bluuebunny/crossref_metadata_2025 huggingface dataset:
Progress toward a solid-state ionic field effect transistor
Authors: Deml Ann M. , Bunge Annette L. , Reznikov Michael A. , Kolessov Alex , O’Hayre Ryan P.
Published: April 2012

This paper reports on the development and characterization of a solid-state ionic field effect transistor (IFET), a device integrating the principles of metal-oxide-semiconductor field effect transistors, electric double layer modeling, and solid-state ionic transport as a platform to investigate and manipulate nanoionic effects. The described solid-state IFET utilizes a sinusoidal external electric field to induce a time-modulated ionic space charge layer conduction channel in an ion-conducting material, such as Nafion, the chosen proton-conducting polymer in this study. The application of double layer modeling to this system establishes a theoretical foundation for device performance, including predicted values for the modulation of the membrane resistance in response to a gating bias. Experimental studies of device prototypes constructed from 25-175-μm-thick Nafion membranes demonstrate indications of ionic space charge layer manipulation for gating voltages of 0.5–10 V in amplitude. Strategies to improve device performance by reducing current leakage and increasing reproducibility include reduction of the gate electrode area and the membrane thickness. Our results show important progress in the development of solid-state IFETs and, as such, demonstrate a promising outlook for improved understanding of nanoionic phenomena.
Construction and operation of a microrobot based on magnetotactic bacteria in a microfluidic chip
Authors: Ma Qiufeng , Chen Changyou , Wei Shufeng , Chen Chuanfang , Wu Long-Fei , Song Tao
Published: April 2012

Magnetotactic bacteria (MTB) are capable of swimming along magnetic field lines. This unique feature renders them suitable in the development of magnetic-guided, auto-propelled microrobots to serve in target molecule separation and detection, drug delivery, or target cell screening in a microfluidic chip. The biotechnology to couple these bacteria with functional loads to form microrobots is the critical point in its application. Although an immunoreaction approach to attach functional loads to intact MTB was suggested, details on its realization were hardly mentioned. In the current paper, MTB-microrobots were constructed by attaching 2 μm diameter microbeads to marine magnetotactic ovoid MO-1 cells through immunoreactions. These microrobots were controlled using a special control and tracking system. Experimental results prove that the attachment efficiency can be improved to ∼30% via an immunoreaction. The motility of the bacteria attached with different number of loads was also assessed. The results show that MTB can transport one load at a velocity of ∼21 μm/s and still move and survive for over 30 min. The control and tracking system is fully capable of directing and monitoring the movement of the MTB-microrobots. The rotating magnetic fields can stop the microrobots by trapping them as they swim within a circular field with a controllable size. The system has potential use in chemical analyses and medical diagnoses using biochips as well as in nano/microscale transport.
Embedded-gate graphene transistors for high-mobility detachable flexible nanoelectronics
Authors: Lee Jongho , Tao Li , Hao Yufeng , Ruoff Rodney S. , Akinwande Deji
Published: April 2012

A high-mobility graphene field-effect transistor with embedded gate was fabricated on smooth spin-coated polyimide films. Electrostatic transport measurements reveal a maximum electron and hole mobility of 4930 cm2/V s and 1130 cm2/V s, respectively. Temperature dependent measurements indicate that carrier transport is not limited by intrinsic mechanisms but by charged impurities, surface roughness, and defects, suggesting that further increases in mobility are possible. The measured carrier mobilities are the highest reported for graphene transistors on polymeric substrates and hence enable high-speed devices for flexible electronics from graphene grown by size-scalable chemical vapor deposition.
Scaling of the coercivity with the geometrical parameters in epitaxial Fe antidot arrays
Authors: Paz E. , Cebollada F. , Palomares F. J. , González J. M. , Im M.-Y. , Fischer P.
Published: April 2012

We studied a series of square lattice antidot arrays, with diameter and lattice parameter from hundreds of nanometers to some microns, fabricated using two lithography techniques in epitaxial Fe(001) films. The coercivity increase of each array with respect to its base film can be scaled to a simple geometric parameter, irrespective of the lithography technique employed. Magnetic transmission x-ray microscopy studies, in arrays fabricated on polycrystalline Fe films deposited on silicon nitride membranes, evidenced the propagation of reversed domains from the edges of the arrays, in agreement with the coercivity analysis of the epitaxial arrays and with micromagnetic models.
Surface/interface effect around a piezoelectric nano-particle in a polymer matrix under compressional waves
Authors: Fang X. Q. , Yang Q. , Liu J. X. , Feng W. J.
Published: April 2012

In this letter, the scattering of plane harmonic compressional wave around a nanosized piezoelectric particle is studied. The surface/interface model of Gurtin and Murdoch [Arch. Ration. Mech. Anal. 57, 291 (1975)] is extended to the coupling of stress and electric displacement. The results show that the scattering effect of compressional waves is significantly related to the coupling effect of surface/interface. For incident waves with different frequencies, the influence of surface energy on the dynamic stress and electric displacement around the piezoelectric particle is discussed in details.
Communication: Scanning tunneling microscopy study of the reaction of octanethiolate self-assembled monolayers with atomic chlorine
Authors: Jobbins Matthew M. , Lee David Y. , Kandel S. Alex
Published: April 2012

