bluuebunny/crossref_metadata_2025 huggingface dataset:
Intra-uterine undernutrition amplifies age-associated glucose intolerance in pigs via altered DNA methylation at muscle GLUT4 promoter
Authors: Wang Jun , Cao Meng , Yang Mei , Lin Yan , Che Lianqiang , Fang Zhengfeng , Xu Shengyu , Feng Bin , Li Jian , Wu De
Published: June 2016

The present study aimed to investigate the effect of maternal malnutrition on offspring glucose tolerance and the epigenetic mechanisms involved. In total, twelve primiparous Landrace×Yorkshire gilts were fed rations providing either 100 % (control (CON)) or 75 % (undernutrition (UN)) nutritional requirements according to the National Research Council recommendations, throughout gestation. Muscle samples of offspring were collected at birth (dpn1), weaning (dpn28) and adulthood (dpn189). Compared with CON pigs, UN pigs showed lower serum glucose concentrations at birth, but showed higher serum glucose and insulin concentrations as well as increased area under the blood glucose curve during intravenous glucose tolerance test at dpn189 (P<0·05). Compared with CON pigs, GLUT-4 gene and protein expressions were decreased at dpn1 and dpn189 in the muscle of UN pigs, which was accompanied by increased methylation at the GLUT4 promoter (P<0·05). These alterations in methylation concurred with increased mRNA levels of DNA methyltransferase (DNMT) 1 at dpn1 and dpn28, DNMT3a at dpn189 and DNMT3b at dpn1 in UN pigs compared with CON pigs (P<0·05). Interestingly, although the average methylation levels at the muscle GLUT4 promoter were decreased at dpn189 compared with dpn1 in pigs exposed to a poor maternal diet (P<0·05), the methylation differences in individual CpG sites were more pronounced with age. Our results indicate that in utero undernutrition persists to silence muscle GLUT4 likely through DNA methylation during the ageing process, which may lead to the amplification of age-associated glucose intolerance.
Canine echinococcosis: the predominance of immature eggs in adult tapeworms of Echinococcus granulosus in stray dogs from Tunisia
Authors: Iraqi W.
Published: June 2016

Canine echinococcosis is caused by the adult tapeworm of Echinococcus granulosus. As intermediate hosts, humans and livestock become infected following ingestion of eggs that are passed in the faeces of dogs. Mature eggs develop into hydatid cysts in different organs, leading to hydatid disease, which is a serious public health problem. In the present study, we investigated the proportion of mature eggs of E. granulosus in 140 dogs from three regions of Tunisia. The results showed the predominance of immature E. granulosus eggs in infected dogs and the occurrence of a small proportion of oncospheres. The ability of immature eggs to infect humans and livestock is discussed.
Awareness and attitudes towards external auditory canal exostosis and its preventability in surfers in the UK: cross-sectional study
Authors: Morris S , Martin T , Mccahon D , Bennett S
Published: June 2016

Objectives:

To determine the proportion of UK surfers aware of external auditory canal exostosis, to identify surfer characteristics associated with knowledge of the condition and to explore attitudes to earplug use.

Method:

An online, cross-sectional survey of UK-based surfers.

Results:

Of 375 surfers, 86.1 per cent (n = 323; 95 per cent confidence interval = 82.3–89.3) reported awareness of external auditory canal exostosis. Further investigation revealed that, despite their awareness of the condition, 23.4 per cent of these surfers (88 out of 323; 95 per cent confidence interval = 19.5–28.0) had little or no knowledge about external auditory canal exostosis. Predictors of knowledge included: distance from nearest surfing beach (p = 0.001), surfing standard (ability) (p = 0.008), earplug use (p = 0.024) and positive external auditory canal exostosis diagnosis (p = 0.009).

Conclusion:

The findings suggest that a significant minority of UK surfers have no knowledge about this condition. Knowledge of external auditory canal exostosis was significantly associated with earplug use when surfing. Efforts to improve surfers’ knowledge are required to enable surfers to better protect themselves, which could reduce the incidence of external auditory canal exostosis.
Non-indigenous amphipods and mysids in coastal food webs of eastern Baltic Sea estuaries
Authors: Berezina Nadezhda A. , Razinkovas-Baziukas Arturas , Tiunov Alexei V.
Published: June 2016

The study analyses the role of non-indigenous invertebrates in the food webs of two eutrophic brackish estuarine ecosystems of the Baltic Sea: the Neva River estuary and the Curonian Lagoon, with the aim of clarifying several questions such as what trophic levels were occupied by newly established species (mainly amphipods and mysids) and whether they can affect the native benthic invertebrates as a result of their possible carnivorous nature. Stable isotope analysis (δ15N values) and gut contents analysis of field-collected specimens were used to estimate trophic level and trophic links of the newly established malacostracan crustaceans, while their consumption rates when feeding as carnivores were measured experimentally. The δ15N analysis allocated four trophic levels (TL) in the coastal food webs of both studied ecosystems with the lowest δ15N (2–4‰) for detritus and algae and the highest for fish (12–14‰). Through their high abundance, non-indigenous crustaceans (Pontogammarus robustoides, Gmelinoides fasciatus, Obessogammarus crassus, Gammarus tigrinus, Limnomysis benedeni and Paramysis lacustris) have become important members of food chains of the studied ecosystems. Their trophic position varied significantly within species during ontogenesis. This suggests that they turned from being typically detritivores/plantivorous (TL 2–2.4) at juvenile stages to omnivores (2.5–3) or to carnivores (>3) as adults. Assessment of the predation pressure by the adult amphipods on other coexisting invertebrates (in the example of the Neva Estuary) showed a low or medium impact, depending on species of predator and productivity of its potential prey organisms.
Functional codeswitching and register in educated Negev Arabic interview style
Authors: Henkin Roni
Published: June 2016

