bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance and Emissions of a Turbocharged, High-Pressure Common Rail Diesel Engine Operating on Biodiesel/Diesel Blends
Authors: Wang X-G , Zheng B , Huang Z-H , Zhang N , Zhang Y-J , Hu E-J
Published: September 2010

The effect of biodiesel addition to diesel on engine performance, combustion, and emissions were studied in a turbocharged, high-pressure common rail diesel engine. Biodiesel/diesel blends with different biodiesel fractions were used and compared with neat biodiesel and diesel at different engine loads and speeds. The results show that the brake thermal efficiency increases slightly as biodiesel is added to diesel. Exhaust gas temperature is not significantly affected at low engine speeds and decreases gradually at high engine speeds with an increase in biodiesel fraction. Fuel injection includes both pilot and main injections. Diesel and biodiesel give a similar start to the heat release. The first peak in the heat release rate for biodiesel is lower than that of diesel, while the second peak is higher for biodiesel. The heat release rate curve for biodiesel indicates that the use of biodiesel increases thermal efficiency and NO x emission compared to that of diesel especially at high engine loads. Hydrocarbon and CO emissions maintain very low values and little variation is seen for the different fuels. CO2 emission decreases with increasing biodiesel fraction in the blends. The level of NO x emission decreases slightly at low engine loads and increases at high engine loads with increasing biodiesel fraction. Biodiesel reduces particulate matter (PM) emission significantly and PM reduction effectiveness is increased at high engine loads and/or speed. The oxygen in biodiesel plays a key role in reducing PM emission. Biodiesel/diesel blends can improve performance and decrease emissions for turbocharged, high-pressure common rail diesel engines.
Effects of CaCO3 whisker on the sliding wear behaviour of poly(etheretherketone) under water-lubricated condition
Authors: Lin Y-X , Gao C-H , Li Y
Published: September 2010

Polyetheretherketone (PEEK) composite specimens filled in 0–30 wt% content of CaCO3 whisker were prepared by compression moulding. Tribological testing of composites was carried out on an MM200 block-on-ring apparatus in water lubricated wear mode against carbon steel. The morphologies of wear traces were observed by scanning electron microscopy (SEM). The effects of CaCO3 whisker on the mechanical and tribological properties of composites were investigated. It was revealed that the inclusion of CaCO3 whisker significantly improved the wear resistance and reduced the friction coefficient of PEEK composites under water-lubricated condition. With an increase in CaCO3 whisker contents, the friction coefficient decreased and showed minima for 15 per cent CaCO3 inclusion. The specific wear rate of composites showed minima as 2.04×10−6 mm3/N m for 20 per cent CaCO3 inclusion as 5.2 per cent of that for pure PEEK, followed by a slow increase for further CaCO3 whisker addition. In terms of friction applications under water lubrication, when the tribological and mechanical properties were combined, the optimal content of CaCO3 whisker in the filled PEEK should be recommended as 15–20 per cent. The SEM observation of the wear traces indicated that CaCO3 whisker contributed to increase the load-carrying capacity and abate the scuffing and adhesion of filled composites, which conformed to the better wear resistance of CaCO3/PEEK composites than pure PEEK. No transfer film could be observed on the counterface of the mating ring under water-lubricated condition. It is confirmed that the transfer film is not the main reason for the enhancement of wear resistance of the composites in water lubrication.
A hexagonal boron nitride-based model of porous bearings with reduced friction and increased load
Authors: Pawlak Z , Kaldonski T , Urbaniak W
Published: September 2010

An attempt has been made to learn how a two-phase fluid used as a lubricant of porous bearings could improve their load-carrying capacity. Two sets of bearings were chosen for friction and loading experiments. The first one comprised a self-lubricating porous bearing impregnated with oil and the two-phase fluid, and in the other the two-phase fluid was externally delivered to the bearings. The results showed that the two-phase fluid had a better friction-reducing capacity and a higher load-carrying performance than ordinary porous bearings impregnated with the oil. It is demonstrated that the novel model of the bearings (the so-called second-generation bearings) with the two-phase fluid ensures a fairly efficient lubrication under low friction and high load-carrying capacity. A novel lubrication mechanism, involving a lamellar particulate phase in blocking and unblocking the pores during contact load, has been suggested.
Effect of the Tidal Currents at the Amphidromes on the Characteristics of an N-Wave-Type Tsunami
Authors: Behera M R , Murali K , Sundar V
Published: September 2010

The disturbance due to a tsunami is always coupled with permanent harmonic ocean tides. The tsunami based on its time of occurrence will combine with a particular tidal phase. Thus, a coast will experience a modified water level due to a high- or low-tide situation. On the other hand, the tidal current at the amphidromes may act as an attenuator or amplifier of the tsunami prior to its arrival at the shore. A one-dimensional numerical study has been carried out to demonstrate the effect of the amphidromic current on tsunami characteristics. A realistic N-wave profile of the initial perturbation has been considered for the initiation of a tsunami. The interaction of the amphidromic current with the phase velocity of an N-wave-type tsunami and the subsequent run-up along the shore has been investigated in this paper.
Low-Altitude Terrain following and Collision Avoidance in a Flight-Class Autonomous Underwater Vehicle
Authors: McPhail S , Furlong M , Pebody M
Published: September 2010

