bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and functional characterisation of aquaporins in the grapevine, Vitis vinifera
Authors: Shelden Megan C. , Howitt Susan M. , Kaiser Brent N. , Tyerman Stephen D.
Published: December 2009

Plant aquaporins belong to a large superfamily of conserved proteins called the major intrinsic proteins (MIPs). There is limited information about the diversity of MIPs in grapevine, and their water transport capacity. The aim of the present study was to identify MIPs from grapevine and functionally characterise water transport of a subset of MIPs. Candidate genes were identified, by screening a Vitis vinifera L. (cv. Cabernet Sauvignon) cDNA library with gene specific probes, for aquaporin cDNAs encoding members of the plasma membrane intrinsic protein (PIP) and tonoplast intrinsic protein (TIP) subfamilies. The screen resulted in the identification of 11 full-length and two partial length aquaporin cDNAs. VvTIP2;1 isoforms had different 3′ UTRs, immediately upstream of the poly(A) tail, suggesting the presence of multiple cleavage sites for polyadenylation. Using published genome sequences of grapevine, we conducted a phylogenetic analysis of the MIPs with previously characterised MIPs from Arabidopsis. We identified 23 full-length MIP genes from the V. vinifera genome sequence of a near homozygous line (PN40024) that cluster into the four main subfamilies (and subgroups within) identified in other species. However, based on the identification of PIP2 genes in Cabernet Sauvignon that were not present in the PN40024 genome, there are likely to be more than 23 MIP genes in other heterozygous grapevine cultivars. Water transport capacity was determined for several PIPs and TIPs, by expression in Xenopus oocytes. Only VvPIP2 and VvTIP proteins function as water channels with the exception of VvPIP2;5. VvPIP2;5 differs from the water conducting VvPIP2;1 by the substitution of two highly conserved amino acids in Loop B (G97S, G100W), which was shown by homology modelling to likely form a hydrophobic block of the water pore.
Tomato mitogen activated protein kinases regulate the expression of extracellular invertase Lin6 in response to stress related stimuli
Authors: Hyun Tae Kyung , Hoffmann Anja , Sinha Alok K. , Roitsch Thomas
Published: December 2009

Activation of mitogen-activated protein kinases (MAPKs) is a common reaction of plant cells in defence-related signal transduction pathways. Since the downstream events after the activation of MAPKs are largely unknown in plants, the role of MAPKs in the coordinate regulation of defence reactions and primary carbon metabolism by stress related stimuli has been analysed in tomato (Lycopersicon peruvianum Mill.). Thus, the relationship between MAPK, LpMPK2 and LpMPK3 and extracellular invertase Lin6, as the key enzyme of an apoplasmic phloem unloading pathway, has been analysed. It was observed that the mRNAs of LpMPK3 and Lin6 are sequentially induced by the same set of stress related stimuli, wounding, a fungal elicitor derived from Fusarium oxysporum lycopersici, the endogenous plant derived elicitor PGA and salt stress, while LpMPK2 transcripts are constitutively expressed. In a gain of function approach, a His-tagged version of LpMPK2 and a HA-tagged version of LpMPK3 were transiently and functionally expressed in leaves of transgenic tobacco (Nicotiana tabacum L.) plants expressing the β-glucuronidase reporter gene under control of the Lin6 promoter via agro-infection. The induction of the Lin6 promoter, as revealed by an increase in β-glucuronidase activity after 24 h, was dependent both on the expression and activation of both LpMPK2 and LpMPK3. These data suggest that the induction of extracellular invertase Lin6 by stress-related stimuli requires LpMPK2 and LpMPK3, and thus demonstrate that MAPK signalling might be involved in the regulation of primary carbon metabolism in general and sink metabolism in particular.
Seasonal flowering and evolution: the heritage from Charles Darwin
Authors: King R. W. , Heide O. M.
Published: December 2009

To survive, plants optimise their seasonal flowering time and set seed to avoid extremes of the environment including frost, heat and drought. Additionally, pollination may need to be tightly regulated in time so that it coincides with flowering of other individuals and/or with the presence of bird or insect pollinators. It is now clear that plants use seasonal changes in natural light intensity, daylight duration and temperature to achieve reproducible timing of flowering year-in-year-out. In more recent studies, genetic and molecular approaches are beginning to provide a basis for understanding heritability, an essential component of Darwin’s concept of evolution.
Agricultural intensification and changes in cultivated areas, 1970–2005
Authors: Rudel Thomas K. , Schneider Laura , Uriarte Maria , Turner B. L. , DeFries Ruth , Lawrence Deborah , Geoghegan Jacqueline , Hecht Susanna , Ickowitz Amy , Lambin Eric F. , Birkenholtz Trevor , Baptista Sandra , Grau Ricardo
Published: December 2009

Does the intensification of agriculture reduce cultivated areas and, in so doing, spare some lands by concentrating production on other lands? Such sparing is important for many reasons, among them the enhanced abilities of released lands to sequester carbon and provide other environmental services. Difficulties measuring the extent of spared land make it impossible to investigate fully the hypothesized causal chain from agricultural intensification to declines in cultivated areas and then to increases in spared land. We analyze the historical circumstances in which rising yields have been accompanied by declines in cultivated areas, thereby leading to land-sparing. We use national-level United Nations Food and Agricultural Organization data on trends in cropland from 1970–2005, with particular emphasis on the 1990–2005 period, for 10 major crop types. Cropland has increased more slowly than population during this period, but paired increases in yields and declines in cropland occurred infrequently, both globally and nationally. Agricultural intensification was not generally accompanied by decline or stasis in cropland area at a national scale during this time period, except in countries with grain imports and conservation set-aside programs. Future projections of cropland abandonment and ensuing environmental services cannot be assumed without explicit policy intervention.
Direct photonic–plasmonic coupling and routing in single nanowires
Authors: Yan Ruoxue , Pausauskie Peter , Huang Jiaxing , Yang Peidong
Published: December 2009