The sociolinguistic phenomenon of codeswitching, both diglossic and bilingual (Arabic–Hebrew), is extremely pervasive in all varieties of Palestinian Arabic, including Negev Arabic. Surprisingly, neither of these types of codeswitching in Palestinian Arabic has received due scholarly attention; moreover, their interplay has not been studied for any type of Arabic. This article analyses quantitative and functional aspects of diglossic and bilingual codeswitching in the personal interview style of 11 Negev Bedouin female students, focusing on their functional interaction. In the five distinct registers analysed, ratios of both diglossic and bilingual codeswitching were found to rise from childhood narratives to recounts of the period of academic studies and expository sections, with the use of Hebraisms dropping in the more formal registers. Although mixed bilingual discourse with intensive codeswitching is the default style for in-group discourse of the young generation, I show that many switches are not random, but fulfil discourse-pragmatic, communicative, social and textual functions typical of each of the registers. For example, in the narrative registers, switching may mark evaluation (commenting, explaining, self-repair, sidetracking, repetition). In both narrative and non-narrative discourse it may mark quotations, rephrasing or paraphrasing, with or without a metalinguistic introducing particle such as ‘as they say’. The result is redundancy at the referential level, with pragmatic functions of emphasizing or elaborating at the discourse level. This is in keeping with functions identified for bilingual codeswitching in general and also for diglossic codeswitching in Arabic; but it is the first effort, as far as I know, to combine analysis of the two codeswitching dimensions in any given code; and, moreover, to study the interplay of this bi-dimensional switching with relation to the stylistic factors of genre and register.
Erroneous Gazes: Lucretian Poetics in Catullus 64
Authors: Tamás Ábel
Published: June 2016

This article argues for a ‘reciprocal intertextuality’ between Catullus 64 and Lucretius anticipating the poetic interplays of Augustan poets with theDe Rerum Natura. Catullus’ wedding guests (proto-readers), Ariadne (proto-Narcissus), and Aegeus (proto-Dido) are interpreted here aserrantesin the Lucretian sense: through their erroneous gazes presented in Poem 64, they all exemplify hownotto gaze at the structure of the universe. In the Lucretio-Catullan intertextual space — generated, as it seems, by the Catullan text — a reciprocal way of reading emerges: while, on the one hand, ‘Catullus’ uses ‘Lucretius’ to show that the aesthetic experience he offers is dependent upon an erroneous, unLucretian gaze/reading which deprives us of the external spectator position, ‘Lucretius’, on the other hand, uses ‘Catullan’ characters as deterrent examples in order to teach us hownotto submerge in ‘Catullus’ poetics of illusion’.
Patronage, Logrolls, and “Polarization”: Congressional Parties of the Gilded Age, 1876–1896
Authors: Lee Frances E.
Published: June 2016

According to the quantitative indicators scholars use to measure political polarization, the Gilded Age stands out for some of the most party-polarized Congresses of all time. By contrast, historians of the era depict the two major parties as presenting few programmatic alternatives to one another. I argue that a large share of the party-line votes in the Congress of this period are poorly suited to the standard conceptualization as “polarization,” meaning wide divergence on an ideological continuum structuring alternative views on national policy. Specifically, the era's continuous battles over the distribution of particularized benefits, patronage, and control of political office make little sense conceived as stemming from individual members' preferences on an underlying ideological dimension. They are better understood as fights between two long coalitions competing for power and distributive gains. In short, the Gilded Age illustrates that political parties are fully capable of waging ferocious warfare over spoils and office, even despite a relative lack of sharp party differences over national policy.
In vivo dosimetry using radiochromic films (EBT-2) during intraoperative radiotherapy
Authors: Yekta Zahra Rahimzade , Mahdavi Seied Rabi Mehdi , Baghani Hamid Reza , Robatjazi Mostafa , Mostaar Ahmad , Mirzaie Hamidreza , Sardari Dariush , Akbari Mohammad Esmaeil , Nafisi Nahid
Published: June 2016

Background

Intraoperative radiotherapy is a method of choice to deliver a critical radiation dose to the tumour bed immediately after surgical excision.

Aim

The purpose of this work is to check the dose delivered to the patients during intraoperative electron beam radiation therapy (IOERT) in the conservative treatment of breast cancer, by means of reference dose measurement using radiochromic (EBT-2) films.

Material and methods

Ninety patients with early-stage breast cancer underwent exclusive IOERT to the tumour bed using a LIAC linear accelerator. Absolute dose measurements were done with film pieces. After irradiation, the pixel values of the films were obtained via MATLAB and ImageJ softwares. Calibration curve was also used for calculating net optical density. Expected dose was compared to the patient delivered dose.

Results

The mean deviation of the delivered dose from the expected one was 2·56% that is well in the accepted criteria. Only in one case, there was a larger deviation due to barometer miscalibration.

