bluuebunny/crossref_metadata_2025 huggingface dataset:
Raman, dielectric and variable range hopping nature of Gd2O3-doped K0.5N0.5NbO3 piezoelectric ceramics
Authors: Peddigari Mahesh , Dobbidi Pamu
Published: October 2015

(K0.5Na0.5)NbO3 (KNN) + x wt% Gd2O3 (x = 0 -1.5) ceramics have been prepared by conventional solid state reaction method. The effect of Gd2O3 on the structural, microstructural and dielectric properties of KNN ceramics were studied systematically. The effect of Gd2O3 on phase transformation from orthorhombic to psuedocubic structure is explained interms of changes in the internal vibration modes of NbO6 octahedra. The Raman intensity of the stretching mode v1 enhanced and shifted toward higher wavenumber with Gd2O3 concentration, which is attributed to the increase in polarizability and change in the O-Nb-O bond angles. Microstructural analysis revealed that the grain size of the KNN ceramics decreases from 2.26 ± 1.07 μm to 0.35 ± 0.13 μm and becomes homogenous with an increase in Gd2O3 concentration. The frequency dependent dielectric spectra are analyzed by using Havriliak-Negami function. The fitted symmetry parameter and relaxation time (τ) are found to be 0.914 and 8.78 × 10−10 ± 5.5 × 10−11 s, respectively for the sample doped with x = 1.0. The addition of Gd2O3 to the KNN shifted the polymorphic phase transition orthorhombic to tetragonal transition temperature (TO-T) from 199oC to 85oC with enhanced dielectric permittivity (ε′ = 1139 at 1 MHz). The sample with x = 1.0, shown a high dielectric permittivity (ε′ = 879) and low dielectric loss (<5%) in the broad temperature range (-140oC – 150oC) with the Curie temperature 307 oC can have the potential for high temperature piezoelectric and tunable RF circuit applications. The temperature dependent AC-conductivity follows the variable range hopping conduction mechanism by obtaining the slope -0.25 from the ln[ln(ρac)] versus ln(T) graph in the temperature range of 133 K-308 K. The effect of Gd2O3 on the Mott’s parameters such as density of states (N(EF)), hopping length (RH), and hopping energy (WH) have been discussed.
Radio-collared squirrel glider (Petaurus norfolcensis) struck by vehicle and transported 500 km along freeway
Authors: Soanes Kylie , Lobo Melissa Carmody , van der Ree Rodney
Published: October 2015

Roadkill (the mortality of animals through wildlife–vehicle collisions) is one of the main impacts of roads on wildlife. Studies quantifying the location and rate of roadkill to identify ‘hot spots’ are often used to guide the location of mitigation efforts, such as fencing or wildlife crossing structures. However, sometimes quantifying rates of roadkill can be challenging, particularly for species that are small and difficult to detect. In our study, a squirrel glider that was trapped and radio-collared in north-east Victoria was found as roadkill more than 500 km away, suggesting that a vehicle struck the animal and carried the carcass away from the site of impact. Our observation is the first evidence that this occurs for squirrel gliders.
Experimental effects of ash deposition on macroinvertebrate assemblages in peatland streams
Authors: Johnston K. , Robson B. J.
Published: October 2015

Rotational burn management has been practiced for >150 years in UK peatlands; however, little information exists on its effects on streams. An experiment investigated effects of ash input on four UK headwater streams by depositing ash onto trays filled with natural stream substrata. Before the experiment, streambed samples (SS) were taken to describe ambient macroinvertebrate assemblages. Macroinvertebrate response after 21 days was compared among SS, low (50g), high (100g) and top-up (50g + 50g dosed twice) ash-addition treatments and control trays (0g ash addition). Additions increased tray ash-free dry mass (AFDM), and by the end of the experiment, some trays retained more ash than did others (F12,72=5.15, P<0.001). Macroinvertebrate assemblages differed among streams (r=0.84, P<0.001) and treatments (r=0.23, P<0.001). SS contained fewer shredders than did other treatments (range: r=0.35–0.52, P=0.005). A significant relationship was found between assemblages and environmental conditions (Spearmans rho: 0.203, P=0.001). Stream depth and AFDM showed strongest correlations with assemblages. Ash deposition affects macroinvertebrate assemblages when deposited onto streambeds. However, the high among-stream variation in assemblage composition typical of UK headwaters is a stronger source of variation, suggesting that the effect of deposition is reasonably small in these streams.
Transcriptomic characterization of fibrolamellar hepatocellular carcinoma
Authors: Simon Elana P. , Freije Catherine A. , Farber Benjamin A. , Lalazar Gadi , Darcy David G. , Honeyman Joshua N. , Chiaroni-Clarke Rachel , Dill Brian D. , Molina Henrik , Bhanot Umesh K. , La Quaglia Michael P. , Rosenberg Brad R. , Simon Sanford M.
Published: October 2015

Significance

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare pediatric liver cancer. A deletion of ∼400 kb in one copy of chromosome 19 results in a chimeric protein, an activated protein kinase A. No other deletions, amplifications, mutations, or structural variants were found. This strongly implicates the chimera as the driving mutation. This paper examines gene expression in FLHCC. The results establish FLHCC as a single disease distinct from other cancers, including hepatocellular carcinoma. The results help explain some of the known pathophysiology: the collagen fibers that give fibrolamellar its name and the gynecomastia reported in young male patients. Finally, this work identifies oncogenes whose expression is increased and that may serve as targets for therapeutic intervention.
Mitochondrial retrograde signaling regulates neuronal function
Authors: Cagin Umut , Duncan Olivia F. , Gatt Ariana P. , Dionne Marc S. , Sweeney Sean T. , Bateman Joseph M.
Published: October 2015

