bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduction of dynatomic curves
Authors: DOYLE JOHN R. , KRIEGER HOLLY , OBUS ANDREW , PRIES RACHEL , RUBINSTEIN-SALZEDO SIMON , WEST LLOYD
Published: January 2018

In this paper, we make partial progress on a function field version of the dynamical uniform boundedness conjecture for certain one-dimensional families${\mathcal{F}}$of polynomial maps, such as the family$f_{c}(x)=x^{m}+c$, where$m\geq 2$. We do this by making use of the dynatomic modular curves$Y_{1}(n)$(respectively$Y_{0}(n)$) which parametrize maps$f$in${\mathcal{F}}$together with a point (respectively orbit) of period$n$for$f$. The key point in our strategy is to study the set of primes$p$for which the reduction of$Y_{1}(n)$modulo$p$fails to be smooth or irreducible. Morton gave an algorithm to construct, for each$n$, a discriminant$D_{n}$whose list of prime factors contains all the primes of bad reduction for$Y_{1}(n)$. In this paper, we refine and strengthen Morton’s results. Specifically, we exhibit two criteria on a prime$p$dividing$D_{n}$: one guarantees that$p$is in fact a prime of bad reduction for$Y_{1}(n)$, yet this same criterion implies that$Y_{0}(n)$is geometrically irreducible. The other guarantees that the reduction of$Y_{1}(n)$modulo$p$is actually smooth. As an application of the second criterion, we extend results of Morton, Flynn, Poonen, Schaefer, and Stoll by giving new examples of good reduction of$Y_{1}(n)$for several primes dividing$D_{n}$when$n=7,8,11$, and$f_{c}(x)=x^{2}+c$. The proofs involve a blend of arithmetic and complex dynamics, reduction theory for curves, ramification theory, and the combinatorics of the Mandelbrot set.
Faraday effect measurements of holmium oxide (Ho2O3) ceramics-based magneto-optical materials
Authors: Vojna David , Yasuhara Ryo , Furuse Hiroaki , Slezak Ondrej , Hutchinson Simon , Lucianetti Antonio , Mocek Tomas , Cech Miroslav
Published: January 2018

Faraday effect measurements of holmium oxide (Ho2O3) ceramics-based magneto-optical materials, highly potential material candidates for high-energy laser Faraday isolators, are presented in this paper. Temperature dependence of the Verdet constant of nondoped Ho2O3 ceramics was measured for temperatures 15–305 K at $1.064~\unicode[STIX]{x03BC}\text{m}$ wavelength. The Verdet constant dispersion for wavelengths 0.5–$1~\unicode[STIX]{x03BC}\text{m}$ and $1.064~\unicode[STIX]{x03BC}\text{m}$ was measured for both nondoped Ho2O3 ceramics and Ho2O3 ceramics doped with terbium Tb3+ (0.2 at. %) and cerium Ce3+ (0.1 at. %) ions. The results suggest that the relatively low level of doping of Ho2O3 with these ions has no significant boosting impact on the Faraday effect. Therefore, other compositions of Ho2O3 ceramics-based magneto-optical materials, as well as various doping concentrations, should be further examined.
Interaction between the Blasius boundary layer and a free surface
Authors: Tsang Jonathan Michael Foonlan , Dalziel Stuart B. , Vriend N. M.
Published: January 2018

We consider the steady supercritical flow of a fluid layer. The layer is bounded above by a free surface and below by a rigid no-slip base. The base is in two parts: the downstream part of the base is stationary, while the upstream part translates in the streamwise direction with a uniform speed; there is an abrupt transition. At high Reynolds number, a boundary layer forms in the fluid above the base downstream of the transition point. The displacement due to this boundary layer creates a perturbation to the outer flow and therefore to the free surface. We show that the Blasius boundary layer solution, which applies in an infinitely deep fluid, also applies at high Froude numbers. The Blasius solution no longer applies for flows that are just supercritical, as the outer flow is strongly affected by the presence of the boundary layer. We outline possible applications of this work to depth-averaged models of gravity currents.
Comparisons of the Thermomechanical Fatigue Behavior of C/SIC and SIC/SIC Ceramic-Matrix Composites Subjected to Different Phase Angle
Authors: Li L. B.
Published: January 2018

In this paper, the comparisons of thermomechanical fatigue behavior of C/SiC and SiC/SiC fiber-reinforced ceramic-matrix composites (CMCs) subjected to different phase angles of θ = 0, π/3, π/2 and π have been investigated. The relationships between the fatigue damage mechanisms, phase angle, fatigue hysteresis dissipated energy, fatigue hysteresis modulus and fatigue peak strain, fiber/matrix interface debonding and sliding have been established. The differences between C/SiC and SiC/SiC composites under thermomechanical fatigue loading with different phase angles have been analyzed. The damage accumulation of 2.5D C/SiC and 2D SiC/SiC composites under thermomechanical fatigue loading have been predicted. With increasing of the phase angle, the fatigue hysteresis dissipated energy, fatigue peak strain and interface debonded length decrease for the SiC/SiC composite; however, for the C/SiC composite, the fatigue hysteresis dissipated energy, fatigue peak strain and the interface debonded length increase at the same cycle number.
Commercializing LanzaTech, from waste to fuel: An effectuation case
Authors: Karlson Brian , Bellavitis Cristiano , France Nadine
Published: January 2018