Findings

EBT-2 film response is independent from dose-per-pulse and as it was shown in this study it can be robustly used during breast IOERT for dosimetric and also positioning verifications.
How much do means-tested benefits reduce the demand for annuities?
Authors: BÜTLER MONIKA , PEIJNENBURG KIM , STAUBLI STEFAN
Published: June 2016

Means-tested retirement benefits create incentives to cash out pension wealth. Individuals trade off the advantages from annuitization, receiving longevity risk insurance, to the disadvantages, giving up ‘free’ wealth in the form of means-tested supplemental income. We quantify the impact of means-tested benefits with a calibrated life-cycle model, demonstrating that they substantially reduce the desire to annuitize especially for low and intermediate levels of pension wealth. Using an administrative dataset on pension choices, we show that the model's predicted fraction of retirees choosing the annuity is able to match the annuitization pattern of occupational pension wealth observed in Switzerland. On the base of our model, we also assess alternative policies such as mandatory annutization and tougher asset tests.
The future of Spanish pensions
Authors: DÍAZ-GIMÉNEZ JAVIER , DÍAZ-SAAVEDRA JULIÁN
Published: June 2016

We use an overlapping generations model economy with endogenous retirement to study the 2011 and 2013 reforms of the Spanish public pension system. These reforms delay the legal retirement ages, increase the contributivity of the system, and adopt a sustainability factor and a pension revualuation index that effectively transform the Spanish pension system into a defined-contribution pension system. We find that these reforms improve the sustainability of Spanish pensions substantially, and that they limit the tax increases that would have been necessary to finance the pension system deficits. But these results are achieved at the expense of large reductions in the real value of the average pension. This reduction is progressive and, by 2050, the average pension is approximately 30% smaller in real terms than what it would have been under the pension system rules that prevailed in 2010. We also show that these reforms are costly in welfare terms and that households born between 1950 and 1970, young disabled workers who are alive at the time of the reform, and future cohorts bear the highest welfare costs. The substantial reduction of pensions and the high welfare costs that these reforms bring about lead us to conjecture that further reforms lurk in the future of Spanish pensions.
Organic agriculture in post-war Uganda: emergence of pioneer-led niches between 1986 and 1993
Authors: Hauser Michael , Lindtner Mara
Published: June 2016

Uganda is the largest producer of organic commodities in Africa. While most of the literature associate the start of organic agriculture in Uganda with the first certified project, no accounts exist about non-certified organic agriculture before 1993. Both in Europe and in the USA, pioneers drove non-certified organic agriculture as a response to economic, ecological and social crises. Uganda suffered two decades of civil war ending in 1986 causing multiple crises. We explore how post-war conditions influenced the emergence of organic agriculture in Uganda. We conducted individual semi-structured interviews with 12 organic agriculture experts from Central and Southwestern Uganda. Interviews were held in English using interview guides informed by a transition theoretical perspective. Interviews were tape-recorded, transcribed and analyzed using deductive and inductive coding. Our analysis shows that the degraded environment, food insecurity and economic instability after the war created a sense of urgency for the rehabilitation of livelihoods. Pioneers, including civil society activists, farmers, entrepreneurs and researchers, responded by promoting low-cost, resource-conserving technologies and agronomic practices to smallholder farmers. Economic liberalization, decentralization and institutional vacuum eased pioneers’ activities, despite facing opponents from the government and research. Through experimental learning, demonstration farms and cooperation with the Catholic Church, public extension services, researchers and international development-oriented non-governmental organizations, pioneers reached out to farmers in Eastern, Central and Southwestern Uganda. As challenging as post-war crises may be, they offer opportunities for changing development trajectories. Therefore, reconstruction and rehabilitation efforts can accommodate sustainability concerns and allow the introduction of course-changing measures in any sector.
Automated design of balanced wideband bandpass filters based on mirrored stepped impedance resonators (SIRs) and interdigital capacitors
Authors: Sans Marc , Selga Jordi , Vélez Paris , Rodríguez Ana , Bonache Jordi , Boria Vicente E. , Martín Ferran
Published: June 2016

This paper presents small balanced bandpass filters exhibiting wide differential-mode pass bands and high common-mode suppression. The filters are implemented in microstrip technology and their topology consists of multisection mirrored stepped impedance resonators (SIRs) alternating with mirrored interdigital capacitors. The mirrored SIRs provide the required common-mode transmission zeros to achieve effective rejection of that mode in the region of interest, i.e. the differential-mode pass band. An automated design method for such filters, based on aggressive space mapping, is reported. The method uses the equivalent circuit model of both the mirrored SIRs and the interdigital capacitors, and filter synthesis is based on a quasi-Newton iterative algorithm where parameter extraction is the key aspect. The automated design approach is illustrated through an order-3 filter, where it is demonstrated that the filter topology is generated from the specifications. As compared with previous balanced filters based on mirrored SIRs coupled through admittance inverters, the proposed filters of this work are smaller and the design method is simplified, since bandwidth compensation due to the narrowband functionality of the inverters is avoided.
Segmented quarter cylindrical dielectric resonator antenna: simulation and experimental investigation in composite form for wideband applications
Authors: Ranjan Pinku , Gangwar Ravi Kumar
Published: June 2016

A probe feed wideband multi-element dual segments quarter cylindrical dielectric resonator antenna (q-CDRA) in composite forms have been proposed. The q-CDRA has been introduced by splitting CDRA into four uniform quarters and multi-segmentation approach has been castoff for further improvement in bandwidth of q-CDRA. The dual segments q-CDRA has been designed and analyzed using theoretical analysis and Ansoft HFSS simulation software. Further the dual segment multi-element q-CDRAs in composite form have been designed. A coaxial probe has been placed at the center of the ground plane for the excitation of proposed multi-element and multi-segmented composite form of q-CDRA, which excite TM01δ mode in the proposed antenna. The input characteristics and radiation patterns of the proposed composite antennas have been studied and their results are compared with corresponding experimental results. Prototype of single, two, and four elements dual-segment composite q-CDRAs have been fabricated and input characteristics of the proposed composite antennas have been compared with each other. Four elements dual-segment composite q-CDRA has shown wide impedance bandwidth (|S11| ≤ −10 dB) of 85.13% with monopole-like radiation pattern. The peak gain of 4.85 dBi with 98.5% radiation efficiency has been achieved for dual-segment four elements composite q-CDRA. The proposed multi-element dual-segment composite q-CDRAs may find suitable applications in C and X-band with complete covering of the 5.0 GHZ wireless local area network (WLAN) and worldwide interoperability for microwave access (WiMAX) band.
HPV-Impfung
Authors: Stronski Huwiler Susanne , Spaar Anne
Published: June 2016