Metallic nanoscale structures are capable of supporting surface plasmon polaritons (SPPs), propagating collective electron oscillations with tight spatial confinement at the metal surface. SPPs represent one of the most promising structures to beat the diffraction limit imposed by conventional dielectric optics. Ag nano wires have drawn increasing research attention due to 2D sub-100 nm mode confinement and lower losses as compared with fabricated metal structures. However, rational and versatile integration of Ag nanowires with other active and passive optical components, as well as Ag nanowire based optical routing networks, has yet to be achieved. Here, we demonstrate that SPPs can be excited simply by contacting a silver nanowire with a SnO
2
nanoribbon that serves both as an unpolarized light source and a dielectric waveguide. The efficient coupling makes it possible to measure the propagation-distance-dependent waveguide spectra and frequency-dependent propagation length on a single Ag nanowire. Furthermore, we have demonstrated prototypical photonic-plasmonic routing devices, which are essential for incorporating low-loss Ag nanowire waveguides as practical components into high-capacity photonic circuits.
Attention and biased competition in multi-voxel object representations
Authors: Reddy Leila , Kanwisher Nancy G. , VanRullen Rufin
Published: December 2009

The biased-competition theory accounts for attentional effects at the single-neuron level: It predicts that the neuronal response to simultaneously-presented stimuli is a weighted average of the response to isolated stimuli, and that attention biases the weights in favor of the attended stimulus. Perception, however, relies not on single neurons but on larger neuronal populations. The responses of such populations are in part reflected in large-scale multivoxel fMRI activation patterns. Because the pooling of neuronal responses into blood-oxygen-level-dependent signals is nonlinear, fMRI effects of attention need not mirror those observed at the neuronal level. Thus, to bridge the gap between neuronal responses and human perception, it is fundamental to understand attentional influences in large-scale multivariate representations of simultaneously-presented objects. Here, we ask how responses to simultaneous stimuli are combined in multivoxel fMRI patterns, and how attention affects the paired response. Objects from four categories were presented singly, or in pairs such that each category was attended, unattended, or attention was divided between the two. In a multidimensional voxel space, the response to simultaneously-presented categories was well described as a weighted average. The weights were biased toward the preferred category in category-selective regions. Consistent with single-unit reports, attention shifted the weights by ≈30% in favor of the attended stimulus. These findings extend the biased-competition framework to the realm of large-scale multivoxel brain activations.
Calcium participates in feedback regulation of the oscillating ROP1 Rho GTPase in pollen tubes
Authors: Yan An , Xu Guanshui , Yang Zhen-Biao
Published: December 2009

Biological oscillation occurs at various levels, from cellular signaling to organismal behaviors. Mathematical modeling has allowed a quantitative understanding of slow oscillators requiring changes in gene expression (e.g., circadian rhythms), but few theoretical studies have focused on the rapid oscillation of cellular signaling. The tobacco pollen tube, which exhibits growth bursts every 80 s or so, is an excellent system for investigating signaling oscillation. Pollen tube growth is controlled by a tip-localized ROP1 GTPase, whose activity oscillates in a phase about 90 degrees ahead of growth. We constructed a mathematical model of ROP1 activity oscillation consisting of interlinking positive and negative feedback loops involving F-actin and calcium, ROP1-signaling targets that oscillate in a phase about 20 degrees and 110 degrees behind ROP1 activity, respectively. The model simulates the observed changes in ROP1 activity caused by F-actin disruption and predicts a role for calcium in the negative feedback regulation of the ROP1 activity. Our experimental data strongly support this role of calcium in tip growth. Thus, our findings provide insight into the mechanism of pollen tube growth and the oscillation of cellular signaling.
The nuclear receptor RORα exerts a bi-directional regulation of IL-6 in resting and reactive astrocytes
Authors: Journiac Nathalie , Jolly Sarah , Jarvis Christopher , Gautheron Vanessa , Rogard Monique , Trembleau Alain , Blondeau Jean-Paul , Mariani Jean , Vernet-der Garabedian Béatrice
Published: December 2009

Astrocytes and one of their products, IL-6, not only support neurons but also mediate inflammation in the brain. Retinoid-related orphan receptor-α (RORα) transcription factor has related roles, being neuro-protective and, in peripheral tissues, anti-inflammatory. We examined the relation of RORα to astrocytes and IL-6 using normal and RORα loss-of-function mutant mice. We have shown RORα expression in astrocytes and its up-regulation by pro-inflammatory cytokines. We have also demonstrated that RORα directly trans-activates theIl-6gene. We suggest that this direct control is necessary to maintain IL-6 basal level in the brain and may be a link between the neuro-supportive roles of RORα, IL-6, and astrocytes. Furthermore, after inflammatory stimulation, the absence of RORα results in excessive IL-6 up-regulation, indicating that RORα exerts an indirect repression probably via the inhibition of the NF-κB signaling. Thus, our findings indicate that RORα is a pluripotent molecular player in constitutive and adaptive astrocyte physiology.
Medical Students’ Attitudes toward Substance Abuse
Authors: Clayton Anita H. , Weeks Ruth B. , Vieweg W. V. R.
Published: December 2009