Significance

Mitochondrial retrograde signaling is an ancient mechanism defined as the cellular response to changes in the functional state of mitochondria. We find that in the
Drosophila
nervous system, mitochondrial dysfunction activates a retrograde response controlling hundreds of nuclear genes. We identify the
Drosophila
ortholog of hypoxia inducible factor alpha (HIFα) as a potential regulator of the neuronal mitochondrial retrograde response. Remarkably, knockdown of HIFα restores neuronal function without affecting the primary mitochondrial defect. Mitochondrial retrograde signaling is therefore partly responsible for neuronal pathology. Knockdown of HIFα also restores function in
Drosophila
models of Leigh syndrome and Parkinson’s disease. Our results demonstrate that mitochondrial retrograde signaling has a key role in neuronal homeostasis and that manipulation of retrograde signaling may have therapeutic potential in mitochondrial diseases and Parkinson’s.
An intrinsic mechanism of secreted protein aging and turnover
Authors: Yang Won Ho , Aziz Peter V. , Heithoff Douglas M. , Mahan Michael J. , Smith Jeffrey W. , Marth Jamey D.
Published: October 2015

Significance

In the blood, secreted proteins have different life spans that determine their abundance and function. Measurements of plasma protein composition and biological activities remain important for many clinical diagnoses. However the molecular mechanisms by which secreted proteins age and turnover have remained unidentified. The findings of this research have established an intrinsic and constitutive mechanism of secreted protein aging and turnover. This mechanism involves multiple factors including circulating glycosidases that progressively remodel the N-glycan linkages attached to most secreted proteins. N-glycan remodeling with time exposes glycan ligands of various endocytic lectin receptors that then eliminate these aged secreted proteins. This mechanism thereby determines the life spans and abundance of secreted proteins, and modulates the pathogenesis and outcomes of disease.
Xist
imprinting is promoted by the hemizygous (unpaired) state in the male germ line
Authors: Sun Sha , Payer Bernhard , Namekawa Satoshi , An Jee Young , Press William , Catalan-Dibene Jovani , Sunwoo Hongjae , Lee Jeannie T.
Published: October 2015

Significance

Mammals with imprinted X inactivation demonstrate exclusive silencing of the paternal X chromosome. X-inactivation–specific transcript (Xist) RNA directs this silencing and is imprinted to be expressed only from the father’s X chromosome. Here we investigate how
Xist
is imprinted. Using a transgenesis system, we find that
Xist
imprinting depends on its unpaired state in the father’s germ line. When
Xist
is present in two copies (one each on homologous chromosomes) and therefore is paired during meiosis, the gene does not demonstrate paternal-specific expression in the female embryo. However, when
Xist
is present in only one copy and therefore lacks a pairing partner during meiosis, the gene shows strong imprinted expression. Thus, the unpaired state plays a critical role in epigenetic transmission between generations.
Effects of Water Temperature and Fish Size on Predation Vulnerability of Juvenile Humpback Chub to Rainbow Trout and Brown Trout
Authors: Ward David L. , Morton‐Starner Rylan
Published: October 2015

Predation on juvenile native fish by introduced Rainbow Trout and Brown Trout is considered a significant threat to the persistence of endangered Humpback Chub Gila cypha in the Colorado River in the Grand Canyon. Diet studies of Rainbow Trout and Brown Trout in Glen and Grand canyons indicate that these species do eat native fish, but impacts are difficult to assess because predation vulnerability is highly variable, depending on prey size, predator size, and the water temperatures under which the predation interactions take place. We conducted laboratory experiments to evaluate how short‐term predation vulnerability of juvenile native fish changes in response to fish size and water temperature using captivity‐reared Humpback Chub, Bonytail, and Roundtail Chub. Juvenile chub 45–90 mm total length (TL) were exposed to adult Rainbow and Brown trouts at 10, 15, and 20°C to measure predation vulnerability as a function of water temperature and fish size. A 1°C increase in water temperature decreased short‐term predation vulnerability of Humpback Chub to Rainbow Trout by about 5%, although the relationship is not linear. Brown Trout were highly piscivorous in the laboratory at any size > 220 mm TL and at all water temperatures we tested. Understanding the effects of predation by trout on endangered Humpback Chub is critical in evaluating management options aimed at preserving native fishes in Grand Canyon National Park.
Influence of Hydrographic Conditions on the Distribution of Spiny Lobster Larvae off the West Coast of Baja California
Authors: Funes‐Rodríguez René , Ruíz‐Chavarría José A. , González‐Armas Rogelio , Durazo Reginaldo , Guzmán‐del Proó Sergio A.
Published: October 2015