Zusammenfassung. Humane Papilloma Viren sind assoziiert mit diversen genitalen (Zervix-, Anal-, Vulva- und Vagina-, Peniskarzinome) und nicht-genitalen Karzinomen (Oropharyngealkarzinome), sowie mit Genitalwarzen. In der Schweiz sind zwei hochwirksame Impfstoffe erhältlich, die über ein sehr gutes Sicherheitsprofil verfügen. Die Sicherheit der Impfstoffe wurde immer wieder kontrovers diskutiert, konnte jedoch bis anhin stets bestätigt werden. In der Schweiz wird seit 2008 im Rahmen von kantonalen Programmen die Impfung für Mädchen und junge Frauen angeboten. Seit 2015 gibt es neu die Impfempfehlung für Knaben und junge Männer, die auf Juli 2016 mit Kostenübernahme in die Programme integriert wird. Im Artikel werden die Krankheitslast, die Wirksamkeit und die Sicherheit der Impfung diskutiert, sowie die Anwendung der Impfstoffe vorgestellt. Speziell wird der ärztliche Umgang mit der Urteilsfähigkeit von Jugendlichen zur Einwilligung zu Impfungen besprochen. Es folgt ein Ausblick auf die Zukunft v.a. auf einen neuen Impfstoff mit erweitertem Spektrum von HPV-Typen.
Aktiv impfen gegen die Frühsommer-Meningoenzephalitis
Authors: Krause Martin , Majer Sabine
Published: June 2016

Zusammenfassung. Die Frühsommer-Meningoenzephalitis ist eine virale Infektion, welche einen fatalen Verlauf nehmen kann. Da keine spezifische Therapie existiert, hat die aktive Impfung den bedeutendsten Stellenwert in der Kontrolle dieser Krankheit. Die Vakzine wird allen Erwachsenen und Kindern > 6 Jahre empfohlen, welche in einem Endemiegebiet leben oder sich dort zeitweise aufhalten. In der Schweiz stehen zwei Totimpfstoffe zur Verfügung. Das Impfschema beider Impfstoffe besteht aus einer Primo-Vakzine mit 3 Teilimpfungen und einer Auffrischimpfung alle 10 Jahre. Obwohl keine kontrollierten Daten vorliegen, gilt die Wirksamkeit der Vakzine als unbestritten. Die Sicherheit beider Impfstoffe ist hoch. Zwar sind lokale Impfreaktionen an der Injektionsstelle oder leichte systemische Symptome relativ häufig, aber sie dauern nur kurz und sind harmlos. Anaphylaktische Reaktionen und schwere zentralnervöse Nebenwirkungen sind sehr selten.
Impfung gegen Tollwut
Authors: Jelinek Tomas
Published: June 2016

Zusammenfassung. Tollwut ist nahezu auf der gesamten Welt verbreitet. Die durch Säugetiere verbreitete Infektion verläuft praktisch ausnahmslos tödlich und verursacht daher mehr Todesfälle, als jede andere Zoonose. Aufgrund der fehlenden Therapieoptionen bleibt die prä- bzw. post-expositionelle Impfung die einzige effektive Maßnahme zur Verhinderung der Erkrankung. Seit Jahrzehnten sind sichere Zellkulturimpfstoffe verfügbar, die einen langfristigen, effektiven Schutz bieten. Je nach Dringlichkeit der Indikation können diese nach verschiedenen Impfschemata appliziert werden.
Impfungen bei Patienten mit Autoimmunerkrankungen
Authors: Bühler Silja , Hatz Christoph
Published: June 2016

Zusammenfassung. Die Zahl von Patienten mit Autoimmunerkrankungen, die unter immunsupprimierender Therapie stehen, nimmt stetig zu. Dabei steigt die Vielfalt der eingesetzten immunsupprimierenden Medikamente, insbesondere die Gruppe der sogenannten Biologika. Patienten mit Autoimmunerkrankungen sind durch die Grunderkrankung an sich, aber insbesondere auch durch die eingenommene Medikation einem erhöhten Infektionsrisiko ausgesetzt. Viele dieser Infektionen sind durch Impfungen verhütbar, weshalb sie in dieser Gruppe speziell wichtig sind. In der Abteilung für übertragbare Krankheiten am Institut für Epidemiologie, Biostatistik und Prävention der Universität Zürich wurde von der Eidgenössischen Kommission für Impffragen eine Übersichtsarbeit zu Impfungen bei Patienten mit rheumatischen Erkrankungen, gastroenterologischen (Auto-)Immunerkrankungen und Multipler Sklerose in Auftrag gegeben. Die Datenlage ist insgesamt eingeschränkt. Die wichtigsten Ergebnisse lassen sich wie folgt zusammenfassen: die Gabe von Totimpfstoffen ist in allen drei Patientengruppen sicher; die Wirksamkeit kann unter immunsupprimierender Therapie jedoch reduziert sein. Neben den generell empfohlenen Basisimpfungen sind spezielle Impfungen zum Schutz dieser vulnerablen Gruppen indiziert, wie z. B. die Grippeimpfung und die Impfung gegen Pneumokokken. Lebendimpfungen sind generell aus Sicherheitsbedenken unter Immunsuppression kontraindiziert. Es gibt jedoch gewisse Ausnahmen, sowie Zeitabstände, die nach Absetzen oder Pausieren eines immunsupprimierenden Medikaments zu beachten sind.
Impfungen bei Immunsupprimierten
Authors: Staehelin Cornelia , Hirzel Cédric , Hauser Christoph , Furrer Hansjakob
Published: June 2016

