bluuebunny/crossref_metadata_2025 huggingface dataset:
Vision, Haptics, and Attention: New Data from a Multisensory Necker Cube
Authors: Bertamini Marco , Masala Luigi , Meyer Georg , Bruno Nicola
Published: January 2010

When looking monocularly at a three-dimensional (3-D) Necker cube two percepts alternate: a cube and a truncated pyramid. The latter is due to a depth reversal. We studied the effect of haptic information by having participants hold the cube with their hands and explore two of its vertices. Touch reduces the likelihood of the pyramid, consistent with a multisensory view of 3-D form perception. In addition, when the hand alternates between stationary and haptic exploration, the onset of the hand movement plays a crucial role in inhibiting reversals. A temporal analysis revealed that suppression occurred within a window lasting a few seconds from motion onset. In experiment 1, we monitored eye movements and instructed participants where to fixate. Although the percept does depend on which vertex is fixated, we ruled out a role of changes of fixation as a mediating factor for the effect of motion onset. In experiment 2, we introduced a change of position of the exploring hand as a new type of transition. This type of change did not produce the same inhibition generated by the motion onset. We conclude that motion onset does not simply draw attention towards haptic information. Rather, the influence of haptics peaks briefly after new information becomes available.
LIM protein Ajuba functions as a nuclear receptor corepressor and negatively regulates retinoic acid signaling
Authors: Hou Zhaoyuan , Peng Hongzhuang , White David E. , Negorev Dmitri G. , Maul Gerd G. , Feng Yunfeng , Longmore Gregory D. , Waxman Samuel , Zelent Arthur , Rauscher Frank J.
Published: January 2010

Corepressors play an essential role in nuclear receptor-mediated transcriptional repression. In general, corepressors directly bind to nuclear receptors via CoRNR boxes (L/I-X-X-I/V-I) in the absence of ligand and appear to act as scaffolds to further recruit chromatin remodeling complexes to specific target genes. Here, we describe the identification of the multiple LIM domain protein Ajuba as a unique corepressor for a subset of nuclear hormone receptors. Ajuba contains functional nuclear-receptor interacting motifs and selectively interacts with retinoic acid receptors (RARs) and rexinoid receptor (RXRs) subtypes in a ligand-dependent manner. Simultaneous mutation of these motifs abolishes RAR binding and concomitantly leads to loss of repression on RARE reporter genes. P19 cells depleted of Ajuba are highly sensitized to all-trans retinoic acid (atRA)-induced transcription and differentiation. In the absence of atRA, Ajuba can be readily found at the RARE control elements of RAR endogenous target genes. Stimulation of cells with atRA results in the dissociation of Ajuba from these regions. Moreover, we observed that coexpression of the known Ajuba binding partner Prmt5 (protein arginine methyltransferase-5) inhibited the Ajuba/RAR interaction. The high-affinity Ajuba-RAR/RXR interaction site overlaps the region responsible for Ajuba/Prmt5 binding, and thus binding appears to be mutually exclusive, providing a potential mechanism for these observations. Identification of Ajuba as a unique corepressor for nuclear receptors sheds new light on mechanisms for nuclear receptor-mediated repression and provides a unique target for developing more effective therapeutics to modulate this important pathway.
Predicting the reaction coordinates of millisecond light-induced conformational changes in photoactive yellow protein
Authors: Vreede Jocelyne , Juraszek Jarek , Bolhuis Peter G.
Published: January 2010

Understanding the dynamics of large-scale conformational changes in proteins still poses a challenge for molecular simulations. We employ transition path sampling of explicit solvent molecular dynamics trajectories to obtain atomistic insight in the reaction network of the millisecond timescale partial unfolding transition in the photocycle of the bacterial sensor photoactive yellow protein. Likelihood maximization analysis predicts the best model for the reaction coordinates of each substep as well as tentative transition states, without further simulation. We find that the unfolding of the α-helical region 43–51 is followed by sequential solvent exposure of both Glu46 and the chromophore. Which of these two residues is exposed first is correlated with the presence of a salt bridge that is part of the N-terminal domain. Additional molecular dynamics simulations indicate that the exposure of the chromophore does not result in a productive pathway. We discuss several possibilities for experimental validation of these predictions. Our results open the way for studying millisecond conformational changes in other medium-sized (signaling) proteins.
NleH effectors interact with Bax inhibitor-1 to block apoptosis during enteropathogenic
Escherichia coli
infection
Authors: Hemrajani Cordula , Berger Cedric N. , Robinson Keith S. , Marchès Olivier , Mousnier Aurelie , Frankel Gad
Published: January 2010

The human pathogens enteropathogenic (EPEC) and enterohemorrhagic
Escherichia coli
and the related mouse pathogen
Citrobacter rodentium
subvert a variety of host cell signaling pathways via their plethora of type III secreted effectors, including triggering of an early apoptotic response. EPEC-infected cells do not develop late apoptotic symptoms, however. In this study we demonstrate that the NleH family effectors, homologs of the
Shigella
effector kinase OspG, blocks apoptosis. During EPEC infection, NleH effectors inhibit elevation of cytosolic Ca
2+
concentrations, nuclear condensation, caspase-3 activation, and membrane blebbing and promote cell survival. NleH1 alone is sufficient to prevent procaspase-3 cleavage induced by the proapoptotic compounds staurosporine, brefeldin A, and tunicamycin. Using
C. rodentium
, we found that NleH inhibits procaspase-3 cleavage at the bacterial attachment sites in vivo. A yeast two-hybrid screen identified the endoplasmic reticulum six-transmembrane protein Bax inhibitor-1 (BI-1) as an NleH-interacting partner. We mapped the NleH-binding site to the N-terminal 40 amino acids of BI-1. Knockdown of BI-1 resulted in the loss of NleH’s antiapoptotic activity. These results indicate that NleH effectors are inhibitors of apoptosis that may act through BI-1 to carry out their cytoprotective function.
A
Drosophila
model for TDP-43 proteinopathy
Authors: Li Yan , Ray Payal , Rao Elizabeth J. , Shi Chen , Guo Weirui , Chen Xiaoping , Woodruff Elvin A. , Fushimi Kazuo , Wu Jane Y.
Published: January 2010