We surveyed 297 medical students regarding their attitudes about the use of substances which act on the central nervous system, particularly when these substances are used by professional colleagues. The preferred methods for dealing with a colleague impaired by alcohol or drug use were, in order of preference, talking directly to the affected colleague and informing the colleague's supervisor. We found no significant difference in responses across year groups, across sexes, and comparing impairment by alcohol versus other drug abuse. Twenty percent thought it was acceptable to have an alcoholic beverage before seeing a patient; 80% felt any use of illicit drugs, even while not on duty, was inappropriate. We discuss possible implications for medical student education.
Emergency Department Detection and Referral Rates for Patients with Problem Drinking
Authors: Bernstein Edward , Tracey Audrey , Bernstein Judith , Williams Carol
Published: December 2009

Alcohol-related problems cause 100,000 deaths annually, costing society more than $150 billion/year. This study was designed to establish provider detection and referral rates in a large inner-city Emergency Department, using three established measurement tools: the Ever a Problem (EAP), the four-question CAGE screen, and the QED Saliva Alcohol TEST (SAT). Two hundred ten patients met sample criteria; 172 (81%) were enrolled. Among those who were enrolled, 40% were positive on at least one measure: 13% on the SAT, 19% on the EAP, and 31% on the CAGE. The provider detection rate was high for SAT+ (intoxicated) patients (69.5%), but less so for those who were EAP+ and/or CAGE+ without an elevated SAT (32.6%). On retrospective record review, only 23.5% of those patients who were SAT+ and either CAGE+ or EAP+ could be shown to have been referred for treatment. We conclude that (1) the prevalence of alcohol problems is high in our ED setting (2) detection is possible with minimal disruption of the usual ED processing of care, and (3) significant opportunities for referral are currently being missed.
Runners’ Alcohol use and Responses to the Brief MAST
Authors: Gutgesell Margaret E. , Schorling John B. , Gressard Charles F.
Published: December 2009

We assessed drinking habits and responses to the Brief Michigan Alcoholism Screening Test (BMAST) in runners (student and nonstudent) participating in a 10-mi race. Questionnaires were sent to 1445 race registrants: 483 nonstudent men, 153 student men, 154 nonstudent women, and 105 student women responded (62% total response rate). We compared the student runners’ responses to BMAST questions, as well as binge rates and family history of problem drinking, to those of a reference college-student (slightly younger) population from the same state (n = 3726). The male student-runner binge drinking rate was 50% and the women student-runner rate was 47.6%, similar to those of the comparison group. There was no difference in rates of an “alcoholic score” on the BMAST among student runners (10.4% men, 5.1% women) compared to other runners. Student runners were more likely to have sought help for their drinking compared to nonrunner students. Nearly 20% of subjects in the student groups (runners and nonrunners) reported at least one parent with problem drinking significantly lower than the 28% reported by nonstudent runners. These data suggest that running may be a healthy substitute for drinking and warrant further investigation.
Development of an Instrument to Assess Problem Behavior in First-Grade Students Prenatally Exposed to Cocaine: Part I
Authors: Covington Chandice , Delaney-Black Virginia , Sokol Robert J. , Ager Joel , Knoll James , Templin Thomas
Published: December 2009

Teachers report that children exposed prenatally to cocaine display unique academic, social, and conduct problems in the school setting. No measure nor data exist that specifically identify these alleged behaviors. Experienced teachers (N = 24) participated in a consensus process to identify first-grade student behaviors considered specific to prenatal cocaine exposure. The Problem Behavior Scale (PROBS-14), a 14-item, visual analogue scale, was developed from the beliavior classifications generated Teachers then recalled the behaviors of students (N = 140) from the previous semester and scored the PROBS-14 and the Conners’ Teacher Rating Scale (CTRS-39). Concurrent validity was established between the PROBS-14 and the CTRS with factor analysis. The analysis yielded a hyperactivity-impulsivity factor, composed of both CTRS and PROBS items, and a central processing factor, composed of only PROBS items. Assessment of behavioral outcomes of prenatal exposure will require specialized instruments responsive to empirical data. Ongoing instrument development is addressing predictive validity of the PROBS-14 in identifying cocaine-exposed children.
LAAM-Pharmacology and Pharmacokinetics, Developmental History, and Therapeutic Considerations
Authors: Fudala Paul J.
Published: December 2009

LAAM (levo-α-acetylmethadol; methadyl acetate) was approved by the Food and Drug Administration on July 9, 1993, as a treatment for opioid dependence. It is a synthetic μ-opioid agonist that produces pharmacodynamic effects qualitatively similar to methadone. LAAM can produce a competitive blockade of the effects of other opioids and can suppress opioid-withdrawal signs and symptoms. However, unlike methadone, LAAM may be administered on an alternate-day or three-times-weekly dosing schedule due to its long duration of action and that of its pharmacologically active metabolites. LAAM provides clinicians and patients with a pharmacotherapeutic alternative to methadone when opioid-substitution therapy is indicated.
Acute Exposure to Ethanol in Pregnancy-Assessment of Cardiovascular Effects in the Isolated Perfused Rat Heart
Authors: Broughton Justin J. G. , Thorp John M. , Spielman F. G. , Cefalo R. C. , Mueller R. A.
Published: December 2009