Zusammenfassung. Personen mit einer HIV-Infektion, nach einer Organ- oder einer hämatologischen Stammzelltransplantation oder mit einer funktionalen oder anatomischen Asplenie sind gegenüber Infektionen anfälliger. Sie haben eine grössere Komplikationsrate und ein höheres Risiko für einen chronifizierten Verlauf. Impfungen wären eine ideale primäre Präventionsmassnahme, sind aber – durch dieselben Mechanismen des Immundefektes der zu schwereren Krankheitsverläufen führt – in ihrer Wirksamkeit vermindert. Die Impfungen sollen daher, wenn immer möglich, vor Beginn der Immunsuppression oder später zum Zeitpunkt der minimalsten Immunsuppression, durchgeführt werden. Trotzdem bleibt der Benefit von Impfungen bei immunsupprimierten Personen unbestritten, sofern die Indikationsstellung bezüglich Zeitpunkt und Dosierung (Dosismenge und -anzahl), die zu einem maximalen Ansprechen führt, beachtet wird. Lebendimpfungen sind wegen der Gefahr der unkontrollierten Vermehrung der Impfviren bei schwerer Immunsuppression kontraindiziert. Die Serologie soll unspezifischer gemessen werden, da schwer immunsupprimierte Personen im Falle einer relevanten Exposition durch passive Immunisierung mittels spezifischer oder unspezifischer intravenöser Immunglobuline geschützt werden können.
Trust, but verify. The errors and misinterpretations in the Cochrane analysis by O. J. Storebo and colleagues on the efficacy and safety of methylphenidate for the treatment of children and adolescents with ADHD
Authors: Banaschewski T. , Gerlach M. , Becker K. , Holtmann M. , Döpfner M. , Romanos M.
Published: June 2016

Abstract. Objective: A recent Cochrane review published by O. J. Storebo and colleagues (2015) raised substantial doubts about the benefit from stimulant medication with methylphenidate in the treatment of childhood ADHD due to the overall poor quality of studies. The systematic review thus contradicts all previous reviews and meta-analyses. Method: We here detail various examples of errors, inconsistencies, and misinterpretations in the review which led to false results and inadequate conclusions. Results:We demonstrate that the study selection is flawed and undertaken without sufficient scientific justification resulting in an underestimation of effect sizes, which, furthermore, are inadmissibly clinically interpreted. The methodology of the assessment of bias and quality is not objective and cannot be substantiated by the data. Conclusions: Cochrane reviews lay claim to a high scientific quality and substantial relevance for evidence-based clinical decisions. The systematic review by Storebo and colleagues (2015) illustrates that, despite adhering to strict standards and high-quality protocols, even Cochrane works should be critically read and verified, sometimes with surprising results.
Multi-analyte biosensor interface for real-time monitoring of 3D microtissue spheroids in hanging-drop networks
Authors: Misun Patrick M. , Rothe Jörg , Schmid Yannick R.F. , Hierlemann Andreas , Frey Olivier
Published: June 2016

Microfluidics is becoming a technology of growing interest for building microphysiological systems with integrated read-out functionalities. Here we present the integration of enzyme-based multi-analyte biosensors into a multi-tissue culture platform for ‘body-on-a-chip’ applications. The microfluidic platform is based on the technology of hanging-drop networks, which is designed for the formation, cultivation, and analysis of fluidically interconnected organotypic spherical three-dimensional (3D) microtissues of multiple cell types. The sensor modules were designed as small glass plug-ins featuring four platinum working electrodes, a platinum counter electrode, and an Ag/AgCl reference electrode. They were placed directly into the ceiling substrate from which the hanging drops that host the spheroid cultures are suspended. The electrodes were functionalized with oxidase enzymes to enable continuous monitoring of lactate and glucose through amperometry. The biosensors featured high sensitivities of 322±41 nA mM−1 mm−2 for glucose and 443±37 nA mM−1 mm−2 for lactate; the corresponding limits of detection were below 10 μM. The proposed technology enabled tissue-size-dependent, real-time detection of lactate secretion from single human colon cancer microtissues cultured in the hanging drops. Furthermore, glucose consumption and lactate secretion were monitored in parallel, and the impact of different culture conditions on the metabolism of cancer microtissues was recorded in real-time.
The MDM2–p53–pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells
Authors: Li Xiaomu , Cheng Kenneth K. Y. , Liu Zhuohao , Yang Jin-Kui , Wang Baile , Jiang Xue , Zhou Yawen , Hallenborg Philip , Hoo Ruby L. C. , Lam Karen S. L. , Ikeda Yasuhiro , Gao Xin , Xu Aimin
Published: June 2016