Neuropathology involving TAR DNA binding protein-43 (TDP-43) has been identified in a wide spectrum of neurodegenerative diseases collectively named as TDP-43 proteinopathy, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). To test whether increased expression of wide-type human TDP-43 (hTDP-43) may cause neurotoxicity in vivo, we generated transgenic flies expressing hTDP-43 in various neuronal subpopulations. Expression in the fly eyes of the full-length hTDP-43, but not a mutant lacking its amino-terminal domain, led to progressive loss of ommatidia with remarkable signs of neurodegeneration. Expressing hTDP-43 in mushroom bodies (MBs) resulted in dramatic axon losses and neuronal death. Furthermore, hTDP-43 expression in motor neurons led to axon swelling, reduction in axon branches and bouton numbers, and motor neuron loss together with functional deficits. Thus, our transgenic flies expressing hTDP-43 recapitulate important neuropathological and clinical features of human TDP-43 proteinopathy, providing a powerful animal model for this group of devastating diseases. Our study indicates that simply increasing hTDP-43 expression is sufficient to cause neurotoxicity in vivo, suggesting that aberrant regulation of TDP-43 expression or decreased clearance of hTDP-43 may contribute to the pathogenesis of TDP-43 proteinopathy.
General trend for pressurized superconducting hydrogen-dense materials
Authors: Kim Duck Young , Scheicher Ralph H. , Mao Ho-kwang , Kang Tae W. , Ahuja Rajeev
Published: January 2010

The long-standing prediction that hydrogen can assume a metallic state under high pressure, combined with arguments put forward more recently that this state might even be superconducting up to high temperatures, continues to spur tremendous research activities toward the experimental realization of metallic hydrogen. These efforts have however so far been impeded by the enormous challenges associated with the exceedingly large required pressure. Hydrogen-dense materials, of the MH
4
form (where M can be, e.g., Si, Ge, or Sn) or of the MH
3
form (with M being, e.g., Al, Sc, Y, or La), allow for the rather exciting opportunity to carry out a proxy study of metallic hydrogen and associated high-temperature superconductivity at pressures within the reach of current techniques. At least one experimental report indicates that a superconducting state might have been observed already in SiH
4
, and several theoretical studies have predicted superconductivity in pressurized hydrogen-rich materials; however, no systematic dependence on the applied pressure has yet been identified so far. In the present work, we have used first-principles methods in an attempt to predict the superconducting critical temperature (
T

c

) as a function of pressure (
P
) for three metal-hydride systems of the MH
3
form, namely ScH
3
, YH
3
, and LaH
3
. By comparing the obtained results, we are able to point out a general trend in the
T

c

-dependence on
P
. These gained insights presented here are likely to stimulate further theoretical studies of metallic phases of hydrogen-dense materials and should lead to new experimental investigations of their superconducting properties.
Enhancement of GABA
A
-current run-down in the hippocampus occurs at the first spontaneous seizure in a model of temporal lobe epilepsy
Authors: Mazzuferi Manuela , Palma Eleonora , Martinello Katiuscia , Maiolino Francesca , Roseti Cristina , Fucile Sergio , Fabene Paolo F. , Schio Federica , Pellitteri Michele , Sperk Guenther , Miledi Ricardo , Eusebi Fabrizio , Simonato Michele
Published: January 2010

Refractory temporal lobe epilepsy (TLE) is associated with a dysfunction of inhibitory signaling mediated by GABA
A
receptors. In particular, the use-dependent decrease (run-down) of the currents (I
GABA
) evoked by the repetitive activation of GABA
A
receptors is markedly enhanced in hippocampal and cortical neurons of TLE patients. Understanding the role of I
GABA
run-down in the disease, and its mechanisms, may allow development of medical alternatives to surgical resection, but such mechanistic insights are difficult to pursue in surgical human tissue. Therefore, we have used an animal model (pilocarpine-treated rats) to identify when and where the increase in I
GABA
run-down occurs in the natural history of epilepsy. We found: (
i
) that the increased run-down occurs in the hippocampus at the time of the first spontaneous seizure (i.e., when the diagnosis of epilepsy is made), and then extends to the neocortex and remains constant in the course of the disease; (
ii
) that the phenomenon is strictly correlated with the occurrence of spontaneous seizures, because it is not observed in animals that do not become epileptic. Furthermore, initial exploration of the molecular mechanism disclosed a relative increase in α4-, relative to α1-containing GABA
A
receptors, occurring at the same time when the increased run-down appears, suggesting that alterations in the molecular composition of the GABA receptors may be responsible for the occurrence of the increased run-down. These observations disclose research opportunities in the field of epileptogenesis that may lead to a better understanding of the mechanism whereby a previously normal tissue becomes epileptic.
Reactive oxygen species–independent activation of the IL-1β inflammasome in cells from patients with chronic granulomatous disease
Authors: van de Veerdonk Frank L. , Smeekens Sanne P. , Joosten Leo A. B. , Kullberg Bart Jan , Dinarello Charles A. , van der Meer Jos W. M. , Netea Mihai G.
Published: January 2010

