bluuebunny/crossref_metadata_2025_split huggingface dataset:
The c-Jun N-terminal kinase prevents oxidative stress induced by UV and thermal stresses in corals and human cells
Authors: Courtial Lucile , Picco Vincent , Grover Renaud , Cormerais Yann , Rottier Cécile , Labbe Antoine , Pagès Gilles , Ferrier-Pagès Christine 
Published: April 2017

AbstractCoral reefs are of major ecological and socio-economic interest. They are threatened by global warming and natural pressures such as solar ultraviolet radiation. While great efforts have been made to understand the physiological response of corals to these stresses, the signalling pathways involved in the immediate cellular response exhibited by corals remain largely unknown. Here, we demonstrate that c-Jun N-terminal kinase (JNK) activation is involved in the early response of corals to thermal and UV stress. Furthermore, we found that JNK activity is required to repress stress-induced reactive oxygen species (ROS) accumulation in both the coral Stylophora pistillata and human skin cells. We also show that inhibiting JNK activation under stress conditions leads to ROS accumulation, subsequent coral bleaching and cell death. Taken together, our results suggest that an ancestral response, involving the JNK pathway, is remarkably conserved from corals to human, protecting cells from the adverse environmental effects.
Reprogramming MHC specificity by CRISPR-Cas9-assisted cassette exchange
Authors: Kelton William , Waindok Ann Cathrin , Pesch Theresa , Pogson Mark , Ford Kyle , Parola Cristina , Reddy Sai T. 
Published: April 2017

AbstractThe development of programmable nucleases has enabled the application of new genome engineering strategies for cellular immunotherapy. While targeted nucleases have mostly been used to knock-out or knock-in genes in immune cells, the scarless exchange of entire immunogenomic alleles would be of great interest. In particular, reprogramming the polymorphic MHC locus could enable the creation of matched donors for allogeneic cellular transplantation. Here we show a proof-of-concept for reprogramming MHC-specificity by performing CRISPR-Cas9-assisted cassette exchange. Using murine antigen presenting cell lines (RAW264.7 macrophages), we demonstrate that the generation of Cas9-induced double-stranded breaks flanking the native MHC-I H2-Kd locus led to exchange of an orthogonal H2-Kb allele. MHC surface expression allowed for easy selection of reprogrammed cells by flow cytometry, thus obviating the need for additional selection markers. MHC-reprogrammed cells were fully functional as they could present H2-Kd-restricted peptide and activate cognate T cells. Finally, we investigated the role of various donor template formats on exchange efficiency, discovering that templates that underwent in situ linearization resulted in the highest MHC-reprogramming efficiency. These findings highlight a potential new approach for the correcting of MHC mismatches in cellular transplantation.
In search of evidence for the experience of pain in honeybees: A self-administration study
Authors: Groening Julia , Venini Dustin , Srinivasan Mandyam V. 
Published: April 2017

AbstractDespite their common use as model organisms in scientific experiments, pain and suffering in insects remains controversial and poorly understood. Here we explore potential pain experience in honeybees (Apis mellifera) by testing the self-administration of an analgesic drug. Foragers were subjected to two different types of injuries: (i) a clip that applied continuous pressure to one leg and (ii) amputation of one tarsus. The bees were given a choice between two feeders, one offering pure sucrose solution, the other sucrose solution plus morphine. We found that sustained pinching had no effect on the amount of morphine consumed, and hence is unlikely to be experienced as painful. The amputated bees did not shift their relative preference towards the analgesic either, but consumed more morphine and more solution in total compared to intact controls. While our data do not provide evidence for the self-administration of morphine in response to pain, they suggest that injured bees increase their overall food intake, presumably to meet the increased energy requirements for an immune response caused by wounding. We conclude that further experiments are required to gain insights into potential pain-like states in honeybees and other insects.
Sexually-trimorphic interactions with colour polymorphism determine nectar quality in a herbaceous perennial
Authors: Varga Sandra , Soulsbury Carl D. 
Published: April 2017