Scanning tunneling microscopy was used to investigate the reaction of octanethiolate self-assembled monolayers (SAMs) with atomic chlorine. We have found that exposing a SAM to low fluxes of radical Cl results primarily in the formation of new defects in areas with close-packed alkanethiolates, but has little to no effect on the domain boundaries of the SAM. Dosing high quantities of atomic chlorine results in the near-complete loss of surface order at room temperature, but not the complete removal of the thiolate monolayer. These observations are in stark contrast to the results of previous measurements of the reaction of atomic hydrogen with alkanethiolate SAMs.
Giving Subjects the Eye and Showing Them the Finger: Socio-Biological Cues and Saccade Generation in the Anti-Saccade Task
Authors: Gregory Nicola J , Hodgson Timothy L
Published: April 2012

Pointing with the eyes or the finger occurs frequently in social interaction to indicate direction of attention and one's intentions. Research with a voluntary saccade task (where saccade direction is instructed by the colour of a fixation point) suggested that gaze cues automatically activate the oculomotor system, but non-biological cues, like arrows, do not. However, other work has failed to support the claim that gaze cues are special. In the current research we introduced biological and non-biological cues into the anti-saccade task, using a range of stimulus onset asynchronies (SOAs). The anti-saccade task recruits both top–down and bottom–up attentional mechanisms, as occurs in naturalistic saccadic behaviour. In experiment 1 gaze, but not arrows, facilitated saccadic reaction times (SRTs) in the opposite direction to the cues over all SOAs, whereas in experiment 2 directional word cues had no effect on saccades. In experiment 3 finger pointing cues caused reduced SRTs in the opposite direction to the cues at short SOAs. These findings suggest that biological cues automatically recruit the oculomotor system whereas non-biological cues do not. Furthermore, the anti-saccade task set appears to facilitate saccadic responses in the opposite direction to the cues.
How Long is Your Arm? Using Multisensory Illusions to Modify Body Image from the Third Person Perspective
Authors: Preston Catherine , Newport Roger
Published: April 2012

Updating body representations from the 3rd person perspectives (3PP) seems to require viewing the real body, unlike when viewing from a 1st person perspective. Here, 3PP updating was investigated through induction of a physically impossible multisensory illusion in which participants viewed real-time 3PP video of themselves having their arm pulled until it stretched to twice its normal length. The illusion elicited the subjective experience that the participant's own arm had been stretched and caused an overestimation of reaching distance, although actual reaches were unaffected. Multisensory illusions from the 3PP can alter body image when applied to real bodies.
Development of a 15-Item Odour Discrimination Test (Düsseldorf Odour Discrimination Test)
Authors: Weierstall Roland , Pause Bettina M
Published: April 2012

A key function of the olfactory system is the detection of differences in odour quality. Therefore, a test was developed to assess odour discrimination ability in normosmic humans. Out of six monomolecular substances (capric acid, coumarin, eugenol, geraniol, phenylethyl alcohol, and vanillin) quaternary mixtures were prepared. Within one item, three odour mixtures were presented (triangle forced-choice procedure). The deviant odour contained the same substances as the two remaining odours; however, the proportions were changed. Study 1 (120 participants) aimed to select items that contribute to a high internal consistency. Study 2 (104 participants) assessed test–retest reliability, parallel test reliability and test validity. Out of 45 items, a 15-item test (Düsseldorf Odour Discrimination Test, DODT) with an internal consistency of 0.61 and medium item difficulties was prepared. The test–retest reliability of the DODT was 0.66 (test interval = 4 weeks) and the parallel test reliability 0.42. The DODT correlated significantly with the University of Pennsylvania Smell Identification Test and to a lesser extent with the phenylethyl alcohol odour threshold test. As the DODT did not correlate with the odour discrimination test of the Sniffin' Sticks, the two tests seem to measure different performances of the olfactory system.
Healin' Groovy: Movement Affects the Appearance of the Healing Grid Illusion
Authors: Fukuda Haruaki , Seno Takeharu
Published: April 2012

Vection alters the perception of a visual illusion. It enhances the illusory completion of the healing grid (Kanai, 2005, Best Illusion of the Year Contest, Vision Sciences Society). When we perceive our self-motion, the mode of vision is different from that of when we are stationary.
Independent Effects of Local and Global Binocular Disparity on the Perceived Convexity of Stereoscopically Presented Faces in Scenes
Authors: Matthews Harold , Hill Harold , Palmisano Stephen
Published: April 2012

Evidence suggests that experiencing the hollow-face illusion involves perceptual reversal of the binocular disparities associated with the face even though the rest of the scene appears unchanged. This suggests stereoscopic processing of object shape may be independent of scene-based processing of the layout of objects in depth. We investigated the effects of global scene-based and local object-based disparity on the compellingness of the perceived convexity of the face. We took stereoscopic photographs of people in scenes, and independently reversed the binocular disparities associated with the head and scene. Participants rated perceived convexity of a natural disparity (“convex”) or reversed disparity (“concave”) face shown either in its original context with reversed or natural disparities or against a black background. Faces with natural disparity were rated as more convincingly convex independent of the background, showing that the local disparities can affect perceived convexity independent of disparities across the rest of the image. However, the apparent convexity of the faces was also greater in natural disparity scenes compared to either a reversed disparity scene or a zero disparity black background. This independent effect of natural scene disparity suggests that the ‘solidity’ associated with natural scene disparities spread to enhance the perceived convexity of the face itself. Together, these findings suggest that global and local disparity exert independent and additive effects upon the perceived convexity of the face.
The Tilted Hermann Grid Illusion: ‘Illusory Spots’ versus ‘Phantom Bands’
Authors: Hamburger Kai , Baier Franziska , Spillmann Lothar
Published: April 2012

