bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced zirconia thermal barrier coating systems
Authors: Clarke D. R. , Levi C. G. , Evans A. G.
Published: February 2006

The results of a research programme sponsored by the Department of Energy and directed at establishing some of the scientific issues underpinning the development of enhanced zirconia thermal barrier coatings (TBCs) are reviewed. Our studies have established the stability ranges for both yttria stabilized and codoped zirconia coating materials and identified the mechanisms responsible for failure of current coating systems. These reveal that it is likely that present EB-PVD coatings systems are limited by the performance of current bond-coats and their oxidation behaviour, especially under thermal cycle conditions, rather than the zirconia coating material itself. These studies provide the scientific framework for the development of enhanced zirconia-based thermal barrier coating systems for advanced industrial gas turbine engine applications.
Influence of upstream stator on rotor flutter stability in a low pressure steam turbine stage
Authors: Huang X. Q. , He L , Bell D. L.
Published: February 2006

Conventional blade flutter prediction is normally based on an isolated blade row model, however, little is known about the influence of adjacent blade rows. In this article, an investigation is presented into the influence of the upstream stator row on the aero-elastic stability of rotor blades in the last stage of a low pressure (LP) steam turbine. The influence of the upstream blade row is computed directly by a time-marching, unsteady, Navier-Stokes flow solver in a stator-rotor coupled computational domain. The three-dimensional flutter solution is obtained, with adequate mesh resolution, in a single passage domain through application of the Fourier-transform based Shape-Correction method. The capability of this single-passage method is examined through comparison with predictions obtained from a complete annulus model, and the results demonstrate a good level of accuracy, while achieving a speed up factor of 25. The present work shows that the upstream stator blade row can significantly change the aero-elastic behaviour of an LP steam turbine rotor. Caution is, therefore, advised when using an isolated blade row model for blade flutter prediction. The results presented also indicate that the intra-row interaction is of a strong three-dimensional nature.
System automation for measuring coal combustion efficiency
Authors: Ouazzane K , Benhadj R
Published: February 2006

Monitoring the combustion process for electricity generation using coal as a primary resource is of a major concern to the pertinent industries, power generation companies in particular. The carbon content of fly ash is indicative of the combustion efficiency. The determination of this parameter is useful to characterize the efficiency of coal burning furnaces. Traditional methods such as thermo-gravimetric analysis and loss on ignition, which are based on ash collection and subsequent analysis, proved to be tediously difficult, time consuming, and costly. Thus, a new technology was inevitable and needed to monitor the process in a more efficient method, yielding a better exploitation of the resources at a lower cost. The main aim of this work is to introduce a new automated system, which can be bolted onto a furnace and work online. The system consists of three main components, namely, a laser instrument for signal acquisition, a neural network tool for training, learning and simulation, and a database system for storage and retrieval. The components have been designed, adapted and tuned for knowledge acquisition of this multi-dimensional problem.

When the particles are dispersed across the test space, the instrument observed single particle counts simultaneously on the two photomultipliers. The output voltages displayed represent the intensity of horizontally and vertically polarized light, and the polarization ratio is calculated from the ratio of these voltages. It was found that the carbon-in-ash is related to the polarization ratio and the carbon mass fraction could be determined to within ± 1 per cent of the carbon content. However, if a proximate analysis is performed on the coal, the prediction could be improved to within ± 0.05 per cent using neural network simulation. The system has been tested for a range of coal ashes and proved to be efficient.
An investigation of wind power potential required in installation of wind energy conversion systems
Authors: Akpinar E. K. , Akpinar S
Published: February 2006

In the present study, the wind power potential of all the regions (Maden, Agin, Elazig, and Keban) is analysed on the basis of measured hourly time-series wind speed data for the year 2003. The probability density distributions are derived from time-series data and distributional parameters are identified. Two probability density functions are fitted to the measured probability distributions. The wind energy characteristic of all the regions is studied on the basis of the Weibull and the Rayleigh distributions. Using the Weibull probability density function, we estimated the wind energy output and the capacity factor for six different wind turbines between 300 and 2300 kW. It was found that Maden is the best region, among the regions analyzed, for wind energy and wind turbine characteristics.
Investigation of the scroll compressor porting process. Part II: local characteristics of the porting process and properties of the ports
Authors: Cui M. M.
Published: February 2006

As the flow field experiences drastic changes at the discharge and dummy ports of a scroll compressor, the local geometry and movement, including the sizes, shapes, and movement of the ports and scrolls, have significant impact on the porting process. To assess quantitatively the performance of a given design during porting, the local characteristics of the porting process are studied. The study is conducted both on the field quantity distributions and area-averaged parameters. These field quantities define both temporal and spatial changes of the flow field at the discharge and dummy ports. The investigation on these field quantities, provides a basic understanding of the porting process. The fundamental phenomena controlling the porting process are identified. The area-averaged parameters describe the dynamic features of the porting process. The components involved in the porting process, especially the scrolls, dummy and discharge ports, are studied. The area schedule, mass flowrate, pressure, temperature changes at the dummy and discharge ports are quantified. The impact of the porting process on the compressor efficiency, vibration, and noise generation is analysed.
Characterization of plasma-sprayed alumina as thermal control coating for micro-satellite applications
Authors: Li R M , Joshi S C , Ng H W
Published: February 2006

