kind of adjunction relation, called a local adjunction, that is weaker than the standard concept from category theory. We shall give several examples, the most important of which is the functor of parabolic induction in the tempered representation theory of real reductive groups. Each local adjunction gives rise to an ordinary adjunction of functors between categories of Hilbert space representations. In this way we shall show that the parabolic induction functor has a simultaneous left and right adjoint, namely the parabolic restriction functor constructed in Clareet al.[Parabolic induction and restriction via$C^{\ast }$-algebras and Hilbert$C^{\ast }$-modules,Compos. Math.FirstView(2016), 1–33, 2].
THE RENORMALIZED VOLUME AND UNIFORMIZATION OF CONFORMAL STRUCTURES
Authors: Guillarmou Colin , Moroianu Sergiu , Schlenker Jean-Marc
Published: June 2016

We study the renormalized volume of asymptotically hyperbolic Einstein (AHE in short) manifolds $(M,g)$ when the conformal boundary $\unicode[STIX]{x2202}M$ has dimension $n$ even. Its definition depends on the choice of metric $h_{0}$ on $\unicode[STIX]{x2202}M$ in the conformal class at infinity determined by $g$, we denote it by $\text{Vol}_{R}(M,g;h_{0})$. We show that $\text{Vol}_{R}(M,g;\cdot )$ is a functional admitting a ‘Polyakov type’ formula in the conformal class $[h_{0}]$ and we describe the critical points as solutions of some non-linear equation $v_{n}(h_{0})=\text{constant}$, satisfied in particular by Einstein metrics. When $n=2$, choosing extremizers in the conformal class amounts to uniformizing the surface, while if $n=4$ this amounts to solving the $\unicode[STIX]{x1D70E}_{2}$-Yamabe problem. Next, we consider the variation of $\text{Vol}_{R}(M,\cdot ;\cdot )$ along a curve of AHE metrics $g^{t}$ with boundary metric $h_{0}^{t}$ and we use this to show that, provided conformal classes can be (locally) parametrized by metrics $h$ solving $v_{n}(h)=\text{constant}$ and $\text{Vol}(\unicode[STIX]{x2202}M,h)=1$, the set of ends of AHE manifolds (up to diffeomorphisms isotopic to the identity) can be viewed as a Lagrangian submanifold in the cotangent space to the space ${\mathcal{T}}(\unicode[STIX]{x2202}M)$ of conformal structures on $\unicode[STIX]{x2202}M$. We obtain, as a consequence, a higher-dimensional version of McMullen’s quasi-Fuchsian reciprocity. We finally show that conformal classes admitting negatively curved Einstein metrics are local minima for the renormalized volume for a warped product type filling.
Electoral rule choice in transitional economies
Authors: CLEMENT JESSICA
Published: June 2016

The Arab Spring and subsequent global unrest sparked a debate about whether a fourth wave of democracy emerged in the global political arena starting in 2010. A key issue arises from these emerging democracies, or ‘countries in transition’, about what types of government institutions will be adopted by the new democracies. The previous literature on advanced democracies shows the economic structure of a nation impacted its choice of electoral rule system. This paper looks at what determines electoral rule choice in transitional nations. Using a panel database with 65 transitional countries with data for 18 years (1995 to 2012), this paper tests the argument that more coordinated market economies (CMEs) tend to adopt more proportional representative electoral rule systems during a political transition. Findings show that countries characterized as CMEs due to widespread primary education, which supports co-specific assets, and prominent industrial sectors have more proportional electoral rule systems.
Basic numerical processing, calculation, and working memory in children with dyscalculia and/or ADHD symptoms
Authors: Kuhn Jörg-Tobias , Ise Elena , Raddatz Julia , Schwenk Christin , Dobel Christian
Published: June 2016