The distribution of phyllosoma of California spiny lobster Panulirus interruptus was investigated in relation to the seasonal variability of hydrographic conditions off the west coast of the Baja California Peninsula between 2006 and 2008. Early larval stages were recorded mostly from summer to fall, immediately following the reproductive period. The duration of larval development in plankton is variable (8–12 months), and hence, larvae are found at different times of the year; thus, intermediate and late stages did not show a well‐defined seasonal pattern. The highest phyllosoma density was associated with the relatively warm transitional water mass. However, the peak frequency of occurrence was observed in the colder subarctic water mass. A canonical correspondence analysis identified two distinct seasonal periods: (1) a warm period (summer–autumn), when the abundance of early and intermediate stages was highly correlated with a higher sea surface temperature, and (2) a cold period (winter–spring), when the most advanced stages were associated with a lower water temperature and higher dissolved oxygen. The distribution of larvae and the geostrophic flow patterns suggest that transport by the California Current and mesoscale eddies are the primary dispersal and retention mechanisms from the various breeding centers along the peninsula: northern (Ensenada–Punta Baja), central (Punta Eugenia), and southern (Golfo de Ulloa). In contrast, the data obtained suggest that the recruitment of late larval stages and pueruli in settlement areas might be regulated by the formation of meanders and poleward currents, in addition to the ability of pueruli (self‐recruitment) to reach settlement areas via swimming.
Mapping creativity in the Hungarian National Core Curriculum: a content analysis of the overall statements of intent, curricular areas and education levels
Authors: Bereczki Enikő Orsolya
Published: October 2015

In the past 20 years, creativity has increasingly been recognised as an important aspect of young people's education around the world. The global interest in creativity is fuelled by various economic and social considerations. One concern of the approach to creativity in education is the curriculum. The research reported in this paper aimed at identifying the curriculum‐level enablers and barriers to nurturing creativity in Hungarian public education by investigating the place of creativity, as well as that of creative pedagogy, in the Hungarian National Core Curriculum (HNCC) using content analysis. Findings revealed that creativity and the components of creative pedagogy were recurring elements of the HNCC. In Arts and Mathematics, the high importance of creativity was also supported by the strong presence of the elements of creative pedagogy. The barriers identified include the lack of clear and consistent definitions of creativity, the varied incidences of creativity and components of creative pedagogy, with extremely low attention to nurturing creativity in Foreign languages, Man and nature (science), and The Earth – our environment (geography). It has been concluded, therefore, that a more coherent and consistent approach to creativity across the HNCC is required.
We are More Selfish than We Think: The Endowment Effect and Reward Processing within the Human Medial-Frontal Cortex
Authors: Hassall Cameron D. , Silver Amy , Turk David J. , Krigolson Olave E.
Published: October 2015

Perceived ownership has been shown to impact a variety of cognitive processes: attention, memory, and—more recently—reward processing. In the present experiment we examined whether or not perceived ownership would interact with the construct of value—the relative worth of an object. Participants completed a simple gambling game in which they gambled either for themselves or for another while electroencephalographic data were recorded. In a key manipulation, gambles for oneself or for another were for either small or large rewards. We tested the hypothesis that value affects the neural response to self-gamble outcomes, but not other-gamble outcomes. Our experimental data revealed that while participants learned the correct response option for both self and other gambles, the reward positivity evoked by wins was impacted by value only when gambling for oneself. Importantly, our findings provide additional evidence for a self-ownership bias in cognitive processing and further demonstrate the insensitivity of the medial-frontal reward system to gambles for another.
Caenorhabditis eleganspolo-like kinase PLK-1 is required for merging parental genomes into a single nucleus
Authors: Rahman Mohammad M. , Munzig Mandy , Kaneshiro Kiyomi , Lee Brandon , Strome Susan , Müller-Reichert Thomas , Cohen-Fix Orna
Published: October 2015

Before the first zygotic division, the nuclear envelopes of the maternal and paternal pronuclei disassemble, allowing both sets of chromosomes to be incorporated into a single nucleus in daughter cells after mitosis. We found that in Caenorhabditis elegans, partial inactivation of the polo-like kinase PLK-1 causes the formation of two nuclei, containing either the maternal or paternal chromosomes, in each daughter cell. These two nuclei gave rise to paired nuclei in all subsequent cell divisions. The paired-nuclei phenotype was caused by a defect in forming a gap in the nuclear envelopes at the interface between the two pronuclei during the first mitotic division. This was accompanied by defects in chromosome congression and alignment of the maternal and paternal metaphase plates relative to each other. Perturbing chromosome congression by other means also resulted in failure to disassemble the nuclear envelope between the two pronuclei. Our data further show that PLK-1 is needed for nuclear envelope breakdown during early embryogenesis. We propose that during the first zygotic division, PLK-1–dependent chromosome congression and metaphase plate alignment are necessary for the disassembly of the nuclear envelope between the two pronuclei, ultimately allowing intermingling of the maternal and paternal chromosomes.
PLCβ3 mediates cortactin interaction with WAVE2 in MCP1-induced actin polymerization and cell migration
Authors: Janjanam Jagadeesh , Chandaka Giri Kumar , Kotla Sivareddy , Rao Gadiparthi N.
Published: October 2015

