bluuebunny/crossref_metadata_2025 huggingface dataset:
The G1-S checkpoint in fission yeast is not a general DNA damage checkpoint
Authors: Krohn Marit , Skjølberg Henriette C. , Soltani Héla , Grallert Beáta , Boye Erik
Published: November 2008

Inhibitory mechanisms called checkpoints regulate progression of the cell cycle in the presence of DNA damage or when a previous cell-cycle event is not finished. In fission yeast exposed to ultraviolet light the G1-S transition is regulated by a novel checkpoint that depends on the Gcn2 kinase. The molecular mechanisms involved in checkpoint induction and maintenance are not known. Here we characterise the checkpoint further by exposing the cells to a variety of DNA-damaging agents. Exposure to methyl methane sulphonate and hydrogen peroxide induce phosphorylation of eIF2α, a known Gcn2 target, and an arrest in G1 phase. By contrast, exposure to psoralen plus long-wavelength ultraviolet light, inducing DNA adducts and crosslinks, or to ionizing radiation induce neither eIF2α phosphorylation nor a cell-cycle delay. We conclude that the G1-S checkpoint is not a general DNA-damage checkpoint, in contrast to the one operating at the G2-M transition. The tight correlation between eIF2α phosphorylation and the presence of a G1-phase delay suggests that eIF2α phosphorylation is required for checkpoint induction. The implications for checkpoint signalling are discussed.
AQP4 knockout impairs proliferation, migration and neuronal differentiation of adult neural stem cells
Authors: Kong Hui , Fan Yi , Xie Juan , Ding Jianhua , Sha Luolin , Shi Xueru , Sun Xiulan , Hu Gang
Published: November 2008

Aquaporin-4 (AQP4), a key molecule for maintaining water and ion homeostasis in the central nervous system, is expressed in adult neural stem cells (ANSCs) as well as astrocytes. However, little is known about the functions of AQP4 in the ANSCs in vitro. Here we show that AQP4 knockout inhibits the proliferation, survival, migration and neuronal differentiation of ANSCs derived from the subventricular zone of adult mice. Flow cytometric cell cycle analysis revealed that AQP4 knockout increased the basal apoptosis and induced a G2-M arrest in ANSCs. Using Fluo-3 Ca2+ imaging, we show that AQP4 knockout alters the spontaneous Ca2+ oscillations by frequency enhancement and amplitude suppression, and suppresses KCl-induced Ca2+ influx. AQP4 knockout downregulated the expression of connexin43 and the L-type voltage-gated Ca2+ channel CaV1.2 subtype in ANSCs. Together, these findings suggest that AQP4 plays a crucial role in regulating the proliferation, migration and differentiation of ANSCs, and this function of AQP4 is probably mediated by its action on intracellular Ca2+ dynamics.
Loss of SUMO1 in mice affects RanGAP1 localization and formation of PML nuclear bodies, but is not lethal as it can be compensated by SUMO2 or SUMO3
Authors: Evdokimov Evgenij , Sharma Prashant , Lockett Stephen J. , Lualdi Margaret , Kuehn Michael R.
Published: November 2008

Conjugation of the small ubiquitin-like modifier (SUMO) to target proteins regulates numerous biological processes and has been implicated in tumorigenesis and metastasis. The three SUMO isoforms in vertebrates, SUMO1 and the highly similar SUMO2 and SUMO3, can be conjugated to unique as well as overlapping subsets of target proteins. Yet, it is still not clear whether roles for each family member are distinct or whether redundancy exists. Here we describe a mutant mouse line that completely lacks SUMO1, but surprisingly is viable and lacks any overt phenotype. Our study points to compensatory utilization of SUMO2 and/or SUMO3 for sumoylation of SUMO1 targets. The ability of SUMO isoforms to substitute for one another has important implications for rational targeting of the SUMO pathway.
Computational procedure for assessing lifetime performance Index of products for a one-parameter exponential lifetime model with the upper record values
Authors: Wu J-W , Lee H-M , Lei C-L
Published: November 2008