The Hermann grid illusion became a cause célèbre, when it was reported that small figural changes from straight to curved bars abolish the dark illusory spots. We demonstrate that this is not an all-or-none effect; rather, the visual system tolerates some tilt/curviness. We transformed straight and curved Hermann grids to rhombic Motokawa grids by gradually tilting the horizontal bars. Initially we observed only dark illusory spots, then dark spots combined with phantom bands traversing the rhomb along the minor axis, and finally dark phantom bands only. This shows that two kinds of illusions can coexist in the same grid pattern.
Single female offspring born to primiparous ewe-lambs are lighter than those born to adult multiparous ewes but their reproduction and milk production are unaffected
Authors: Loureiro M. F. P. , Pain S. J. , Kenyon P. R. , Peterson S. W. , Blair H. T.
Published: April 2012

Little is known about the long-term impacts of selecting progeny born to ewe-lambs (EL) as replacements. This study investigated whether being born to a ewe-lamb affected the liveweight, milk production and reproductive performance of the offspring to 3 years of age in comparison with those born to adult multiparous ewes. Twenty-seven and 28 single-born Romney ewe progeny (G1) were born to either EL or to adult ewes (AE), respectively. Offspring born to ewe-lambs (ELG1) were lighter (P < 0.001) at birth and up to 12 months of age compared with offspring born to adult ewes (AEG1). Reproductive performance of AEG1 and ELG1 did not differ in regards to puberty attainment, pregnancy rate and number of fetuses. First lactation milk production, fat, crude protein, total protein, casein, lactose and total solids yield did not differ (P > 0.05). The second generation offspring born to ELG1 and AEG1 did not differ in birthweight in the first parity, but it did differ in the second parity and those lambs born to ELG1 were heavier from birth to weaning compared with those lambs born to AEG1. Combined, these results indicate, in the animals used in our study that productive performance of ewes born to EL does not differ to 3 years of age to that of ewes born to AE.
The effect of liveweight and liveweight gain of ewes immediately post-weaning on the liveweight and survival of subsequent lambs
Authors: Hickson R. E. , Kenyon P. R. , Blair H. T. , Harding J. E. , Oliver M. H. , Jaquiery A. L. , Nicoll G. B. , Burt K. G.
Published: April 2012

Thirteen-hundred and sixty-seven Romney mixed-aged ewes were randomly allocated to one of two liveweight gain treatments (high vs maintenance) from weaning of one litter of lambs until 71 days before the subsequent breeding (a period of 42 days). The aims of this study were first to determine whether ewe liveweight or liveweight gain treatment before rebreeding affected the number and liveweight of lambs produced and reared in the following season, and second, to identify whether the birth rank of the dam or the grand-dam affected the number, survival or liveweight of their lambs. Liveweight gain during the 42-day treatment period was greater (P < 0.05) in the high than maintenance treatment (87 ± 6 vs 4 ± 6 g/day, respectively), although it did not influence (P > 0.05) number of fetuses, lambs born or reared per ewe or total weight of lambs born or weaned per ewe. Ewe liveweight at weaning (113 days before rebreeding), and liveweight gain between the weaning and rebreeding, explained only a minor proportion of the variation in lamb liveweight at birth and weaning in the following season. Birth rank of the ewe or of the ewe’s dam did not (P > 0.05) influence liveweight or number of lambs born or weaned. In conclusion, this experiment indicated that liveweight and liveweight gain from weaning until rebreeding in the flock investigated had only a very minor influence on lamb production. Therefore, there appears to be little advantage in specifically managing ewes during this period to gain considerable amounts of liveweight.
The prediction of meat yield in lamb carcasses using primal cut weights, carcass measures and the Hennessy Grading Probe
Authors: Siddell J. , McLeod B. M. , Toohey E. S. , van de Ven R. , Hopkins D. L.
Published: April 2012

A wide selection of crossbred lambs (n = 268) of mixed sex (ewes and wethers) were slaughtered at a commercial abattoir. Tissue depth at the GR site (thickness of tissue over the 12th rib 110 mm from the midline) was measured in the chiller using a GR knife (GR) and fatscore (1–5) was assessed on each carcass by abattoir personnel. Each carcass was subsequently broken down to a range of trimmed cuts (subprimals) and the meat yield in kilograms determined as the sum of the weights of these cuts. The best model for the prediction of meat yield was based on the weight of the 4-rib, untrimmed forequarter, fatscore and GR, which had a mean-squared prediction error of 0.96, but a simpler model based on weight of the forequarter and GR only had a marginally higher mean-squared prediction error at 0.97. In both models as either forequarter weight, GR or fatscore increased the meat yield increased. The predominant industry model for predicting meat yield in Australia uses carcass weight and tissue depth at the GR site, but these predictors were less useful than models based on forequarter weight. There was no significant improvement for the prediction of meat yield from the use of muscle or fat depths measured with a Hennessy Grading Probe or directly on the carcass with a ruler when a subset of 97 carcasses was examined. In this case the final model was based on the weight of the forequarter and the weight of the hind leg (R2 = 95%). It is feasible to collect the weight of the forequarter before subprimal cut preparation and if this can be achieved under commercial conditions, a method for predicting meat yield automatically during this procedure could be applied.
The effect of sex on some carcass and meat quality traits in Texel ewe and ram lambs
Authors: Craigie C. R. , Lambe N. R. , Richardson R. I. , Haresign W. , Maltin C. A. , Rehfeldt C. , Roehe R. , Morris S. T. , Bunger L.
Published: April 2012