Abstract. Objective: Deficits in basic numerical skills, calculation, and working memory have been found in children with developmental dyscalculia (DD) as well as children with attention-deficit/hyperactivity disorder (ADHD). This paper investigates cognitive profiles of children with DD and/or ADHD symptoms (AS) in a double dissociation design to obtain a better understanding of the comorbidity of DD and ADHD. Method: Children with DD-only (N = 33), AS-only (N = 16), comorbid DD+AS (N = 20), and typically developing controls (TD, N = 40) were assessed on measures of basic numerical processing, calculation, working memory, processing speed, and neurocognitive measures of attention. Results: Children with DD (DD, DD+AS) showed deficits in all basic numerical skills, calculation, working memory, and sustained attention. Children with AS (AS, DD+AS) displayed more selective difficulties in dot enumeration, subtraction, verbal working memory, and processing speed. Also, they generally performed more poorly in neurocognitive measures of attention, especially alertness. Children with DD+AS mostly showed an additive combination of the deficits associated with DD-only and A_Sonly, except for subtraction tasks, in which they were less impaired than expected. Conclusions: DD and AS appear to be related to largely distinct patterns of cognitive deficits, which are present in combination in children with DD+AS.
Aufmerksamkeit und Leseleistungen bei Kindern mit ADHS, Lese- und Rechtschreibstörung und der komorbiden Störung
Authors: Günther Thomas , Peters Katharina , Scharke Wolfgang , Horbach Josefine , Kraatz Christina , Herpertz-Dahlmann Beate , Konrad Kerstin , Vloet Timo D.
Published: June 2016

Zusammenfassung. Eine Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) und eine Lese-Rechtschreibstörung (LRS) treten überdurchschnittlich häufig gemeinsam auf und können die Entwicklung betroffener Kinder negativ beeinflussen. Das Ziel der vorliegenden Studie war ein Vergleich der Aufmerksamkeits- und Leseleistungen von Kindern mit ADHS, LRS und ADHS plus LRS. Es wurden 99 Kinder der dritten und vierten Klasse (ADHS n = 26, LRS n = 22, ADHS plus LRS n = 24, Kontrollkinder n = 27) mittels verschiedener Lese-Rechtschreibtests und einer modellorientierten Aufmerksamkeitsdiagnostik untersucht. Zudem wurden mögliche Begleitstörungen erfasst. Die Kinder mit ADHS hatten Schwierigkeiten sowohl im Pseudowortlesen als auch im Wortverständnis, während die Kinder mit LRS zusätzliche Auffälligkeiten in der Aufmerksamkeitsleistung zeigten. Psychometrisch zeigten alle Kinder mit LRS Auffälligkeiten im internalisierenden und externalisierenden Bereich, wobei Kinder mit ADHS plus LRS in fast allen Skalen die höchsten Werte aufwiesen. Die Ergebnisse deuten darauf hin, dass die Probleme von Kindern mit ADHS beim Lesen z. T. ein Epiphänomen darstellen, das unter dem Zeitdruck des Testverfahrens entsteht. Die gefundenen Einschränkungen der Aufmerksamkeit bei Kindern mit LRS unterstreichen die Bedeutung einer ausführlichen Diagnostik im Hinblick auf eine möglicherweise vorliegende subklinische ADHS bei bestehendem LRS. Es bleibt zu klären, welchen Einfluss die frühzeitige Behandlung von Aufmerksamkeitsdefiziten auf den Leseerwerb und die Prognose betroffener Kinder hat.
Transferrin receptor facilitates TGF-β and BMP signaling activation to control craniofacial morphogenesis
Authors: Lei R , Zhang K , Liu K , Shao X , Ding Z , Wang F , Hong Y , Zhu M , Li H , Li H
Published: June 2016

The Pierre Robin Sequence (PRS), consisting of cleft palate, glossoptosis and micrognathia, is a common human birth defect. However, how this abnormality occurs remains largely unknown. Here we report that neural crest cell (NCC)-specific knockout of transferrin receptor (Tfrc), a well known transferrin transporter protein, caused micrognathia, cleft palate, severe respiratory distress and inability to suckle in mice, which highly resemble human PRS. Histological and anatomical analysis revealed that the cleft palate is due to the failure of palatal shelves elevation that resulted from a retarded extension of Meckel’s cartilage. Interestingly, Tfrc deletion dramatically suppressed both transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling in cranial NCCs-derived mandibular tissues, suggesting that Tfrc may act as a facilitator of these two signaling pathways during craniofacial morphogenesis. Together, our study uncovers an unknown function of Tfrc in craniofacial development and provides novel insight into the etiology of PRS.
ZnCl2 sustains the adriamycin-induced cell death inhibited by high glucose
Authors: Garufi A , Trisciuoglio D , Cirone M , D'Orazi G
Published: June 2016