An autonomous underwater vehicle (AUV), Autosub6000, has been shown to operate safely at altitudes as low as 3 m above rugged and complex sea floor environments. This capability is essential for future AUV missions in such environments, e.g. high-resolution surveys using colour photography or multi-beam sonar bathymetry. This was achieved through the development of an obstacle avoidance system for the AUV, incorporating relatively low-cost off-the-shelf components and simple algorithms. This paper details the specification, design, and testing at sea of Autosub6000's obstacle avoidance system. It describes how the specification of the system was influenced by the need to retrofit it into the existing control architecture, together with the pragmatic need to minimize overall complexity. The sensor used in the obstacle avoidance system is a mechanically scanned forward-looking sonar, and the control algorithm is based upon the detection of the range and elevation of the horizon relative to the AUV. The avoidance behaviour is by default to fly over obstacles but, if this is not possible, a turn-around and retry collision avoidance algorithm is invoked. Results are presented of the system's performance during recent deep-water trials of the AUV over the Casablanca Seamount region of the Atlantic Ocean.
Design and Deployment of a Four-Degrees-of-Freedom Hovering Autonomous Underwater Vehicle for sub-Ice Exploration and Mapping
Authors: Stone W , Hogan B , Flesher C , Gulati S , Richmond K , Murarka A , Kuhlman G , Sridharan M , Siegel V , Price R M , Doran P T , Priscu J
Published: September 2010

This paper describes the 2008 and 2009 Antarctic deployments of the National Aeronautics and Space Administration ENDURANCE autonomous underwater vehicle (AUV). The goal of this project was to conduct three autonomous tasks beneath the ice cap 4 m thick of West Lake Bonney: first, to measure the three-dimensional (3D) water chemistry of the lake at prespecified coordinates; second, to map the underwater face of the Taylor Glacier; third, to chart the bathymetry of the lake bottom. At the end of each mission the AUV had to locate and return through a hole in the ice slightly larger than the outer diameter of the vehicle. During two 10-week deployments to Antarctica, in the austral summers of 2008 and 2009, ENDURANCE logged 243 h of sub-ice operational time, conducted 275 aqueous chemistry sonde casts, completed a 3D bathymetry survey over an area of 1.06 km2 at a resolution of 22 cm, and traversed 74 km beneath the ice cap of West Lake Bonney. Many of the characteristics and capabilities of ENDURANCE are similar to the behaviours that will be needed for sub-ice autonomous probes to Europa, Enceladus, and other outer-planet icy moons. These characteristics are also of great utility for terrestrial operations in which there is a need for an underwater vehicle to manoeuvre precisely to desired positions in 3D space or to manoeuvre and explore complicated 3D environments.
The Impact of Continuing Professional Development Versus Traditional Continuing Pharmacy Education on Pharmacy Practice
Authors: McConnell Karen J , Newlon Carey L , Delate Thomas
Published: September 2010

Background:

The Institute of Medicine states that the new vision for continuing education (CE) for health-care professionals will be based on continuing professional development (CPD); however, information on the utility of CPD is lacking.

Objective:

To assess the effect of CPD, compared with that of traditional continuing pharmacy education (CPE), on perceptions of factors related to pharmacy practice.

Methods:

This 10-month, nonblinded, randomized controlled study recruited licensed pharmacists employed at a health maintenance organization (HMO). After completing a basic CPD course, participants were randomized to the intervention or control group. The control group was instructed to continue with traditional CPE. The intervention group participants completed 3 CPD workshops and were instructed to utilize the CPD approach for their learning needs. At baseline and follow-up, all participants completed a study questionnaire on perceptions of their pharmacy practices. The outcome measures were comparisons on follow-up and changes from baseline to follow-up in responses to the study questionnaire.

Results:

One hundred pharmacists were enrolled. The intervention (n = 44, 7 lost to follow-up) and control (n = 47, 2 lost to follow-up) groups were similar at baseline. At follow-up, a higher percentage of intervention participants reported that they had better interactions with other health-care providers (always/frequently 32% vs 6%, respectively) and initiated practice/work changes (always/frequently 21% vs 0%, respectively) (both p < 0.01) as a result of their education activities. Compared with control participants at follow-up, intervention participants reported that their education activities improved patient care changes (46% vs 23%), professional knowledge (34% vs 6%), skills (48% vs 17%), and attitudes/values (43% to 11%) (all p < 0.05). However, intervention participants reported more often that time was a barrier to completing education activities (75% vs 32%, p < 0.001).

Conclusions:

Pharmacists who participated in CPD reported more often that their perceptions of various aspects of their pharmacy practice improved as a result of their education activities compared with pharmacists who participated in traditional CPE.
Stress Ulcer Prophylaxis: Reducing Non-Indicated Prescribing After Hospital Discharge
Authors: Hatch Jacob B , Schulz Lucas , Fish Jeffrey T
Published: September 2010

Background:

Gastric acid suppressant medications used as stress ulcer prophylaxis (SUP) in the intensive care unit (ICU) are often prescribed inappropriately after discharge. We present tools to reduce the use and cost of non-indicated SUP.

Objective:

To reduce the non-indicated use of SUP after hospital discharge originally started in the ICU, using an education intervention and pharmacist-led medication reconciliation on patient care rounds and at hospital discharge.