Much of the past research into gender effects on lamb meat quality has focussed on comparing ram lambs with castrated males, but more recent comparisons between ram and ewe lambs have yielded variable results. The objective of the current research was to compare meat quality parameters of M. longissimus lumborum (LL), and M. semimembranosus (SM) from pasture-fed Texel ram (n = 94) and ewe (n = 114) lambs slaughtered at an average age of 144 days in a commercial abattoir. After aging carcasses for between 7 and 9 days, LL and SM were significantly tougher (higher shear values) for ram compared with ewe lambs (P < 0.001). LL from rams had significantly lower intramuscular fat percentage, and higher moisture content than LL from ewes. Differences in LL intramuscular fat percentage or ultimate pH did not explain the sex effect on LL shear force when tested individually or together as additional covariates in the model. Ram SM was lighter in colour (higher L*) and had a higher cooking loss than that of ewes (P < 0.001). The correlations between some of the traits within and between muscles clearly differed between the sexes. Finishing ram lambs to the specifications used in this experiment resulted in meat with relatively minor, but statistically significant differences in quality relative to that from ewe lambs.
Biosynthesis of oestrogen by the early equine embryo proper
Authors: Raeside James I. , Christie Heather L. , Waelchli Rudolf O. , Betteridge Keith J.
Published: April 2012

The embryo proper in early equine pregnancy has recently been shown to have a remarkable capacity for metabolism of oestrogens. High concentrations of oestrogens in yolk-sac fluid could provide substrate for local metabolism in tissues of the embryo proper and this activity could have significance for early development. Due to the high level of oestrogen metabolism in the embryo proper we examined the possibility that it could also biosynthesise oestrogens. Conceptuses were collected in the fourth week of pregnancy (n = 23) and the embryo was separated from extraembryonic tissues for incubation with [3H]androstenedione. Steroids were recovered from media by solid-phase extraction and eluted as unconjugated and conjugated fractions. Profiles of free and sulfoconjugated fractions, as well as the phenolic steroids extracted from them, were obtained by chromatography. Oestrone and oestradiol were seen clearly, indicating oestrogen biosynthesis, and the presence of more polar products, arising from metabolism of the primary oestrogens, gave further evidence that the embryo was capable of oestrogen biosynthesis. Aromatase activity was also demonstrated by detection of tritium loss, as 3H2O, from incubations (n = 3) with [1β-3H]androstenedione. It is suggested that its oestrogen biosynthesis may have significance for the remarkable development of the vasculature in the embryo proper at this stage.
Caloric restriction, but not caloric loading, affects circulating fetal and maternal C-type natriuretic peptide concentrations in late ovine gestation
Authors: McNeill B. A. , Barrell G. K. , Ridgway M. J. , Wellby M. P. , Prickett T. C. R. , Espiner E. A.
Published: April 2012

The factors regulating the greatly elevated concentrations of maternal plasma C-type natriuretic peptide (CNP) forms in ruminant pregnancy are largely unknown, but nutrient status is likely to be important. Previous work has shown that increases in maternal plasma CNP, sourced from the placenta, occur in response to caloric restriction in late gestation. Whether oversupply of nutrients also regulates CNP secretion in pregnancy has not been studied. Hypothesising that CNP in fetal and maternal tissues will be responsive to both deficiency and excess, we studied changes in CNP and a cosecreted fragment, namely N-terminal pro-CNP (NTproCNP), during short-term periods of caloric restriction (CR) and loading (CL). Twin-bearing ewes received CR (fasted Days 121–124), CL (Days 110–124) or control maintenance diets. During CR, fetal plasma CNP forms, insulin-like growth factor (IGF)-1 and liveweight all fell, and maternal plasma NTproCNP increased. During CL, fetal IGF-1 increased, whereas CNP forms and liveweight were unchanged, as were maternal concentrations of CNP forms. The high abundance of CNP peptides in placental tissues was unaffected by these short-term changes in nutrient supply. We conclude that CNP in the fetal–maternal unit is acutely responsive to undernutrition, but is unaffected by oversupply in late gestation.
The effects of N-acetyl-L-cysteine supplementation on in vitro porcine oocyte maturation and subsequent fertilisation and embryonic development
Authors: Whitaker B. D. , Casey S. J. , Taupier R.
Published: April 2012