Hyperglycemia, the condition of high blood glucose, is typical of diabetes and obesity and represents a significant clinical problem. The relationship between hyperglycemia and cancer risk has been established by several studies. Moreover, hyperglycemia has been shown to reduce cancer cell response to therapies, conferring resistance to drug-induced cell death. Therefore, counteracting the negative effects of hyperglycemia may positively improve the cancer cell death induced by chemotherapies. Recent studies showed that zinc supplementation may have beneficial effects on glycemic control. Here we aimed at evaluating whether ZnCl2 could counteract the high-glucose (HG) effects and consequently restore the drug-induced cancer cell death. At the molecular level we found that the HG-induced expression of genes known to be involved in chemoresistance (such as HIF-1α, GLUT1, and HK2 glycolytic genes, as well as NF-κB activity) was reduced by ZnCl2 treatment. In agreement, the adryamicin (ADR)-induced apoptotic cancer cell death was significantly impaired by HG and efficiently re-established by ZnCl2 cotreatment. Mechanistically, the ADR-induced c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) phosphorylation, inhibited by HG, was efficiently restored by ZnCl2. The JNK involvement in apoptotic cell death was assessed by the use of JNK dominant-negative expression vector that indeed impaired the ZnCl2 ability to restore drug-induced cell death in HG condition. Altogether, these findings indicate that ZnCl2 supplementation efficiently restored the drug-induced cancer cell death, inhibited by HG, by both sustaining JNK activation and counteracting the glycolytic pathway.
Tubular epithelial cells in renal clear cell carcinoma express high RIPK1/3 and show increased susceptibility to TNF receptor 1-induced necroptosis
Authors: Al-Lamki R S , Lu W , Manalo P , Wang J , Warren A Y , Tolkovsky A M , Pober J S , Bradley J R
Published: June 2016

We previously reported that renal clear cell carcinoma cells (RCC) express both tumor necrosis factor receptor (TNFR)-1 and -2, but that, in organ culture, a TNF mutein that only engages TNFR1, but not TNFR2, causes extensive cell death. Some RCC died by apoptosis based on detection of cleaved caspase 3 in a minority TUNEL-positive cells but the mechanism of death in the remaining cells was unexplained. Here, we underpin the mechanism of TNFR1-induced cell death in the majority of TUNEL-positive RCC cells, and show that they die by necroptosis. Malignant cells in high-grade tumors displayed threefold to four fold higher expression of both receptor-interacting protein kinase (RIPK)1 and RIPK3 compared with non-tumor kidney tubular epithelium and low-grade tumors, but expression of both enzymes was induced in lower grade tumors in organ culture in response to TNFR1 stimulation. Furthermore, TNFR1 activation induced significant MLKLSer358 and Drp1Ser616 phosphorylation, physical interactions in RCC between RIPK1-RIPK3 and RIPK3-phospho-MLKLSer358, and coincidence of phospho-MLKLser358 and phospho-Drp1Ser616 at mitochondria in TUNEL-positive RCC. A caspase inhibitor only partially reduced the extent of cell death following TNFR1 engagement in RCC cells, whereas three inhibitors, each targeting a different step in the necroptotic pathway, were much more protective. Combined inhibition of caspases and necroptosis provided additive protection, implying that different subsets of cells respond differently to TNF-α, the majority dying by necroptosis. We conclude that most high-grade RCC cells express increased amounts of RIPK1 and RIPK3 and are poised to undergo necroptosis in response to TNFR1 signaling.
Does murine spermatogenesis require WNT signalling? A lesson from Gpr177 conditional knockout mouse models
Authors: Chen Su-Ren , Tang J-X , Cheng J-M , Hao X-X , Wang Y-Q , Wang X-X , Liu Y-X
Published: June 2016