Mitochondrial metabolism is pivotal for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. However, little is known about the molecular machinery that controls the homeostasis of intermediary metabolites in mitochondria. Here we show that the activation of p53 in β-cells, by genetic deletion or pharmacological inhibition of its negative regulator MDM2, impairs GSIS, leading to glucose intolerance in mice. Mechanistically, p53 activation represses the expression of the mitochondrial enzyme pyruvate carboxylase (PC), resulting in diminished production of the TCA cycle intermediates oxaloacetate and NADPH, and impaired oxygen consumption. The defective GSIS and mitochondrial metabolism in MDM2-null islets can be rescued by restoring PC expression. Under diabetogenic conditions, MDM2 and p53 are upregulated, whereas PC is reduced in mouse β-cells. Pharmacological inhibition of p53 alleviates defective GSIS in diabetic islets by restoring PC expression. Thus, the MDM2–p53–PC signalling axis links mitochondrial metabolism to insulin secretion and glucose homeostasis, and could represent a therapeutic target in diabetes.
Ligand-induced substrate steering and reshaping of [Ag2(H)]+ scaffold for selective CO2 extrusion from formic acid
Authors: Zavras Athanasios , Khairallah George N. , Krstić Marjan , Girod Marion , Daly Steven , Antoine Rodolphe , Maitre Philippe , Mulder Roger J. , Alexander Stefanie-Ann , Bonačić-Koutecký Vlasta , Dugourd Philippe , O’Hair Richard A. J.
Published: June 2016

Metalloenzymes preorganize the reaction environment to steer substrate(s) along the required reaction coordinate. Here, we show that phosphine ligands selectively facilitate protonation of binuclear silver hydride cations, [LAg2(H)]+by optimizing the geometry of the active site. This is a key step in the selective, catalysed extrusion of carbon dioxide from formic acid, HO2CH, with important applications (for example, hydrogen storage). Gas-phase ion-molecule reactions, collision-induced dissociation (CID), infrared and ultraviolet action spectroscopy and computational chemistry link structure to reactivity and mechanism. [Ag2(H)]+and [Ph3PAg2(H)]+react with formic acid yielding Lewis adducts, while [(Ph3P)2Ag2(H)]+is unreactive. Using bis(diphenylphosphino)methane (dppm) reshapes the geometry of the binuclear Ag2(H)+scaffold, triggering reactivity towards formic acid, to produce [dppmAg2(O2CH)]+and H2. Decarboxylation of [dppmAg2(O2CH)]+via CID regenerates [dppmAg2(H)]+. These gas-phase insights inspired variable temperature NMR studies that show CO2and H2production at 70 °C from solutions containing dppm, AgBF4, NaO2CH and HO2CH.
Unravelling the structural plasticity of stretched DNA under torsional constraint
Authors: King Graeme A. , Peterman Erwin J. G. , Wuite Gijs J. L.
Published: June 2016

Regions of the genome are often held under torsional constraint. Nevertheless, the influence of such constraint on DNA–protein interactions during genome metabolism is still poorly understood. Here using a combined optical tweezers and fluorescence microscope, we quantify and explain how torsional constraint influences the structural stability of DNA under applied tension. We provide direct evidence that concomitant basepair melting and helical unwinding can occur in torsionally constrained DNA at forces >∼50 pN. This striking result indicates that local changes in linking number can be absorbed by the rest of the DNA duplex. We also present compelling new evidence that an overwound DNA structure (likely P-DNA) is created (alongside underwound structures) at forces >∼110 pN. These findings substantiate previous theoretical predictions and highlight a remarkable structural plasticity of torsionally constrained DNA. Such plasticity may be required in vivo to absorb local changes in linking number in DNA held under torsional constraint.
111 oriented gold nanoplatelets on multilayer graphene as visible light photocatalyst for overall water splitting
Authors: Mateo Diego , Esteve-Adell Iván , Albero Josep , Royo Juan F. Sánchez , Primo Ana , Garcia Hermenegildo
Published: June 2016

Development of renewable fuels from solar light appears as one of the main current challenges in energy science. A plethora of photocatalysts have been investigated to obtain hydrogen and oxygen from water and solar light in the last decades. However, the photon-to-hydrogen molecule conversion is still far from allowing real implementation of solar fuels. Here we show that 111 facet-oriented gold nanoplatelets on multilayer graphene films deposited on quartz is a highly active photocatalyst for simulated sunlight overall water splitting into hydrogen and oxygen in the absence of sacrificial electron donors, achieving hydrogen production rate of 1.2 molH2 per gcomposite per h. This photocatalytic activity arises from the gold preferential orientation and the strong gold–graphene interaction occurring in the composite system.
PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery
Authors: Zhao Yi , Wang Wei , Guo Shutao , Wang Yuhua , Miao Lei , Xiong Yang , Huang Leaf
Published: June 2016