Methods:

In a retrospective medical record review using a historic control, 356 consecutively admitted patients to the medical/surgical ICU at the University of Wisconsin Hospital were assessed for the appropriate use of SUP at admission to the ICU, at transfer to a general care unit, and at hospital discharge. The education intervention involved teaching both the medical and pharmacist staff about indications for SUP using a memorandum and a pocket guide. Pharmacists also conducted medication reconciliation during daily patient care rounds and at discharge to justify medication use. The outcome of this study is the percentage of patients prescribed non-indicated gastric acid suppressants at hospital discharge. This outcome is compared to a previous study conducted at our hospital.

Results:

Of 356 eligible patients, 308 (86.5%) received SUP while in the ICU. Thirty-nine (11%) were given continuing SUP after discharge from the hospital, of which 31 (8.7%) had no clear indication. This was a 64.3% reduction from the 24.4% found in the prior study (p < 0.0001).

Conclusions:

Educational materials that guide prescribing, pharmacist interaction on patient care rounds, and pharmacist-conducted medication reconciliation significantly reduced the prescribing of non-indicated gastric acid suppressant medications after hospital discharge.
Continuous Terlipressin Infusion as Rescue Treatment in a Case Series of Children with Refractory Septic Shock
Authors: Rodríguez-Núñez Antonio , Oulego-Erroz Ignacio , Gil-Antón Javier , Pérez-Caballero César , López-Herce Jesús , Gaboli Mireia , Milano Guillermo
Published: September 2010

Background:

Despite intensive therapy, refractory pediatric septic shock has a high rate of morbidity and mortality. Additional treatments are needed to improve outcomes in such cases.

Objective:

To report the clinical effects of continuous terlipressin infusion as rescue treatment for children with septic shock refractory to high catecholamine doses.

Methods:

Sixteen episodes of catecholamine-resistant septic shock were recorded in 15 children (aged from newborn to 15 years) who received compassionate rescue treatment with terlipressin at 6 pediatric intensive care units. Terlipressin treatment consisted of a loading dose (20 μg/kg) followed by continuous infusion at a rate of 4–20 μg/kg/h. Terlipressin was titrated at increases of 1 μg/kg/h to maintain mean arterial pressure (MAP) in normal range for age and to reduce catecholamine dosage. The main outcome was survival of the episode. Secondary outcomes included hemodynamic effects, ischemia, and terlipressin-related adverse events.

Results:

Terlipressin increased median MAP from 48 (range 42–63) to 68 (45–115) mm Hg 30 minutes after terlipressin administration (p < 0.01). MAP was subsequently sustained, which allowed for the reduction of norepinephrine infusion from 2 μg/kg/min (1–4) at baseline to 1.5 μg/kg/min (0.4–4) at 1 hour, 1.3 μg/kg/min (0–8) at 4 hours, 1 μg/kg/min (0–2) at 12 hours, 0.45 μg/kg/min (0–1.4) at 24 hours, and 0 μg/kg/min (0–0.6) at 48 hours (p < 0.05 vs baseline in all cases). In 8 (50%) of the 16 septic shock episodes the patients survived, 7 (44%) without sequelae. One patient survived with sequelae (minor amputation and mild cutaneous ischemia). Eight patients had signs of ischemia at admission; terlipressin induced reversible ischemia in another 4 patients. Meningococcal infection, prior ischemia, and MAP were risk factors for mortality.

Conclusions:

Continuous terlipressin infusion may improve hemodynamics and survival in some children with refractory septic shock. Terlipressin could contribute to tissue ischemia.
Oncology: Fixed-Dose Rasburicase 6 mg for Hyperuricemia and Tumor Lysis Syndrome in High-Risk Cancer Patients
Authors: Vines Ashleigh N , Shanholtz Carl B , Thompson Jennifer L
Published: September 2010

Background:

Rasburicase is indicated for the initial management of plasma uric acid levels in adults receiving anticancer therapy who are at risk for acute tumor lysis syndrome (TLS) and subsequent hyperuricemia. The labeled dose is 0.2 mg/kg/day administered intravenously over 30 minutes for up to 5 days. Our institutional adult guidelines recommend rasburicase 6 mg for uric acid levels >8 mg/dL in most adults with TLS, or 4–8 mg/dL in high-risk patients. Repeat closing is indicated for uric acid levels >4 mg/dL determined ≥12 hours following the initial dose.

Objective:

To determine the efficacy of a single dose of rasburicase 6 mg per institutional adult TLS guidelines to decrease uric acid levels to <4 mg/dL by day 3, as well as to determine the effect on serum creatinine and phosphorus concentrations. The secondary objectives were to evaluate the appropriateness of our institutional guidelines and identify TLS risk factors.

Methods:

The study was approved by the University of Maryland Medical Center Institutional Review Board. A retrospective review of all adults between July 2008 and February 2009 who received at least one 6-mg dose of rasburicase, with redosing, if indicated, before day 3, was conducted. Subsequent TLS monitoring over 7 days after initial dosing was recorded. Patients were excluded if dosing did not adhere to institutional guidelines.

Results:

We observed a decline in median uric acid levels from 9.2 mg/dL (interquartile range 8.1–10.4) on day 1 to between 1.8 (1.0–3.8) on day 3 and 3.8 mg/dL (2.1–4.4) on day 7 (p < 0.0001) with 2 patients requiring repeat dosing before day 3 (n = 34). The majority of the population was hyperuricemic (>8 mg/dL; 76%) or at high risk for TLS (85%).