Monocyte chemotactic protein 1 (MCP1) stimulates vascular smooth muscle cell (VSMC) migration in vascular wall remodeling. However, the mechanisms underlying MCP1-induced VSMC migration have not been understood. Here we identify the signaling pathway associated with MCP1-induced human aortic smooth muscle cell (HASMC) migration. MCP1, a G protein–coupled receptor agonist, activates phosphorylation of cortactin on S405 and S418 residues in a time-dependent manner, and inhibition of its phosphorylation attenuates MCP1-induced HASMC G-actin polymerization, F-actin stress fiber formation, and migration. Cortactin phosphorylation on S405/S418 is found to be critical for its interaction with WAVE2, a member of the WASP family of cytoskeletal regulatory proteins required for cell migration. In addition, the MCP1-induced cortactin phosphorylation is dependent on PLCβ3-mediated PKCδ activation, and siRNA-mediated down-regulation of either of these molecules prevents cortactin interaction with WAVE2, affecting G-actin polymerization, F-actin stress fiber formation, and HASMC migration. Upstream, MCP1 activates CCR2 and Gαq/11 in a time-dependent manner, and down-regulation of their levels attenuates MCP1-induced PLCβ3 and PKCδ activation, cortactin phosphorylation, cortactin–WAVE2 interaction, G-actin polymerization, F-actin stress fiber formation, and HASMC migration. Together these findings demonstrate that phosphorylation of cortactin on S405 and S418 residues is required for its interaction with WAVE2 in MCP1-induced cytoskeleton remodeling, facilitating HASMC migration.
CARTS biogenesis requires VAP–lipid transfer protein complexes functioning at the endoplasmic reticulum–Golgi interface
Authors: Wakana Yuichi , Kotake Richika , Oyama Nanako , Murate Motohide , Kobayashi Toshihide , Arasaki Kohei , Inoue Hiroki , Tagaya Mitsuo
Published: October 2015

Vesicle-associated membrane protein–associated protein (VAP) is an endoplasmic reticulum (ER)-resident integral membrane protein that controls a nonvesicular mode of ceramide and cholesterol transfer from the ER to the Golgi complex by interacting with ceramide transfer protein and oxysterol-binding protein (OSBP), respectively. We report that VAP and its interacting proteins are required for the processing and secretion of pancreatic adenocarcinoma up-regulated factor, whose transport from the trans-Golgi network (TGN) to the cell surface is mediated by transport carriers called “carriers of the trans-Golgi network to the cell surface” (CARTS). In VAP-depleted cells, diacylglycerol level at the TGN was decreased and CARTS formation was impaired. We found that VAP forms a complex with not only OSBP but also Sac1 phosphoinositide phosphatase at specialized ER subdomains that are closely apposed to the trans-Golgi/TGN, most likely reflecting membrane contact sites. Immobilization of ER–Golgi contacts dramatically reduced CARTS production, indicating that association–dissociation dynamics of the two membranes are important. On the basis of these findings, we propose that the ER–Golgi contacts play a pivotal role in lipid metabolism to control the biogenesis of transport carriers from the TGN.
Hope and the Task of the Self
Authors: Bernier Mark
Published: October 2015

This chapter analyzes the notion of the task, and how this relates to the concept of hope. In the Kierkegaardian sense, a task always pertains to the self, as an attempt to have a meaningful life. Such a task has the following structure: one has a task when one has made one’s highest good one’s highest hope. One has made a total commitment. And just as there are two forms of hope, there are two forms of the task: (1) the central task of the self, which is constituted by a mundane hope for a mundane good; and (2) the authentic task, which is constituted by religious hope for a spiritual good. Communicating these results is one of the primary achievements of the study, since it sheds light on the role and importance of hope for the self—hope is essential to the self, since it constitutes the task.
Hope and the Knight of Faith
Authors: Bernier Mark
Published: October 2015

In this chapter, the second movement of faith is described, and its relation to hope analyzed. The primary example for the knight of faith is Abraham, who accepts the impossibility of keeping Isaac while simultaneously trusting God that Isaac will not be lost. Abraham’s movement is ‘absurd,’ in the sense that he grounds his belief in Isaac’s return on his trust in God, not his own judgment. He entrusts to God his highest good, and relinquishes control. He can only do this if there is a ‘teleological suspension of the ethical,’ which is to suspend his highest mundane good, and with it, his central task, for the sake of the higher spiritual good and the authentic task. Faith thus provides the ground for hope; for the possibility of the good. In trusting God, one is willing to hope, which stands in opposition to despair’s unwillingness to hope.
Transonic Flows
Authors: Ruban Anatoly I.
Published: October 2015

This chapter considers the far field in the two-dimensional flow past an arbitrary body, assuming that M∞ = 1 .The corresponding solution of the Euler equations can be found in a self-similar form. In this solution, the flow, that is subsonic in front of the body, experiences acceleration to become supersonic before it reaches a shock wave which makes it subsonic again downstream of the body. It is then assumed that the body is an aerofoil of a small thickness, and the chapter shows that in this case the Euler equations can be reduced to the Karman–Guderley equation. Though this equation is nonlinear and difficult to solve, it turns into the Tricomi equation if considered in the hodograph plane. The chapter presents two exact solutions of the Tricomi equation: the first describes the transonic flow separation at a corner of a rigid body contour, the second the flow accelerating into the Prandtl–Meyer expansion fan.
Hypersonic Flows
Authors: Ruban Anatoly I.
Published: October 2015