AbstractAmongst gynodioecious plant breeding systems, there can exist intermediate morphs with a reduction in their male function (i.e. reduced number of functional anthers). Along with this sexual trimorphism, plants can also show floral colour polymorphism. Such intricate mixtures of phenotypes within a species may have complex effects on floral rewards. Floral rewards are known to vary between sexually dimorphic species and to a lesser extent between colour morphs. However, the interactive effect of sexual trimorphism and colour polymorphism is unexplored. We measured nectar’s sugar content in the sexually trimorphic Geranium sylvaticum, a gynodioecious plant with a light/dark floral polymorphism. We found that nectar reward differed across genders and colour morphs. Results were not however consistent within the three genders; dark female and hermaphrodite flowers had higher sugar content than light morphs, whereas intermediate flowers did not. As expected, females and hermaphrodites had different nectar reward, with intermediate morphs being midway between the other genders. In intermediates, the sugar content was not related to the number of functional stamens. We show for the first time the existence of sex-specific differences between flower gender and colour morphs in nectar rewards. Our results demonstrate the importance of considering multiple and conflicting selection pressures to explain rewards.
Dynamic Wavelength-Tunable Photodetector Using Subwavelength Graphene Field-Effect Transistors
Authors: Léonard François , Spataru Catalin D. , Goldflam Michael , Peters David W. , Beechem Thomas E. 
Published: April 2017

AbstractDynamic wavelength tunability has long been the holy grail of photodetector technology. Because of its atomic thickness and unique properties, graphene opens up new paradigms to realize this concept, but so far this has been elusive experimentally. Here we employ detailed quantum transport modeling of photocurrent in graphene field-effect transistors (including realistic electromagnetic fields) to show that wavelength tunability is possible by dynamically changing the gate voltage. We reveal the phenomena that govern the behavior of this type of device and show significant departure from the simple expectations based on vertical transitions. We find strong focusing of the electromagnetic fields at the contact edges over the same length scale as the band-bending. Both of these spatially-varying potentials lead to an enhancement of non-vertical optical transitions, which dominate even in the absence of phonon or impurity scattering. We also show that the vanishing density of states near the Dirac point leads to contact blocking and a gate-dependent modulation of the photocurrent. Several of the effects discussed here should be applicable to a broad range of one- and two-dimensional materials and devices.
Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects
Authors: Mueller F , Lenz C , Dolder P C , Harder S , Schmid Y , Lang U E , Liechti M E , Borgwardt S 
Published: April 2017

AbstractLysergic acid diethylamide (LSD) induces profound changes in various mental domains, including perception, self-awareness and emotions. We used functional magnetic resonance imaging (fMRI) to investigate the acute effects of LSD on the neural substrate of emotional processing in humans. Using a double-blind, randomised, cross-over study design, placebo or 100 μg LSD were orally administered to 20 healthy subjects before the fMRI scan, taking into account the subjective and pharmacological peak effects of LSD. The plasma levels of LSD were determined immediately before and after the scan. The study (including the a priori-defined study end point) was registered at ClinicalTrials.gov before study start (NCT02308969). The administration of LSD reduced reactivity of the left amygdala and the right medial prefrontal cortex relative to placebo during the presentation of fearful faces (P<0.05, family-wise error). Notably, there was a significant negative correlation between LSD-induced amygdala response to fearful stimuli and the LSD-induced subjective drug effects (P<0.05). These data suggest that acute administration of LSD modulates the engagement of brain regions that mediate emotional processing.
How Long Does It Take for Clopidogrel and Ticagrelor to Inhibit Platelets in Patients Undergoing Primary Percutaneous Coronary Intervention? A Detailed Pharmacodynamic Analysis: Time Course of Platelet Reactivity in STEMI (TOPS)
Authors: Bergmeijer Thomas , Godschalk Thea , Janssen Paul , Berge Kim , Breet Nicoline , Kelder Johannes , Hackeng Christian , Ten Berg Jurriën 
Published: April 2017

AbstractAntiplatelet therapy plays a pivotal role in patients with an ST-segment elevation myocardial infarction (STEMI) to prevent further atherothrombotic events, such as stent thrombosis. Although the risk of stent thrombosis is highest in the first hours after primary percutaneous coronary intervention (pPCI), little is known about when an adequate level of platelet inhibition is achieved following a clopidogrel or ticagrelor loading dose in STEMI patients. Patients presenting with STEMI in whom pPCI was performed and who were loaded with 600 mg clopidogrel or 180 mg ticagrelor were eligible for enrolment in this nonrandomized, open label, single-center study. Platelet reactivity was measured before PCI, 6 and 24 hours after loading dose and after 2, 7, and 14 days, using the VerifyNow P2Y12 assay as well as 20 µmol/L adenosine diphosphate stimulated light transmittance aggregometry (LTA). We analyzed the time until a VerifyNow result of < 236 P2Y12 reaction units or LTA maximum platelet aggregation of < 64.5% was reached. A total of 28 patients were participated in this study. Platelet reactivity dropped below the high platelet reactivity cutoff level after 11.4 (VerifyNow) and 5.7 (LTA) hours in patients who were loaded with clopidogrel, and after 2.4 (VerifyNow) and 3.9 (LTA) hours in patients who were loaded with ticagrelor. Despite the administration of a clopidogrel or ticagrelor loading dose, it still takes multiple hours (2–11) to reach adequate platelet inhibition in STEMI patients. This might indicate the need for additional antiplatelet therapy in the first hours after loading in patients undergoing pPCI with stenting.
Effect of an Educational Presentation about Extremely Preterm Infants on Knowledge and Attitudes of Health Care Providers
Authors: Doucette Stefani , Lemyre Brigitte , Daboval Thierry , Dunn Sandra , Akiki Salwa , Barrowman Nick , Moore Gregory 
Published: April 2017