This case describes the extraordinary growth story of LanzaTech, a New Zealand (NZ)-based company cofounded in 2005 by scientists Sean Simpson and Richard Forster. LanzaTech developed a microbe which fermented the waste gases generated from steel manufacturing to produce ethanol and other chemicals. This case builds on effectuation logic and entrepreneurial discovery to highlight the challenges and opportunities of research commercialization. The case is structured chronologically and outlines the steps that the entrepreneur has taken to build the technology from scratch. It covers the early phases of the company, focussing particularly on how LanzaTech developed, refined, patented and began to commercialize its research. A key strength of the case is its multidisciplinary focus. The case describes some of the crucial aspects of research commercialization including capital raising, developing a business model, forming partnerships and expanding internationally. The case also describes a company committed to retaining its research base in NZ, and some of the opportunities and drawbacks of operating in a small economy at a distance from key market players.
Avalanche dynamics by Newton. Reply to comments on avalanche flow models based on the concept of random kinetic energy
Authors: BARTELT PERRY , BUSER OTHMAR
Published: January 2018

The critique by Issler and other (2017) of our avalanche dynamics model maintains that we disregard well-established results of particulate gravity flows. Here we show that the arguments of Issler and others (1) violate Newton's laws of motion in the avalanche core and (2) ignore size-dependent drag forces on snow particles (Stokes law) that lead to the formation of avalanche suspension layers. We explain why we cannot amend our model equations to accommodate their suggestions. The goal of our approach is to describe highly non-stationary processes in the avalanche core that lead to a wide range of avalanche flow types and therefore different flow behavior. This is important for practical applications.
INTENSIFICATION BENEFIT INDEX: HOW MUCH CAN RURAL HOUSEHOLDS BENEFIT FROM AGRICULTURAL INTENSIFICATION?
Authors: HARRIS D.
Published: January 2018

Sustainable intensification (SI) of agriculture is the predominant objective for agricultural research and extension worldwide. Researchers and policymakers consider SI to be essential to avoid global hunger, improve human nutrition and reduce rural poverty while avoiding all manner of environmental disasters. To achieve these global public goods requires a large number of rural households – ‘small farmers’ – in less developed countries to improve their agriculture. Household size and farm size from 11,789 households in 15 countries from sub-Saharan Africa were used to calculate an intensification benefit index (IBI) that reflects how much a household will benefit if intensification occurs. IBI is defined as the increase in personal daily income (cents/person/day) as returns to land (dollars/hectare/year) increase. Actual net farm income from 160 rural households in each of three countries was compared with their IBI values to explore the gap between potential intensification and current smallholder farm performance. Fifty percent of all households had IBI values less than 0.075 cents/dollar, 70% less than 0.125 cents/dollar and 90% less than 0.225 cents/dollar. Returns of $1000/ha/year would result in fewer than 15% of households crossing a $2/person/day poverty line; $2500/ha/year would be required to lift 50% of the sample above the line; and even with $4000/ha/year, more than 30% of households would remain below the line. Since mean net returns from three sub-sampled sites were only $78, $83 and $424/ha/year the gap between potential- and actual performance is large but, theoretically, amenable to closure through adoption of improved technologies. However, surveys have shown that the available technologies would struggle to bridge the gap completely for rural households with small farms. For many small farms, the gains from adopting improved technologies are unlikely by themselves to lift them out of poverty and so might not be as attractive as scientists would wish.
Tabligh Jama‘at in China: Sacred self, worldly nation, transnational imaginary
Authors: STEWART ALEXANDER
Published: January 2018

This article will evaluate how the experience of participating in the Tabligh Jama‘at affects the formation of Chinese Muslims’ subjectivities in relation to their local, national, and global communities by using data gleaned from interviews with participants in the movement and participation in Tabligh activities in and around Xining, Qinghai Province. Intensively structured practices make the movement seem restrictive, but observing the variety permitted in individual performances and autonomy allowed by grassroots governance reveals that the movement imbues participants with a high degree of agency. A sense of belonging in a pious transnational community grants individuals the means and confidence to reshape their everyday behaviours and comportment in a way that transcends traditional sectarian structures of authority and conflicts with the predominant materialism of modern China. The movement's inward focus and apolitical stance make the movement a subtle and peaceful means of tacitly undermining both atheist state and Muslim hierarchies, reinventing oneself, and expressing membership in the global ummah.
Low-temperature plasmas induced in nitrogen by extreme ultraviolet (EUV) pulses
Authors: Bartnik A. , Skrzeczanowski W. , Fiedorowicz H. , Wachulak P. , Fok T.
Published: January 2018