Numerous pregnant women are exposed to ethanol. Given the marked cardiovascular changes induced by pregnancy and the known cardiac toxicity of ethanol, we conducted this study to explore the effects of pregnancy on the cardiac toxicity of ethanol. Isolated, perfused rat hearts obtained from pregnant and nonpregnant Sprague-Dawley rats were exposed to increasing doses of ethanol (0.1, 0.2, 0.4, 0.6%). Heart rate, changes in left ventricular pressure over time (dP/dt), left ventricular systolic pressure, and coronary artery flow rate were measured. Ethanol induced profound cardiac depression in all parameters. Pregnancy neither exacerbated nor attenuated this cardiac toxicity. In the isolated perfused rat heart model, pregnancy does not affect the cardiac toxicity of acute ethanol exposure.
Substance Abuse Education for Nurse Anesthetists: Differences in Knowledge of Substance Abuse between Student Nurse Anesthetists who have Completed a Substance Abuse Workshop and those who have Not
Authors: Clark Gary D.
Published: December 2009

The purpose of this study was to determine whether student nurse anesthetists who took a substance abuse workshop had more knowledge of substance abuse than those who did not take the workshop. The problem of substance abuse among members of the medical professions has been known for at least a century. However, there are little documentation and few articles that exist providing evidence to the American Association of Nurse Anesthetists (AANA), Certified Registered Nurse Anesthetists (CRNAs), practitioners, administrators, faculty, or students in anesthesia that substance abuse education provided in workshops or through the curriculum enhances the knowledge of student nurse anesthetists. Many program administrators assume that a substance abuse curriculum has been introduced during their undergraduate studies. In fact, an average of only 3 hr is dedicated to the subject of substance abuse during undergraduate studies. A study was done to determine if a substance abuse workshop enhanced the knowledge of student nurse anesthetists. Test scores of those who took the workshop were compared to those who did not take the workshop in order to assess current knowledge. It was concluded from this study that there was a difference between those who took the substance abuse workshop and those who did not take the workshop. A two-tailed t test was performed on the average test grades between the groups. The workshop was found to be an effective tool, though not exclusive, for the dissemination of substance abuse information to student nurse anesthetists. Since Knowles’ adult education philosophy was used for presentation of the workshop, it was determined that this methodology was appropriate for the delivery of information. Finally, it was concluded that the lack of substance abuse education in the undergraduate and graduate nursing curriculum still remains evident. It is recommended that the NCADA substance abuse workshop can be added to the curriculum. The previous educational experience for nurse anesthetists concerning the topic of substance abuse was limited. It is recommended that additional research focusing on substance abuse and the nurse anesthetist continue. The addition of a substance abuse workshop to the curriculum is beneficial.
A Case for Enhanced Linkage of Substance Abusers to Primary Medical Care
Authors: Samet Jeffrey H. , Saitz Richard , Larson Mary Jo
Published: December 2009

Alcohol and drug abuse continue to be problems of major significance throughout the United States. Although experts have advocated linking substance abusers with primary medical care to help achieve both individual and public health goals, few successful and generalizable methods for linkage have been developed. Specific potential benefits for such linkage include HIV testing and initiation of therapy, treatment of tuberculosis and sexually transmitted diseases, appropriate immunizations, cervical cancer screening, promotion of healthy behaviors regarding sexual and drug practices, and encouragement of cessation of substance use. Distributive or decentralized models linking patients receiving addiction treatment to existing primary medical care services need evaluation, as they may be more generalizable and cost-effective compared with on-site integrated programs. Health care providers and policy makers need to explore innovative approaches to bring substance abusers into a medical care system in a way that will provide continuity, comprehensiveness, and prevention so as to improve health care utilization patterns and reap benefits of improved addiction, behavioral, and health outcomes.
A Voice-Based Computer Interview for Drug Dependence
Authors: Gastfriend David R. , Gitlow Stuart , Hackney Janel , Gerber Emily , Baer Lee
Published: December 2009

The Recovery Attitudes and Treatment Evaluator (RAATE), via 94 true/false questions, assesses resistance and obstacles to chemical dependence treatment. We computerized the RAATE to offer questions via digitized human voice and to recognize patient responses spoken into the computer's microphone. Sixty-eight consecutive adults seeking addictions treatment were randomized to one of four formats. The voice-input/voice-output version yielded the shortest mean duration of administration. Patients reported high satisfaction ratings and confidence that their answers were accurate. They perceived their responses to be useful in treatment planning. Group mean ratings did not significantly differ by version. There was a statistical trend in which the voice-based versions reduced the intragroup variability on test duration and patient confidence. Computerized voice-interactive interviewing may shorten test durations, increase the uniformity of administration, increase access for the vision-impaired, and increase the data entry efficiency and accuracy. The method provides a consistent, controlled, and nonjudgmental interview interaction.
Novel neutron guides
Authors: Allenspach Peter , Zsigmond Geza , Stahn Jochen
Published: December 2009