Humans with chronic granulomatous diseases (CGDs) due to mutations in p47-phox have defective NADPH activity and thus cannot generate NADPH-dependent reactive oxygen species (ROS). The role of ROS in inflammation is controversial; some in vitro studies suggest that ROS are crucial for secretion of IL-1β via inflammasome activation, whereas mice defective for ROS and patients with CGD have a proinflammatory phenotype. In this study, we evaluated activation of the IL-1β inflammasome in cells from CGD patients. In contrast to previous studies using the small molecule diphenylene iodonium (DPI) as a ROS inhibitor, we found no decrease in either caspase-1 activation or secretion of IL-1β and IL-18 in primary CGD monocytes. Moreover, activation of CGD monocytes by uric acid crystals induced a 4-fold higher level of IL-1β secretion compared with that seen in monocytes from unaffected subjects, and this increase was not due to increased synthesis of the IL-1β precursor. In addition, Western blot analysis of CGD cells revealed that caspase-1 activation was not decreased, but rather was increased compared with control cells. Examination of the effects exerted by the inhibition of ROS activity by DPI revealed that the decrease in IL-1β secretion by DPI was actually due to inhibition of IL-1β gene expression. Thus, inconsistent with the proinflammatory role of ROS, the present findings support the concept that ROS likely dampen inflammasome activation. The absence of ROS in CGD monocytes may explain the presence of an inflammatory phenotype characterized by granulomas and inflammatory bowel disease occurring in CGD patients.
Discovery of a distinct domain in cyclin A sufficient for centrosomal localization independently of Cdk binding
Authors: Pascreau Gaetan , Eckerdt Frank , Churchill Mair E. A. , Maller James L.
Published: January 2010

Centrosomes have recently emerged as key regulators of the cell cycle. The G1/S transition requires a functional centrosome, and centrosomal localization of numerous proteins, including cyclin/Cdk complexes, is important for the G2/M transition. Here we identify a modular centrosomal localization signal (CLS) localizing cyclin A to centrosomes independently of Cdk binding. The cyclin A CLS is located in a distinct part of the molecule compared with the cyclin E CLS and includes the MRAIL hydrophobic patch involved in substrate recognition. The cyclin A CLS interacts with p27
KIP1
, and expression of p27
KIP1
removes cyclin A but not cyclin E from centrosomes. Expression of the cyclin A CLS displaces both endogenous cyclin A and E from centrosomes and inhibits DNA replication, supporting an emerging concept that DNA replication is linked to centrosomal events. Structural analysis indicates that differences in surface charge and length of the C-terminal helix explain why the MRAIL region in cyclin E is not a functional CLS. These results indicate that the cyclin A CLS may contribute to targeting and recognition of centrosomal Cdk substrates and is required for specific effects of p27
KIP1
on cyclin A-Cdk2.
DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway
Authors: Aleyasin Hossein , Rousseaux Maxime W. C. , Marcogliese Paul C. , Hewitt Sarah J. , Irrcher Isabella , Joselin Alvin P. , Parsanejad Mohammad , Kim Raymond H. , Rizzu Patrizia , Callaghan Steve M. , Slack Ruth S. , Mak Tak W. , Park David S.
Published: January 2010

Loss-of-function DJ-1 (PARK7) mutations have been linked with a familial form of early onset Parkinson disease. Numerous studies have supported the role of DJ-1 in neuronal survival and function. Our initial studies using DJ-1-deficient neurons indicated that DJ-1 specifically protects the neurons against the damage induced by oxidative injury in multiple neuronal types and degenerative experimental paradigms, both in vitro and in vivo. However, the manner by which oxidative stress-induced death is ameliorated by DJ-1 is not completely clear. We now present data that show the involvement of DJ-1 in modulation of AKT, a major neuronal prosurvival pathway induced upon oxidative stress. We provide evidence that DJ-1 promotes AKT phosphorylation in response to oxidative stress induced by H
2
O
2
in vitro and in vivo following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Moreover, we show that DJ-1 is necessary for normal AKT-mediated protective effects, which can be bypassed by expression of a constitutively active form of AKT. Taken together, these data suggest that DJ-1 is crucial for full activation of AKT upon oxidative injury, which serves as one explanation for the protective effects of DJ-1.
Expression of cancer testis antigen CT45 in classical Hodgkin lymphoma and other B-cell lymphomas
Authors: Chen Yao-Tseng , Chadburn Amy , Lee Peishan , Hsu Melinda , Ritter Erika , Chiu April , Gnjatic Sacha , Pfreundschuh Michael , Knowles Daniel M. , Old Lloyd J.
Published: January 2010