In this work, a comparative study of low-temperature plasmas, induced in a gaseous nitrogen by photoionization of the gas using two different irradiation systems, was performed. Both systems were based on laser-produced Xe plasmas, emitting intense extreme ultraviolet (EUV) radiation pulses in a wide wavelength range. The essential difference between the systems concerned formation of the EUV beam. The first one utilized a dedicated ellipsoidal mirror for collecting and focusing of the EUV radiation. This way a high radiation fluence could be obtained for ionization of the N2 gas injected into the vacuum chamber. The second system did not contain any EUV collector. In this case, the nitrogen to be ionized was injected into the vicinity of the Xe plasma. In both cases, energies of emitted photons were sufficient for dissociative ionization, ionization of atoms or even ions. The resulting photoelectrons had also sufficiently high energy for further ionizations or excitations. Low-temperature plasmas, created this way, were investigated by spectral measurements in the EUV, ultraviolet (UV) and visible (VIS) spectral ranges. Time-resolved UV/VIS spectra, corresponding to single-charged ions, molecules, and molecular ions, were recorded. Numerical simulations of the molecular spectra were performed allowing one to estimate vibrational and rotational temperatures of plasmas created using both irradiation systems.
Kinematic calibration of serial manipulators using Bayesian inference
Authors: Shammas Elie , Najjar Shadi
Published: January 2018

In this paper, a new calibration method for open-chain robotic arms is developed. By incorporating both prior parameter information and artifact measurement data, and by taking recourse to Bayesian inference methods, not only are the robot kinematic parameters updated but also confidence bounds are computed for all measurement data. In other words, for future measurement data not only the most likely end-effector configuration is estimated but also the uncertainty represented as 95% confidence bounds of that pose is computed. To validate the proposed calibration method, a three degree-of-freedom robotic arm was designed, constructed, and calibrated using both typical regression methods and the proposed calibration method. The results of an extensive set of experiments are presented to gauge the accuracy and utility of the proposed calibration method.
Virtual world anonymity and foreign language oral interaction
Authors: Melchor-Couto Sabela
Published: January 2018

In recent years, a considerably high number of research studies have looked into the use of virtual worlds (VWs) for language learning. A number of authors have hypothesised about the effects of anonymity when foreign language interactions are conducted via VWs. This study addresses the effect that the anonymity experienced in VW interaction may have on participants that present different affective profiles. The participants are 18 students (five male, 13 female) aged between 19 and 20 years old and registered in a Spanish undergraduate degree at the University of Roehampton (London). They were involved in four tandem oral interaction activities in the VW Second Life with a group of native Spanish students from the Universidad de Cádiz (Spain). A mixed-methods research design with quantitative and qualitative data was applied. Data were collected about the participants’ foreign language anxiety (FLA) levels, self-efficacy beliefs, and psychological profile (introvert/extrovert). Participants were also asked to answer three open-ended questions about how they felt during the interaction in the VW. The results obtained reveal a strong relationship between self-efficacy beliefs and the anonymity effect experienced by students, although no correlation was found between the participants’ FLA levels or personality profiles and their experience of the anonymity afforded by the VW.
Arguments for the Age of Serpent Mound
Authors: Lepper Bradley T. , Duncan James R. , Diaz-Granádos Carol , Frolking Tod A.
Published: January 2018

Serpent Mound, in northern Adams County, Ohio, USA, is one of the most iconic symbols of ancient America and yet there is no widely agreed upon date for the age of its original construction. Some archaeologists consider it to have been built by the Adena culture around 300bc, while others contend it was built by the Fort Ancient culture aroundad1100. There have been three attempts to obtain radiometric ages for the effigy, but they have yielded inconclusive results. The iconography of the earthwork offers an alternative means of placing the mound in its cultural context. Serpent imagery is abundant in the Fort Ancient culture as well as in the more encompassing Mississippian Ideological Interaction Sphere. Pictographs from Picture Cave in Missouri include a serpent, a humanoid female and a vulvoid in close association. We interpret these elements, in the light of Siouan oral traditions, as First Woman and her consort the Great Serpent. The Picture Cave imagery dates to betweenad950 and 1025. We argue that these same three elements are represented in the original configuration of Serpent Mound and therefore situate its design and original construction in the Early Fort Ancient period.
Effect of simulated flooding during rice seed development and maturation on subsequent seed quality
Authors: Tejakhod Sujittra , Ellis Richard H.
Published: January 2018

The resilience of seed quality in rice (Oryza sativaL.) to flooding was investigated. Pot-grown plants of thejaponicacv. Gleva, theindicacv. IR64, and the introgressed line IR64-Sub1 were submerged in water, to simulate flooding, for 3‒5 days at different stages of seed development and maturation. Mean seed weight, pre-harvest sprouting, ability to germinate, and subsequent longevity in air-dry storage were assessed. Whereas seed quality in both IR64 and IR64-Sub1 was resilient to submergence, in Gleva the longer the duration of submergence and the later in development when plants were submerged the greater the pre-harvest sprouting. Thousand seed dry weight was reduced more by submergence in Gleva than IR64 or IR64-Sub1. At harvest maturity, few pre-harvest sprouted seeds were able to germinate upon rehydration after desiccation to 11‒12% moisture content. Seed longevity of the non-sprouted seed fraction in air-dry hermetic storage (40°C, 15% moisture content) was not affected greatly by submergence, but longevity of thejaponicarice was less than that of theindicarices due to the former's steeper seed survival curves. Longevity of the twoindicarices was predicted well by the seed viability equation and previously published estimates of viability constants for rice. The greater dormancy of IR64 and IR64-Sub1, compared with Gleva, enhanced resilience to pre-harvest sprouting and reduced thousand seed dry weight from plant submergence. There was little or no effect of plant submergence on subsequent air-dry storage longevity of non-sprouted seeds in any genotype.
Priming effects on seed germination of two perennial herb species in a disturbed lava field in central Mexico
Authors: Belmont Jafet , Sánchez-Coronado María E. , Osuna-Fernández Helia R. , Orozco-Segovia Alma , Pisanty Irene
Published: January 2018