Wingless-related MMTV integration site (WNT) proteins and several other components of the WNT signalling pathway are expressed in the murine testes. However, mice mutant for WNT signalling effector β-catenin using different Cre drivers have phenotypes that are inconsistent with each other. The complexity and overlapping expression of WNT signalling cascades have prevented researchers from dissecting their function in spermatogenesis. Depletion of the Gpr177 gene (the mouse orthologue of Drosophila Wntless), which is required for the secretion of various WNTs, makes it possible to genetically dissect the overall effect of WNTs in testis development. In this study, the Gpr177 gene was conditionally depleted in germ cells (Gpr177flox/flox, Mvh-Cre; Gpr177flox/flox, Stra8-Cre) and Sertoli cells (Gpr177flox/flox, Amh-Cre). No obvious defects in fertility and spermatogenesis were observed in these three Gpr177 conditional knockout (cKO) mice at 8 weeks. However, late-onset testicular atrophy and fertility decline in two germ cell-specific Gpr177 deletion mice were noted at 8 months. In contrast, we did not observe any abnormalities of spermatogenesis and fertility, even in 8-month-old Gpr177flox/flox, Amh-Cre mice. Elevation of reactive oxygen species (ROS) was detected in Gpr177 cKO germ cells and Sertoli cells and exhibited an age-dependent manner. However, significant increase in the activity of Caspase 3 was only observed in germ cells from 8-month-old germ cell-specific Gpr177 knockout mice. In conclusion, GPR177 in Sertoli cells had no apparent influence on spermatogenesis, whereas loss of GPR177 in germ cells disrupted spermatogenesis in an age-dependent manner via elevating ROS levels and triggering germ cell apoptosis.
Actin polymerization‐dependent activation of Cas‐L promotes immunological synapse stability
Authors: Santos Luís C , Blair David A , Kumari Sudha , Cammer Michael , Iskratsch Thomas , Herbin Olivier , Alexandropoulos Konstantina , Dustin Michael L , Sheetz Michael P
Published: June 2016

The immunological synapse formed between a T‐cell and an antigen‐presenting cell is important for cell–cell communication during T‐cell‐mediated immune responses. Immunological synapse formation begins with stimulation of the T‐cell receptor (TCR). TCR microclusters are assembled and transported to the center of the immunological synapse in an actin polymerization‐dependent process. However, the physical link between TCR and actin remains elusive. Here we show that lymphocyte‐specific Crk‐associated substrate (Cas‐L), a member of a force sensing protein family, is required for transport of TCR microclusters and for establishing synapse stability. We found that Cas‐L is phosphorylated at TCR microclusters in an actin polymerization‐dependent fashion. Furthermore, Cas‐L participates in a positive feedback loop leading to amplification of Ca2+ signaling, inside–out integrin activation, and actomyosin contraction. We propose a new role for Cas‐L in T‐cell activation as a mechanical transducer linking TCR microclusters to the underlying actin network and coordinating multiple actin‐dependent structures in the immunological synapse. Our studies highlight the importance of mechanotransduction processes in T‐cell‐mediated immune responses.
Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia
Authors: Gao Xue , Lin Shu-Hai , Ren Feng , Li Jin-Tao , Chen Jia-Jia , Yao Chuan-Bo , Yang Hong-Bin , Jiang Shu-Xia , Yan Guo-Quan , Wang Di , Wang Yi , Liu Ying , Cai Zongwei , Xu Ying-Ying , Chen Jing , Yu Wenqiang , Yang Peng-Yuan , Lei Qun-Ying
Published: June 2016

Besides the conventional carbon sources, acetyl-CoA has recently been shown to be generated from acetate in various types of cancers, where it promotes lipid synthesis and tumour growth. The underlying mechanism, however, remains largely unknown. We find that acetate induces a hyperacetylated state of histone H3 in hypoxic cells. Acetate predominately activates lipogenic genes ACACA and FASN expression by increasing H3K9, H3K27 and H3K56 acetylation levels at their promoter regions, thus enhancing de novo lipid synthesis, which combines with its function as the metabolic precursor for fatty acid synthesis. Acetyl-CoA synthetases (ACSS1, ACSS2) are involved in this acetate-mediated epigenetic regulation. More importantly, human hepatocellular carcinoma with high ACSS1/2 expression exhibit increased histone H3 acetylation and FASN expression. Taken together, this study demonstrates that acetate, in addition to its ability to induce fatty acid synthesis as an immediate metabolic precursor, also functions as an epigenetic metabolite to promote cancer cell survival under hypoxic stress.
LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development
Authors: Lee Da-Hye , Park Jae Oh , Kim Tae-Shin , Kim Sang-Kyum , Kim Tack-hoon , Kim Min-chul , Park Gun Soo , Kim Jeong-Hwan , Kuninaka Shinji , Olson Eric N. , Saya Hideyuki , Kim Seon-Young , Lee Ho , Lim Dae-Sik
Published: June 2016