Metformin, a widely implemented anti-diabetic drug, exhibits potent anticancer efficacies. Herein a polymeric construction of Metformin, PolyMetformin (PolyMet) is successfully synthesized through conjugation of linear polyethylenimine (PEI) with dicyandiamide. The delocalization of cationic charges in the biguanide groups of PolyMet reduces the toxicity of PEI bothin vitroandin vivo. Furthermore, the polycationic properties of PolyMet permits capture of siRNA into a core-membrane structured lipid-polycation-hyaluronic acid (LPH) nanoparticle for systemic gene delivery. Advances herein permit LPH-PolyMet nanoparticles to facilitate VEGF siRNA delivery for VEGF knockdown in a human lung cancer xenograft, leading to enhanced tumour suppressive efficacy. Even in the absence of RNAi, LPH-PolyMet nanoparticles act similarly to Metformin and induce antitumour efficacy through activation of the AMPK and inhibition of the mTOR. In essence, PolyMet successfully combines the intrinsic anticancer efficacy of Metformin with the capacity to carry siRNA to enhance the therapeutic activity of an anticancer gene therapy.
Erratum: The somatic mutation profiles of 2,433 breast cancers refine their genomic and transcriptomic landscapes
Authors: Pereira Bernard , Chin Suet-Feung , Rueda Oscar M. , Vollan Hans-Kristian Moen , Provenzano Elena , Bardwell Helen A. , Pugh Michelle , Jones Linda , Russell Roslin , Sammut Stephen-John , Tsui Dana W. Y. , Liu Bin , Dawson Sarah-Jane , Abraham Jean , Northen Helen , Peden John F. , Mukherjee Abhik , Turashvili Gulisa , Green Andrew R. , McKinney Steve , Oloumi Arusha , Shah Sohrab , Rosenfeld Nitzan , Murphy Leigh , Bentley David R. , Ellis Ian O. , Purushotham Arnie , Pinder Sarah E. , Børresen-Dale Anne-Lise , Earl Helena M. , Pharoah Paul D. , Ross Mark T. , Aparicio Samuel , Caldas Carlos
Published: June 2016

Nature Communications 7 Article number:11479 (2016); Published: 10 May 2016; Updated: 6 June 2016. The original version of this Article contained an error in the spelling of ‘refine’ in the title of the paper. This has now been corrected in both the PDF and HTML.
Plasma concentrations of coffee polyphenols and plasma biomarkers of diabetes risk in healthy Japanese women
Authors: Lee A H , Tan L 'B , Hiramatsu N , Ishisaka A , Alfonso H , Tanaka A , Uemura N , Fujiwara Y , Takechi R
Published: June 2016

Coffee consumption has been reported to reduce the risk of type 2 diabetes in experimental and epidemiological studies. This anti-diabetic effect of coffee may be attributed to its high content in polyphenols especially caffeic acid and chlorogenic acid. However, the association between plasma coffee polyphenols and diabetic risks has never been investigated in the literature. In this study, fasting plasma samples were collected from 57 generally healthy females aged 38–73 (mean 52, s.d. 8) years recruited in Himeji, Japan. The concentrations of plasma coffee polyphenols were determined by liquid chromatography coupled with mass tandem spectrometer. Diabetes biomarkers in the plasma/serum samples were analysed by a commercial diagnostic laboratory. Statistical associations were assessed using Spearman’s correlation coefficients. The results showed that plasma chlorogenic acid exhibited negative associations with fasting blood glucose, glycated hemoglobin and C-reactive protein, whereas plasma total coffee polyphenol and plasma caffeic acid were weakly associated with these biomarkers. Our preliminary data support previous findings that coffee polyphenols have anti-diabetic effects but further replications with large samples of both genders are recommended.
NIK regulates MT1-MMP activity and promotes glioma cell invasion independently of the canonical NF-κB pathway
Authors: Duran C L , Lee D W , Jung J-U , Ravi S , Pogue C B , Toussaint L G , Bayless K J , Sitcheran R
Published: June 2016

A growing body of evidence implicates the noncanonical NF-κB pathway as a key driver of glioma invasiveness and a major factor underlying poor patient prognoses. Here, we show that NF-κB-inducing kinase (NIK/MAP3K14), a critical upstream regulator of the noncanonical NF-κB pathway, is both necessary and sufficient for cell-intrinsic invasion, as well as invasion induced by the cytokine TWEAK, which is strongly associated with tumor pathogenicity. NIK promotes dramatic alterations in glioma cell morphology that are characterized by extensive membrane branching and elongated pseudopodial protrusions. Correspondingly, NIK increases the phosphorylation, enzymatic activity and pseudopodial localization of membrane type-1 matrix metalloproteinase (MT1-MMP/MMP14), which is associated with enhanced tumor cell invasion of three-dimensional collagen matrices. Moreover, NIK regulates MT1-MMP activity in cells lacking the canonical NF-κB p65 and cRel proteins. Finally, increased expression of NIK is associated with elevated MT1-MMP phosphorylation in orthotopic xenografts and co-expression of NIK and MT1-MMP in human tumors is associated with poor glioma patient survival. These data reveal a novel role of NIK to enhance pseudopodia formation, MT1-MMP enzymatic activity and tumor cell invasion independently of p65. Collectively, our findings underscore the therapeutic potential of approaches targeting NIK in highly invasive tumors.
Electricity, water, and natural gas consumption of a residential house in Canada from 2012 to 2014
Authors: Makonin Stephen , Ellert Bradley , Bajić Ivan V. , Popowich Fred
Published: June 2016

With the cost of consuming resources increasing (both economically and ecologically), homeowners need to find ways to curb consumption. The Almanac of Minutely Power dataset Version 2 (AMPds2) has been released to help computational sustainability researchers, power and energy engineers, building scientists and technologists, utility companies, and eco-feedback researchers test their models, systems, algorithms, or prototypes on real house data. In the vast majority of cases, real-world datasets lead to more accurate models and algorithms. AMPds2 is the first dataset to capture all three main types of consumption (electricity, water, and natural gas) over a long period of time (2 years) and provide 11 measurement characteristics for electricity. No other such datasets from Canada exist. Each meter has 730 days of captured data. We also include environmental and utility billing data for cost analysis. AMPds2 data has been pre-cleaned to provide for consistent and comparable accuracy results amongst different researchers and machine learning algorithms.
The Birmingham Urban Climate Laboratory—A high density, urban meteorological dataset, from 2012–2014
Authors: Warren Elliott L. , Young Duick T. , Chapman Lee , Muller Catherine , Grimmond C.S.B. , Cai Xiao-Ming
Published: June 2016