Conventional thermal control materials (TCMs) used in satellites tend to deteriorate in the severe space environment, many times leading to unanticipated mission problems. New and better TCMs are constantly sought to reduce difficulties in satellite thermal design. In this paper, the possibility of using plasma-sprayed alumina (PSA) coating for thermal control of a satellite is examined. Such PSA coatings have proved to be a good thermal barrier coating material for hot section components in aircraft engines. Panels of aluminum alloys such as 2024-T3, 6061-T6, 7075, and so on which are commonly used for satellite applications, form a very compatible substrate for PSA coatings. Various physical and processing parameters and simulated in-service behaviour for PSA were studied analytically and experimentally. Preliminary investigations reveal that the PSA coatings have good potential as a substitute to conventional TCMs for micro-satellite panels, including solar arrays.
Wear response of crystalline nanocomposite and glassy Al2O3-SiC coatings subjected to simulated piston ring/cylinder wall tests
Authors: Dearnley P A , Kern E , Dahm K L
Published: February 2006

The present paper describes the major part of a recent research investigation whose main purpose was to develop a series of novel functional coatings based on the Al2O3-SiC system that ideally would have a nanocomposite microstructure. Such coatings should be well suited for the wear protection of steel and cast-iron piston rings used in automotive internal combustion engines. Two methods were investigated: (i) plasma spraying and (ii) magnetron sputtering. The former was applied to cast-iron and plain carbon steel, whereas the latter was applied to stainless steel piston rings. The plasma sprayed coatings were porous with a hardness of 900-1150 HV, whereas the sputtered coatings were glassy and dense with a hardness of 701-788 HV. High-speed reciprocation wear tests, which simulate the piston ring/cylinder wall environment, were used to assess all coatings. CKS-36 coated cast-iron rings, one of the more common industry standards for this application, were also evaluated. Results showed these to be the most wear resistant. They were smoothly worn, possibly by a microabrasion wear process. The plasma sprayed coatings displayed two main types of wear surface: rough and smooth. The former were mainly generated by a process of grain or particle pull-out, whereas the latter resulted from a combination of microabrasion and microflaking mechanisms. The use of diamond grinding, for finishing the plasma sprayed coatings, mitigated failure through grain pull-out, but wear rates still remained slightly too high compared with uncoated stainless steel and CKS-36 coated cast-iron rings. Most of the sputtered coatings displayed varying degrees of smooth wear which was mitigated as the coating hardness increased. However, this trend was masked by sporadic coating loss through adhesive and/or cohesive failure. The creation of a gradated sputter coating having a core composition based on the Al2O3-SiC variant containing most Si and C and incorporating a bond layer enriched in Cr, adjacent the substrate, eliminated cohesive and adhesive coating failures. Future work should concentrate on the development and evaluation of sputtered crystalline Al2O3-SiC coatings and HVOF sprayed Al2O3-SiC variants. There may also be significant potential in investigating glassy Al2O3-SiC coatings containing significantly higher quantities of Si and C to those reported here.
A summary review of mechanical properties prediction methods for textile reinforced polymer composites
Authors: Crookston J J , Long A C , Jones I A
Published: February 2006

The use of textile reinforcements for polymer composite components has become a common practice due to the favourable material costs and labour requirements compared with traditional unidirectional prepreg composites, and the high stiffness and strength compared with the use of randomly orientated reinforcements. As a result, determination of both elastic properties and failure behaviour of textile composites has been the subject of substantial research in recent years. This paper presents a review of some of the analytical and numerical models pertaining to the mechanics of textile composites which have been published in the literature. Particular consideration is given to the suitability of models for the analysis of non-orthogonal weave structures such as those which have been deformed in shear during component manufacture. The intention of the paper is not to provide a detailed analysis of the underlying mathematics of the models discussed, but rather to provide an overview of the work conducted in order to direct further reading.
The changing role of the otolaryngology Senior House Officer
Authors: Arya AK , Gibbin KP
Published: February 2006

The European Working Time Directive (EWTD) has led to a reduction in the number of hours that a junior doctor is allowed to work. The Hospital at Night project aims to reduce juniors' presence at night through more efficient working. Otolaryngology has been considered to be one of the surgical specialties in which generic junior doctors covering more than one specialty could effectively function. The hope is to reduce junior doctors' hours sufficiently without compromising their training or patient safety.
Future opportunities for research in primary dental care: developing research to support the commissioning of care
Authors: Eaton Kenneth
Published: February 2006

In November 2005 there was a first for the Faculty of General Dental Practice (UK) when it hosted a national research study day funded by the Department of Health. A key goal for the Faculty is to develop the research skills of its members and to provide leaders to address the current dearth of research-based evidence for all aspects of primary dental care.
BST applications – what is the current popularity of a surgical career in the UK?
Authors: Osborn GD , De Souza J , Telli M , Lewis MH
Published: February 2006

The introduction of the foundation year programme as part of Modernising Medical Careers (MMC) will involve major changes in the way aspiring surgeons are to be trained. Newly qualified doctors will enter a first foundation year (FY1), much like the current PRHO year, which will be followed by a second foundation year (FY2) with placements in a variety of specialties. Having completed the two foundation years, trainees will be eligible to enter either specialist training or general practice.
Flexible training for a modern surgical workforce
Authors: Walls Janet
Published: February 2006