The Hippo pathway regulates the self-renewal and differentiation of various adult stem cells, but its role in cell fate determination and differentiation during liver development remains unclear. Here we report that the Hippo pathway controls liver cell lineage specification and proliferation separately from Notch signalling, using mice and primary hepatoblasts with liver-specific knockout of Lats1 and Lats2 kinase, the direct upstream regulators of YAP and TAZ. During and after liver development, the activation of YAP/TAZ induced by loss of Lats1/2 forces hepatoblasts or hepatocytes to commit to the biliary epithelial cell (BEC) lineage. It increases BEC and fibroblast proliferation by up-regulating TGFβ signalling, but suppresses hepatoblast to hepatocyte differentiation by repressing Hnf4α expression. Notably, oncogenic YAP/TAZ activation in hepatocytes induces massive p53-dependent cell senescence/death. Together, our results reveal that YAP/TAZ activity levels govern liver cell differentiation and proliferation in a context-dependent manner.
Prosaposin is a regulator of progranulin levels and oligomerization
Authors: Nicholson Alexandra M. , Finch NiCole A. , Almeida Marcio , Perkerson Ralph B. , van Blitterswijk Marka , Wojtas Aleksandra , Cenik Basar , Rotondo Sergio , Inskeep Venette , Almasy Laura , Dyer Thomas , Peralta Juan , Jun Goo , Wood Andrew R. , Frayling Timothy M. , Fuchsberger Christian , Fowler Sharon , Teslovich Tanya M. , Manning Alisa K. , Kumar Satish , Curran Joanne , Lehman Donna , Abecasis Goncalo , Duggirala Ravindranath , Pottier Cyril , Zahir Haaris A. , Crook Julia E. , Karydas Anna , Mitic Laura , Sun Ying , Dickson Dennis W. , Bu Guojun , Herz Joachim , Yu Gang , Miller Bruce L. , Ferguson Shawn , Petersen Ronald C. , Graff-Radford Neill , Blangero John , Rademakers Rosa
Published: June 2016

Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia. Reports also indicated PGRN-mediated neuroprotection in models of Alzheimer’s and Parkinson’s disease; thus, increasing PGRN levels is a promising therapeutic for multiple disorders. To uncover novel PGRN regulators, we linked whole-genome sequence data from 920 individuals with plasma PGRN levels and identified the prosaposin (PSAP) locus as a new locus significantly associated with plasma PGRN levels. Here we show that both PSAP reduction and overexpression lead to significantly elevated extracellular PGRN levels. Intriguingly, PSAP knockdown increases PGRN monomers, whereas PSAP overexpression increases PGRN oligomers, partly through a protein–protein interaction. PSAP-induced changes in PGRN levels and oligomerization replicate in human-derived fibroblasts obtained from a GRN mutation carrier, further supporting PSAP as a potential PGRN-related therapeutic target. Future studies should focus on addressing the relevance and cellular mechanism by which PGRN oligomeric species provide neuroprotection.
Deficient methylation and formylation of mt-tRNAMet wobble cytosine in a patient carrying mutations in NSUN3
Authors: Van Haute Lindsey , Dietmann Sabine , Kremer Laura , Hussain Shobbir , Pearce Sarah F. , Powell Christopher A. , Rorbach Joanna , Lantaff Rebecca , Blanco Sandra , Sauer Sascha , Kotzaeridou Urania , Hoffmann Georg F. , Memari Yasin , Kolb-Kokocinski Anja , Durbin Richard , Mayr Johannes A. , Frye Michaela , Prokisch Holger , Minczuk Michal
Published: June 2016