The effects of supplementation with 1.5 mM n-acetyl-l-cysteine (NAC) during in vitro oocyte maturation were studied. Oocytes were supplemented with 1.5 mM NAC during maturation for 0 to 24 h, 24 to 48 h, or 0 to 48 h then subjected to IVF and embryo development. Oocytes were evaluated after maturation for intracellular glutathione concentration, superoxide dismutase and glutathione peroxidase activities and DNA fragmentation. Fertilisation and embryonic development success were also evaluated. There was no effect of treatment on intracellular glutathione concentrations, enzyme activities or fertilisation success rates. Supplementing NAC during maturation significantly decreased (P < 0.05) the percentage of oocytes with fragmented DNA compared with no NAC supplementation. Supplementing NAC from 24 to 48 h or 0 to 48 h resulted in a significantly higher (P < 0.05) percentage of oocytes with male pronuclei than for oocytes from the other treatment groups. There was no difference in the percentage of embryos cleaved by 48 h after IVF between treatment groups. Supplementing NAC from 24 to 48 h or 0 to 48 h resulted in a significantly higher (P < 0.05) percentage of embryos reaching the blastocyst stage by 144 h after IVF compared with the other treatment groups. These results indicate that supplementation of the oocyte maturation medium with 1.5 mM NAC, specifically during the last 24 h, improves male pronucleus formation and blastocyst development in pigs.
Effects of self-motion on auditory scene analysis
Authors: Kondo Hirohito M. , Pressnitzer Daniel , Toshima Iwaki , Kashino Makio
Published: April 2012

Auditory scene analysis requires the listener to parse the incoming flow of acoustic information into perceptual “streams,” such as sentences from a single talker in the midst of background noise. Behavioral and neural data show that the formation of streams is not instantaneous; rather, streaming builds up over time and can be reset by sudden changes in the acoustics of the scene. Here, we investigated the effect of changes induced by voluntary head motion on streaming. We used a telepresence robot in a virtual reality setup to disentangle all potential consequences of head motion: changes in acoustic cues at the ears, changes in apparent source location, and changes in motor or attentional processes. The results showed that self-motion influenced streaming in at least two ways. Right after the onset of movement, self-motion always induced some resetting of perceptual organization to one stream, even when the acoustic scene itself had not changed. Then, after the motion, the prevalent organization was rapidly biased by the binaural cues discovered through motion. Auditory scene analysis thus appears to be a dynamic process that is affected by the active sensing of the environment.
Contributions of local knowledge to the physical limnology of Lake Como, Italy
Authors: Laborde Sarah , Imberger Jörg , Toussaint Sandy
Published: April 2012

This article shows how local knowledge may be valuably integrated into a scientific approach in the study of large and complex hydrological systems where data collection at high resolution is a challenge. This claim is supported through a study of the hydrodynamics of a large lake where qualitative data collected from professional fishers was combined with theory to develop a hypothesis that was then verified by numerical modeling. First the fishermen’s narratives were found to describe with accuracy internal wave motions that were evident in water column temperature records, which revealed their practical knowledge of the lake’s hydrodynamics. Second, local knowledge accounts emphasized the recurrent formation of mesoscale gyres and return flows in certain zones of the lake in stratified conditions, which did not appear in the physical data because of limitations of sampling resolution. We hypothesized that these features developed predominantly because of the interaction of wind-driven internal motions with the lake’s bathymetry, and the Earth’s rotation in the widest areas of the basin. Numerical simulation results corroborated the fishers’ descriptions of the flow paths and supported the hypothesis about their formation. We conclude that the collaboration between scientific and local knowledge groups, although an unusual approach for a physical discipline of the geosciences, is worth exploring in the pursuit of a more comprehensive understanding of complex geophysical systems such as large lakes.
The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis
Authors: Rajurkar Mihir , De Jesus-Monge Wilfredo E. , Driscoll David R. , Appleman Victoria A. , Huang He , Cotton Jennifer L. , Klimstra David S. , Zhu Lihua J. , Simin Karl , Xu Lan , McMahon Andrew P. , Lewis Brian C. , Mao Junhao
Published: April 2012

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive human malignancies, is thought to be initiated by
KRAS
activation. Here we find that transcriptional activation mediated by the Gli family of transcription factors, although dispensable for pancreatic development, is required for Kras-induced proliferation and survival in primary pancreatic epithelial cells in culture and for Kras-driven pancreatic intraepithelial neoplasia and PDAC formation in vivo. Further, ectopic Gli1 activation in the mouse pancreas accelerates Kras-driven tumor formation, underscoring the importance of Gli transcription factors in pancreatic tumorigenesis. Interestingly, we demonstrate Gli-regulated I-kappa-B kinase epsilon (IKBKE) and NF-κB activity in pancreatic cancer cells and show that this activity is a critical downstream mediator for Gli-dependent PDAC cell transformation and survival. Together, these studies demonstrate the requirement for Gli in Kras-dependent pancreatic epithelial transformation, suggest a mechanism of Gli-NF-κB oncogenic activation, and provide genetic evidence supporting the therapeutic targeting of Gli activity in pancreatic cancer.
Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions
Authors: Kashio Makiko , Sokabe Takaaki , Shintaku Kenji , Uematsu Takayuki , Fukuta Naomi , Kobayashi Noritada , Mori Yasuo , Tominaga Makoto
Published: April 2012