Priming has proved to enhance seed germination, but most of the research dealing with this topic has been carried out with cultivated species. The potential applications that this process has on wild species, which can be useful for restoration, are usually overlooked. This study analyses the germination response after natural priming and hydropriming ofPenstemon roseusandCastilleja tenuiflora, two perennial herbs growing in a protected area known as ‘Parque Ecológico de la Ciudad de México’. Photoblastism was evaluated for both species. Seeds were exposed to a hydration/dehydration cycle and then placed in germination chambers to determine responses to hydropriming. To identify the effects of natural priming, seeds were buried in natural conditions and then recovered every two months and placed in germination chambers. Germination percentages and rates were then quantified. Both species proved to have permeable seed coats.Penstemon roseusseeds are positive photoblastic whereasC. tenuifloraseeds are indifferent to light. Priming methods increasedC. tenuifloragermination rates, but they did not affect germination capacity. ForP. roseus, priming methods did not improve germination rates, and germination capacity of recovered seeds decreased after the rainy season, suggesting thatP. roseusforms a short-term, transient, seed bank. The germination strategies of these two species allow them to occupy suitable microsites for germination and establishment. These responses can be helpful in developing restoration programmes based on the accelerated establishment of native and characteristic successional species.
Manage Your Life Online: A Web-Based Randomized Controlled Trial Evaluating the Effectiveness of a Problem-Solving Intervention in a Student Sample
Authors: Bird Timothy , Mansell Warren , Wright Jason , Gaffney Hannah , Tai Sara
Published: January 2018

Background: Evidence for the efficacy of computer-based psychological interventions is growing. A number of such interventions have been found to be effective, especially for mild to moderate cases. They largely rely on psychoeducation and ‘homework tasks’, and are specific to certain diagnoses (e.g. depression). Aims: This paper presents the results of a web-based randomized controlled trial of Manage Your Life Online (MYLO), a program that uses artificial intelligence to engage the participant in a conversation across any problem topic. Method: Healthy volunteers (n = 213) completed a baseline questionnaire and were randomized to the MYLO program or to an active control condition where they used the program ELIZA, which emulates a Rogerian psychotherapist. Participants completed a single session before completing post-study and 2-week follow-up measures. Results: Analyses were per protocol with intent to follow-up. Both programs were associated with improvements in problem distress, anxiety and depression post-intervention, and again 2 weeks later, but MYLO was not found to be more effective than ELIZA. MYLO was rated as significantly more helpful than ELIZA, but there was no main effect of intervention on problem resolution. Conclusions: Findings are consistent with those of a previous smaller, laboratory-based trial and provide support for the acceptability and effectiveness of MYLO delivered over the internet for a non-clinical sample. The lack of a no-treatment control condition means that the effect of spontaneous recovery cannot be ruled out.
Supplementary physicians’ fees: a sustainable system?
Authors: Calcoen Piet , van de Ven Wynand P. M. M.
Published: January 2018

In Belgium and France, physicians can charge a supplementary fee on top of the tariff set by the mandatory basic health insurance scheme. In both countries, the supplementary fee system is under pressure because of financial sustainability concerns and a lack of added value for the patient. Expenditure on supplementary fees is increasing much faster than total health expenditure. So far, measures taken to curb this trend have not been successful. For certain categories of physicians, supplementary fees represent one-third of total income. For patients, however, the added value of supplementary fees is not that clear. Supplementary fees can buy comfort and access to physicians who refuse to treat patients who are not willing to pay supplementary fees. Perceived quality of care plays an important role in patients’ willingness to pay supplementary fees. Today, there is no evidence that physicians who charge supplementary fees provide better quality of care than physicians who do not. However, linking supplementary fees to objectively proven quality of care and limiting access to top quality care to patients able and willing to pay supplementary fees might not be socially acceptable in many countries. Our conclusion is that supplementary physicians’ fees are not sustainable.
HOMERIC MOTIVATION AND MODERN NARRATOLOGY: THE CASE OF PENELOPE
Authors: Grethlein Jonas
Published: January 2018

Forged mostly in readings of the modern novel, the tools of narratology have allowed us to detect many features that ancient literature shares with modern texts. At the same time, they have detracted from crucial differences between ancient and modern narratives. This article argues that, while being at the origin of the classical western plot, theOdysseyalso features a narrative logic that differs significantly from what the modern novel has taught us to expect. It focuses on the case of Penelope. Various theories have been advanced to explain Penelope's intervention in books 18 and 19. The difficulties that modern scholars have had with Penelope, it is suggested, are due to a special kind of motivation which is also prominent in medieval narrative.
Visualizing Music in the Silent Era: The Collaborative Experiments of Visual Symphony Productions
Authors: SIMONSON MARY
Published: January 2018