Objective To determine healthcare providers' knowledge (HCP) about survival rates of extremely preterm infants (EPI) and attitudes toward resuscitation before and after an educational presentation and, to examine the relationship between knowledge and attitudes toward resuscitation.
Study Design Participants completed a survey before and after attending a presentation detailing evidence-based estimates of survival rates and surrounding ethical issues. Respondents included neonatologists, obstetricians, pediatricians, maternal-fetal medicine specialists, trainees in pediatrics, obstetrics, neonatal-perinatal medicine and neonatal and obstetrical nurses.
Results In total, 166 participants attended an educational presentation and 130 participants completed both pre- and postsurveys (response rate 78%). Prepresentation, for all gestations, ≤ 50% of respondents correctly identified survival/intact survival rates. Postpresentation, correct responses regarding survival/intact survival rates ranged from 49 to 86% (p < 0.001) and attitudes shifted toward being more likely to resuscitate at all gestations regardless of parental wishes. There was a weak-to-modest relationship (Spearman's coefficient 0.24–0.40, p < 0.001–0.004) between knowledge responses and attitudes.
Conclusion Attendance at an educational presentation did improve HCP knowledge about survival and long term outcomes for EPI, but HCP still underestimated survival and were not always willing to resuscitate in accordance with parental wishes. These findings may represent barriers to some experts' recommendation to use shared decision-making with parents when considering the resuscitation options for their EPI.
Association of Nursing Overtime, Nurse Staffing, and Unit Occupancy with Health Care–Associated Infections in the NICU
Authors: Blais Régis , Lacroix Guy , Cabot Michèle , Piedboeuf Bruno , Beltempo Marc 
Published: April 2017

Objective This study aims to assess the association of nursing overtime, nurse staffing, and unit occupancy with health care–associated infections (HCAIs) in the neonatal intensive care unit (NICU).
Study Design A 2-year retrospective cohort study was conducted for 2,236 infants admitted in a Canadian tertiary care, 51-bed NICU. Daily administrative data were obtained from the database “Logibec” and combined to the patient outcomes database. Median values for the nursing overtime hours/total hours worked ratio, the available to recommended nurse staffing ratio, and the unit occupancy rate over 3-day periods before HCAI were compared with days that did not precede infections. Adjusted odds ratios (aOR) that control for the latter factors and unit risk factors were also computed.
Results A total of 122 (5%) infants developed a HCAI. The odds of having HCAI were higher on days that were preceded by a high nursing overtime ratio (aOR, 1.70; 95% confidence interval [95% CI], 1.05–2.75, quartile [Q]4 vs. Q1). High unit occupancy rates were not associated with increased odds of infection (aOR, 0.85; 95% CI, 0.47–1.51, Q4 vs. Q1) nor were higher available/recommended nurse ratios (aOR, 1.16; 95% CI, 0.67–1.99, Q4 vs. Q1).
Conclusion Nursing overtime is associated with higher odds of HCAI in the NICU.
Retinaler Venenverschluss – wann, womit und wie therapieren?
Authors: Bajor A. , Pielen A. , Danzmann L. 
Published: April 2017