For almost three decades neutron guides have been built as multipurpose installations: essentially straight and with a rectangular cross section. At that time instruments on guides were planned and designed from the guide exit to the detectors. With the development of large area supermirror coating in the 1990s, the availability and standardization of Monte-Carlo neutron ray-tracing packages and the entering of new companies in the previously monopolistic market the situation has changed remarkably. Nowadays instruments are simulated, designed and built as a whole entity, including all parts from the source to the detectors, outperforming existing conventional instruments by an order of magnitude as far as the neutron optics is concerned. We will present some examples of advanced supermirror neutron guides at instruments which are being built or are planned for the future as well as some other concepts which have not yet been realized.
Curved neutron guide of the cold neutron disk-chopper spectrometer at J-PARC
Authors: Kajimoto R. , Nakajima K. , Nakamura M. , Osakabe T. , Sato T.J. , Arai M.
Published: December 2009

We have investigated the usefulness of a curved guide for the cold neutron disk-chopper spectrometer (CNDCS), which is under construction for the Japan Proton Accelerator Research Complex (J-PARC), by Monte Carlo simulation. By comparing with a model with a straight guide and a T0 chopper, we found that the curved guide can show comparable performance with the straight guide in the whole energy range of CNDCS when L1 ≥ 30 m. Interestingly, the curved guide surpasses the straight guide in neutron flux at E ≤ 20 meV, where CNDCS is optimized, because of the loss of flux at the gap for the T0 chopper in the straight guide.
Conceptual design of MAGIC chopper used for 4SEASONS at J-PARC
Authors: Nakamura M. , Arai M. , Kajimoto R. , Yokoo T. , Nakajima K. , Krist TH.
Published: December 2009

4SEASONS is designed to utilize the multiple incident energies (MIE) selected by a special Fermi chopper and enhance the measurement efficiency. Chopper opening time determined by a conventional Fermi chopper is inevitably constant, and thus we cannot realize the optimal experimental condition for each incident energy. Therefore, a new concept of Fermi chopper is required for the success of MIE measurement at 4SEASONS. In this paper, we present a new concept of supermirror-coated Fermi chopper (MAGIC chopper) specialized for MIE measurement at 4SEASONS. MAGIC chopper increases the effective opening time at lower incident energies, and consequently the energy dependence of effective opening time gets close to that of moderator pulse width. In addition to the matching of experimental condition, MAGIC chopper also realizes almost constant energy resolution in the wide range of incident energy.
New high-field actively shielded split-coil magnet for neutron scattering
Authors: Gilardi Raffaele
Published: December 2009

A new 16 T split-coil magnet system is being developed by Bruker BioSpin. This will represent the first high-field actively shielded split-coil magnet for neutron scattering experiments. The new magnet system will be installed at the Spallation Neutron Source (SNS) in the USA in 2009. The magnet is a symmetrical split coil, which can be operated in both symmetric and asymmetric field modes (for experiments with polarized neutrons).
Virtual experiments: the ultimate aim of neutron ray-tracing simulations
Authors: Lefmann K. , Willendrup P.K. , Udby L. , Lebech B. , Mortensen K. , Birk J.O. , Klenø K. , Knudsen E. , Christiansen P. , Saroun J. , Kulda J. , Filges U. , Konnecke M. , Tregenna-Piggott P. , Peters J. , Lieutenant K. , Zsigmond G. , Bentley P. , Farhi E.
Published: December 2009

We define a virtual neutron experiment as a complete simulation of an experiment, from source over sample to detector. The virtual experiment (VE) will ideally interface with the instrument control software for the input and with standard data analysis packages for the virtual data output. Virtual experiments are beginning to make their way into neutron scattering science with applications as diverse as instrument design/upgrade, experiment planning, data analysis, test of analysis software, teaching, and outreach. In this paper, we summarize the recent developments in this field and make suggestions for future developments and use of VEs.
High-intensity and versatile chopper spectrometer project for J-PARC
Authors: Sato T.J. , Yamamuro O. , Hirota K. , Shibayama M. , Yoshizawa H. , Itoh S. , Watanabe S. , Asami T. , Kindo K. , Uwatoko Y. , Kanaya T.
Published: December 2009

We have proposed a versatile inelastic neutron spectrometer (VINS) for the spallation neutron source at the Materials and Life Science Facility, Japan Proton Accelerator Research Complex. This is a direct- geometry Fermi chopper spectrometer, aimed at realizing a very high neutron flux with reasonable energy and Q resolutions. A wide energy-transfer range of 0.5 < E < 1000 meV will be covered with two energy-resolution modes, ΔE/Ei ∼ 5 and 2.5%. Q range will also be considerably large as up to 40 Å−1 at Ei = 1000 meV, enabled by an array of detectors covering −30 < 2θ < 130° (2.8 Sr). Preliminary Monte Carlo simulation predicts the maximum flux of 106 neutrons/cm2/s at the sample position for Ei = 10 meV (assuming that the neutron source is running at 1 MW). With the remarkably high neutron flux, VINS will be a unique tool for various types of condensed matter research, in particular, those which have never been explored by inelastic neutron scattering due to sample size restriction.
Plasticity of cell migration: a multiscale tuning model
Authors: Friedl Peter , Wolf Katarina
Published: December 2009