The chapter starts its analysis with blunt-nosed bodies. In a supersonic flow, a blunt-nosed body produces a bow shock wave. The chapter shows that the shape of the shock and the entire flow between the shock and the body become independent of the Mach number, M∞, provided it is large enough. This result is known as the hypersonic stabilization principle. The chapter then presents the Newton–Busemann theory that exploits the fact that hypersonic flow undergoes significant compression in the bow shock. The chapter then turns to flows past thin bodies. These are characterized by the hypersonic interaction parameter, χ = M∞δ. If χ is small, then the Ackeret theory appears applicable. If χ is an order one quantity or large, then the flow can be studied using the so-called unsteady flow analogy. In particular, the effect of a rounded nose on the hypersonic flow past a thin body may be described using analogy with the blast wave.
An algorithm to detect and communicate the differences in computational models describing biological systems
Authors: Scharm Martin , Wolkenhauer Olaf , Waltemath Dagmar
Published: October 2015

Motivation: Repositories support the reuse of models and ensure transparency about results in publications linked to those models. With thousands of models available in repositories, such as the BioModels database or the Physiome Model Repository, a framework to track the differences between models and their versions is essential to compare and combine models. Difference detection not only allows users to study the history of models but also helps in the detection of errors and inconsistencies. Existing repositories lack algorithms to track a model’s development over time.

Results: Focusing on SBML and CellML, we present an algorithm to accurately detect and describe differences between coexisting versions of a model with respect to (i) the models’ encoding, (ii) the structure of biological networks and (iii) mathematical expressions. This algorithm is implemented in a comprehensive and open source library called BiVeS. BiVeS helps to identify and characterize changes in computational models and thereby contributes to the documentation of a model’s history. Our work facilitates the reuse and extension of existing models and supports collaborative modelling. Finally, it contributes to better reproducibility of modelling results and to the challenge of model provenance.

Availability and implementation: The workflow described in this article is implemented in BiVeS. BiVeS is freely available as source code and binary from sems.uni-rostock.de. The web interface BudHat demonstrates the capabilities of BiVeS at budhat.sems.uni-rostock.de.

Contact:  martin.scharm@uni-rostock.de

Supplementary information:  Supplementary data are available at Bioinformatics online.
Xtalk: a path-based approach for identifying crosstalk between signaling pathways
Authors: Tegge Allison N. , Sharp Nicholas , Murali T. M.
Published: October 2015

Motivation: Cells communicate with their environment via signal transduction pathways. On occasion, the activation of one pathway can produce an effect downstream of another pathway, a phenomenon known as crosstalk. Existing computational methods to discover such pathway pairs rely on simple overlap statistics.

Results: We present Xtalk, a path-based approach for identifying pairs of pathways that may crosstalk. Xtalk computes the statistical significance of the average length of multiple short paths that connect receptors in one pathway to the transcription factors in another. By design, Xtalk reports the precise interactions and mechanisms that support the identified crosstalk. We applied Xtalk to signaling pathways in the KEGG and NCI-PID databases. We manually curated a gold standard set of 132 crosstalking pathway pairs and a set of 140 pairs that did not crosstalk, for which Xtalk achieved an area under the receiver operator characteristic curve of 0.65, a 12% improvement over the closest competing approach. The area under the receiver operator characteristic curve varied with the pathway, suggesting that crosstalk should be evaluated on a pathway-by-pathway level. We also analyzed an extended set of 658 pathway pairs in KEGG and to a set of more than 7000 pathway pairs in NCI-PID. For the top-ranking pairs, we found substantial support in the literature (81% for KEGG and 78% for NCI-PID). We provide examples of networks computed by Xtalk that accurately recovered known mechanisms of crosstalk.

Availability and implementation: The XTALK software is available at http://bioinformatics.cs.vt.edu/~murali/software. Crosstalk networks are available at http://graphspace.org/graphs?tags=2015-bioinformatics-xtalk.

Contact:  ategge@vt.edu, murali@cs.vt.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Enhanced habit formation in Gilles de la Tourette syndrome
Authors: Delorme Cécile , Salvador Alexandre , Valabrègue Romain , Roze Emmanuel , Palminteri Stefano , Vidailhet Marie , de Wit Sanne , Robbins Trevor , Hartmann Andreas , Worbe Yulia
Published: October 2015

Tics are sometimes described as voluntary movements performed in an automatic or habitual way. Here, we addressed the question of balance between goal-directed and habitual behavioural control in Gilles de la Tourette syndrome and formally tested the hypothesis of enhanced habit formation in these patients. To this aim, we administered a three-stage instrumental learning paradigm to 17 unmedicated and 17 antipsychotic-medicated patients with Gilles de la Tourette syndrome and matched controls. In the first stage of the task, participants learned stimulus-response-outcome associations. The subsequent outcome devaluation and ‘slip-of-action’ tests allowed evaluation of the participants’ capacity to flexibly adjust their behaviour to changes in action outcome value. In this task, unmedicated patients relied predominantly on habitual, outcome-insensitive behavioural control. Moreover, in these patients, the engagement in habitual responses correlated with more severe tics. Medicated patients performed at an intermediate level between unmedicated patients and controls. Using diffusion tensor imaging on a subset of patients, we also addressed whether the engagement in habitual responding was related to structural connectivity within cortico-striatal networks. We showed that engagement in habitual behaviour in patients with Gilles de la Tourette syndrome correlated with greater structural connectivity within the right motor cortico-striatal network. In unmedicated patients, stronger structural connectivity of the supplementary motor cortex with the sensorimotor putamen predicted more severe tics. Overall, our results indicate enhanced habit formation in unmedicated patients with Gilles de la Tourette syndrome. Aberrant reinforcement signals to the sensorimotor striatum may be fundamental for the formation of stimulus-response associations and may contribute to the habitual behaviour and tics of this syndrome.
High pCO2 affects body size, but not gene expression in larvae of the California mussel (Mytilus californianus)
Authors: Kelly Morgan W. , Padilla-Gamiño Jacqueline L. , Hofmann Gretchen E.
Published: October 2015