Further to the short article on flexible training, which appeared in the Bulletin in September 2005, I am pleased to report a positive response from many trainees regarding the benefits of undertaking less than full-time training. Many stated an improvement in their work–life balance and, since many were slightly older than their peers when applying for consultant posts, they felt they had the advantage of maturity and a greater breadth of experience.
Overseas team waiting list initiatives – at what cost?
Authors: Kennard A , Purohit N , Davis BJ
Published: February 2006

Recently, we have witnessed the arrival of several government initiatives designed to reduce the length of NHS waiting lists. All are agreed that reducing waiting list sizes is a high priority. Kennard et al have conducted a local audit and have raised concerns about the means to that end. Of particular concern to the current generation of trainees is the perception that the current investment is not directed adequately directed towards the improvement of the existing infrastructure or of the surgeons of the future.
Surgical training - can we learn from aviation?
Authors: Hirst Guy , Wilkins Denis
Published: February 2006

The following two articles identify similarities between professional air crew and surgeons, both being leaders of multidisciplinary teams and holding ultimate legal responsibility. In the first article, British Airways training captain Guy Hirst illustrates the non-adversarial teamwork inherent in effective crew resource management with confidential reporting of adverse incidents and the care with which flight instructors are selected and nurtured. Denis Wilkins, a senior surgeon, demonstrates in the second article that nobody takes responsibility for the 'signing off' of trainees for any particular surgical procedure.

There are, of course, differences in the training environments of the professions. Advance flying training requires a student pilot to put an aircraft into critical situations and to demonstrate the ability to recover. Mostly, this can be performed repetitively either at sufficient altitude or in the safety of a simulator. In surgery, one cannot purposely put a patient 'at risk' to enable trainees to demonstrate their skills at 'recovery' and surgical simulators are in their infancy and do not achieve priority in a cash-strapped NHS.

The authors recognise the need for properly selected trainers who are remunerated accordingly. Having been both a flying instructor and a surgical trainer, I can testify that both professions require patience, rapid reactions and the ability to remain calm. These papers are fascinating and timely in the era of introduction of new surgical curricula. Surgical training requires considerable funding at grass-roots level to catch up with the standards of aviation.
Is patient care affected by the recent changes in junior doctors' training?
Authors: Mauffrey C
Published: February 2006

An article in the British Medical Journal stated, 'In the time it will take you to read this editorial eight patients will be injured, and one will die, from preventable medical errors. … When all sources of error are added up the likelihood that a mishap will injure a patient in hospital is at least 3% and probably much higher.' This is a serious public health problem. In recent years, patients' expectations of our healthcare system have shifted from 'the right to receive treatment' to 'the right to be cured'. This fact is illustrated by the growing numbers of trials involving cases of negligence or incompetence.
Pharmaceutical Care in Community Pharmacies: Practice and Research in Switzerland
Authors: Guignard Emmanuèle , Bugnon Olivier
Published: February 2006

Objective:

To describe the current situation and prospects for community pharmacy practice in Switzerland, a confederation of 26 cantons with a population of approximately 7 million, located in the center of Europe.

Findings:

For the past 10 years, the Swiss Association of Pharmacists has directed an in-depth reform of the profession, with measures such as a system of remuneration based on pharmaceutical cognitive services, a quality care program named QMS–Pharmacy, a postgraduate education program (including specific titles and certificates) and obligatory continuous education, programs of public relations and health promotion, innovative services of managed care, generics substitution, and others.

Discussion:

The implemented changes in management represent a pharmaceutical care solution for Swiss community pharmacies, which face intense competition and a very liberal policy regarding healthcare organization, relating in particular to the important cantonal autonomy, free establishment of ownership of pharmacies, pharmacy chains, dispensing physicians, chemist shops, mail order, and others.

Conclusions:

Community pharmacy in Switzerland is making modernization of its role in public health policy a clear orientation. Priorities for the future include reinforcement of education and academic research in pharmacy practice, demonstration of the added value of pharmacists, integration of new information technologies with pharmacies, and development of new pharmaceutical services for managed care network in collaboration with physicians and other healthcare professionals.
A Novel Role for Sema3A in Neuroprotection from Injury Mediated by Activated Microglia
Authors: Majed Henry H. , Chandran Siddharthan , Niclou Simone P. , Nicholas Richard S. , Wilkins Alastair , Wing Mark G. , Rhodes Kate E. , Spillantini Maria Grazia , Compston Alastair
Published: February 2006

Microglia exist under physiological conditions in a resting state but become activated after neuronal injury. Recent studies have highlighted the reciprocal role of neurons in controlling both the number and activity of microglia. In this study, microglia derived from newborn rat cortices were cultured and activated by interferon-γ (IFNγ) treatment, then exposed to recombinant Sema3A or conditioned medium derived from stressed embryonic cortical neurons. We found that activation of microglia by IFNγ induced differential upregulation of the semaphorin receptors Plexin-A1 and Neuropilin-1. This result was confirmed by Northern blotting, reverse transcription-PCR, and Western blotting. Furthermore, recombinant Sema3A induced apoptosis of microglia when added to thein vitroculture, and a similar result was obtained on activated microglia when Sema3A was produced by stressed neurons. Using anin vivomodel of microglia activation by striatal injection of lipopolysaccharide demonstrated a corresponding upregulation of Plexin-A1 and Neuropilin-1 in activated microglia and enhanced production of Sema3A by stressed adult neurons. These results suggest a novel semaphorin-mediated mechanism of neuroprotection whereby stressed neurons can protect themselves from further damage by activated microglia.
Presynaptic Terminals Independently Regulate Synaptic Clustering and Autophagy of GABAAReceptors inCaenorhabditis elegans
Authors: Rowland Aaron M. , Richmond Janet E. , Olsen Jason G. , Hall David H. , Bamber Bruce A.
Published: February 2006