Cell migration underlies tissue formation, maintenance, and regeneration as well as pathological conditions such as cancer invasion. Structural and molecular determinants of both tissue environment and cell behavior define whether cells migrate individually (through amoeboid or mesenchymal modes) or collectively. Using a multiparameter tuning model, we describe how dimension, density, stiffness, and orientation of the extracellular matrix together with cell determinants—including cell–cell and cell–matrix adhesion, cytoskeletal polarity and stiffness, and pericellular proteolysis—interdependently control migration mode and efficiency. Motile cells integrate variable inputs to adjust interactions among themselves and with the matrix to dictate the migration mode. The tuning model provides a matrix of parameters that control cell movement as an adaptive and interconvertible process with relevance to different physiological and pathological contexts.
Efficacy of Goshajinkigan for Peripheral Neurotoxicity of Oxaliplatin in Patients with Advanced or Recurrent Colorectal Cancer
Authors: Kono Toru , Mamiya Noriaki , Chisato Naoyuki , Ebisawa Yosiaki , Yamazaki Hirotaka , Watari Jiro , Yamamoto Yasuhiro , Suzuki Shigetaka , Asama Toshiyuki , Kamiya Kazunori
Published: December 2009

Peripheral neurotoxicity is the major limiting factor for oxaliplatin therapy. Goshajinkigan (GJG), a traditional Japanese herbal medicine, was recently shown to be effective in protecting against the neurotoxicity of taxanes in Japan. We retrospectively investigated the effect of GJG on peripheral neurotoxicity associated with oxaliplatin therapy. Ninety patients with metastatic colorectal cancer that received FOLFOX4 or modified FOLFOX6 therapy were assigned to receive one of the following adjuncts: oral GJG at 7.5 g day−1 (Group A, n = 11), intravenous supplementation of calcium gluconate and magnesium sulfate (1 g each before and after FOLFOX) (Group B, n = 14), combined GJG and calcium gluconate and magnesium sulfate therapies (Group C, n = 21), or no concomitant therapy (Group D, n = 44). The incidence of peripheral neurotoxicity was investigated when the cumulative dose of oxaliplatin exceeded 500 mg m−2. When the cumulative dose of oxaliplatin exceeded 500 mg m−2, the incidence of neuropathy (all grades) in Groups A–D was 50.0%, 100%, 78.9%, and 91.7%, respectively. It was lowest in the group that received GJG alone. Concomitant administration of GJG reduced the neurotoxicity of oxaliplatin in patients that received chemotherapy for colorectal cancer.
Estimating population genetic parameters and comparing model goodness-of-fit using DNA sequences with error
Authors: Liu Xiaoming , Fu Yun-Xin , Maxwell Taylor J. , Boerwinkle Eric
Published: December 2009

It is known that sequencing error can bias estimation of evolutionary or population genetic parameters. This problem is more prominent in deep resequencing studies because of their large sample size n, and a higher probability of error at each nucleotide site. We propose a new method based on the composite likelihood of the observed SNP configurations to infer population mutation rate θ = 4Neμ, population exponential growth rate R, and error rate ɛ, simultaneously. Using simulation, we show the combined effects of the parameters, θ, n, ɛ, and R on the accuracy of parameter estimation. We compared our maximum composite likelihood estimator (MCLE) of θ with other θ estimators that take into account the error. The results show the MCLE performs well when the sample size is large or the error rate is high. Using parametric bootstrap, composite likelihood can also be used as a statistic for testing the model goodness-of-fit of the observed DNA sequences. The MCLE method is applied to sequence data on the ANGPTL4 gene in 1832 African American and 1045 European American individuals.
Reflux symptoms in wind instrument players
Authors: CAMMAROTA G. , MASALA G. , CIANCI R. , PALLI D. , BENDINELLI B. , GALLI J. , PANDOLFI F. , GASBARRINI A. , LANDOLFI R.
Published: December 2009

Aliment Pharmacol Ther 31, 593–600

Background  An occupation‐related susceptibility of orchestral wind instrument players to gastro‐oesophageal reflux was hypothesized.

Aim  To compare reflux symptoms reported by wind instrument players with those reported by players of other instruments.

Methods  A questionnaire was distributed to 1083 musicians (414 wind instrument players and 669 players of other instruments) from 21 Italian orchestras to obtain information on reflux symptoms in the year preceding the survey together with selected individual characteristics and lifestyle habits. Crude and adjusted prevalence rate ratios (PRR) were computed by a model including gender, age, body mass index, smoking status, alcohol consumption and other confounding factors.

Results  Wind instrument players reported a higher prevalence of heartburn in the previous year than the other instrument players (adjusted PRR 1.23, CI 95% 1.04–1.46). Wind instrument players also reported higher, although not fully significant, prevalence of regurgitation (adjusted PRR 1.22, CI 95% 0.97–1.54). Flute and double‐reed instrument players seem to carry a higher risk of reflux symptoms.

Conclusions  Wind instrument players reported a prevalence of typical reflux symptoms higher than other instrument players.
Pleiotropic effects of intravascular haemolysis on vascular homeostasis
Authors: Kato Gregory J. , Taylor James G.
Published: December 2009