Conclusions:

A 6-mg dose of rasburicase effectively decreased uric acid to <4 mg/dL by day 3, rarely requiring repeat dosing, in a high-risk population.
The Pharmacotherapy of the HeartMate II, a Continuous Flow Left Ventricular Assist Device, in Patients with Advanced Heart Failure: Integration of Disease, Device, and Drug
Authors: Jennings Douglas L , Chambers Rachel M , Schillig Jessica M
Published: September 2010

Advanced heart failure continues to be a significant cause of morbidity and mortality in the US. Patients with advanced heart failure have a poor prognosis without cardiac transplantation. The use of left ventricular assist devices (LVADs) as destination therapy for these patients is therefore expected to increase in the coming years as technology advances. The HeartMate II, a continuous flow implantable device, is currently the only LVAD that has been approved by the Food and Drug Administration for destination therapy in patients with advanced heart failure. The pharmacotherapy associated with this device is very complex and, therefore, the need for expertly trained clinical pharmacists to care for this expanding patient population wilt also likely increase. Unfortunately, most pharmacists are unfamiliar with the effect of LVADs on the physiology and pharmacotherapy of a patient's heart failure. The purpose of this article is to give clinical pharmacists an introduction to the most common pharmacotherapeutic issues for patients with LVADs and present practical solutions for managing common drug therapy problems.
How Important Are Brands? A Cross-Category, Cross-Country Study
Authors: Fischer Marc , Völckner Franziska , Sattler Henrik
Published: September 2010

This article focuses on the measurement of the overall importance of brands for consumer decision making—that is, brand relevance in category, or BRiC—across multiple categories and countries. Although brand equity measures for specific brands have attracted a large body of literature, the questions of how important brands are within an entire product category and the extent to which BRiC differs across categories and countries have been neglected. The authors introduce the concept of BRiC (a category-level measure, not a brand-level measure). They develop a conceptual framework to measure BRiC and the drivers of BRiC, test the framework empirically with a sample of more than 5700 consumers, and show how the construct varies across 20 product categories and five countries (France, Japan, Spain, the United Kingdom, and the United States). The results suggest a high validity of the proposed BRiC measure and show substantial differences between categories and countries. A replication study two-and-a-half years later confirms the psychometric properties of the suggested scale and shows remarkable stability of the findings. The findings have important implications for the management of brand investments.
Personal Selling Elasticities: A Meta-Analysis
Authors: Albers Sönke , Mantrala Murali K. , Sridhar Shrihari
Published: September 2010

This article presents a meta-analysis of prior econometric estimates of personal selling elasticity—that is, the ratio of the percentage change in an objective, ratio-scaled measure of sales output (e.g., dollar or unit purchases) to the corresponding percentage change in an objective, ratio-scaled measure of personal selling input (e.g., dollar expenditures). The authors conduct a meta-analysis of 506 personal selling elasticity estimates drawn from analyses of 88 empirical data sets across 75 previous articles. They find a mean estimate of current-period personal selling elasticity of .34. They also find that elasticity estimates are higher for early life-cycle-stage offerings, higher from studies set in Europe than from those set in the United States, and smaller in more recent years. In addition, elasticity estimates are affected significantly by analysts’ use of relative rather than absolute sales output measures, by cross-sectional rather than panel data, by omission of promotions, by lagged effects, by marketing interaction effects, and by the neglect of endogeneity in model estimation. The method bias–corrected mean personal selling elasticity is approximately .31. The authors discuss the implications of their results for sales managers and researchers.
The Long-Term Effect of Marketing Strategy on Brand Sales
Authors: Ataman M. Berk , Van Heerde Harald J. , Mela Carl F.
Published: September 2010

Few studies have considered the relative role of the integrated marketing mix (advertising, price promotion, product, and place) on the long-term performance of mature brands, instead emphasizing advertising and price promotion. Thus, little guidance is available to firms regarding the relative efficacy of their various marketing expenditures over the long run. To investigate this issue, the authors apply a multivariate dynamic linear transfer function model to five years of advertising and scanner data for 25 product categories and 70 brands in France. The findings indicate that the total (short-term plus long-term) sales elasticity is 1.37 for product and .74 for distribution. Conversely, the total elasticities for advertising and discounting are only .13 and .04, respectively. This result stands in marked contrast to the previous emphasis in the literature on price promotions and advertising. The authors further find that the long-term effects of discounting are one-third the magnitude of the short-term effects. The ratio is reversed from other aspects of the mix (in which long-term effects exceed four times the short-term effects), underscoring the strategic role of these tools in brand sales.
Trade-Offs and Depletion in Choice
Authors: Wang Jing , Novemsky Nathan , Dhar Ravi , Baumeister Roy F.
Published: September 2010

Four experiments examine why choices deplete executive resources. The authors show that the resolution of trade-offs is a driver of depletion effects arising from choice, and the larger the trade-offs, the greater is the depletion effect. The authors also find that choice difficulty not related to trade-offs does not influence the depleting effect of the choices. Finally, the authors find that though people can intuit some depletion effects, they do not intuit that choices or trade-offs within choices might be depleting and therefore fail to predict that larger trade-offs are more depleting.
Procrastination of Enjoyable Experiences
Authors: Shu Suzanne B. , Gneezy Ayelet
Published: September 2010