Synaptic clustering of GABAAreceptors is important for the function of inhibitory synapses, influencing synapse strength and, consequently, the balance of excitation and inhibition in the brain. Presynaptic terminals are known to induce GABAAreceptor clustering during synaptogenesis, but the mechanisms of cluster formation and maintenance are not known. To study how presynaptic neurons direct the formation of GABAAreceptor clusters, we have investigated GABAAreceptor localization in postsynaptic cells that fail to receive presynaptic contacts inCaenorhabditis elegans. Postsynaptic muscles inC. elegansreceive acetylcholine and GABA motor innervation, and GABAAreceptors cluster opposite GABA terminals. Selective loss of GABA inputs caused GABAAreceptors to be diffusely distributed at or near the muscle cell surface, confirming that GABA presynaptic terminals induce GABAAreceptor clustering. In contrast, selective loss of acetylcholine innervation had no effect on GABAAreceptor localization. However, loss of both GABA and acetylcholine inputs together caused GABAAreceptors to traffic to intracellular autophagosomes. Autophagosomes normally transport bulk cytoplasm to the lysosome for degradation. However, we show that GABAAreceptors traffic to autophagosomes after endocytic removal from the cell surface and that acetylcholine receptors in the same cells do not traffic to autophagosomes. Thus, autophagy can degrade cell-surface receptors and can do so selectively. Our results show that presynaptic terminals induce GABAAreceptor clustering by independently controlling synaptic localization and surface stability of GABAAreceptors. They also demonstrate a novel function for autophagy in GABAAreceptor degradative trafficking.
Cell-Specific Repressor or Enhancer Activities of Deaf-1 at a Serotonin 1A Receptor Gene Polymorphism
Authors: Czesak Margaret , Lemonde Sylvie , Peterson Erica A. , Rogaeva Anastasia , Albert Paul R.
Published: February 2006

The serotonin-1A (5-HT1A) receptor is the primary somatodendritic autoreceptor that inhibits the activity of serotonergic raphe neurons and is also expressed in nonserotonergic cortical and limbic neurons. Alterations in 5-HT1Areceptor levels are implicated in mood disorders, and a functional C(-1019)G 5-HT1Apromoter polymorphism has been associated with depression, suicide, and panic disorder. We examined the cell-specific activity of identified transcription factors, human nuclear deformed epidermal autoregulatory factor-1 (DEAF-1)-related (NUDR)/Deaf-1 and Hes5, at the 5-HT1AC(-1019) site. In serotonergic raphe RN46A cells, Deaf-1 and Hes5 repressed the 5-HT1Areceptor gene at the C(-1019)-allele but not the G(-1019)-allele. However, in nonserotonergic cells that express 5-HT1Areceptors (septal SN48, neuroblastoma SKN-SH, and neuroblastoma/glioma NG108–15 cells), Deaf-1 enhanced 5-HT1Apromoter activity at the C(-1019)-allele but not the G-allele, whereas Hes5 repressed in all cell types. The enhancer activity of Deaf-1 was orientation independent and competed out Hes5 repression. To test whether Deaf-1 activity is intrinsic, the activity of a Gal4DBD (DNA binding domain)-Deaf-1 fusion protein at a heterologous Gal4 DNA element was examined. Gal4DBD-Deaf-1 repressed transcription in RN46A cells but enhanced transcription in SN48 cells, indicating that these opposite activities are intrinsic to Deaf-1. Repressor or enhancer activities of Deaf-1 or Gal4DBD-Deaf-1 were blocked by histone deacetylase inhibitor trichostatin A. Thus, the intrinsic activity of Deaf-1 at the 5-HT1Apromoter is opposite in presynaptic versus postsynaptic neuronal cells and requires deacetylation. Cell-specific regulation by Deaf-1 could underlie region-specific alterations in 5-HT1Areceptor expression in different mood disorders.
Telencephalin Slows Spine Maturation
Authors: Matsuno Hitomi , Okabe Shigeo , Mishina Masayoshi , Yanagida Toshio , Mori Kensaku , Yoshihara Yoshihiro
Published: February 2006