The breakdown of senescent or defective red blood cells releases red cell contents, especially haemoglobin, which scavenges nitric oxide (NO) and decomposes to haem and free iron. These are potent oxidants, all of which have promoted the evolution of inducible and vasculoprotective compensatory pathways to rapidly clear and detoxify haemoglobin, haem and iron. Chronic haemolytic red cell disorders as diverse as sickle cell disease, thalassaemia, unstable haemoglobinopathy, cytoskeletal defects and enzymopathies have been linked to a clinical constellation of pulmonary hypertension, priapism, leg ulceration and possibly cerebrovascular disease and thrombosis. Besides free haemoglobin, haemolysis has been associated with extracellular arginase that limits substrate availability to NO synthase, endogenous inhibitors of NO synthase activity, and inappropriate activation of haemostatic pathways. This article reviews the haemolytic disorders that have been reported to manifest vascular complications, and explores the speculative possibility that haemolysis mediates some of the vascular complications of inflammation and diabetes.
The proteasome inhibitor CEP‐18770 enhances the anti‐myeloma activity of bortezomib and melphalan
Authors: Sanchez Eric , Li Mingjie , Steinberg Jeffrey A. , Wang Cathy , Shen Jing , Bonavida Benjamin , Li Zhi‐Wei , Chen Haiming , Berenson James R.
Published: December 2009

The anti‐multiple myeloma (MM) efficacy of bortezomib has led to the development of other proteasome inhibitors (PI), including CEP‐18770 which has shown anti‐MM effects in preclinical studies. However, the efficacy of orally (PO) or intravenously (IV) administered CEP‐18770 in multiple MM models and in combination with conventional anti‐MM therapies has not been evaluated. Herein, we show that CEP‐18770 combined with melphalan or bortezomib induces synergistic inhibition of MM cell viability in vitro. In MM xenograft models, the addition of CEP‐18770 IV to melphalan completely prevented the growth of both melphalan‐sensitive and melphalan‐resistant tumours. The combination of CEP‐18770 IV and bortezomib induced complete regression of bortezomib‐sensitive tumours and markedly delayed progression of bortezomib‐resistant tumours compared to treatment with either agent alone. Single agent CEP‐18770 PO also showed marked anti‐MM effects in these xenograft models. These studies provide strong preclinical rationale for further development of this novel PI in the treatment of MM as a monotherapy as well as combined with either melphalan or bortezomib.
ITD‐ and FL‐induced FLT3 signal transduction leads to increased C/EBPβ‐LIP expression and LIP/LAP ratio by different signalling modules
Authors: Haas Sandra C. , Huber René , Gutsch Romina , Kandemir Judith D. , Cappello Christian , Krauter Jürgen , Duyster Justus , Ganser Arnold , Brand Korbinian
Published: December 2009

FLT3 receptor‐associated signalling plays a role in proliferation and leukaemia. The transcription factor C/EBPβ may be involved in malignancy with its alternative translation product C/EBPβ‐LIP. We investigated a potential connection between FLT3 signalling and the C/EBPβ system in FLT3‐internal tandem duplication (ITD)‐positive leukaemia cells and FLT3‐ITD‐ or FLT3‐wild type (WT)‐transfected 32D cells. In FLT3‐ITD‐positive cells or when ITD sequences were inserted into the FLT3‐WT receptor, significant LIP levels, increased LIP/LAP ratios, and enhanced proliferation rates were detected, which were reduced by FLT3 inhibition. In FLT3‐WT cells, incubation with FLT3 receptor ligand (FL) also elevated LIP, LIP/LAP, and proliferation, albeit to a lesser extent. CEBPB‐directed siRNA decreased both LIP and proliferation rates in FLT3‐ITD‐positive and FL‐stimulated FLT3‐WT‐positive cells. PI3K inhibition affected ITD‐associated and FL‐induced LIP levels. Rapamycin, an inhibitor of mTOR involved in CEBPB translation, completely blocked the increase in LIP in FL‐stimulated FLT3‐WT‐ but not FLT3‐ITD‐positive cells. In contrast, the ITD‐associated LIP elevation was mediated by p90‐ribosomal‐S6‐kinase. This is the first report showing a LIP increase in the presence of ITD or following FL exposure. Our data suggest fundamental differences in the signalling cascades activated via ITD mutations or following FL stimulation, indicating the need for adapted molecular therapy.
Mimotope vaccination for therapy of allergic asthma: anti‐inflammatory effects in a mouse model
Authors: Wallmann J. , Epstein M. M. , Singh P. , Brunner R. , Szalai K. , El‐Housseiny L. , Pali‐Schöll I. , Jensen‐Jarolim E.
Published: December 2009

Background
One of the concerns of allergen‐specific immunotherapy is the possible boost of inflammatory allergen‐specific T lymphocytes. To address this problem, treatment with B cell epitopes devoid of allergen‐specific T cell epitopes would be a promising alternative.

Objective
In this study, we examined the therapeutic potency of a single mimotope, mimicking a structural IgE epitope of grass pollen allergen Phl p 5 in an established memory mouse model of acute allergic asthma.

Methods
In the experimental set‐up, BALB/c mice were primed with intraperitoneal injections of recombinant Phl p 5a (rPhl p 5a) and subsequently aerosol challenged with the nebulized allergen. Mice developed signs of bronchial asthma including hypereosinophilia around bronchi, goblet cell hyperplasia and enhanced mucus production.

Results
When the mice were subsequently treated with the grass pollen mimotope coupled to keyhole limpet haemocyanin, bronchial eosinophilic inflammation and mucus hypersecretion decreased. Further, a decrease of Th2 cytokines IL‐4 and IL‐5 could be observed in the bronchoalveolar lavage (BAL). In contrast to rPhl p 5a, the mimotope was in vitro not able to stimulate splenocytes to proliferation or IL‐5 production. Despite not affecting the levels of pre‐existing IgE, vaccination with the single mimotope thus rendered anti‐inflammatory effects in a mouse model of acute asthma.