We have shown previously that cancer/testis (CT) antigen, CT45, is expressed in various epithelial cancers at a frequency of <5% to ∼35%. In this study, the protein expression of CT45 was examined in non-Hodgkin B-cell lymphomas and classical Hodgkin lymphoma by immunohistochemical analysis. Serological response to CT45 was also evaluated by ELISA using CT45 recombinant protein and sera from patients with Hodgkin lymphoma. None of the 80 low-grade B-cell lymphomas, including chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, and mantle cell lymphoma, expressed CT45. In comparison, CT45 was expressed in 28 of 126 (22%) diffuse large B-cell lymphomas (DLBCL). A remarkably high percentage (42/72, 58%) of classical Hodgkin lymphoma contained CT45-positive Reed–Sternberg cells. Nodular sclerosis and mixed-cellularity subtypes had similar frequency of CT45 expression, but most EBV-positive cases were CT45 negative. Gray-zone lymphoma (cases with features of both DLBCL and classical Hodgkin lymphoma) also showed frequent (64%) CT45 expression. Evaluation of reactive lymphoid tissues showed scattered CT45-positive lymphocytes in a single case of florid follicular hyperplasia, raising the possibility that this case was an evolving malignancy. Despite frequent CT45 expression, only 1 of 67 Hodgkin lymphoma patients had detectable anti-CT45 antibodies in the serum, suggesting that the immune response to CT45 may be suppressed. In conclusion, classical Hodgkin lymphoma has the highest frequency of CT45 expression among all malignancies tested to date, the frequency of CT45 expression in DLBCL is similar to that seen in epithelial cancers, and low-grade non-Hodgkin B-cell lymphomas do not express CT45.
Drift and “Statistically Abstractive Explanation”
Authors: Matthen Mohan
Published: January 2010

A hitherto neglected form of explanation is explored, especially its role in population genetics. “Statistically abstractive explanation” (SA explanation) mandates the suppression of factors probabilistically relevant to an explanandum when these factors are extraneous to the theoretical project being pursued. When these factors are suppressed, the explanandum is rendered uncertain. But this uncertainty traces to the theoretically constrained character of SA explanation, not to any real indeterminacy. Random genetic drift is an artifact of such uncertainty, and it is therefore wrong to reify it as a cause of evolution or as a process in its own right.
Understanding Thermodynamic Singularities: Phase Transitions, Data, and Phenomena
Authors: Bangu Sorin
Published: January 2010

According to standard (quantum) statistical mechanics, the phenomenon of a phase transition, as described in classical thermodynamics, cannot be derived unless one assumes that the system under study is infinite. This is naturally puzzling since real systems are composed of a finite number of particles; consequently, a well-known reaction to this problem was to urge that the thermodynamic definition of phase transitions (in terms of singularities) should not be “taken seriously.” This article takes singularities seriously and analyzes their role by using the well-known distinction between data and phenomena, in an attempt to better understand the origin of the puzzle.
An approximate analytic expression for neoclassical toroidal plasma viscosity in tokamaks
Authors: Shaing K.C. , Sabbagh S.A. , Chu M.S.
Published: January 2010

An approximate analytic expression for neoclassical toroidal plasma viscosity in tokamaks that have error fields or magnetohydrodynamic activities is presented. The expression smoothly joins transport fluxes or plasma viscosity in all the known collisionality regimes derived from the solution of the bounce averaged drift kinetic equation and should be useful in modelling results of existing and future tokamak experiments. It also incorporates some of the extensions of the known expressions to include the effects of finite ∇Bdrift in the non-resonant transport processes. Here,Bis the magnitude of the magnetic field. The toroidal momentum balance equation is a nonlinear function of the radial electric field when the neoclassical plasma viscosity is dominant. It can have bifurcated solutions for the radial electric field and may lead to better plasma confinement as a result.
Effect of neutron irradiation on the characteristics of laser-produced plasma
Authors: Khaydarov R.T. , Beisinbaeva H.B. , Sabitov M.M. , Terentev V.B. , Berdiyorov G.R.
Published: January 2010

Using the mass-spectrometric method we studied the formation of multi-charged plasma ions during the interaction of laser radiation with solid targets irradiated by neutron beams. We found that structural defects, caused by the neutron irradiation, influence not only the efficiency of the process of material evaporation and emission of plasma, but also the ionization and recombination processes taking place at the initial stage of plasma formation and expansion. We also show the effect of the dose of neutron irradiation on the threshold of plasma formation from the surface of the target.
Population Pharmacokinetic–Pharmacodynamic Modeling of Epidural Anesthesia
Authors: Olofsen Erik , Burm Antonius G. L. , Simon Mischa J. G. , Veering Bernadette Th. , van Kleef Jack W. , Dahan Albert
Published: January 2010

Background

In previous studies, the authors reported on the absorption and disposition kinetics of levobupivacaine and ropivacaine. The current study was designed to develop a population pharmacokinetic-pharmacodynamic model capable of linking the kinetic data to the analgesic effects of these local anesthetics (i.e., sensory neural blockade).

Methods

A disposition compartmental model was fitted to concentration data of the intravenously administered deuterium-labeled anesthetics, and a model consisting of two parallel absorption compartments and the identified disposition compartments was fitted to concentration data of the concomitantly epidurally administered unlabeled anesthetics. The epidural segments were modeled by individual central and peripheral absorption compartments and effect sites, which were fitted to the simultaneously acquired pinprick data. A covariate model incorporated the effects of age.

Results

The threshold for epidural anesthesia increased from the lower to the higher segments. The central effect compartment equilibration half-lives were approximately 15 min for levobupivacaine and 25 min for ropivacaine. For levobupivacaine, age reduced the equilibration half-lives at all segments; for ropivacaine, age increased the anesthetic sensitivity at segments T12 and higher.