The ability to sense temperature is essential for organism survival and efficient metabolism. Body temperatures profoundly affect many physiological functions, including immunity. Transient receptor potential melastatin 2 (TRPM2) is a thermosensitive, Ca
2+
-permeable cation channel expressed in a wide range of immunocytes. TRPM2 is activated by adenosine diphosphate ribose and hydrogen peroxide (H
2
O
2
), although the activation mechanism by H
2
O
2
is not well understood. Here we report a unique activation mechanism in which H
2
O
2
lowers the temperature threshold for TRPM2 activation, termed “sensitization,” through Met oxidation and adenosine diphosphate ribose production. This sensitization is completely abolished by a single mutation at Met-214, indicating that the temperature threshold of TRPM2 activation is regulated by redox signals that enable channel activity at physiological body temperatures. Loss of TRPM2 attenuates zymosan-evoked macrophage functions, including cytokine release and fever-enhanced phagocytic activity. These findings suggest that redox signals sensitize TRPM2 downstream of NADPH oxidase activity and make TRPM2 active at physiological body temperature, leading to increased cytosolic Ca
2+
concentrations. Our results suggest that TRPM2 sensitization plays important roles in macrophage functions.
Phosphodiesterases coordinate cAMP propagation induced by two stimulatory G protein-coupled receptors in hearts
Authors: Liu Shubai , Li Ying , Kim Sungjin , Fu Qin , Parikh Dippal , Sridhar Bharat , Shi Qian , Zhang Xiaoying , Guan Yinzheng , Chen Xiongwen , Xiang Yang K.
Published: April 2012

Inflammation is a significant player in the progression of heart failure and has detrimental effects on cardiac function. Prostaglandin (PG)E2, a major proinflammatory prostanoid in the cardiovascular system, is a potent stimulus in inducing intracellular cAMP but minimally affects cardiac contractile function. Here, we show that the PGE2 stimulation attenuates the adrenergic-induced cardiac contractile response in animal hearts. Stimulation with PGE2 leads to stimulatory G protein (Gs)-dependent production of cAMP. However, the induced cAMP is spatially restricted because of its degradation by phosphodiesterase (PDE)4 and cannot access the intracellular sarcoplasmic reticulum (SR) for increasing calcium signaling and myocyte contraction. Moreover, pretreatment with PGE2 significantly inhibits PKA activities at the SR induced by a β-adrenergic agonist, isoproterenol, and subsequently blocks isoproterenol-induced PKA phosphorylation of phospholamban and contractile responses in myocytes. Further analysis reveals that the PGE2-induced cAMP/PKA is sufficient to phosphorylate and activate PDE4D isoforms, which, in turn, spatially inhibits the diffusion of adrenergic-induced cAMP from the plasma membrane to the SR. Inhibition of PDE4 rescues the adrenergic-induced increase in cAMP/PKA activities at the SR, PKA phosphorylation of phospholamban, and contractile responses in PGE2-pretreated myocytes. Thus, this offers an example that one Gs-coupled receptor is able to inhibit the intracellular signaling transduction initiated by another Gs-coupled receptor via controlling the diffusion of cAMP, presenting a paradigm for G protein-coupled receptor (GPCR) signal transduction. It also provides a mechanism for the integration of signaling initiated by different neurohormonal stimuli, as well as long-term effects of chronically circulating proinflammatory factors in myocardium.
Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na
V
1.6-resurgent and persistent current
Authors: Sittl Ruth , Lampert Angelika , Huth Tobias , Schuy E. Theresa , Link Andrea S. , Fleckenstein Johannes , Alzheimer Christian , Grafe Peter , Carr Richard W.
Published: April 2012

Infusion of the chemotherapeutic agent oxaliplatin leads to an acute and a chronic form of peripheral neuropathy. Acute oxaliplatin neuropathy is characterized by sensory paresthesias and muscle cramps that are notably exacerbated by cooling. Painful dysesthesias are rarely reported for acute oxaliplatin neuropathy, whereas a common symptom of chronic oxaliplatin neuropathy is pain. Here we examine the role of the sodium channel isoform Na
V
1.6 in mediating the symptoms of acute oxaliplatin neuropathy. Compound and single-action potential recordings from human and mouse peripheral axons showed that cooling in the presence of oxaliplatin (30–100 μM; 90 min) induced bursts of action potentials in myelinated A, but not unmyelinated C-fibers. Whole-cell patch-clamp recordings from dissociated dorsal root ganglion (DRG) neurons revealed enhanced tetrodotoxin-sensitive resurgent and persistent current amplitudes in large, but not small, diameter DRG neurons when cooled (22 °C) in the presence of oxaliplatin. In DRG neurons and peripheral myelinated axons from
Scn8a
med/med
mice, which lack functional Na
V
1.6, no effect of oxaliplatin and cooling was observed. Oxaliplatin significantly slows the rate of fast inactivation at negative potentials in heterologously expressed mNa
V
1.6r in ND7 cells, an effect consistent with prolonged Na
V
open times and increased resurgent and persistent current in native DRG neurons. This finding suggests that Na
V
1.6 plays a central role in mediating acute cooling-exacerbated symptoms following oxaliplatin, and that enhanced resurgent and persistent sodium currents may provide a general mechanistic basis for cold-aggravated symptoms of neuropathy.
Aristolochic acid-associated urothelial cancer in Taiwan
Authors: Chen Chung-Hsin , Dickman Kathleen G. , Moriya Masaaki , Zavadil Jiri , Sidorenko Viktoriya S. , Edwards Karen L. , Gnatenko Dmitri V. , Wu Lin , Turesky Robert J. , Wu Xue-Ru , Pu Yeong-Shiau , Grollman Arthur P.
Published: April 2012