The tendency to procrastinate applies not only to aversive tasks but also to positive experiences with immediate benefits. The authors propose that models of time discounting can explain this behavior, and they test these predictions with field data and experiments. A multicity study shows that people with unlimited time windows delay visiting desirable landmarks; however, procrastination is reduced when the window of opportunity is constrained. Similarly, people procrastinate in redeeming gift certificates and gift cards with long deadlines more than those with short deadlines, resulting in overall lower redemption rates. These results run counter to participants’ predictions and typical models of impulsive behavior.
Power Distance Belief and Impulsive Buying
Authors: Zhang Yinlong , Winterich Karen Page , Mittal Vikas
Published: September 2010

The authors propose that power distance belief (PDB) (i.e., accepting and expecting power disparity) influences impulsive buying beyond other related cultural dimensions, such as individualism–collectivism. This research supports an associative account that links PDB and impulsive buying as a manifestation of self-control, such that those with high PDB display less impulsive buying. Furthermore, this effect manifests for vice products but not for virtue products. The authors also find that restraint from temptations can occur automatically for people who have repeated practice (i.e., chronically high PDBs). Taken together, these results imply that products should be differentially positioned as vice or virtue products in accordance with consumers’ PDBs.
Atypical Reflexive Gaze Patterns on Emotional Faces in Autism Spectrum Disorders
Authors: Kliemann Dorit , Dziobek Isabel , Hatri Alexander , Steimke Rosa , Heekeren Hauke R.
Published: September 2010

Atypical scan paths on emotional faces and reduced eye contact represent a prominent feature of autism symptomatology, yet the reason for these abnormalities remains a puzzle. Do individuals with autism spectrum disorders (ASDs) fail to orient toward the eyes or do they actively avoid direct eye contact? Here, we used a new task to investigate reflexive eye movements on fearful, happy, and neutral faces. Participants (ASDs: 12; controls: 11) initially fixated either on the eyes or on the mouth. By analyzing the frequency of participants' eye movements away from the eyes and toward the eyes, respectively, we explored both avoidance and orientation reactions. The ASD group showed a reduced preference for the eyes relative to the control group, primarily characterized by more frequent eye movements away from the eyes. Eye-tracking data revealed a pronounced influence of active avoidance of direct eye contact on atypical gaze in ASDs. The combination of avoidance and reduced orientation into an individual index predicted emotional recognition performance. Crucially, this result provides evidence for a direct link between individual gaze patterns and associated social symptomatology. These findings thereby give important insights into the social pathology of ASD, with implications for future research and interventions.
Rule-Based Learning Explains Visual Perceptual Learning and Its Specificity and Transfer
Authors: Zhang Jun-Yun , Zhang Gong-Liang , Xiao Lu-Qi , Klein Stanley A. , Levi Dennis M. , Yu Cong
Published: September 2010

Visual perceptual learning models, as constrained by orientation and location specificities, propose that learning either reflects changes in V1 neuronal tuning or reweighting specific V1 inputs in either the visual cortex or higher areas. Here we demonstrate that, with a training-plus-exposure procedure, in which observers are trained at one orientation and either simultaneously or subsequently passively exposed to a second transfer orientation, perceptual learning can completely transfer to the second orientation in tasks known to be orientation-specific. However, transfer fails if exposure precedes the training. These results challenge the existing specific perceptual learning models by suggesting a more general perceptual learning process. We propose a rule-based learning model to explain perceptual learning and its specificity and transfer. In this model, a decision unit in high-level brain areas learns the rules of reweighting the V1 inputs through training. However, these rules cannot be applied to a new orientation/location because the decision unit cannot functionally connect to the new V1 inputs that are unattended or even suppressed after training at a different orientation/location, which leads to specificity. Repeated orientation exposure or location training reactivates these inputs to establish the functional connections and enable the transfer of learning.
Oligodendrocyte-Myelin Glycoprotein and Nogo Negatively Regulate Activity-Dependent Synaptic Plasticity
Authors: Raiker Stephen J. , Lee Hakjoo , Baldwin Katherine T. , Duan Yuntao , Shrager Peter , Giger Roman J.
Published: September 2010

In the adult mammalian CNS, the growth inhibitors oligodendrocyte-myelin glycoprotein (OMgp) and the reticulon RTN4 (Nogo) are broadly expressed in oligodendrocytes and neurons. Nogo and OMgp complex with the neuronal cell surface receptors Nogo receptor-1 (NgR1) and paired Ig-like receptor-B (PirB) to regulate neuronal morphology. In the healthy CNS, NgR1 regulates dendritic spine shape and attenuates activity-driven synaptic plasticity at Schaffer collateral–CA1 synapses. Here, we examine whether Nogo and OMgp influence functional synaptic plasticity, the efficacy by which synaptic transmission occurs. In acute hippocampal slices of adult mice, Nogo-66 and OMgp suppress NMDA receptor-dependent long-term potentiation (LTP) when locally applied to Schaffer collateral–CA1 synapses. Neither Nogo-66 nor OMgp influences basal synaptic transmission or paired-pulse facilitation, a form of short-term synaptic plasticity.PirB−/−andNgR1−/−single mutants andNgR1−/−;PirB−/−double mutants show normal LTP, indistinguishable from wild-type controls. In juvenile mice, LTD inNgR1−/−, but notPirB−/−, slices is absent. Mechanistic studies revealed that Nogo-66 and OMgp suppress LTP in anNgR1-dependent manner. OMgp inhibits LTP in part throughPirBbut independently ofp75. This suggests that NgR1 and PirB participate in ligand-dependent inhibition of synaptic plasticity. Loss ofNgR1leads to increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), signaling intermediates known to regulate neuronal growth and synaptic function. In primary cortical neurons, BDNF elicited phosphorylation of AKT and p70S6 kinase is attenuated in the presence of myelin inhibitors. Collectively, we provide evidence that mechanisms of neuronal growth inhibition and inhibition of synaptic strength are related. Thus, myelin inhibitors and their receptors may coordinate structural and functional neuronal plasticity in CNS health and disease.
Increased BMP6 Levels in the Brains of Alzheimer's Disease Patients and APP Transgenic Mice Are Accompanied by Impaired Neurogenesis
Authors: Crews Leslie , Adame Anthony , Patrick Christina , DeLaney Alexandra , Pham Emiley , Rockenstein Edward , Hansen Lawrence , Masliah Eliezer
Published: September 2010