In July 1922, theNew York Timesreported that the “encouraging little film”Danse Macabrewas screening at the Rialto Theater in New York City. Directed by filmmaker Dudley Murphy, it starred dancers Adolph Bolm and Ruth Page in a visual interpretation of Saint-Saëns'sDanse Macabrethat synchronized perfectly with live performances of the composition. While film scholars have occasionally citedDanse Macabreand Murphy's other shorts from this period as examples of early avant-garde filmmaking in the United States, discussions of the films are mired in misunderstanding. In this article, I use advertisements, reviews, and other archival materials to trace the production, exhibition, and reception of Murphy's Visual Symphony project. These films, I argue, were not Murphy's alone: rather, they were a collaborative endeavor guided as heavily by musician and film exhibitor Hugo Riesenfeld as by Murphy himself. Recast in this way, the Visual Symphony project highlights evolving approaches to sound–image synchronization in the 1920s, the centrality of theater conductors and musicians to filmmaking in this period, and the various ways in which filmmakers, performers, and exhibitors conceptualized the relationship between music and film, and the live and the mediated, in the final decade of the silent era.
The Barker hypothesis confirmed: association of low birth weight with all-cause natural deaths in young adult life in a remote Australian Aboriginal community
Authors: Hoy Wendy E. , Nicol Jennifer L.
Published: January 2018

Barkeret al. proposed that low birth weight predisposes to higher death rates in adult life. We previously confirmed this fact in a cohort of young adults who were born in a remote Australian Aboriginal community between 1956 and 1985. We now present data in these same people with four more years of follow-up and a greater number of deaths. The fates of participants were documented from age 15 years until death, start of dialysis, or until the end of 2010 and causes of death were derived from clinic narratives and dialysis records. Rates of natural deaths were compared by birth cohorts and birth weight, and hazard ratios were calculated using Cox proportional hazards methods, by birth weight and adjusted for birth cohort and sex. Over follow-up of 19,661 person-years, 61 people died of natural causes between age 15 and the censor date. Low birth weights (<2.5 kg) were associated with higher rates of natural death, with HR (95% CI) 1.76 (1.1–2.9,P=0.03), after adjustment for year of birth and sex. The effect was particularly prominent for deaths at <41 years of age, and with deaths from respiratory conditions/sepsis and unusual causes. A predisposing effect of low birth weight on adult deaths was confirmed. This phenomenon, occurring in the context of dramatically improved survivals of lower birth weight infants and children since the early 1960s, helps explain the current epidemic of chronic disease in Aboriginal people. Birth weights continue to improve, so excess deaths from this source should progressively be minimized.
Genetic and Environmental Contributions of Negative Valence Systems to Internalizing Pathways
Authors: Cecilione Jennifer L. , Rappaport Lance M. , Hahn Shannon E. , Anderson Audrey E. , Hazlett Laura E. , Burchett Jason R. , Moore Ashlee A. , Savage Jeanne E. , Hettema John M. , Roberson-Nay Roxann
Published: January 2018

The genetic and environmental contributions of negative valence systems (NVS) to internalizing pathways study (also referred to as the Adolescent and Young Adult Twin Study) was designed to examine varying constructs of the NVS as they relate to the development of internalizing disorders from a genetically informed perspective. The goal of this study was to evaluate genetic and environmental contributions to potential psychiatric endophenotypes that contribute to internalizing psychopathology by studying adolescent and young adult twins longitudinally over a 2-year period. This report details the sample characteristics, study design, and methodology of this study. The first wave of data collection (i.e., time 1) is complete; the 2-year follow-up (i.e., time 2) is currently underway. A total of 430 twin pairs (N = 860 individual twins; 166 monozygotic pairs; 57.2% female) and 422 parents or legal guardians participated at time 1. Twin participants completed self-report surveys and participated in experimental paradigms to assess processes within the NVS. Additionally, parents completed surveys to report on themselves and their twin children. Findings from this study will help clarify the genetic and environmental influences of the NVS and their association with internalizing risk. The goal of this line of research is to develop methods for early internalizing disorder risk detection.
How Does Snow Affect the Intensity of Mountain Precipitation?
Authors: Cook Terri
Published: January 2018

A new investigation into the sensitivity of extreme precipitation in a changing climate indicates that more winter rainfall and protracted snowmelt may require local adaptations to winter flooding impacts.
Defining the role of the tumor vasculature in antitumor immunity and immunotherapy
Authors: Schaaf Marco B. , Garg Abhishek D. , Agostinis Patrizia
Published: January 2018