Aristolochic acid, a potent human carcinogen produced by
Aristolochia
plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the
TP53
tumor-suppressor gene. Using AL-DNA adducts and
TP53
mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where
Aristolochia
herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The
TP53
mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent
TP53
mutational hotspots include the adenine bases of
5′
AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the
FGFR3
and
HRAS
oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in
TP53
,
FGFR3
, or
HRAS
. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.
Drosophila
Golgi membrane protein Ema promotes autophagosomal growth and function
Authors: Kim Sungsu , Naylor Sarah A. , DiAntonio Aaron
Published: April 2012

Autophagy is a self-degradative process in which cellular material is enclosed within autophagosomes and trafficked to lysosomes for degradation. Autophagosomal biogenesis is well described; however mechanisms controlling the growth and ultimate size of autophagosomes are unclear. Here we demonstrate that the
Drosophila
membrane protein Ema is required for the growth of autophagosomes. In an
ema
mutant, autophagosomes form in response to starvation and developmental cues, and these autophagosomes can mature into autolysosomes; however the autophagosomes are very small, and autophagy is impaired. In fat body cells, Ema localizes to the Golgi complex and is recruited to the membrane of autophagosomes in response to starvation. The
Drosophila
Golgi protein Lva also is recruited to the periphery of autophagosomes in response to starvation, and this recruitment requires
ema
. Therefore, we propose that Golgi is a membrane source for autophagosomal growth and that Ema facilitates this process. Clec16A, the human ortholog of Ema, is a candidate autoimmune susceptibility locus. Expression of Clec16A can rescue the autophagosome size defect in the
ema
mutant, suggesting that regulation of autophagosome morphogenesis may be a fundamental function of this gene family.
Transcranial direct-current stimulation modulates synaptic mechanisms involved in associative learning in behaving rabbits
Authors: Márquez-Ruiz Javier , Leal-Campanario Rocío , Sánchez-Campusano Raudel , Molaee-Ardekani Behnam , Wendling Fabrice , Miranda Pedro C. , Ruffini Giulio , Gruart Agnès , Delgado-García José María
Published: April 2012

Transcranial direct-current stimulation (tDCS) is a noninvasive brain stimulation technique that has been successfully applied for modulation of cortical excitability. tDCS is capable of inducing changes in neuronal membrane potentials in a polarity-dependent manner. When tDCS is of sufficient length, synaptically driven after-effects are induced. The mechanisms underlying these after-effects are largely unknown, and there is a compelling need for animal models to test the immediate effects and after-effects induced by tDCS in different cortical areas and evaluate the implications in complex cerebral processes. Here we show in behaving rabbits that tDCS applied over the somatosensory cortex modulates cortical processes consequent to localized stimulation of the whisker pad or of the corresponding area of the ventroposterior medial (VPM) thalamic nucleus. With longer stimulation periods, poststimulation effects were observed in the somatosensory cortex only after cathodal tDCS. Consistent with the polarity-specific effects, the acquisition of classical eyeblink conditioning was potentiated or depressed by the simultaneous application of anodal or cathodal tDCS, respectively, when stimulation of the whisker pad was used as conditioned stimulus, suggesting that tDCS modulates the sensory perception process necessary for associative learning. We also studied the putative mechanisms underlying immediate effects and after-effects of tDCS observed in the somatosensory cortex. Results when pairs of pulses applied to the thalamic VPM nucleus (mediating sensory input) during anodal and cathodal tDCS suggest that tDCS modifies thalamocortical synapses at presynaptic sites. Finally, we show that blocking the activation of adenosine A1 receptors prevents the long-term depression (LTD) evoked in the somatosensory cortex after cathodal tDCS.
Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice
Authors: Wu Lan , Parekh Vrajesh V. , Gabriel Curtis L. , Bracy Deanna P. , Marks-Shulman Pamela A. , Tamboli Robyn A. , Kim Sungjune , Mendez-Fernandez Yanice V. , Besra Gurdyal S. , Lomenick Jefferson P. , Williams Brandon , Wasserman David H. , Van Kaer Luc
Published: April 2012