During aging and in the progression of Alzheimer's disease (AD), synaptic plasticity and neuronal integrity are disturbed. In addition to the alterations in plasticity in mature neurons, the neurodegenerative process in AD has been shown to be accompanied by alterations in neurogenesis. Members of the bone morphogenetic protein (BMP) family of growth factors have been implicated as important regulators of neurogenesis and neuronal cell fate determination during development; however, their role in adult neurogenesis and in AD is less clear. We show here by qRT-PCR analysis that BMP6 mRNA levels were significantly increased in the hippocampus of human patients with AD and in APP transgenic mice compared to controls. Immunoblot and immunohistochemical analyses confirmed that BMP6 protein levels were increased in human AD brains and APP transgenic mouse brains compared to controls and accumulated around hippocampal plaques. The increased levels of BMP6 were accompanied by defects in hippocampal neurogenesis in AD patients and APP transgenic mice. In support of a role for BMP6 in defective neurogenesis in AD, we show in anin vitromodel of adult neurogenesis that treatment with amyloid-β1-42protein (Aβ) resulted in increased expression of BMP6, and that exposure to recombinant BMP6 resulted in reduced proliferation with no toxic effects. Together, these results suggest that Aβ-associated increases in BMP6 expression in AD may have deleterious effects on neurogenesis in the hippocampus, and therapeutic approaches could focus on normalization of BMP6 levels to protect against AD-related neurogenic deficits.
Molecular Dynamics and Social Regulation of Context-Dependent Plasticity in the Circadian Clockwork of the Honey Bee
Authors: Shemesh Yair , Eban-Rothschild Ada , Cohen Mira , Bloch Guy
Published: September 2010

The social environment influences the circadian clock of diverse animals, but little is known about the functional significance, the specifics of the social signals, or the dynamics of socially mediated changes in the clock. Honey bees switch between activities with and without circadian rhythms according to their social task. Forager bees have strong circadian rhythms, whereas “nurse” bees typically care for the brood around-the-clock with no circadian rhythms in behavior or clock gene expression. Here we show that nurse-age bees that were restricted to a broodless comb inside or outside the hive showed robust behavioral and molecular circadian rhythms. By contrast, young nurses tended brood with no circadian rhythms in behavior or clock gene expression, even under a light-dark illumination regime or when placed with brood—but no queen—in a small cage outside the hive. This behavior is context-dependent because nurses showed circadian rhythms in locomotor activity shortly after removal from the hive, and in clock gene expression after ∼16 h. These findings suggest that direct interaction with the brood modulates the circadian system of honey bees. The dynamics of rhythm development best fit models positing that at least some pacemakers continue to oscillate and be entrained by the environment in nurses that are active around the clock. These cells set the phase to the clock network when the nurse is removed from the hive. These findings suggest that despite its robustness, the circadian system exhibits profound plasticity, enabling adjustment to rapid changes in the social environment.
β-Adrenoceptor Blockers Increase Cardiac Sympathetic Innervation by Inhibiting Autoreceptor Suppression of Axon Growth
Authors: Clarke Gwenaëlle L. , Bhattacherjee Aritra , Tague Sarah E. , Hasan Wohaib , Smith Peter G.
Published: September 2010

β-Adrenoceptor antagonists are used widely to reduce cardiovascular sympathetic tone, but withdrawal is accompanied by sympathetic hyperactivity. Receptor supersensitivity accounts for some but not all aspects of this withdrawal syndrome. Therefore, we investigated effects of β-blockers on sympathetic innervation. Rats received infusions of adrenergic receptor blockers or saline for 1 week. The nonselective β-blocker propranolol and the β1-antagonist metoprolol both increased myocardial sympathetic axon density. At 2 d after propranolol discontinuation, β-receptor sensitivity and responsiveness to isoproterenol were similar to controls. However, tyramine-induced mobilization of norepinephrine stores produced elevated ventricular contractility consistent with enhanced sympathetic neuroeffector properties. In addition, rats undergoing discontinuation showed exaggerated increases in mean arterial pressure in response to air puff or noise startle. In sympathetic neuronal cell cultures, both propranolol and metoprolol increased axon outgrowth but the β2-blocker ICI 118551 did not. Norepinephrine synthesis suppression by α-methyl-p-tyrosine also increased sprouting and concurrent dobutamine administration reduced it, confirming that locally synthesized norepinephrine inhibits outgrowth via β1-adrenoceptors. Immunohistochemistry revealed β1-adrenoceptor protein on sympathetic axon terminations. In rats with coronary artery ligation, propranolol reversed heart failure-induced ventricular myocardial sympathetic axon depletion, but did not affect infarct-associated sympathetic hyperinnervation. We conclude that sympathetic neurons possess β1-autoreceptors that negatively regulate axon outgrowth. Chronic β-adrenoceptor blockade disrupts this feedback system, leading to ventricular sympathetic axon proliferation and increased neuroeffector gain, which are likely to contribute to β-blocker withdrawal syndrome.
Mitochondrial Protection Attenuates Inflammation-Induced Impairment of NeurogenesisIn VitroandIn Vivo
Authors: Voloboueva Ludmila A. , Lee Star W. , Emery John F. , Palmer Theo D. , Giffard Rona G.
Published: September 2010