There is a paucity of urban meteorological observations worldwide, hindering progress in understanding and mitigating urban meteorological hazards and extremes. High quality urban datasets are required to monitor the impacts of climatological events, whilst providing data for evaluation of numerical models. The Birmingham Urban Climate Laboratory was established as an exemplar network to meet this demand for urban canopy layer observations. It comprises of an array of 84 wireless air temperature sensors nested within a coarser array of 24 automatic weather stations, with observations available between June 2012 and December 2014. data routinely underwent quality control, follows the ISO 8601 naming format and benefits from extensive site metadata. The data have been used to investigate the structure of the urban heat island in Birmingham and its associated societal and infrastructural impacts. The network is now being repurposed into a testbed for the assessment of crowd-sourced and satellite data, but the original dataset is now available for further analysis, and an open invitation is extended for its academic use.
Nanomaterial datasets to advance tomography in scanning transmission electron microscopy
Authors: Levin Barnaby D.A. , Padgett Elliot , Chen Chien-Chun , Scott M.C. , Xu Rui , Theis Wolfgang , Jiang Yi , Yang Yongsoo , Ophus Colin , Zhang Haitao , Ha Don-Hyung , Wang Deli , Yu Yingchao , Abruña Hector D. , Robinson Richard D. , Ercius Peter , Kourkoutis Lena F. , Miao Jianwei , Muller David A. , Hovden Robert
Published: June 2016

Electron tomography in materials science has flourished with the demand to characterize nanoscale materials in three dimensions (3D). Access to experimental data is vital for developing and validating reconstruction methods that improve resolution and reduce radiation dose requirements. This work presents five high-quality scanning transmission electron microscope (STEM) tomography datasets in order to address the critical need for open access data in this field. The datasets represent the current limits of experimental technique, are of high quality, and contain materials with structural complexity. Included are tomographic series of a hyperbranched Co2P nanocrystal, platinum nanoparticles on a carbon nanofibre imaged over the complete 180° tilt range, a platinum nanoparticle and a tungsten needle both imaged at atomic resolution by equal slope tomography, and a through-focal tilt series of PtCu nanoparticles. A volumetric reconstruction from every dataset is provided for comparison and development of post-processing and visualization techniques. Researchers interested in creating novel data processing and reconstruction algorithms will now have access to state of the art experimental test data.
Microprofiling of nitrogen patches in paddy soil: Analysis of spatiotemporal nutrient heterogeneity at the microscale
Authors: Li Yilin , Kronzucker Herbert J. , Shi Weiming
Published: June 2016

Flooded paddy soil ecosystems in the tropics support the cultivation of the majority of the world’s leading crop, rice, and nitrogen (N) availability in the paddy-soil rooting zone limits rice production more than any other nutritional factor. Yet, little is known about the dynamic response of paddy soil to N-fertiliser application, in terms of horizontal and vertical patchiness in N distribution and transformation. Here, we present a microscale analysis of the profile of ammonium (NH4+) and nitrate (NO3−), nitrification, oxygen (O2waterand O2soil), and pH (pHwaterand pHsoil) in paddy soils, collected from two representative rice-production areas in subtropical China. NH4+and NO3−exhibited dramatic spatiotemporal profiles within N patches on the microscale. We show that pHsoilbecame constant at 1.0–3.5 mm depth, and O2soilbecame undetectable at 1.7–4.0 mm. Fertiliser application significantly increased pH, and decreased O2, within N patches. Path analysis showed that the factors governing nitrification scaled in the order: pHwater > pHsoil > NH4+ > O2water > NO3− > O2soil. We discuss the soil properties that decide the degree of nutrient patchiness within them and argue that such knowledge is critical to intelligent appraisals of nutrient-use efficiencies in the field.
Tinnitus is associated with reduced sound level tolerance in adolescents with normal audiograms and otoacoustic emissions
Authors: Sanchez Tanit Ganz , Moraes Fernanda , Casseb Juliana , Cota Jaci , Freire Katya , Roberts Larry E.
Published: June 2016

Recent neuroscience research suggests that tinnitus may reflect synaptic loss in the cochlea that does not express in the audiogram but leads to neural changes in auditory pathways that reduce sound level tolerance (SLT). Adolescents (N = 170) completed a questionnaire addressing their prior experience with tinnitus, potentially risky listening habits, and sensitivity to ordinary sounds, followed by psychoacoustic measurements in a sound booth. Among all adolescents 54.7% reported by questionnaire that they had previously experienced tinnitus, while 28.8% heard tinnitus in the booth. Psychoacoustic properties of tinnitus measured in the sound booth corresponded with those of chronic adult tinnitus sufferers. Neither hearing thresholds (≤15 dB HL to 16 kHz) nor otoacoustic emissions discriminated between adolescents reporting or not reporting tinnitus in the sound booth, but loudness discomfort levels (a psychoacoustic measure of SLT) did so, averaging 11.3 dB lower in adolescents experiencing tinnitus in the acoustic chamber. Although risky listening habits were near universal, the teenagers experiencing tinnitus and reduced SLT tended to be more protective of their hearing. Tinnitus and reduced SLT could be early indications of a vulnerability to hidden synaptic injury that is prevalent among adolescents and expressed following exposure to high level environmental sounds.