Dendritic filopodia are highly dynamic structures, and morphological maturation from dendritic filopodia to spines is intimately associated with the stabilization and strengthening of synapses during development. Here, we report that telencephalin (TLCN), a cell adhesion molecule belonging to the Ig superfamily, is a negative regulator of spine maturation. Using cultured hippocampal neurons, we examined detailed localization and functions of TLCN in spine development and synaptogenesis. At early stages of synaptogenesis, TLCN immunoreactivity gradually increased and was present in dendritic shafts and filopodia. At later stages, TLCN tended to be excluded from mature spine synapses in which PSD-95 (postsynaptic density-95) clusters were apposed to presynaptic synaptophysin clusters. To elucidate the function of TLCN in spine maturation, we analyzed the dendrite morphology of TLCN-overexpressing and TLCN-deficient neurons. Overexpression of TLCN caused a dramatic increase in the density of dendritic filopodia and a concomitant decrease in the density of spines. Conversely, TLCN-deficient mice showed a decreased density of filopodia and an acceleration of spine maturationin vitroas well asin vivo. These results demonstrate that TLCN normally slows spine maturation by promoting the filopodia formation and negatively regulating the filopodia-to-spine transition. In addition, we found that spine heads of mature neurons were wider in TLCN-deficient mice compared with wild-type mice. Thus, the preservation of immature synapses by TLCN may be an essential step for refinement of functional neural circuits in the telencephalon, that take charge of higher brain functions such as learning, memory, and emotion.
Molecular Reconstruction of Nodes of Ranvier after Remyelination by Transplanted Olfactory Ensheathing Cells in the Demyelinated Spinal Cord
Authors: Sasaki Masanori , Black Joel A. , Lankford Karen L. , Tokuno Hajime A. , Waxman Stephen G. , Kocsis Jeffery D.
Published: February 2006

Myelin-forming glial cells transplanted into the demyelinated spinal cord can form compact myelin and improve conduction properties. However, little is known of the expression and organization of voltage-gated ion channels in the remyelinated central axons or whether the exogenous cells provide appropriate signaling for the maturation of nodes of Ranvier. Here, we transplanted olfactory ensheathing cells from green fluorescent protein (GFP)-expressing donor rats [GFP-olfactory ensheathing cells (OECs)] into a region of spinal cord demyelination and found extensive remyelination, which included the development of mature nodal, paranodal, and juxtaparanodal domains, as assessed by ultrastructural, immunocytochemical, and electrophysiological analyses. In remyelinated axons, Nav1.6 was clustered at nodes, whereas Kv1.2 was aggregated in juxtaparanodal regions, recapitulating the distribution of these channels within mature nodes of uninjured axons. Moreover, the recruitment of Navand Kvchannels to specific membrane domains at remyelinated nodes persisted for at least 8 weeks after GFP-OEC transplantation.In vivoelectrophysiological recordings demonstrated enhanced conduction along the GFP-OEC-remyelinated axons. These findings indicate that, in addition to forming myelin, engrafted GFP-OECs provide an environment that supports the development and maturation of nodes of Ranvier and the restoration of impulse conduction in central demyelinated axons.
Block of Inferior Olive Gap Junctional Coupling Decreases Purkinje Cell Complex Spike Synchrony and Rhythmicity
Authors: Blenkinsop Timothy A. , Lang Eric J.
Published: February 2006

Inferior olivary (IO) neurons are electrotonically coupled by gap junctions. This coupling is thought to underlie synchronous complex spike (CS) activity generated by the olivocerebellar system in Purkinje cells, and also has been hypothesized to be necessary for IO neurons to generate spontaneous oscillatory activity. These characteristics of olivocerebellar activity have been proposed to be central to the role of this system in motor coordination. However, the relationship of gap junction coupling between IO neurons to synchronous and rhythmic CS activity has never been directly tested. Thus, to address this issue, multiple electrode recordings were obtained from crus 2a Purkinje cells, and carbenoxolone, a gap junction blocker, was injected into the IO. Carbenoxolone reduced CS synchrony by 50% overall, but in some experiments, >80% reductions were achieved. Carbenoxolone also reduced the average firing rate by 50%, suggesting that electrical coupling is a significant source of excitation for IO neurons. Moreover, carbenoxolone caused a reduction in the ∼10 Hz rhythmicity of CS activity, and this reduction was correlated with the extent to which the injection reduced CS synchrony. Lastly, carbenoxolone was found to reverse or prevent changes in synchrony that are normally induced by injection of GABAAand glutamate receptor antagonists into the IO, suggesting that the effects of these drugs on CS synchrony patterns require electrical coupling of IO neurons. In sum, our results provide direct evidence that electrical coupling of IO neurons underlies synchronous CS activity, and suggest important roles for this coupling in shaping other aspects of IO spiking patterns.
Astrocytes Induce Hemeoxygenase-1 Expression in Microglia: A Feasible Mechanism for Preventing Excessive Brain Inflammation
Authors: Min Kyoung-Jin , Yang Myung-soon , Kim Seung-Up , Jou Ilo , Joe Eun-hye
Published: February 2006

Microglia are the major inflammatory cells in the brain, in which microglial inflammatory responses are modulated by interactions with other brain cells. Here, we show that astrocytes, the most abundant cells in the brain, can secrete one or more factors capable of modulating microglial activation by regulating the microglial levels of reactive oxygen species (ROS). Treatment of microglia with astrocyte culture-conditioned media (ACM) increased the expression level and activity of hemeoxygenase-1 (HO-1). ACM also induced nuclear translocation of the nuclear factor E2-related factor 2 transcription factor, increased the binding activity of the antioxidant response element (ARE), and enhanced HO-1 promoter activity in an ARE-dependent manner. Furthermore, treatment with ACM suppressed interferon-γ (IFN-γ)-induced ROS production, leading to reduced inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) release. In agreement with these results, mimickers of HO-1 products, such as bilirubin, ferrous iron, and a carbon monoxide-releasing molecule, reduced IFN-γ-induced iNOS expression and/or NO release. Finally, we found that the active component(s) in ACM was heat labile and smaller than 3 kDa. Together, these results suggest that astrocytes could cooperate with microglia to prevent excessive inflammatory responses in the brain by regulating microglial expression of HO-1 and production of ROS.
Synaptic Transmission Mediated by Internal Calcium Stores in Rod Photoreceptors
Authors: Suryanarayanan Anuradha , Slaughter Malcolm M.
Published: February 2006