It is now well established that cancer cells co-exist within a complex environment with stromal cells and depend for their growth and dissemination on tight and plastic interactions with components of the tumor microenvironment (TME). Cancer cells incite the formation of new blood and lymphatic vessels from preexisting vessels to cope with their high nutrient/oxygen demand and favor tumor outgrowth. Research over the past decades has highlighted the crucial role played by tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T-cell-mediated immunosurveillance, which are the main hallmarks of cancers. The structurally and functionally aberrant tumor vasculature contributes to the protumorigenic and immunosuppressive TME by maintaining a cancer cell’s permissive environment characterized by hypoxia, acidosis, and high interstitial pressure, while simultaneously generating a physical barrier to T cells' infiltration. Recent research moreover has shown that blood endothelial cells forming the tumor vessels can actively suppress the recruitment, adhesion, and activity of T cells. Likewise, during tumorigenesis the lymphatic vasculature undergoes dramatic remodeling that facilitates metastatic spreading of cancer cells and immunosuppression. Beyond carcinogenesis, the erratic tumor vasculature has been recently implicated in mechanisms of therapy resistance, including those limiting the efficacy of clinically approved immunotherapies, such as immune checkpoint blockers and adoptive T-cell transfer. In this review, we discuss emerging evidence highlighting the major role played by tumor-associated blood and lymphatic vasculature in thwarting immunosurveillance mechanisms and antitumor immunity. Moreover, we also discuss novel therapeutic approaches targeting the tumor vasculature and their potential to help overcoming immunotherapy resistance.
Cell death-based treatment of childhood cancer
Authors: Westhoff Mike-Andrew , Marschall Nicolas , Grunert Michael , Karpel-Massler Georg , Burdach Stefan , Debatin Klaus-Michael
Published: January 2018

Any therapy that aims at eradicating a cancerous growth will have at its core a cell death-inducing component. Here we argue that paediatric oncology presents with its unique set of considerations and problems, which—while taking the lead from oncological research experiences obtained from the adult population—need to be clinically evaluated independently. This is particularly true when considering long-term side effects. Precision medicine offers a promising new approach in therapy, but given as a monotherapy and in a limited combination, as found in an apoptosis inducer/sensitiser combination, it will most likely lead to mutation escape of the target cell population and the emergence of resistance. However, using the increasing amount of the molecular data as the basis for a complex combination therapy combining several key components such as cell death-inducing agents, kinase inhibitors and BH3 mimetics, holds great promise.
Functional and structural damage of neurons by innate immune mechanisms during neurodegeneration
Authors: Ising Christina , Heneka Michael T.
Published: January 2018

Over the past decades, our view on neurodegenerative diseases has been mainly centered around neurons and their networks. Only recently it became evident that immunological processes arise alongside degenerating neurons, raising the question whether these represent just meaningless bystander reactions or in turn, contribute to pathogenesis and disease symptoms. When considering any effect of inflammatory events on the CNS one has to consider the site, duration and nature of immune activation. Likewise, one has to distinguish between mechanisms which directly impact the neuronal compartment and indirect mechanisms, which affect cells that are important for neuronal functioning and survival. As discussed in this review, both types of mechanisms may be present at the same time and additively or synergistically lead to neuronal demise. Inflammatory mediators released by the principle innate immune cells of the brain, microglia and astrocytes, can compromise the function and structure of neurons, thereby playing important roles in the pathogenesis of neurodegenerative diseases.
Practical device-independent quantum cryptography via entropy accumulation
Authors: Arnon-Friedman Rotem , Dupuis Frédéric , Fawzi Omar , Renner Renato , Vidick Thomas
Published: January 2018

Device-independent cryptography goes beyond conventional quantum cryptography by providing security that holds independently of the quality of the underlying physical devices. Device-independent protocols are based on the quantum phenomena of non-locality and the violation of Bell inequalities. This high level of security could so far only be established under conditions which are not achievable experimentally. Here we present a property of entropy, termed “entropy accumulation”, which asserts that the total amount of entropy of a large system is the sum of its parts. We use this property to prove the security of cryptographic protocols, including device-independent quantum key distribution, while achieving essentially optimal parameters. Recent experimental progress, which enabled loophole-free Bell tests, suggests that the achieved parameters are technologically accessible. Our work hence provides the theoretical groundwork for experimental demonstrations of device-independent cryptography.
A naturally occurring epiallele associates with leaf senescence and local climate adaptation in Arabidopsis accessions
Authors: He Li , Wu Wenwu , Zinta Gaurav , Yang Lan , Wang Dong , Liu Renyi , Zhang Huiming , Zheng Zhimin , Huang Huan , Zhang Qingzhu , Zhu Jian-Kang
Published: January 2018

Epigenetic variation has been proposed to facilitate adaptation to changing environments, but evidence that natural epialleles contribute to adaptive evolution has been lacking. Here we identify a retrotransposon, named “NMR19” (naturally occurring DNA methylation variation region 19), whose methylation and genomic location vary amongArabidopsis thalianaaccessions. We classify NMR19 as NMR19-4 and NMR19-16 based on its location, and uncover NMR19-4 as an epiallele that controls leaf senescence by regulating the expression ofPHEOPHYTIN PHEOPHORBIDE HYDROLASE(PPH). We find that the DNA methylation status of NMR19-4 is stably inherited and independent of genetic variation. In addition, further analysis indicates that DNA methylation of NMR19-4 correlates with local climates, implying that NMR19-4 is an environmentally associated epiallele. In summary, we discover a novel epiallele, and provide mechanistic insights into its origin and potential function in local climate adaptation.
IL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells
Authors: Hsieh Wan-Chen , Hsu Tzu-Sheng , Chang Ya-Jen , Lai Ming-Zong
Published: January 2018