Conclusions

A population pharmacokinetic-pharmacodynamic model was developed that quantitatively described sensory blockade during epidural anesthesia, including the effects of age. The model may be useful to individualize dose requirements, to predict the time course of sensory blockade, and to study new local anesthetics.
Sleep Disturbances after Posterior Scoliosis Surgery with an Intraoperative Wake-up Test Using Remifentanil
Authors: Rehberg Sebastian , Weber Thomas P. , Van Aken Hugo , Theisen Marc , Ertmer Christian , Bröking Katrin , Schulte Tobias , Osada Nani , Asemann Dominique , Bullmann Viola
Published: January 2010

Background

The intraoperative wake-up test is a standard procedure for early recognition of neurologic complications after posterior correction of idiopathic scoliosis. In this prospective, single-blinded cohort study, the impact of the wake-up test and the opioid used for anesthesia on the quality of the patients' sleep after scoliosis surgery was investigated up to 12 months postoperatively.

Methods

Patients were classified into three groups: posterior instrumentation with wake-up test using remifentanil, anterior instrumentation without wake-up test using sufentanil, and posterior instrumentation with wake-up test using sufentanil. The quality of sleep was assessed using the Pittsburgh Sleep Quality Index questionnaire preoperatively as well as 3, 6, and 12 months postoperatively. In addition, data were collected on patients' age, weight, and sex, as well as the duration of the operation and anesthesia, amount of blood loss, specific opioid dosages, and wake-up test times. Statistical analysis was conducted using the Mann-Whitney, Kruskal-Wallis, and Wilcoxon tests.

Results

There were no differences between groups with regard to baseline characteristics. No explicit recall was assessed through all groups. At 3 and 6 months postoperatively, the sleep quality in the posterior-remifentanil group was significantly poorer than preoperatively and compared with the anterior- and posterior-sufentanil groups. No significant differences in wake-up test times between groups undergoing posterior instrumentation occurred.

Conclusions

This study suggests that patients undergoing scoliosis surgery with an intraoperative wake-up test using remifentanil had impaired sleep quality that lasted up to 6 months postoperatively. No deterioration in sleep quality was observed with sufentanil. Large randomized trials are now needed to confirm these preliminary results.
Effect of Nitrous Oxide Anesthesia on Plasma Homocysteine and Endothelial Function
Authors: Myles Paul S. , Chan Matthew T. V. , Kaye David M. , McIlroy David R. , Lau Chung-Wai , Symons Joel A. , Chen Shaohui
Published: January 2010

Background

Endothelial function is impaired with hyperhomocysteinemia. Plasma homocysteine is increased by nitrous oxide anesthesia. The current study was designed to determine whether endothelial function is impaired after surgery and whether this is made worse by exposure to nitrous oxide.

Methods

The authors studied 59 patients with cardiovascular disease undergoing noncardiac surgery. Patients were randomly allocated to nitrous oxide-based anesthesia (n = 25) or nitrous oxide-free anesthesia (control, n = 34). Endothelial function was measured by flow-mediated dilation of the brachial artery before and 24 h after surgery. In addition, blood was drawn at both time points for the measurements of plasma homocysteine, folate, L-arginine, L-citrulline, asymmetric dimethylarginine, and nitrate concentrations.

Results

The median duration of general anesthesia was 4.5 h. Patients had significantly lower flow-mediated dilation after surgery (5.1 +/- 3.3 to 3.0 +/- 4.1%; P = 0.001). Duration of anesthesia affected endothelial function. In the nitrous oxide group, there was an inverse correlation with flow-mediated dilation (r = -0.60, P = 0.004), but in the control group, there was a positive correlation (r = 0.61, P < 0.001). When compared with control, nitrous oxide exposure was associated with a significant increase in postoperative homocysteine (mean difference, 4.9 microm; 95% confidence interval, 2.8-7.0 microm; P < 0.0005) and decrease in flow-mediated dilation (3.2%; 95% confidence interval, 0.1-5.3%; P = 0.001). Nitrous oxide exposure was not associated with change in nitric oxide substrates.

Conclusions

Nitrous oxide-based anesthesia increased plasma homocysteine and significantly impaired endothelial function in patients undergoing noncardiac surgery. Nitrous oxide-based anesthesia could be a risk factor for postoperative cardiovascular morbidity.
Detecting Awareness in Children by Using an Auditory Intervention
Authors: Davidson Andrew J. , Sheppard Suzette J. , Engwerda Anneke L. , Wong Aaron , Phelan Lauren , Ironfield Craig M. , Stargatt Robyn
Published: January 2010

Background

The incidence of awareness has been reported to be higher in children than in adults. Accurately assessing awareness in children is difficult, and the lack of a specific measure of awareness makes it difficult to determine exactly how many and why children are aware. The aim of this study was to determine the incidence and timing of awareness in children by using auditory stimuli applied during anesthesia.

Methods

Three easily identified animal noises were played repeatedly through headphones during three specific phases of anesthesia in 539 children aged 5-12 yr. Children were not told that this would happen. Awareness was determined with a structured interview on days 1 and 3 after the anesthetic. All positive responses were sent to four adjudicators for assessment, and awareness was defined as having occurred if all adjudicators agreed that the child was aware.

Results

Five hundred children were interviewed at least once after the anesthetic. Thirty-five reports were sent to the adjudicators, and one child was classified as aware. This child was deemed to be aware even though he did not report hearing an animal.