Retinal rod photoreceptors are depolarized in darkness to approximately −40 mV, a state in which they maintain sustained glutamate release despite low levels of calcium channel activation. Blocking voltage-gated calcium channels or ryanodine receptors (RyRs) at the rod presynaptic terminal suppressed synaptic communication to bipolar cells. Spontaneous synaptic events were also inhibited when either of these pathways was blocked. This indicates that both calcium influx and calcium release from internal stores are required for the normal release of transmitter of the rod. RyR-independent release can be evoked by depolarization of a rod to a supraphysiological potential (−20 mV) that activates a large fraction of voltage-gated channels. However, this calcium channel-mediated release depletes rapidly if RyRs are blocked, indicating that RyRs support prolonged glutamate release. Thus, the rod synapse couples a small transmembrane calcium influx with a RyR-dependent amplification mechanism to support continuous vesicle release.
Distinct Roles for Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Ras-GRF2 in the Induction of Long-Term Potentiation and Long-Term Depression
Authors: Li Shaomin , Tian Xuejun , Hartley Dean M. , Feig Larry A.
Published: February 2006

NMDA-type glutamate receptors (NMDARs) contribute to many forms of long-term potentiation (LTP) and long-term depression (LTD). NMDARs are heteromers containing calcium-permeating neuronal receptor 1 (NR1) subunits and a variety of NR2 subunits. Evidence suggests that, in the CA1 region of the hippocampus, NR2A-containing NMDARs promote LTP whereas NR2B-containing receptors promote LTD. However, the calcium sensors that distinguish between these signals to promote the appropriate form of synaptic plasticity are not known. Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 are highly similar calcium-stimulated exchange factors that activate Ras and Rac GTPases. Here, using a set of Ras-GRF knock-out mice, we show that Ras-GRF2 contributes predominantly to the induction of NMDAR-dependent LTP, whereas Ras-GRF1 contributes predominantly to the induction of NMDAR-dependent LTD in the CA1 region of the hippocampus of postpubescent mice (postnatal days 25–36). In contrast, neither Ras-GRF protein influences synaptic plasticity in prepubescent mice (postnatal days 14–18). Ras-GRF2 mediates signaling from (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl-phosphonic acid-sensitive (NVP-AAM077-sensitive) (NR2A-containing) NMDARs to the Ras effector extracellular signal-related protein kinase 1/2 (Erk1/2) mitogen-activated protein (MAP) kinase, a promoter of NMDAR-induced LTP at this site. In contrast, Ras-GRF1 mediates signaling from ifenprodil-sensitive (NR2B-containing) NMDARs to the Rac effector p38 MAP kinase, a promoter of LTD. These findings show that, despite their similar functional domain organization, Ras-GRF1 and Ras-GRF2 mediate opposing forms of synaptic plasticity by coupling different classes of NMDARs to distinct MAP kinase pathways. Moreover, the postnatal appearance of Ras-GRF-dependent LTP and LTD coincides with the emergence of hippocampal-dependent behavior, implying that Ras-GRF proteins contribute to forms of synaptic plasticity that are required specifically for mature hippocampal function.
Small-Conductance Ca2+-Activated K+Channel Type 2 (SK2) Modulates Hippocampal Learning, Memory, and Synaptic Plasticity
Authors: Hammond Rebecca S. , Bond Chris T. , Strassmaier Timothy , Jennifer Ngo-Anh Thu , Adelman John P. , Maylie James , Stackman Robert W.
Published: February 2006

Apamin-sensitive, small-conductance, Ca2+-activated K+channels (SK channels) modulate neuronal excitability in CA1 neurons. Blocking all SK channel subtypes with apamin facilitates the induction of hippocampal synaptic plasticity and enhances hippocampal learning. In CA1 dendrites, SK channels are activated by Ca2+through NMDA receptors and restrict glutamate-mediated EPSPs. Studies of SK channel knock-out mice reveal that of the three apamin-sensitive SK channel subunits (SK1–SK3), only SK2 subunits are necessary for the apamin-sensitive currents in CA1 hippocampal neurons. To determine the specific influence of SK2 channels on hippocampal synaptic plasticity, learning, and memory, we used gene targeting through homologous recombination in embryonic stem cells to generate transgenic mice that overexpress SK2 subunits by 10-fold (SK2+/T). In these mice, the apamin-sensitive current in CA1 neurons was increased by approximately fourfold, relative to wild-type (WT) littermates. In addition, the amplitude of synaptically evoked EPSPs recorded from SK2+/T CA1 neurons increased twice as much in response to SK channel blockade relative to EPSPs recorded from WT CA1 neurons. Consistent with this, SK2 overexpression reduced long-term potentiation after high-frequency stimulation compared with WT littermates and severely impaired learning in both hippocampus- and amygdala-dependent tasks. We conclude that SK2 channels regulate hippocampal synaptic plasticity and play a critical role in modulating mechanisms of learning and memory.
Loss of Leukemia Inhibitory Factor Receptor β or Cardiotrophin-1 Causes Similar Deficits in Preganglionic Sympathetic Neurons and Adrenal Medulla
Authors: Oberle Stephan , Schober Andreas , Meyer Verena , Holtmann Bettina , Henderson Christopher , Sendtner Michael , Unsicker Klaus
Published: February 2006