X-linked lymphoproliferative syndrome type-2 (XLP-2) is a primary immunodeficiency disease attributed to XIAP mutation and is triggered by infection. Here, we show that mouse Xiap−/− regulatory T (Treg) cells and human XIAP-deficient Treg cells are defective in suppressive function. The Xiap−/− Treg cell defect is linked partly to decreased SOCS1 expression. XIAP binds SOCS1 and promotes SOCS1 stabilization. Foxp3 stability is reduced in Xiap−/− Treg cells. In addition, Xiap−/− Treg cells are prone to IFN-γ secretion. Transfer of wild-type Treg cells partly rescues infection-induced inflammation in Xiap−/− mice. Notably, inflammation-induced reprogramming of Xiap−/− Treg cells can be prevented by blockade of the IL-6 receptor (IL-6R), and a combination of anti-IL-6R and Xiap−/− Treg cells confers survival to inflammatory infection in Xiap−/− mice. Our results suggest that XLP-2 can be corrected by combination treatment with autologous iTreg (induced Treg) cells and anti-IL-6R antibody, bypassing the necessity to transduce Treg cells with XIAP.
Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics
Authors: MacNair Craig R. , Stokes Jonathan M. , Carfrae Lindsey A. , Fiebig-Comyn Aline A. , Coombes Brian K. , Mulvey Michael R. , Brown Eric D.
Published: January 2018

Plasmid-borne colistin resistance mediated by mcr-1 may contribute to the dissemination of pan-resistant Gram-negative bacteria. Here, we show that mcr-1 confers resistance to colistin-induced lysis and bacterial cell death, but provides minimal protection from the ability of colistin to disrupt the Gram-negative outer membrane. Indeed, for colistin-resistant strains of Enterobacteriaceae expressing plasmid-borne mcr-1, clinically relevant concentrations of colistin potentiate the action of antibiotics that, by themselves, are not active against Gram-negative bacteria. The result is that several antibiotics, in combination with colistin, display growth-inhibition at levels below their corresponding clinical breakpoints. Furthermore, colistin and clarithromycin combination therapy displays efficacy against mcr-1-positive Klebsiella pneumoniae in murine thigh and bacteremia infection models at clinically relevant doses. Altogether, these data suggest that the use of colistin in combination with antibiotics that are typically active against Gram-positive bacteria poses a viable therapeutic alternative for highly drug-resistant Gram-negative pathogens expressing mcr-1.
Engineering yeast for the production of breviscapine by genomic analysis and synthetic biology approaches
Authors: Liu Xiaonan , Cheng Jian , Zhang Guanghui , Ding Wentao , Duan Lijin , Yang Jing , Kui Ling , Cheng Xiaozhi , Ruan Jiangxing , Fan Wei , Chen Junwen , Long Guangqiang , Zhao Yan , Cai Jing , Wang Wen , Ma Yanhe , Dong Yang , Yang Shengchao , Jiang Huifeng
Published: January 2018

The flavonoid extract from Erigeron breviscapus, breviscapine, has increasingly been used to treat cardio- and cerebrovascular diseases in China for more than 30 years, and plant supply of E. breviscapus is becoming insufficient to satisfy the growing market demand. Here we report an alternative strategy for the supply of breviscapine by building a yeast cell factory using synthetic biology. We identify two key enzymes in the biosynthetic pathway (flavonoid-7-O-glucuronosyltransferase and flavone-6-hydroxylase) from E. breviscapus genome and engineer yeast to produce breviscapine from glucose. After metabolic engineering and optimization of fed-batch fermentation, scutellarin and apigenin-7-O-glucuronide, two major active ingredients of breviscapine, reach to 108 and 185 mg l–1, respectively. Our study not only introduces an alternative source of these valuable compounds, but also provides an example of integrating genomics and synthetic biology knowledge for metabolic engineering of natural compounds.
Control of cell morphology and differentiation by substrates with independently tunable elasticity and viscous dissipation
Authors: Charrier Elisabeth E. , Pogoda Katarzyna , Wells Rebecca G. , Janmey Paul A.
Published: January 2018

The mechanical properties of extracellular matrices can control the function of cells. Studies of cellular responses to biomimetic soft materials have been largely restricted to hydrogels and elastomers that have stiffness values independent of time and extent of deformation, so the substrate stiffness can be unambiguously related to its effect on cells. Real tissues, however, often have loss moduli that are 10 to 20% of their elastic moduli and behave as viscoelastic solids. The response of cells to a time-dependent viscous loss is largely uncharacterized because appropriate viscoelastic materials are lacking for quantitative studies. Here we report the synthesis of soft viscoelastic solids in which the elastic and viscous moduli can be independently tuned to produce gels with viscoelastic properties that closely resemble those of soft tissues. Systematic alteration of the hydrogel viscosity demonstrates the time dependence of cellular mechanosensing and the influence of viscous dissipation on cell phenotype.
A phenotype centric benchmark of variant prioritisation tools
Authors: Anderson Denise , Lassmann Timo
Published: January 2018