Many studies have reported reductions in body size and calcification rates for marine larvae exposed to ocean acidification conditions. However, the physiological mechanisms driving these effects, and mechanisms underlying body size variation in general, are poorly understood. Here, we combine transcriptome sequencing with bulked segregant analysis to assess the physiological response to acidification in larvae of the California mussel, Mytilus californianus, and to explore physiological basis of variation in larval size. We reared three families of M. californianus larvae under ambient (∼350 µatm, pHtotal 8.1) and high (∼1300 µatm, pHtotal 7.6) pCO2 conditions, then passed larvae through a mesh filter, separating each family × pCO2 treatment into fractions of larvae with large vs. small body sizes. We sequenced larval mRNA for each family × treatment × body size combination, and assembled a de novo transcriptome. We then mapped reads from each library to this assembly to identify effects of high pCO2 on gene expression, and to identify transcriptomic differences between small vs. large larvae of the same age class. Although larvae reared under elevated pCO2 were smaller, we observed no consistent effect of elevated pCO2 on gene expression. Nevertheless, 1225 transcripts, primarily related to metabolism, were differentially expressed between large vs. small larvae, regardless of CO2 treatment. We conclude that the observed reduction in larval body size under high CO2 may be driven by a direct effect of the environment on phenotype, unmediated by changes in gene expression. Because M. calfornianus has evolved in the context of seasonal upwelling, exposure to 1300 µatm, pCO2 may not produce the large stress-mediated effects on gene expression that might be expected for an organism exposed to conditions far outside those of its typical environment.
Guanosine and its modified derivatives are endogenous ligands for TLR7
Authors: Shibata Takuma , Ohto Umeharu , Nomura Shosaku , Kibata Kayoko , Motoi Yuji , Zhang Yan , Murakami Yusuke , Fukui Ryutaro , Ishimoto Tatsushi , Sano Shigetoshi , Ito Tomoki , Shimizu Toshiyuki , Miyake Kensuke
Published: October 2015

Toll-like receptor (TLR) 7and 8 were considered to recognize single-strand RNA (ssRNA) from viruses. Although these receptors also respond to synthetic small chemical ligands, such as CL075 and R848, it remains to be determined whether these receptors sense natural small molecules or not. In the structure of human TLR8 (huTLR8) with ssRNA, there are two ligand-binding sites: one binds a uridine and the other binds an oligoribonucleotide (ORN). This finding demonstrates that huTLR8 recognizes degradation products of ssRNA, suggesting the presence of natural small ligands. We here show that TLR7 works as the sensor for guanosine (G)/2′-deoxyguanosine (dG) in the presence of ORN where ORN strengthens TLR7 interaction with G/dG. In addition, modified nucleosides such as 7-methylguanosine, 8-hydroxyguanosine (8-OHG) and 8-hydroxydeoxyguanosine (8-OHdG) activated TLR7 with ORNs. Importantly, 8-OHdG—a well-known oxidative DNA damage marker with unknown function—induced strong cytokine production comparable to G and dG both in mouse and human immune cells. Although 8-OHdG bound TLR7/ORN with lower affinity than dG did in isothermal titration calorimetry, administered 8-OHdG was metabolically more stable than dG in the serum, indicating that 8-OHdG acts on TLR7 as an endogenous ligand in vivo. To address a role of G analogs in the disease state, we also examined macrophages from Unc93b1D34A/D34A mice, which suffer from TLR7-dependent systemic inflammation, and found that Unc93b1D34A/D34A macrophages showed significantly enhanced response to G alone or 8-OHdG with ORN. In conclusion, our results provide evidence that G, dG, 8-OHG and 8-OHdG are novel endogenous ligands for TLR7.
Perioperative Mortality, 2010 to 2014
Authors: Whitlock Elizabeth L. , Feiner John R. , Chen Lee-lynn
Published: October 2015

AbstractAbstract

As might be expected, mortality rates were higher in patients with high American Society of Anesthesiologists physical status, having emergency surgery, and in those younger than 1 yr or those older than 65 yr. Mortality was also increased, although, when surgery began after 4:00 pm—even after adjustment for other known confounding factors.

Background

The National Anesthesia Clinical Outcomes Registry collects demographic and outcome data from anesthesia cases, with the goal of improving safety and quality across the specialty. The authors present a preliminary analysis of the National Anesthesia Clinical Outcomes Registry database focusing on the rates of and associations with perioperative mortality (within 48 h of anesthesia induction).

Methods

The authors retrospectively analyzed 2,948,842 cases performed between January 1, 2010, and May 31, 2014. Cases without procedure information and vaginal deliveries were excluded. Mortality and other outcomes were reported by the anesthesia provider. Hierarchical logistic regression was performed on cases with complete information for patient age group, sex, American Society of Anesthesiologists physical status, emergency case status, time of day, and surgery type, controlling for random effects within anesthesia practices.