Conclusions

The incidence of awareness in this study is less than reported previously.
Fluoropolymer-based Emulsions for the Intravenous Delivery of Sevoflurane
Authors: Fast Jonathan P. , Perkins Mark G. , Pearce Robert A. , Mecozzi Sandro
Published: January 2010

Background

The intravenous delivery of halogenated volatile anesthetics has been previously achieved using phospholipid-stabilized emulsions, e.g., Intralipid. However, fluorinated volatile anesthetics, such as sevoflurane, are partially fluorophilic and do not mix well with classic nonfluorinated lipids. This effect limits the maximum amount of sevoflurane that can be stably emulsified in Intralipid to 3.5% vol/vol. This is a significant limitation to the potential clinical use of Intralipid-based emulsions.

Methods

The authors prepared a 20% vol/vol sevoflurane emulsion using a novel fluorinated surfactant and tested its effectiveness and therapeutic index by administering it to male Sprague-Dawley rats via intravenous injection into the jugular vein. The median effective dose to induce anesthesia (ED50), the median lethal dose (LD50), and the therapeutic index (LD50/ED50) were determined. Anesthesia was measured by loss of the forepaw righting reflex.

Results

The ED50 and LD50 values were found to be 0.41 and 1.05 ml emulsion/kg body weight, respectively. These lead to a therapeutic index of 2.6, which compares favorably with previously determined values of emulsified isoflurane, as well as values for propofol and thiopental.

Conclusions

A novel semifluorinated surfactant was able to considerably increase the maximum amount of stably emulsified sevoflurane compared with Intralipid. These formulations can be used to rapidly induce anesthesia with bolus dosing from which recovery is smooth and rapid.
A Rational Approach to Perioperative Fluid Management
Authors: Chappell Daniel , Jacob Matthias , Hofmann-Kiefer Klaus , Conzen Peter , Rehm Markus
Published: January 2010

Replacement of assumed preoperative deficits, in addition to generous substitution of an unsubstantiated increased insensible perspiration and third space loss, plays an important role in current perioperative fluid regimens. The consequence is a positive fluid balance and weight gain of up to 10 kg, which may be related to severe complications. Because the intravascular blood volume remains unchanged and insensible perspiration is negligible, the fluid must accumulate inside the body. This concept brings into question common liberal infusion regimens. Blood volume after fasting is normal, and a fluid-consuming third space has never been reliably shown. Crystalloids physiologically load the interstitial space, whereas colloidal volume loading deteriorates a vital part of the vascular barrier. The endothelial glycocalyx plays a key role and is destroyed not only by ischemia and surgery, but also by acute hypervolemia. Therefore, undifferentiated fluid handling may increase the shift toward the interstitial space. Using the right kind of fluid in appropriate amounts at the right time might improve patient outcome.
Impact of replication timing on non-CpG and CpG substitution rates in mammalian genomes
Authors: Chen Chun-Long , Rappailles Aurélien , Duquenne Lauranne , Huvet Maxime , Guilbaud Guillaume , Farinelli Laurent , Audit Benjamin , d'Aubenton-Carafa Yves , Arneodo Alain , Hyrien Olivier , Thermes Claude
Published: January 2010

Neutral nucleotide substitutions occur at varying rates along genomes, and it remains a major issue to unravel the mechanisms that cause these variations and to analyze their evolutionary consequences. Here, we study the role of replication in the neutral substitution pattern. We obtained a high-resolution replication timing profile of the whole human genome by massively parallel sequencing of nascent BrdU-labeled replicating DNA. These data were compared to the neutral substitution rates along the human genome, obtained by aligning human and chimpanzee genomes using macaque and orangutan as outgroups. All substitution rates increase monotonously with replication timing even after controlling for local or regional nucleotide composition, crossover rate, distance to telomeres, and chromatin compaction. The increase in non-CpG substitution rates might result from several mechanisms including the increase in mutation-prone activities or the decrease in efficiency of DNA repair during the S phase. In contrast, the rate of C → T transitions in CpG dinucleotides increases in later-replicating regions due to increasing DNA methylation level that reflects a negative correlation between timing and gene expression. Similar results are observed in the mouse, which indicates that replication timing is a main factor affecting nucleotide substitution dynamics at non-CpG sites and constitutes a major neutral process driving mammalian genome evolution.
Diploid male production in a leaf‐cutting ant
Authors: ARMITAGE SOPHIE , BOOMSMA JACOBUS , BAER BORIS
Published: January 2010

1. In haplodiploid social insects where males are haploid and females are diploid, inbreeding depression is expressed as the production of diploid males when homozygosity at the sex‐determining locus results in the production of diploid individuals with a male phenotype. Diploid males are often assumed to have reduced fitness compared with their haploid brothers.

2. While studying the reproductive biology of a leaf‐cutting ant, Atta sexdens, in Gamboa, Republic of Panama, we detected the presence of a larger male morph. Using microsatellite markers we were able to confirm that the large male morph was diploid in 87% of cases.

3. We infer that the Gamboa population of A. sexdens experiences inbreeding depression because diploid males were found in three out of five mature colonies. However, their frequencies were relatively low because queens were multiply mated and our estimates suggest that many diploid male larvae may not survive to adulthood.

4. We measured two traits potentially linked to male reproductive success: sperm length and sperm number, and showed that diploid males produced fewer but longer sperm. These results provide indirect evidence that diploid male reproductive success would be reduced compared with haploid males if they were able to copulate.