ZusammenfassungNach neuesten Erkenntnissen ist ein Makulaödem infolge eines retinalen Venenverschlusses am besten mit einer zeitnahen intravitrealen Anti-VEGF-Therapie (Aflibercept, Bevacizumab [off label], Ranibizumab) sicher und effektiv behandelbar. Nach einem anfänglichen Upload von monatlich 3 Injektionen Anti-VEGF sollte in regelmäßigen Kontrollen vor allem OCT-basiert (bevorzugt gegenüber visusbasiert) über eine erneute Injektion entschieden werden. Nach anfänglichen monatlichen Injektionen haben sich derzeit vor allem das „Pro-re-nata“- (PRN) und das „Treat-and-Extend“-Schema in Bezug auf den weiteren Therapieverlauf durchgesetzt. Unter Beachtung des Nebenwirkungsspektrums (insbesondere Kataraktprogression, Augeninnendruckerhöhung) kann auch eine intravitreale Therapie mit einem Dexamethason-Implantat sinnvoll sein. Die Prognose bez. Visus und Rückgang des Makulaödems hängt von einem frühen Behandlungsbeginn mit konsequenter Therapiefortführung ab. Vor Behandlungsbeginn sowie im Verlauf ist eine Fluoresceinangiografie nötig, um ischämische Netzhautareale zu detektieren. Es gibt Hinweise, dass eine frühe gezielte Laserkoagulation ischämischer Netzhautareale die Frequenz der nötigen Injektionen senkt und zu einem besseren Ansprechen des Ödems auf die Therapie führt. Bei signifikanter retinaler Ischämie, die in der Folge zu Proliferationen, Rubeosis iridis und einem Sekundärglaukom führen kann, ist eine Laserbehandlung unumgänglich.
Genetic signatures of high-altitude adaptation in Tibetans
Authors: Yang Jian , Jin Zi-Bing , Chen Jie , Huang Xiu-Feng , Li Xiao-Man , Liang Yuan-Bo , Mao Jian-Yang , Chen Xin , Zheng Zhili , Bakshi Andrew , Zheng Dong-Dong , Zheng Mei-Qin , Wray Naomi R. , Visscher Peter M. , Lu Fan , Qu Jia 
Published: April 2017

SignificanceThe origin of Tibetans and the mechanism of how they adapted to the high-altitude environment remain mostly unknown. We conduct the largest genome-wide study in Tibetans to date. We detect signatures of natural selection at nine gene loci, two of which are strongly associated with blood phenotypes in present day Tibetans. We further show the genetic relatedness of Tibetans with other ethnic groups in China and estimate the divergence time between Tibetans and Han. These findings provide important knowledge to understand the genetic ancestry of Tibetans and the genetic basis of high-altitude adaptation.
Structure–metabolism relationships in
human-
AOX: Chemical insights from a large database of aza-aromatic and amide compounds
Authors: Lepri Susan , Ceccarelli Martina , Milani Nicolò , Tortorella Sara , Cucco Andrea , Valeri Aurora , Goracci Laura , Brink Andreas , Cruciani Gabriele 
Published: April 2017

Significance
The metabolism of xenobiotics is a critical aspect of drug discovery; nowadays, aldehyde oxidase (AOX) has emerged as a key metabolic enzyme having a pivotal role in the failures of several clinical candidates. The lack of homogenous data on possible substrates and not substrates of this enzyme represents a serious limit for the development of an in silico model for metabolism prediction. Here, we present a database of 270 chemically diverse compounds containing aza-aromatic and/or amide moieties (susceptible to human AOX), experimentally tested in vitro. The results herein reported should be useful in the development of a reliable prediction model, which should be of wide interest in chemistry, biology, biotechnology, and medicine.
Resistance to action potential depression of a rat axon terminal in vivo
Authors: Sierksma Martijn C. , Borst J. Gerard G. 
Published: April 2017

Significance
During high-frequency firing, the shape of a presynaptic action potential (AP) can alter, thereby changing neurotransmitter release. In this paper, we describe how a giant terminal in the brainstem of newborn rats called the calyx of Held can fire in vivo at high frequencies without substantial AP depression. The underlying mechanism was found to be the presence of sodium channels that can recover rapidly from depression in combination with a close match between the potential that is attained following an AP with the potential that maximizes AP stability. Surprisingly, this match was already there shortly after formation of the calyx of Held. We speculate that these mechanisms help synapses to maximize timing precision during high-frequency firing.
Conformational equilibria of light-activated rhodopsin in nanodiscs
Authors: Van Eps Ned , Caro Lydia N. , Morizumi Takefumi , Kusnetzow Ana Karin , Szczepek Michal , Hofmann Klaus Peter , Bayburt Timothy H. , Sligar Stephen G. , Ernst Oliver P. , Hubbell Wayne L. 
Published: April 2017