Results

The final analysis included 2,866,141 cases and 944 deaths (crude mortality rate, 33 per 100,000). Increasing American Society of Anesthesiologists physical status, emergency case status, cases beginning between 4:00 pm and 6:59 am, and patient age less than 1 yr or greater than or equal to 65 yr were independently associated with higher perioperative mortality. A post hoc subgroup analysis of 279,154 patients limited to 22 elective case types, post hoc models incorporating either more granular estimate of surgical risk or work relative value units, and a post hoc propensity score–matched cohort confirmed the association with time of day.

Conclusions

Several factors were associated with increased perioperative mortality. A case start time after 4:00 pm was associated with an adjusted odds ratio of 1.64 (95% CI, 1.22 to 2.21) for perioperative death, which suggests a potentially modifiable target for perioperative risk reduction. Limitations of this study include nonstandardized mortality reporting and limited ability to adjust for missing data.
Bedside Ultrasound
Authors: Adler Adam C. , Jablonka Denis H.
Published: October 2015

Supplemental Digital Content is available in the text.
Delay in the Diagnosis of Stable Slipped Capital Femoral Epiphysis
Authors: Hosseinzadeh Pooya , Iwinski Henry J. , Salava Jonathon , Oeffinger Donna
Published: October 2015

Introduction:

Delays in the diagnosis of stable slipped capital femoral epiphysis (SCFE) is common due to the vague symptomatology and the lack of awareness of this entity by healthcare providers. Delays in the diagnosis of this condition can lead to poor outcomes for the patients. This study was designed to identify factors that contributed to delays in the diagnosis or the treatment of patients with SCFE seen at our institution.

Methods:

A retrospective chart review of patients with the diagnosis of a stable SCFE who had undergone screw stabilization between 1989 and 2010 at our hospital was performed. For each patient, demographic data, the date of initial onset of symptoms, the date of the first visit to the medical provider, the type of provider seen initially (orthopaedic surgeon or not), the date of diagnosis of SCFE, the type of physician who made the diagnosis (orthopaedic surgeon or not), and the date of surgery were recorded. For each patient, the presenting symptom was recorded as hip, thigh, or knee pain. The effect of demographic data, presenting symptoms, and the type of initial provider seen on the delay to diagnosis was studied using 2 Cox models.

Results:

A total of 149 patients with 196 stable SCFE were included. The average time from the first physician visit to diagnosis was 94 days in the group seen by a nonorthopaedic provider compared with an average of 2.9 days in the group seen by an orthopaedist (P<0.05). Diagnosis was made in 1 week only in 19% of the group seen by a nonorthopaedic provider versus 97% in the group seen by orthopaedic surgeons. It took significantly longer to be diagnosed with SCFE in patients who presented with initial knee pain (P=0.0097) compared with those who presented with hip pain at the initial visit.

Conclusions:

This study shows a significant delay in the diagnosis of SCFE in the United States, particularly in patients seen by nonorthopaedic providers initially.

Level of Evidence:

Level III—prognostic.
Long-term Outcome of Internal Tibial Derotation Osteotomies in Children With Cerebral Palsy
Authors: Er Mehmet S. , Abousamra Oussama , Rogers Kenneth J. , Bayhan Ilhan A. , Church Chris , Henley John , Niiler Tim , Miller Freeman
Published: October 2015

Background:

External tibial torsion (ETT) is a common bony deformity in children with cerebral palsy (CP). The current recommended treatment is tibial derotation osteotomy (TDO) to improve gait biomechanics. Satisfactory short-term results after TDO have been reported but long-term results have not been studied. The purpose of this study was to evaluate the long-term outcome following TDO to correct ETT in ambulatory children with CP.

Methods:

Following IRB approval, gait kinematics and passive range of motion measurements were retrospectively evaluated in children with spastic CP who underwent TDO due to ETT comparing preoperative (E0), short-term postoperative (E1; 1 to 3 y post), and long-term postoperative (E2; >5 y post) results. Limbs were categorized as corrected, undercorrected, or overcorrected at both E1 and E2, by comparing mean tibial rotation (MTR) in gait to a group of typically developing children. Age at surgery, E0 MTR, E0 gait velocity, gross motor function classification system (GMFCS) score, and foot deformity were evaluated to determine their influence on long-term results.

Results:

The study sample consisted of 43 legs (with E0 and E2) and 22 legs (with E0, E1, and E2). The mean age at surgery was 10.3±3.4 years (range, 6 to 19.2 y). In the group MTR trended toward improvement moving from −26±17 degrees (E0, external negative) to −16±16 degrees (E1) and relapsed to −23±17 degrees at the long term (P=0.071, E0/E1; P=0.589, E0/E2). Improvement was also seen in the transmalleolar axis (P=0.074), mean ankle rotation, and mean foot orientation (P<0.05, E0/E2). At the long-term evaluation, 16 legs (37%) were found to be in the kinematic corrected group, 25 legs (58%) in the kinematic undercorrected group, and 2 legs (5%) in the kinematic overcorrected group. There were no significant differences between the corrected and undercorrected groups of children with respect to age at surgery, GMFCS, E0 MTR, gait velocity, or foot deformity.

Conclusions:

Although internal TDO improves ETT in the short term, recurrence is frequent with an apparent developmental trend toward external rotation of the tibia.