Epitranscriptome modifications are required for structure and function of RNA and defects in these pathways have been associated with human disease. Here we identify the RNA target for the previously uncharacterized 5-methylcytosine (m5C) methyltransferase NSun3 and link m5C RNA modifications with energy metabolism. Using whole-exome sequencing, we identified loss-of-function mutations in NSUN3 in a patient presenting with combined mitochondrial respiratory chain complex deficiency. Patient-derived fibroblasts exhibit severe defects in mitochondrial translation that can be rescued by exogenous expression of NSun3. We show that NSun3 is required for deposition of m5C at the anticodon loop in the mitochondrially encoded transfer RNA methionine (mt-tRNAMet). Further, we demonstrate that m5C deficiency in mt-tRNAMet results in the lack of 5-formylcytosine (f5C) at the same tRNA position. Our findings demonstrate that NSUN3 is necessary for efficient mitochondrial translation and reveal that f5C in human mitochondrial RNA is generated by oxidative processing of m5C.
The multicellularity genes of dictyostelid social amoebas
Authors: Glöckner Gernot , Lawal Hajara M. , Felder Marius , Singh Reema , Singer Gail , Weijer Cornelis J. , Schaap Pauline
Published: June 2016

The evolution of multicellularity enabled specialization of cells, but required novel signalling mechanisms for regulating cell differentiation. Early multicellular organisms are mostly extinct and the origins of these mechanisms are unknown. Here using comparative genome and transcriptome analysis across eight uni- and multicellular amoebozoan genomes, we find that 80% of proteins essential for the development of multicellular Dictyostelia are already present in their unicellular relatives. This set is enriched in cytosolic and nuclear proteins, and protein kinases. The remaining 20%, unique to Dictyostelia, mostly consists of extracellularly exposed and secreted proteins, with roles in sensing and recognition, while several genes for synthesis of signals that induce cell-type specialization were acquired by lateral gene transfer. Across Dictyostelia, changes in gene expression correspond more strongly with phenotypic innovation than changes in protein functional domains. We conclude that the transition to multicellularity required novel signals and sensors rather than novel signal processing mechanisms.
Notch-independent RBPJ controls angiogenesis in the adult heart
Authors: Díaz-Trelles Ramón , Scimia Maria Cecilia , Bushway Paul , Tran Danh , Monosov Anna , Monosov Edward , Peterson Kirk , Rentschler Stacey , Cabrales Pedro , Ruiz-Lozano Pilar , Mercola Mark
Published: June 2016

Increasing angiogenesis has long been considered a therapeutic target for improving heart function after injury such as acute myocardial infarction. However, gene, protein and cell therapies to increase microvascularization have not been successful, most likely because the studies failed to achieve regulated and concerted expression of pro-angiogenic and angiostatic factors needed to produce functional microvasculature. Here, we report that the transcription factor RBPJ is a homoeostatic repressor of multiple pro-angiogenic and angiostatic factor genes in cardiomyocytes. RBPJ controls angiogenic factor gene expression independently of Notch by antagonizing the activity of hypoxia-inducible factors (HIFs). In contrast to previous strategies, the cardiomyocyte-specific deletion ofRbpjincreased microvascularization of the heart without adversely affecting cardiac structure or function even into old age. Furthermore, the loss of RBPJ in cardiomyocytes increased hypoxia tolerance, improved heart function and decreased pathological remodelling after myocardial infarction, suggesting that inhibiting RBPJ might be therapeutic for ischaemic injury.
Pironetin reacts covalently with cysteine-316 of α-tubulin to destabilize microtubule
Authors: Yang Jianhong , Wang Yuxi , Wang Taijing , Jiang Jian , Botting Catherine H. , Liu Huanting , Chen Qiang , Yang Jinliang , Naismith James H. , Zhu Xiaofeng , Chen Lijuan
Published: June 2016