Leukemia inhibitory factor (LIF) receptor β (LIFRβ) is a receptor for a variety of neurotrophic cytokines, including LIF, ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1). These cytokines play an essential role for the survival and maintenance of developing and postnatal somatic motoneurons. CNTF may also serve the maintenance of autonomic, preganglionic sympathetic neurons (PSNs) in the spinal cord, as suggested by its capacity to prevent their death after destruction of one of their major targets, the adrenal medulla. Although somatic motoneurons and PSNs share a common embryonic origin, they are distinct in several respects, including responses to lesions. We have studied PSNs in mice with targeted deletions of the LIFRβ or CT-1 genes, respectively. We show that LIF, CNTF, and CT-1 are synthesized in embryonic adrenal gland and spinal cord and that PSNs express LIFRβ. In embryonic day 18.5 LIFRβ (−/−) and CT-1 (−/−) mice, PSNs were reduced by ∼20%. PSNs projecting to the adrenal medulla were more severely affected (−55%). Although LIFRβ (−/−) mice revealed normal numbers of adrenal chromaffin cells and axons terminating on chromaffin cells, levels of adrenaline and numbers of adrenaline-synthesizing cells were significantly reduced. We conclude that activation of LIFRβ is required for normal development of PSNs and one of their prominent targets, the adrenal medulla. Thus, both somatic motoneurons and PSNs in the spinal cord depend on LIFRβ signaling for their development and maintenance, although PSNs seem to be overall less affected than somatic motoneurons by LIFRβ deprivation.
Preoptic Glutamate Facilitates Male Sexual Behavior
Authors: Dominguez Juan M. , Gil Mario , Hull Elaine M.
Published: February 2006

The medial preoptic area (MPOA) is a critical regulatory site for the control of male sexual behavior. We first measured glutamate in 2 min microdialysate samples from the MPOA before, during, and after copulation by male rats. There was a slight [∼140% of baseline (BL)] rise in extracellular glutamate when the female was presented, a significant increase (∼170% of BL) during periods of mounting and intromitting, and a very large increase in samples collected during ejaculation (∼300% of BL). A precipitous fall in levels occurred in the first postejaculatory sample; the magnitude of this fall was highly correlated with the length of the postejaculatory interval of quiescence. In experiment 2, we reverse-dialyzed a mixture of glutamate uptake inhibitors into the MPOA before and during mating; control animals received artificial CSF. The mixture increased extracellular glutamate (∼280% of BL), increased the number of ejaculations in the 40 min test, decreased ejaculation latency, and decreased the postejaculatory latency to resume copulation. These data, together with other findings that glutamate in the MPOA can elicit genital reflexes in anesthetized rats and that glutamate receptor antagonists in the MPOA impair copulation, strongly suggest that MPOA glutamate is a major facilitator of copulation and that the postejaculatory fall in glutamate regulates the postejaculatory interval.
Disinhibition Opens the Gate to Pathological Pain Signaling in Superficial Neurokinin 1 Receptor-Expressing Neurons in Rat Spinal Cord
Authors: Torsney Carole , MacDermott Amy B.
Published: February 2006

Blockade of local spinal cord inhibition mimics the behavioral hypersensitivity that manifests in chronic pain states. This suggests that there is a pathway capable of mediating allodynia/hyperalgesia that exists but is normally under strong inhibitory control. Lamina I and III neurokinin 1 (NK1) receptor expressing (NK1R+) dorsal horn neurons, many of which are projection neurons, are required for the development of this hypersensitivity and are therefore likely to be a component of this proposed pathway. To investigate, whole-cell patch-clamp recordings were made from lamina I and III NK1R+ neurons in the spinal cord slice preparation with attached dorsal root. Excitatory postsynaptic currents were recorded in response to electrical stimulation of the dorsal root. Lamina I NK1R+ neurons were shown to receive high-threshold (Aδ/C fiber) monosynaptic input, whereas lamina III NK1R+ neurons received low-threshold (Aβ fiber) monosynaptic input. In contrast, lamina I neurons lacking NK1 receptor (NK1R−) received polysynaptic A fiber input. Blockade of local GABAergic and glycinergic inhibition with bicuculline (10 μm) and strychnine (300 nm), respectively, revealed significant A fiber input to lamina I NK1R+ neurons that was predominantly Aβ fiber mediated. This novel A fiber input was polysynaptic in nature and required NMDA receptor activity to be functional. In lamina I NK1R− and lamina III NK1R+ neurons, disinhibition enhanced control-evoked responses, and this was also NMDA receptor dependent. These disinhibition-induced changes, in particular the novel polysynaptic low-threshold input onto lamina I NK1R+ neurons, may be an underlying component of the hypersensitivity present in chronic pain states.
Presynaptic I1-Imidazoline Receptors Reduce GABAergic Synaptic Transmission in Striatal Medium Spiny Neurons
Authors: Tanabe Mitsuo , Kino Yurika , Honda Motoko , Ono Hideki
Published: February 2006