Levels of Evidence:

Level IV—therapeutic study.
Identifying bipolar knapping in the Mesolithic site of Font del Ros (northeast Iberia)
Authors: Roda Gilabert Xavier , Mora Rafael , Martínez-Moreno Jorge
Published: October 2015

Despite recent advances in the identification of bipolar knapping, its role in many sites is not well known. We propose to assess the significance of this technique in the context of changes that occur in the Mesolithic. A lithic assemblage was recovered from unit SG at Font del Ros (Catalunya, Spain) in which pitted stones, cores and products arising from bipolar reduction (flakes, fragments and splintered pieces) were identified. This study indicates that the bipolar technique is fundamental in the settlement. These results are key to defining the organization of Holocene hunter-gatherer subsistence in northeast Iberia.
Variability in an early hominin percussive tradition: the Acheulean versus cultural variation in modern chimpanzee artefacts
Authors: Gowlett J. A. J.
Published: October 2015

Percussion makes a vital link between the activities of early human ancestors and other animals in tool-use and tool-making. Far more of the early human actions are preserved as archaeology, since the percussion was largely used for making hard tools of stone, rather than for direct access to food. Both primate tools and early hominin tools, however, offer a means to exploring variability in material culture, a strong focus of interest in recent primate studies. This paper charts such variability in the Acheulean, the longest-lasting tool tradition, extant form about 1.7 to about 0.1 Ma, and well known for its characteristic handaxes. The paper concentrates on the African record, although the Acheulean was also known in Europe and Asia. It uses principal components and discriminant analysis to examine the measurements from 66 assemblages (whole toolkits), and from 18 sets of handaxes. Its review of evidence confirms that there is deep-seated pattern in the variation, with variability within a site complex often matching or exceeding that between sites far distant in space and time. Current techniques of study allow comparisons of handaxes far more easily than for other components, stressing a need to develop common practice in measurement and analysis. The data suggest, however, that a higher proportion of traits recurs widely in Acheulean toolkits than in the chimpanzee record.
Inferring the correlated fitness effects of nonsynonymous mutations at the same site using triallelic population genomics
Authors: Ragsdale Aaron P. , Coffman Alec J. , Hsieh PingHsun , Struck Travis J. , Gutenkunst Ryan N.
Published: October 2015

The distribution of mutation fitness effects is central to evolutionary genetics. Typical univariate distributions, however, cannot model the effects of multiple mutations at the same site, so we introduce a model in which mutations at the same site have correlated fitness effects. To infer the strength of that correlation, we developed a diffusion approximation to the triallelic frequency spectrum, which we applied to data from D. melanogaster. We found a moderate correlation between the fitness effects of nonsynonymous mutations at the same codon, suggesting that both mutation identity and location are important for determining fitness effects in proteins. We validated our approach by comparing with biochemical mutational scanning experiments, finding strong quantitative agreement, even between different organisms. We also found that the correlation of mutation fitness effects was not affected by protein solvent exposure or structural disorder. Together, our results suggest that the correlation of fitness effects at the same site is a previously overlooked yet fundamental property of protein evolution.
JMJD1C is required for the survival of acute myeloid leukemia by functioning as a coactivator for key transcription factors
Authors: Chen Mo , Zhu Nan , Liu Xiaochuan , Laurent Benoit , Tang Zhanyun , Eng Rowena , Shi Yang , Armstrong Scott A. , Roeder Robert G.
Published: October 2015

RUNX1–RUNX1T1 (formerly AML1-ETO), a transcription factor generated by the t(8;21) translocation in acute myeloid leukemia (AML), dictates a leukemic program by increasing self-renewal and inhibiting differentiation. Here we demonstrate that the histone demethylase JMJD1C functions as a coactivator for RUNX1–RUNX1T1 and is required for its transcriptional program. JMJD1C is directly recruited by RUNX1–RUNX1T1 to its target genes and regulates their expression by maintaining low H3K9 dimethyl (H3K9me2) levels. Analyses in JMJD1C knockout mice also establish a JMJD1C requirement for RUNX1–RUNX1T1's ability to increase proliferation. We also show a critical role for JMJD1C in the survival of multiple human AML cell lines, suggesting that it is required for leukemic programs in different AML cell types through its association with key transcription factors.
A cellular, molecular, and pharmacological basis for appendage regeneration in mice
Authors: Leung Thomas H. , Snyder Emily R. , Liu Yinghua , Wang Jing , Kim Seung K.
Published: October 2015

Regenerative medicine aims to restore normal tissue architecture and function. However, the basis of tissue regeneration in mammalian solid organs remains undefined. Remarkably, mice lacking p21 fully regenerate injured ears without discernable scarring. Here we show that, in wild-type mice following tissue injury, stromal-derived factor-1 (Sdf1) is up-regulated in the wound epidermis and recruits Cxcr4-expressing leukocytes to the injury site. In p21-deficient mice, Sdf1 up-regulation and the subsequent recruitment of Cxcr4-expressing leukocytes are significantly diminished, thereby permitting scarless appendage regeneration. Lineage tracing demonstrates that this regeneration derives from fate-restricted progenitor cells. Pharmacological or genetic disruption of Sdf1–Cxcr4 signaling enhances tissue repair, including full reconstitution of tissue architecture and all cell types. Our findings identify signaling and cellular mechanisms underlying appendage regeneration in mice and suggest new therapeutic approaches for regenerative medicine.