5. We conclude that diploid male production is likely to affect the fitness of A. sexdens queens with a matched mating, as these males are produced at the cost of workers and, if the colony survives to reach mature size, also gynes.
Trophic level modulates carabid beetle responses to habitat and landscape structure: a pan‐European study
Authors: VANBERGEN ADAM J. , WOODCOCK BEN A. , KOIVULA MATTI , NIEMELÄ JARI , KOTZE D. JOHAN , BOLGER TOM , GOLDEN VALERIE , DUBS FLORENCE , BOULANGER GUILLAUME , SERRANO JOSE , LENCINA JOSÉ LUÍS , SERRANO ARTUR , AGUIAR CARLOS , GRANDCHAMP ANNE‐CATHERINE , STOFER SILVIA , SZÉL GYÖZÖ , IVITS EVA , ADLER PETRA , MARKUS JOCHUM , WATT ALLAN D.
Published: January 2010

1. Anthropogenic pressures have produced heterogeneous landscapes expected to influence diversity differently across trophic levels and spatial scales.

2. We tested how activity density and species richness of carabid trophic groups responded to local habitat and landscape structure (forest percentage cover and habitat richness) in 48 landscape parcels (1 km2) across eight European countries.

3. Local habitat affected activity density, but not species richness, of both trophic groups. Activity densities were greater in rotational cropping compared with other habitats; phytophage densities were also greater in grassland than forest habitats.

4. Controlling for country and habitat effects, we found general trophic group responses to landscape structure. Activity densities of phytophages were positively correlated, and zoophages uncorrelated, with increasing habitat richness. This differential functional group response to landscape structure was consistent across Europe, indicated by a lack of a country × habitat richness interaction. Species richness was unaffected by landscape structure.

5. Phytophage sensitivity to landscape structure may arise from relative dependency on seed from ruderal plants. This trophic adaptation, rare in Carabidae, leads to lower phytophage numbers, increasing vulnerability to demographic and stochastic processes that the greater abundance, species richness, and broader diet of the zoophage group may insure against.
Patients with Wegener’s granulomatosis demonstrate a relative deficiency and functional impairment of T‐regulatory cells
Authors: Morgan Matthew D. , Day Clara J. , Piper Karen P. , Khan Naeem , Harper Lorraine , Moss Paul A. , Savage Caroline O. S.
Published: January 2010

An increased proportion of CD4+ CD25+ T cells has been reported in Wegener’s granulomatosis (WG) and may represent an accumulation of regulatory T cells (Treg). CD25 is also expressed on recently activated effector T cells. We have determined the relative proportion of these subsets in a large patient cohort. The fraction of Treg in peripheral blood mononuclear cells from patients and healthy controls was determined by assessment of Foxp3 expression on CD4+ CD25+ T cells. The functional activity of Treg was determined by their ability to suppress proliferation and cytokine production in response to proteinase‐3. Although WG patients demonstrated an increased fraction of CD4+ CD25+ T cells, the percentage of Foxp3‐positive cells was decreased. In addition, the percentage of Treg was inversely related to the rate of disease relapse. CD4+ CD25hi T cells were able to suppress T‐cell proliferation to proteinase‐3 in healthy controls and anti‐neutrophil cytoplasm antibody (ANCA)‐ negative patients (at time of sampling) but not in ANCA‐positive patients. In patients with active disease, an increased proportion of CD4+ Foxp3+ cells was associated with a more rapid disease remission. Patients with WG demonstrate abnormalities in the number and function of Treg and this is most pronounced in those with most active disease. This information is of value in understanding the pathogenesis and potential treatment of this disease.
PD‐1 signalling in CD4+ T cells restrains their clonal expansion to an immunogenic stimulus, but is not critically required for peptide‐induced tolerance
Authors: Konkel Joanne E. , Frommer Friederike , Leech Melanie D. , Yagita Hideo , Waisman Ari , Anderton Stephen M.
Published: January 2010

The ultimate outcome of T‐cell recognition of peptide–major histocompatibility complex (MHC) complexes is determined by the molecular context in which antigen presentation is provided. The paradigm is that, after exposure to peptides presented by steady‐state dendritic cells (DCs), inhibitory signals dominate, leading to the deletion and/or functional inactivation of antigen‐reactive T cells. This has been utilized in a variety of models providing peptide antigen in soluble form in the absence of adjuvant. A co‐inhibitory molecule of considerable current interest is PD‐1. Here we show that there is the opportunity for the PD‐1/PD‐L1 interaction to function in inhibiting the T‐cell response during tolerance induction. Using traceable CD4+ T‐cell receptor (TCR) transgenic cells, together with a blocking antibody to disrupt PD‐1 signalling, we explored the roles of PD‐1 in the induction of tolerance versus a productive immune response. Intact PD‐1 signalling played a role in limiting the extent of CD4+ T‐cell accumulation in response to an immunogenic stimulus. However, PD‐1 signalling was not required for either the induction, or the maintenance, of peptide‐induced tolerance; a conclusion underlined by successful tolerance induction in TCR transgenic cells genetically deficient for PD‐1. These observations contrast with the reported requirement for PD‐1 signals in CD8+ T‐cell tolerance.
The Toll‐like receptor 2 (TLR2) ligand FSL‐1 is internalized via the clathrin‐dependent endocytic pathway triggered by CD14 and CD36 but not by TLR2
Authors: Shamsul Haque M. , Hasebe Akira , Iyori Mitsuhiro , Ohtani Makoto , Kiura Kazuto , Zhang Diya , Totsuka Yasunori , Shibata Ken‐ ichiro
Published: January 2010