Molecules that alter the normal dynamics of microtubule assembly and disassembly include many anticancer drugs in clinical use. So far all such therapeutics target β-tubulin, and structural biology has explained the basis of their action and permitted design of new drugs. However, by shifting the profile of β-tubulin isoforms, cancer cells become resistant to treatment. Compounds that bind to α-tubulin are less well characterized and unexploited. The natural product pironetin is known to bind to α-tubulin and is a potent inhibitor of microtubule polymerization. Previous reports had identified that pironetin reacts with lysine-352 residue however analogues designed on this model had much lower potency, which was difficult to explain, hindering further development. We report crystallographic and mass spectrometric data that reveal that pironetin forms a covalent bond to cysteine-316 in α-tubulin via a Michael addition reaction. These data provide a basis for the rational design of α-tubulin targeting chemotherapeutics.
Eigenspectra optoacoustic tomography achieves quantitative blood oxygenation imaging deep in tissues
Authors: Tzoumas Stratis , Nunes Antonio , Olefir Ivan , Stangl Stefan , Symvoulidis Panagiotis , Glasl Sarah , Bayer Christine , Multhoff Gabriele , Ntziachristos Vasilis
Published: June 2016

Light propagating in tissue attains a spectrum that varies with location due to wavelength-dependent fluence attenuation, an effect that causes spectral corruption. Spectral corruption has limited the quantification accuracy of optical and optoacoustic spectroscopic methods, and impeded the goal of imaging blood oxygen saturation (sO2) deep in tissues; a critical goal for the assessment of oxygenation in physiological processes and disease. Here we describe light fluence in the spectral domain and introduce eigenspectra multispectral optoacoustic tomography (eMSOT) to account for wavelength-dependent light attenuation, and estimate blood sO2 within deep tissue. We validate eMSOT in simulations, phantoms and animal measurements and spatially resolve sO2 in muscle and tumours, validating our measurements with histology data. eMSOT shows substantial sO2 accuracy enhancement over previous optoacoustic methods, potentially serving as a valuable tool for imaging tissue pathophysiology.
Highly selective plasma-activated copper catalysts for carbon dioxide reduction to ethylene
Authors: Mistry Hemma , Varela Ana Sofia , Bonifacio Cecile S. , Zegkinoglou Ioannis , Sinev Ilya , Choi Yong-Wook , Kisslinger Kim , Stach Eric A. , Yang Judith C. , Strasser Peter , Cuenya Beatriz Roldan
Published: June 2016

There is an urgent need to develop technologies that use renewable energy to convert waste products such as carbon dioxide into hydrocarbon fuels. Carbon dioxide can be electrochemically reduced to hydrocarbons over copper catalysts, although higher efficiency is required. We have developed oxidized copper catalysts displaying lower overpotentials for carbon dioxide electroreduction and record selectivity towards ethylene (60%) through facile and tunable plasma treatments. Herein we provide insight into the improved performance of these catalysts by combining electrochemical measurements with microscopic and spectroscopic characterization techniques. Operando X-ray absorption spectroscopy and cross-sectional scanning transmission electron microscopy show that copper oxides are surprisingly resistant to reduction and copper+ species remain on the surface during the reaction. Our results demonstrate that the roughness of oxide-derived copper catalysts plays only a partial role in determining the catalytic performance, while the presence of copper+ is key for lowering the onset potential and enhancing ethylene selectivity.
A self-sustaining atomic magnetometer with τ−1 averaging property
Authors: Xu C. , Wang S. G. , Feng Y. Y. , Zhao L. , Wang L. J.
Published: June 2016

Quantum measurement using coherent superposition of intrinsic atomic states has the advantage of being absolute measurement and can form metrological standards. One example is the absolute measurement of magnetic field by monitoring the Larmor precession of atomic spins whilst another being the Ramsey type atomic clock. Yet, in almost all coherent quantum measurement, the precision is limited by the coherence time beyond which, the uncertainty decreases only as τ−1/2. Here we show that by non-destructively measuring the phase of the Larmor precession and regenerating the coherence via optical pumping, the self-sustaining Larmor precession signal can persist indefinitely. Consequently, the precision of the magnetometer increases with time following a much faster τ−1 rule. A mean sensitivity of 240 "Equation missing" from 1 Hz to 10 Hz is realized, being close to the shot noise level. This method of coherence regeneration may also find important applications in improving the performance of atomic clocks.