The impairment of hippocampal neurogenesis has been linked to the pathogenesis of neurological disorders from chronic neurodegenerative disease to the progressive cognitive impairment of children who receive brain irradiation. Numerous studies provide evidence that inflammation downregulates neurogenesis, with multiple factors contributing to this impairment. Although mitochondria are one of the primary targets of inflammatory injury, the role of mitochondrial function in the modulation of neurogenesis remains relatively unstudied. In this study, we used neurosphere-derived cells to show that immature doublecortin (Dcx)-positive neurons are uniquely sensitive to mitochondrial inhibition, demonstrating rapid loss of mitochondrial potential and cell viability compared with glial cells and more mature neurons. Mitochondrial inhibition for 24 h produced no significant changes in astrocyte or oligodendrocyte viability, but reduced viability of mature neurons by 30%, and reduced survival of Dcx+cells by 60%. We demonstrate that protection of mitochondrial function with mitochondrial metabolites or the mitochondrial chaperone mtHsp75/mortalin partially reverses the inflammation-associated impairment of neurogenesisin vitroand in irradiated micein vivo. Our findings highlight mitochondrial mechanisms involved in neurogenesis and indicate mitochondria as a potential target for protective strategies to prevent the impairment of neurogenesis by inflammation.
Associative Learning and CA3–CA1 Synaptic Plasticity Are Impaired in D1R Null,Drd1a−/−Mice and in Hippocampal siRNA SilencedDrd1aMice
Authors: Ortiz Oskar , Delgado-García José María , Espadas Isabel , Bahí Amine , Trullas Ramón , Dreyer Jean-Luc , Gruart Agnès , Moratalla Rosario
Published: September 2010

Associative learning depends on multiple cortical and subcortical structures, including striatum, hippocampus, and amygdala. Both glutamatergic and dopaminergic neurotransmitter systems have been implicated in learning and memory consolidation. While the role of glutamate is well established, the role of dopamine and its receptors in these processes is less clear. In this study, we used two models of dopamine D1receptor (D1R,Drd1a) loss, D1R knock-out mice (Drd1a−/−) and mice with intrahippocampal injections ofDrd1a-siRNA (small interfering RNA), to study the role of D1R in different models of learning, hippocampal long-term potentiation (LTP) and associated gene expression. D1R loss markedly reduced spatial learning, fear learning, and classical conditioning of the eyelid response, as well as the associated activity-dependent synaptic plasticity in the hippocampal CA1–CA3 synapse. These results provide the first experimental demonstration that D1R is required for trace eyeblink conditioning and associated changes in synaptic strength in hippocampus of behaving mice.Drd1a-siRNA mice were indistinguishable fromDrd1a−/−mice in all experiments, indicating that hippocampal knockdown was as effective as global inactivation and that the observed effects are caused by loss of D1R and not by indirect developmental effects ofDrd1a−/−. Finally,in vivoLTP and LTP-induced expression ofEgr1in the hippocampus were significantly reduced inDrd1a−/−andDrd1a-siRNA, indicating an important role for D1R in these processes. Our data reveal a functional relationship between acquisition of associative learning, increase in synaptic strength at the CA3–CA1 synapse, andEgr1induction in the hippocampus by demonstrating that all three are dramatically impaired when D1R is eliminated or reduced.
Hepatocyte Growth Factor-Met Signaling Is Required forRunx1Extinction and Peptidergic Differentiation in Primary Nociceptive Neurons
Authors: Gascon Eduardo , Gaillard Stéphane , Malapert Pascale , Liu Yang , Rodat-Despoix Lise , Samokhvalov Igor M. , Delmas Patrick , Helmbacher Françoise , Maina Flavio , Moqrich Aziz
Published: September 2010

Nociceptors in peripheral ganglia display a remarkable functional heterogeneity. They can be divided into the following two major classes: peptidergic and nonpeptidergic neurons. Although RUNX1 has been shown to play a pivotal role in the specification of nonpeptidergic neurons, the mechanisms driving peptidergic differentiation remain elusive. Here, we show that hepatocyte growth factor (HGF)-Met signaling acts synergistically with nerve growth factor-tyrosine kinase receptor A to promote peptidergic identity in a subset of prospective nociceptors. We providein vivoevidence that a population of peptidergic neurons, derived from the RUNX1 lineage, require Met activity for the proper extinction ofRunx1and optimal activation ofCGRP(calcitonin gene-related peptide). Moreover, we show that RUNX1 in turn represses Met expression in nonpeptidergic neurons, revealing a bidirectional cross talk between Met and RUNX1. Together, our novel findings support a model in which peptidergic versus nonpeptidergic specification depends on a balance between HGF-Met signaling andRunx1extinction/maintenance.
Gating of Transient Receptor Potential Melastatin 8 (TRPM8) Channels Activated by Cold and Chemical Agonists in Planar Lipid Bilayers
Authors: Zakharian Eleonora , Cao Chike , Rohacs Tibor
Published: September 2010