Obesity triggers a low-grade systemic inflammation, which plays an important role in the development of obesity-associated metabolic diseases. In searching for links between lipid accumulation and chronic inflammation, we examined invariant natural killer T (iNKT) cells, a subset of T lymphocytes that react with lipids and regulate inflammatory responses. We show that iNKT cells respond to dietary lipid excess and become activated before or at the time of tissue recruitment of inflammatory leukocytes, and that these cells progressively increase proinflammatory cytokine production in obese mice. Such iNKT cells skew other leukocytes toward proinflammatory cytokine production and induce an imbalanced proinflammatory cytokine environment in multiple tissues. Further, iNKT cell deficiency ameliorates tissue inflammation and provides protection against obesity-induced insulin resistance and hepatic steatosis. Conversely, chronic iNKT cell stimulation using a canonical iNKT cell agonist exacerbates tissue inflammation and obesity-associated metabolic disease. These findings place iNKT cells into the complex network linking lipid excess to inflammation in obesity and suggest new therapeutic avenues for obesity-associated metabolic disorders.
Interfacial electronic effects in functional biolayers integrated into organic field-effect transistors
Authors: Angione Maria Daniela , Cotrone Serafina , Magliulo Maria , Mallardi Antonia , Altamura Davide , Giannini Cinzia , Cioffi Nicola , Sabbatini Luigia , Fratini Emiliano , Baglioni Piero , Scamarcio Gaetano , Palazzo Gerardo , Torsi Luisa
Published: April 2012

Biosystems integration into an organic field-effect transistor (OFET) structure is achieved by spin coating phospholipid or protein layers between the gate dielectric and the organic semiconductor. An architecture directly interfacing supported biological layers to the OFET channel is proposed and, strikingly, both the electronic properties and the biointerlayer functionality are fully retained. The platform bench tests involved OFETs integrating phospholipids and bacteriorhodopsin exposed to 1–5% anesthetic doses that reveal drug-induced changes in the lipid membrane. This result challenges the current anesthetic action model relying on the so far provided evidence that doses much higher than clinically relevant ones (2.4%) do not alter lipid bilayers’ structure significantly. Furthermore, a streptavidin embedding OFET shows label-free biotin electronic detection at 10 parts-per-trillion concentration level, reaching state-of-the-art fluorescent assay performances. These examples show how the proposed bioelectronic platform, besides resulting in extremely performing biosensors, can open insights into biologically relevant phenomena involving membrane weak interfacial modifications.
Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates
Authors: Senejani Alireza G. , Dalal Shibani , Liu Yanfeng , Nottoli Timothy P. , McGrath James M. , Clairmont Connor S. , Sweasy Joann B.
Published: April 2012

DNA is susceptible to damage by a wide variety of chemical agents that are generated either as byproducts of cellular metabolism or exposure to man-made and harmful environments. Therefore, to maintain genomic integrity, having reliable DNA repair systems is important. DNA polymerase β is known to be a key player in the base excision repair pathway, and mice devoid of DNA polymerase beta do not live beyond a few hours after birth. In this study, we characterized mice harboring an impaired pol β variant. This Y265C pol β variant exhibits slow DNA polymerase activity but WT lyase activity and has been shown to be a mutator polymerase. Mice expressing Y265C pol β are born at normal Mendelian ratios. However, they are small, and 60% die within a few hours after birth. Slow proliferation and significantly increased levels of cell death are observed in many organs of the E14 homozygous embryos compared with WT littermates. Mouse embryo fibroblasts prepared from the Y265C pol β embryos proliferate at a rate slower than WT cells and exhibit a gap-filling deficiency during base excision repair. As a result of this, chromosomal aberrations and single- and double-strand breaks are present at significantly higher levels in the homozygous mutant versus WT mouse embryo fibroblasts. This is study in mice is unique in that two enzymatic activities of pol β have been separated; the data clearly demonstrate that the DNA polymerase activity of pol β is essential for survival and genome stability.
Footprints of positive selection associated with a mutation (
N1575Y
) in the voltage-gated sodium channel of
Anopheles gambiae
Authors: Jones Christopher M. , Liyanapathirana Milindu , Agossa Fiacre R. , Weetman David , Ranson Hilary , Donnelly Martin James , Wilding Craig S.
Published: April 2012

Insecticide resistance is an ideal model to study the emergence and spread of adaptative variants. In the African malaria mosquito,
Anopheles gambiae
, this is complemented by a strong public health rationale. In this insect, resistance to pyrethroid and DDT insecticides is strongly associated with the mutations
L1014F
and
L1014S
within the
para
voltage-gated sodium channel (VGSC). Across much of West Africa,
1014F
frequency approaches fixation. Here, we document the emergence of a mutation,
N1575Y
, within the linker between domains III-IV of the VGSC. In data extending over 40 kbp of the VGSC
1575Y
occurs on only a single long-range haplotype, also bearing
1014F
. The
1014F-1575Y
haplotype was found in both M and S molecular forms of
An. gambiae
in West/Central African sample sites separated by up to 2,000 km. In Burkina Faso M form,
1575Y
allele frequency rose significantly from 0.053 to 0.172 between 2008 and 2010. Extended haplotype homozygosity analysis of the wild-type
1575N
allele showed rapid decay of linkage disequilibrium (LD), in sharp contrast to the extended LD exhibited by
1575Y
. A haplotype with long-range LD and high/increasing frequency is a classical sign of strong positive selection acting on a recent mutant.
1575Y
occurs ubiquitously on a
1014F
haplotypic background, suggesting that the
N1575Y
mutation compensates for deleterious fitness effects of
1014F
and/or confers additional resistance to insecticides. Haplotypic tests of association suggest the latter: The
1014F-1575Y
haplotype confers a significant additive benefit above
1014F-1575N
for survival to DDT (M form
P =
0.03) and permethrin (S form
P =
0.003).