Little is known of how Toll‐like receptor (TLR) ligands are processed after recognition by TLRs. This study was therefore designed to investigate how the TLR2 ligand FSL‐1 is processed in macrophages after recognition by TLR2. FSL‐1 was internalized into the murine macrophage cell line, RAW264.7. Both chlorpromazine and methyl‐β‐cyclodextrin, which inhibit clathrin‐dependent endocytosis, reduced FSL‐1 uptake by RAW264.7 cells in a dose‐dependent manner but nystatin, which inhibits caveolae‐ and lipid raft‐dependent endocytosis, did not. FSL‐1 was co‐localized with clathrin but not with TLR2 in the cytosol of RAW264.7 cells. These results suggest that internalization of FSL‐1 is clathrin dependent. In addition, FSL‐1 was internalized by peritoneal macrophages from TLR2‐deficient mice. FSL‐1 was internalized by human embryonic kidney 293 cells transfected with CD14 or CD36 but not by the non‐transfected cells. Also, knockdown of CD14 or CD36 in the transfectants reduced FSL‐1 uptake. In this study, we suggest that (i) FSL‐1 is internalized into macrophages via a clathrin‐dependent endocytic pathway, (ii) the FSL‐1 uptake by macrophages occurs irrespective of the presence of TLR2, and (iii) CD14 and CD36 are responsible for the internalization of FSL‐1.
Parapatric diversification after post‐glacial range expansion in the gall flyUrophora cardui(Tephritidae)
Authors: Johannesen Jes , Drüeke Uta , Seitz Alfred
Published: January 2010

Aim Primary and secondary genetic clines in post‐glacial colonized regions have different implications for biogeographic distributions and the origin of species. Primary clines arisein situafter colonization as adaptive responses to environmental gradients, while secondary clines are caused by contact between vicariant lineages. Here we analyse primary versus secondary origin of a genetic cline in the tephritid flyUrophora carduiin Jutland, Denmark, in a post‐glacial landscape.

Location Western Palaearctic.

Methods Phylogeographic and demographic analyses ofU. carduibased on mitochondrial DNA (mtDNA) genealogies, hierarchical genetic variance tests based on allozymes and distribution analysis of a rare allele from the Jutland cline.

Results There was no phylogeographic divergence between the Jutland population ofU. carduinorth of the cline and neighbouring western European regional populations, which all shared the common western European mtDNA haplotype H1. At nuclear loci, by contrast, the North Jutland population was diverged above the mean level of divergence among regional populations and had no loss of genetic variation. A rare allozyme allele that was frequent in the cline area (up to 45%) and was missing north of the cline also occurred at low frequency (0–14%) elsewhere in the sampling range. Shallow phylogeographic divergence was observed between Russian and western European populations and between English and continental populations.

Main conclusions The genetic variation patterns support primary cline evolution and parapatric divergence in Jutland following a demographic expansion of a western European ancestral source population ofU. cardui, and suggest cryptic refugia and/or selection in other European population assemblages. The patterns of intra‐specific regional divergence are discussed with respect to the interpretation of cryptic refugia in Europe after the most recent ice age.
Modern analogues from the Southern Urals provide insights into biodiversity change in the early Holocene forests of Central Europe
Authors: Chytrý Milan , Danihelka Jiří , Horsák Michal , Kočí Martin , Kubešová Svatava , Lososová Zdeňka , Otýpková Zdenka , Tichý Lubomír , Martynenko Vasiliy B. , Baisheva El’vira Z.
Published: January 2010

Aim  The diversity changes that occurred in Central European forests during the early Holocene can be better understood using ecological knowledge of modern analogues of these forests, which occur in far Eastern Europe. Here we compare the diversity of vascular plants, bryophytes and snails among different forest types of the Southern Urals to provide insights into the palaeoecology of the vanished Central European forests.

Location  Southern Ural Mountains, Bashkortostan, Russia.

Methods  We recorded all species of vascular plants, ground‐dwelling bryophytes and land snails, and measured biotic and abiotic variables, in 100‐m2 plots located in four forest types dominated by different trees: Pinus sylvestris–Larix sibirica, Betula pendula–Populus tremula, Quercus robur and Acer platanoides–Tilia cordata–Ulmus glabra. These types correspond to the chronosequence of forest communities that occurred in Central Europe in the early Holocene.

Results  The species richness of herb‐layer plants was most affected by the canopy‐transmitted light. The former three forest types had open canopy and were rich in species, whereas the Acer–Tilia–Ulmus forests were darker and poor in species. The species richness of ground‐dwelling bryophytes decreased from coniferous to broad‐leaved deciduous forests. In contrast, the highest species richness of snails was in the Acer–Tilia–Ulmus forests owing to the higher calcium content in the litter of these trees.

Main conclusions  Based on the modern analogue of the Southern Ural forests, we propose the hypothesis that the late‐glacial open‐canopy pine and larch forests of Central European lowlands were rich in light‐demanding species of vascular plants, many of which were also typical of tall‐grass steppes or mesic grasslands. They also contained several species of ground‐dwelling bryophytes. The spread of birch, aspen and oak in the early Holocene reduced the local species richness of ground‐dwelling bryophytes but not of vascular plants. The subsequent spread of elm, lime, maple and ash caused canopy closure, a retreat of the light‐demanding herbs and a decline in the local species richness of vascular plants. Besides the increased shading by these tree species, their litter enriched soils in calcium, and enhanced decomposition and nutrient cycling. This supported an increase in the species richness of land snails.