The transient receptor potential melastatin 8 (TRPM8) ion channel is a major sensor of environmental cold temperatures. It is activated by cold and chemical agonists, such as menthol and icilin. The activation of these channels both by cold and cooling agents requires the presence of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. The mechanism of TRPM8 activation by physical and chemical factors is unknown, and the involvement of cellular signaling pathways has been considered. Here we have characterized the gating mechanism of the rat TRPM8 reconstituted in planar lipid bilayers and its activation by different stimuli. In this system, the influence of cellular signaling pathways can be excluded. We found that TRPM8 activated by cold exhibits steep temperature dependence [temperature coefficient (Q10) of ∼40], and the channel openings are accompanied by large changes in entropy and enthalpy, suggesting a substantial conformation change. TRPM8 channel behavior upon menthol and icilin activation was distinguishable, and the effect of icilin depended on the presence of calcium on the intracellular side of the protein. Here we also demonstrate that PI(4,5)P2is the prime factor that impacts the gating of TRPM8 and that other phosphoinositides are less efficient in supporting channel activity. Menthol increases the potency of PI(4,5)P2to activate the channels and increases binding of phosphoinositides to the full-length channel protein. Our data demonstrate conclusively that TRPM8 is gated by cold and its chemical agonists directly, and that dependence of its gating on PI(4,5)P2is a result of direct specific interactions with the lipid.
Muscle-Derived Collagen XIII Regulates Maturation of the Skeletal Neuromuscular Junction
Authors: Latvanlehto Anne , Fox Michael A. , Sormunen Raija , Tu Hongmin , Oikarainen Tuomo , Koski Anu , Naumenko Nikolay , Shakirzyanova Anastasia , Kallio Mika , Ilves Mika , Giniatullin Rashid , Sanes Joshua R. , Pihlajaniemi Taina
Published: September 2010

Formation, maturation, stabilization, and functional efficacy of the neuromuscular junction (NMJ) are orchestrated by transsynaptic and autocrine signals embedded within the synaptic cleft. Here, we demonstrate that collagen XIII, a nonfibrillar transmembrane collagen, is another such signal. We show that collagen XIII is expressed by muscle and its ectodomain can be proteolytically shed into the extracellular matrix. The collagen XIII protein was found present in the postsynaptic membrane and synaptic basement membrane. To identify a role for collagen XIII at the NMJ, mice were generated lacking this collagen. Morphological and ultrastructural analysis of the NMJ revealed incomplete adhesion of presynaptic and postsynaptic specializations in collagen XIII-deficient mice of both genders. Strikingly, Schwann cells erroneously enwrapped nerve terminals and invaginated into the synaptic cleft, resulting in a decreased contact surface for neurotransmission. Consistent with morphological findings, electrophysiological studies indicated both postsynaptic and presynaptic defects inCol13a1−/−mice, such as decreased amplitude of postsynaptic potentials, diminished probabilities of spontaneous release and reduced readily releasable neurotransmitter pool. To identify the role of collagen XIII at the NMJ, shed ectodomain of collagen XIII was applied to cultured myotubes, and it was found to advance acetylcholine receptor (AChR) cluster maturation. Together with the delay in AChR cluster development observed in collagen XIII-deficient mutantsin vivo, these results suggest that collagen XIII plays an autocrine role in postsynaptic maturation of the NMJ. Altogether, the results presented here reveal that collagen XIII is a novel muscle-derived cue necessary for the maturation and function of the vertebrate NMJ.
Telomerase Recruitment in Saccharomyces cerevisiae Is Not Dependent on Tel1-Mediated Phosphorylation of Cdc13
Authors: Gao Hua , Toro Tasha B , Paschini Margherita , Braunstein-Ballew Bari , Cervantes Rachel B , Lundblad Victoria
Published: September 2010

In Saccharomyces cerevisiae, association between the Est1 telomerase subunit and the telomere-binding protein Cdc13 is essential for telomerase to be recruited to its site of action. A current model proposes that Tel1 binding to telomeres marks them for elongation, as the result of phosphorylation of a proposed S/TQ cluster in the telomerase recruitment domain of Cdc13. However, three observations presented here argue against one key aspect of this model. First, the pattern of Cdc13 phosphatase-sensitive isoforms is not altered by loss of Tel1 function or by mutations introduced into two conserved serines (S249 and S255) in the Cdc13 recruitment domain. Second, an interaction between Cdc13 and Est1, as monitored by a two-hybrid assay, is dependent on S255 but Tel1-independent. Finally, a derivative of Cdc13, cdc13–(S/TQ)11→(S/TA)11, in which every potential consensus phosphorylation site for Tel1 has been eliminated, confers nearly wild-type telomere length. These results are inconsistent with a model in which the Cdc13–Est1 interaction is regulated by Tel1-mediated phosphorylation of the Cdc13 telomerase recruitment domain. We propose an alternative model for the role of Tel1 in telomere homeostasis, which is based on the assumption that Tel1 performs the same molecular task at double-strand breaks (DSBs) and chromosome termini.