SignificanceThe existence of multiple conformational substates of G-protein–coupled receptors in equilibrium may provide for the interaction with multiple partners at the same interface. Here we provide evidence that photoactivated rhodopsin exists in a manifold of conformational substates in a lipid environment, but not in the extensively studied dodecyl maltoside detergent micelles. Moreover, the photoactivated state decays spontaneously to the inactive state on a timescale of minutes. Remarkably, binding of the activated receptor to the cognate G protein strongly biases the receptor to an interacting state that retains more than one conformation, suggesting flexibility in the complex.
NEIL1 protects against aflatoxin-induced hepatocellular carcinoma in mice
Authors: Vartanian Vladimir , Minko Irina G. , Chawanthayatham Supawadee , Egner Patricia A. , Lin Ying-Chih , Earley Lauriel F. , Makar Rosemary , Eng Jennifer R. , Camp Matthew T. , Li Liang , Stone Michael P. , Lasarev Michael R. , Groopman John D. , Croy Robert G. , Essigmann John M. , McCullough Amanda K. , Lloyd R. Stephen 
Published: April 2017

Significance
Human dietary exposures to aflatoxin in some of the most populated and underdeveloped portions of the world are a major contributing factor to the formation of human hepatocellular carcinomas (HCCs) that account for over 700,000 deaths annually. Although the genomic signatures for aflatoxin-driven carcinogenesis are G:C to T:A point mutations arising from bypass of aflatoxin-induced DNA adducts, maintenance of genome stability has been generally attributed to nucleotide excision repair. However, we present three lines of evidence that the DNA base excision repair pathway initiated by the DNA glycosylase NEIL1 is the major contributor in maintaining genomic stability following aflatoxin exposures. These findings suggest that inactivating NEIL1 polymorphic variants in the human population could affect susceptibility to aflatoxin-induced HCC.
CMG–Pol epsilon dynamics suggests a mechanism for the establishment of leading-strand synthesis in the eukaryotic replisome
Authors: Zhou Jin Chuan , Janska Agnieszka , Goswami Panchali , Renault Ludovic , Abid Ali Ferdos , Kotecha Abhay , Diffley John F. X. , Costa Alessandro 
Published: April 2017

Significance
Faithful and efficient genome duplication is essential for the propagation of life. Aberrant DNA replication can lead to genomic instability and cancer. In eukaryotes, the replication machinery is composed of the DNA-unwinding enzyme Cdc45–MCM–GINS (CMG) and dedicated DNA synthesis factors. Three different polymerases act sequentially on the leading-strand template to establish DNA replication. We describe the architecture and dynamics of the main leading-strand polymerase bound to the CMG helicase, and we propose a mechanism for the establishment of efficient leading-strand synthesis. Our findings provide important insights into how the eukaryotic replication machinery functions to ensure that genome integrity is maintained during replication.
Decoupling of surface diffusion and relaxation dynamics of molecular glasses
Authors: Zhang Yue , Fakhraai Zahra 
Published: April 2017

Significance
Diffusion on the surfaces of molecular glasses is observed to be greatly enhanced compared with the bulk diffusion with lower activation energies. However, the physical nature of the fast surface diffusion and its relation to the glassy dynamics remain unclear. Relaxation dynamics of these glasses can be enhanced by up to 14 orders of magnitude by reducing their film thickness below 50 nm. By investigating the relationship between surface diffusion and relaxation times of ultrathin films, we find that the fast surface diffusion remains invariant of the films’ relaxation dynamics even when the activation energy of the film becomes lower than the activation energy for the surface diffusion, indicating a complete decoupling of the relaxation dynamics and surface diffusion.
Phosphatidylinositol 3-phosphate–binding protein AtPH1 controls the localization of the metal transporter NRAMP1 inArabidopsis
Authors: Agorio Astrid , Giraudat Jérôme , Bianchi Michele Wolfe , Marion Jessica , Espagne Christelle , Castaings Loren , Lelièvre Françoise , Curie Catherine , Thomine Sébastien , Merlot Sylvain 
Published: April 2017

SignificanceMetal homeostasis is essential for living organisms. Metal transporters play key roles in metal uptake and compartmentalization. The tight regulation of metal homeostasis thus depends on accurate targeting of these metal transporters. Although the main metal transporters in plants have been identified, the mechanisms involved in their trafficking are still poorly understood. This study reveals that AtPH1, a pleckstrin homology (PH) domain containing protein binding to phosphatidylinositol 3-phosphate (PI3P), controls the subcellular localization of the iron and manganese transporter AtNRAMP1. Our results further indicate that, in addition to proteins containing the FYVE and PHOX domains, proteins containing the PH domain can decode the PI3P signal in endosomal function.