Conclusion
From our data, we conclude that vaccination with a mimotope peptide representing a single IgE epitope of the allergen Phl p 5a and being devoid of allergen‐specific T cell epitopes is able to down‐regulate inflammation in acute asthma.

Cite this as: J. Wallmann, M. M. Epstein, P. Singh, R. Brunner, K. Szalai, L. El‐Housseiny, I. Pali‐Schöll and E. Jensen‐Jarolim, Clinical & Experimental Allergy, 2010 (40) 650–658.
Antigenic dietary protein guides maturation of the host immune system promoting resistance to Leishmania major infection in C57BL/6 mice
Authors: Amaral Joana F. , Gomes‐Santos Ana C. , Paula‐Silva Josiely , Nicoli Jacques R. , Vieira Leda Q. , Faria Ana M. C. , Menezes Juscilene S.
Published: December 2009

The immature immune system requires constant stimulation by foreign antigens during the early stages of life to develop properly and to create efficient immune responses against later infections. We have previously shown that intake of antigenic dietary protein is critical for inducing maturation of the immune system as well as for the development of T helper type 1 (Th1) immunity. In this study, we show that administration of an amino acid (aa)‐based diet during the development of the immune system subsequently resulted in inefficient control of Leishmania major infection in adult C57BL/6 mice. Compared with mice fed a control protein‐containing diet, adult aa‐fed mice showed a decreased interferon (IFN)‐γ response to parasite antigens and insufficient production of nitric oxide (NO), which is crucial to parasite death. However, no deviation towards Th2‐specific immunity to L. major was observed. Phenotypic analysis of antigen‐presenting cells (APCs) from aa‐fed mice revealed deficient levels of the costimulatory molecules CD40 and CD80, and low levels of interleukin (IL)‐12 produced by peritoneal macrophages, revealing an early stage of maturation of these cells. APCs isolated from aa‐fed mice were unable to stimulate a Th1 response in vitro. Both phenotypic features of T cells from aa‐fed mice and their ability to produce a Th1 response in the presence of mature APCs were unaffected when compared with T cells from control mice. The results presented here support the notion that regulation of Th1 immunity to infection includes environmental factors such as dietary proteins, which provide a natural source of stimulation that contributes to the process of maturation of APCs.
Hypoxic stress up‐regulates the expression of Toll‐like receptor 4 in macrophages via hypoxia‐inducible factor
Authors: Kim So Young , Choi Yong Jun , Joung Sun Myung , Lee Byung Ho , Jung Yi‐Sook , Lee Joo Young
Published: December 2009

Toll‐like receptors (TLRs) are germline‐encoded innate immune receptors that recognize invading micro‐organisms and induce immune and inflammatory responses. Deregulation of TLRs is known to be closely linked to various immune disorders and inflammatory diseases. Cells at sites of inflammation are exposed to hypoxic stress, which further aggravates inflammatory processes. We have examined if hypoxic stress modulates the TLR activity of macrophages. Hypoxia and CoCl2(a hypoxia mimetic) enhanced the expression of TLR4 messenger RNA and protein in macrophages (RAW264.7 cells), whereas the messenger RNA of other TLRs was not increased. To determine the underlying mechanism, we investigated the role of hypoxia‐inducible factor 1 (HIF‐1) in the regulation of TLR4 expression. Knockdown of HIF‐1α expression by small interfering RNA inhibited hypoxia‐induced and CoCl2‐induced TLR4 expression in macrophages, while over‐expression of HIF‐1α potentiated TLR4 expression. Chromatin immunoprecipitation assays revealed that HIF‐1α binds to the TLR4 promoter region under hypoxic conditions. In addition, deletion or mutation of a putative HIF‐1‐binding motif in the TLR4 promoter greatly attenuated HIF‐1α‐induced TLR4 promoter reporter expression. Up‐regulation of TLR4 expression by hypoxic stress enhanced the response of macrophages to lipopolysaccharide, resulting in increased expression of cyclooxygenase‐2, interleukin‐6, regulated on activation normal T cell expressed and secreted, and interferon‐inducible protein‐10. These results demonstrate that TLR4 expression in macrophages is up‐regulated via HIF‐1 in response to hypoxic stress, suggesting that hypoxic stress at sites of inflammation enhances susceptibility to subsequent infection and inflammatory signals by up‐regulating TLR4.
Suboptimal engagement of the T‐cell receptor by a variety of peptide–MHC ligands triggers T‐cell anergy
Authors: Sadegh‐Nasseri Scheherazade , Dalai Sarat K. , Korb Ferris Laura C. , Mirshahidi Saied
Published: December 2009

T cells recognize antigen via the T‐cell receptor (TCR) and produce a spectrum of responses that range from activation to anergy or cell death. The variety of outcomes may be dictated by the strength of the signals transmitted upon cognate recognition of the TCR. The physiological outcome of TCR engagement is determined by several factors, including the avidity of the ligand for TCR, the duration of engagement, and the presence and nature of accessory molecules present on antigen‐presenting cells (APCs). In this review, we discuss a model of anergy induced by presentation of low densities of peptide–major histocompatibility complex (MHC) ligand in CD4+ T cells and compare it to anergy induced by altered peptide ligands in an effort to identify a unifying mechanism. We suggest that altered peptide ligand (APL) and low densities of agonist ligands induce anergy by engaging less than optimal numbers of TCRs. The physiological impacts of anergy in memory CD4+ T cells are discussed.