Next generation sequencing is a standard tool used in clinical diagnostics. In Mendelian diseases the challenge is to discover the single etiological variant among thousands of benign or functionally unrelated variants. After calling variants from aligned sequencing reads, variant prioritisation tools are used to examine the conservation or potential functional consequences of variants. We hypothesised that the performance of variant prioritisation tools may vary by disease phenotype. To test this we created benchmark data sets for variants associated with different disease phenotypes. We found that performance of 24 tested tools is highly variable and differs by disease phenotype. The task of identifying a causative variant amongst a large number of benign variants is challenging for all tools, highlighting the need for further development in the field. Based on our observations, we recommend use of five top performers found in this study (FATHMM, M-CAP, MetaLR, MetaSVM and VEST3). In addition we provide tables indicating which analytical approach works best in which disease context. Variant prioritisation tools are best suited to investigate variants associated with well-studied genetic diseases, as these variants are more readily available during algorithm development than variants associated with rare diseases. We anticipate that further development into disease focussed tools will lead to significant improvements.
Transcriptomic responses to biotic stresses in Malus x domestica: a meta-analysis study
Authors: Balan Bipin , Marra Francesco Paolo , Caruso Tiziano , Martinelli Federico
Published: January 2018

RNA-Seq analysis is a strong tool to gain insight into the molecular responses to biotic stresses in plants. The objective of this work is to identify specific and common molecular responses between different transcriptomic data related to fungi, virus and bacteria attacks in Malus x domestica. We analyzed seven transcriptomic datasets in Malus x domestica divided in responses to fungal pathogens, virus (Apple Stem Grooving Virus) and bacteria (Erwinia amylovora). Data were dissected using an integrated approach of pathway- and gene- set enrichment analysis, Mapman visualization tool, gene ontology analysis and inferred protein-protein interaction network. Our meta-analysis revealed that the bacterial infection enhanced specifically genes involved in sugar alcohol metabolism. Brassinosteroids were upregulated by fungal pathogens while ethylene was highly affected by Erwinia amylovora. Gibberellins and jasmonates were strongly repressed by fungal and viral infections. The protein-protein interaction network highlighted the role of WRKYs in responses to the studied pathogens. In summary, our meta-analysis provides a better understanding of the Malus X domestica transcriptome responses to different biotic stress conditions; we anticipate that these insights will assist in the development of genetic resistance and acute therapeutic strategies. This work would be an example for next meta-analysis works aiming at identifying specific common molecular features linked with biotic stress responses in other specialty crops.
Identification of valid reference genes for mRNA and microRNA normalisation in prostate cancer cell lines
Authors: Zhao Hui , Ma Teng-Fei , Lin Jie , Liu Lin-Lin , Sun Wei-Jie , Guo Li-Xia , Wang Si-Qi , Otecko Newton O. , Zhang Ya-Ping
Published: January 2018

RT-qPCR offers high sensitivity, for accurate interpretations of qPCR results however, normalisation using suitable reference genes is fundamental. Androgens can regulate transcriptional expression including reference gene expression in prostate cancer. In this study, we evaluated ten mRNA and six non-protein coding RNA reference genes in five prostate cell lines under varied dihydrotestosterone (DHT) treatments. We validated the effects of DHT-treatments using media containing charcoal-stripped serum prior to DHT stimulation on the test samples by Western blot experiments. Reference gene expression stability was analysed using three programs (geNorm, NormFinder and BestKeeper), and the recommended comprehensive ranking is provided. Our results reveal thatACTBandGAPDH, andmiR-16andmiR-1228-3pare the most suitable mRNA and miRNA reference genes across all cell lines, respectively. Considering prostate cancer cell types,ACTB/GAPDHandACTB/HPRT1are the most suitable reference gene combinations for mRNA analysis, andmiR-16/miR-1228-3pandRNU6-2/RNU43for miRNA analysis in AR+, and AR− and normal cell lines, respectively. Comparison of relative target gene (PCA3andmiR-141) expression reveals different patterns depending on reference genes used for normalisation. To our knowledge, this is the first report on validation of reference genes under different DHT treatments in prostate cancer cells. This study provides insights for discovery of reliable DHT-regulated genes in prostate cells.
A comparative Study of Aptasensor Vs Immunosensor for Label-Free PSA Cancer Detection on GQDs-AuNRs Modified Screen-Printed Electrodes
Authors: Srivastava Monika , Nirala Narsingh R. , Srivastava S. K. , Prakash Rajiv
Published: January 2018

Label-free and sensitive detection of PSA (Prostate Specific Antigen) is still a big challenge in the arena of prostate cancer diagnosis in males. We present a comparative study for label-free PSA aptasensor and PSA immunosensor for the PSA-specific monoclonal antibody, based on graphene quantum dots-gold nanorods (GQDs-AuNRs) modified screen-printed electrodes. GQDs-AuNRs composite has been synthesized and used as an electro-active material, which shows fast electron transfer and catalytic property. Aptamer or anti-PSA has immobilized onto the surface of modified screen printed electrodes. Three techniques are used simultaneously, viz. cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedence spectroscopy (EIS) to investigate the analytical performance of both PSA aptasensor and PSA immunosensor with its corresponding PSA antigen. Under optimum conditions, both sensors show comparable results with an almost same limit of detection (LOD) of 0.14 ng mL−1. The results developed with aptasensor and anti-PSA is also checked through the detection of PSA in real samples with acceptable results. Our study suggests some advantages of aptasensor in terms of better stability, simplicity and cost effectiveness. Further our present work shows enormous potential of our developed sensors for real application using voltammetric and EIS techniques simultaneous to get reliable detection of the disease.