Imidazoline receptors are expressed widely in the CNS. In the present study, whole-cell patch-clamp recordings were made from medium spiny neurons in dorsal striatum slices from the rat brain, and the roles of I1-imidazoline receptors in the modulation of synaptic transmission were studied. Moxonidine, an I1-imidazoline receptor agonist, decreased the GABAAreceptor-mediated IPSCs in a concentration-dependent manner. However, glutamate-mediated EPSCs were hardly affected. The depression of IPSCs by moxonidine was antagonized by either idazoxan or efaroxan, which are both imidazoline receptor antagonists containing an imidazoline moiety. In contrast, yohimbine andSKF86466(6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine), which are α2-adrenergic receptor antagonists with no affinity for imidazoline receptors, did not affect the moxonidine-induced inhibition of IPSCs. Moxonidine increased the paired-pulse ratio and reduced the frequency of miniature IPSCs without affecting their amplitude, indicating that this agent inhibits IPSCs via presynaptic mechanisms. Moreover, the sulfhydryl alkylating agentN-ethylmaleimide (NEM) significantly reduced the moxonidine-induced inhibition of IPSCs. Thus, the activation of presynaptic I1-imidazoline receptors decreases GABA-mediated inhibition of medium spiny neurons in the striatum, in which NEM-sensitive proteins such as Gi/o-type G-proteins play an essential role. The adenylate cyclase activator forskolin partly opposed IPSC inhibition elicited by subsequently applied moxonidine. Furthermore, the protein kinase C (PKC) activator phorbol 12,13-dibutyrate attenuated and the PKC inhibitor chelerythrine potentiated the moxonidine-induced inhibition of IPSCs. These results suggest that IPSC inhibition via presynaptic I1-imidazoline receptors involves intracellular adenylate cyclase activity and is influenced by static PKC activity in the striatum.
Chronic Intermittent Ethanol-Induced Switch of Ethanol Actions from Extrasynaptic to Synaptic Hippocampal GABAAReceptors
Authors: Liang Jing , Zhang Nianhui , Cagetti Elisabetta , Houser Carolyn R. , Olsen Richard W. , Spigelman Igor
Published: February 2006

Alcohol withdrawal syndrome (AWS) symptoms include hyperexcitability, anxiety, and sleep disorders. Chronic intermittent ethanol (CIE) treatment of rats with subsequent withdrawal of ethanol (EtOH) reproduced AWS symptoms in behavioral assays, which included tolerance to the sleep-inducing effect of acute EtOH and its maintained anxiolytic effect. Electrophysiological assays demonstrated a CIE-induced long-term loss of extrasynaptic GABAAreceptor (GABAAR) responsiveness and a gain of synaptic GABAAR responsiveness of CA1 pyramidal and dentate granule neurons to EtOH that we were able to relate to behavioral effects. After CIE treatment, the α4 subunit-preferring GABAAR ligands 4,5,6,7 tetrahydroisoxazolo[5,4-c]pyridin-3-ol, La3+, and Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5α][1,4]benzodiazepine-3-carboxylate) exerted decreased effects on extrasynaptic currents but had increased effects on synaptic currents. Electron microscopy revealed an increase in central synaptic localization of α4 but not δ subunits within GABAergic synapses on the dentate granule cells of CIE rats. Recordings in dentate granule cells from δ subunit-deficient mice revealed that this subunit is not required for synaptic GABAAR sensitivity to low [EtOH]. The profound alterations in EtOH sensitivity and α4 subunit localization at hippocampal GABAARs of CIE rats suggest that such changes in these and other relevant brain circuits may contribute to the development of tolerance to the sleep-inducing effects and long-term dependence on alcohol.
Site of Action Potential Initiation in Layer 5 Pyramidal Neurons
Authors: Palmer Lucy M. , Stuart Greg J.
Published: February 2006

Fundamental to an understanding of how neurons integrate synaptic input is the knowledge of where within a neuron this information is converted into an output signal, the action potential. Although it has been known for some time that action potential initiation occurs within the axon of neurons, the precise location has remained elusive. Here, we provide direct evidence using voltage-sensitive dyes that the site of action potential initiation in cortical layer 5 pyramidal neurons is ∼35 μm from the axon hillock. This was the case during action potential generation under a variety of conditions, after axonal inhibition, and at different stages of development. Once initiated action potentials propagated down the axon in a saltatory manner. Experiments using local application of low-sodium solution and TTX, as well as an investigation of the influence of axonal length on action potential properties, provided evidence that the initial 40 μm of the axon is essential for action potential generation. To morphologically identify the relationship between the site of action potential initiation and axonal myelination, we labeled oligodendrocytes supplying processes to the proximal region of the axon. These experiments indicated that the axon initial segment was ∼40 μm in length, and the first node of Ranvier was ∼90 μm from the axon hillock. Experiments targeting the first node of Ranvier suggested it was not involved in action potential initiation. In conclusion, these results indicate that, in layer 5 pyramidal neurons, action potentials are generated in the distal region of the axon initial segment.