Process capability indices are used to measure the potential and performance of a process. This study constructs a uniformly minimum variance unbiased estimator (UMVUE) of the lifetime performance index based on the upper record values for a one-parameter exponential lifetime model. The UMVUE of the lifetime performance index is subsequently utilized to develop a hypothesis testing procedure for the condition of a known lower specification limit. Finally, three examples and a Monte Carlo simulation are presented to assess the behaviour of this test statistic for testing the null hypothesis under given significance levels. Product managers can use the proposed testing procedure to determine whether or not a process adheres to a required level of performance.
Numerical simulation of single pulse discharge machining insulating Al2O3 ceramic
Authors: Liu Y H , Yu L L , Xu Y L , Ji R J , Li Q Y
Published: November 2008

The technique of electrical discharge milling insulating ceramics with instantaneous high temperature generated by a discharge channel flowing along a workpiece surface has been developed by the authors. The process uses a thin copper sheet fed to the tool electrode along the workpiece surface as the assisting electrode, using a water-based emulsion as the machining fluid. It is able effectively to machine a large surface area on insulating ceramics, as well as other advanced non-conductive materials such as cubic boron nitride (CBN) and polycrystalline diamond (PCD). The mathematical models of thermal eroding non-conductive Al2O3 ceramic with a single pulse discharge are esta lished. The thermal erosion characteristics of insulating Al2O3 ceramic with a single pulse discharge have been numerically simulated. The numerical simulation results have been validated by experiment.
High-resolution three-degrees-of-freedom motion errors measuring system for a single-axis linear moving platform
Authors: Huang H-L , Liu C-H , Jywe W-Y , Wang M-S
Published: November 2008

In this study, a high-resolution three-degrees-of-freedom (3-DOF) motion error measuring system based on interference is described. It can simultaneously measure the linear displacement and two angular errors of a single-axis linear moving platform. The displacement is measured using a polarization interference technique and the two angular errors are also measured based on the geometry optical theorem. The verification results show that the resolution is about 20 nm. The 3-DOF measurement system detected displacements relative to a measurement mirror move with an accuracy of about ±8 μm for a measuring range of ± 50 mm, and detected the angular errors with a related accuracy of about ± 2 arc sec for a measuring range of ± 100 arc sec.
Modelling an ongoing design process utilizing top-down and bottom-up design strategies
Authors: Fathianathan M , Panchal J H
Published: November 2008

The product design process plays a central role in ensuring that new products are realized with improved quality, in a short lead-time and with costs kept to a minimum. It is identified that making decisions dynamically on how the design process should proceed is not trivial. A computational environment that aids dynamic decision making on the design process would be useful in ensuring successful design of new products. A key component of analysing and making decisions on the progression of the design process is a model that captures an ongoing design process. In this paper, an approach to modelling an ongoing design process is proposed based on the use of design nodes. The approach allows an ongoing design process to be modelled that facilitates dynamic decision making on how the design process should progress and accounts for the state of the design problem. The approach allows top-down and bottom-up design strategies to be modelled.
Standards and inference of design information in through-life costing of innovative defence electronic products
Authors: Cheung W M , Marsh R , Newnes L B , Mileham A R , Lanham J D
Published: November 2008

Through-life costing (TLC) is a term used in cost estimation for costing a product from its conception to the end-of-life. However, there seems to be no common representation of the terminologies in the various stages of TLC. This paper reports the findings of research into TLC practices for defence electronic products and includes the terms and elements used in the TLC methods. The terminologies used for this research are adopted from the International Organisation for Standardisation (ISO), including ISO 15288 and ISO 10303 Application Protocols 233 and 239. A TLC spectrum diagram representing how design information is inferred to support the application of top-down and bottom-up approaches is also discussed. A case study focused on the concept and the development stages of design is presented and is followed by suggestions on how the proposed method can be applied to the succeeding stages of manufacturing, in-service, and disposal.
Image-based retrieval in case-based reasoning systems for polyurethane manufacture
Authors: Velandia D M Segura , West A A
Published: November 2008

The formulation of polyurethanes is a complex poorly understood problem and it has developed more as an art rather than a science. Although polyurethane formulations can be developed from first principles, this approach requires both a detailed knowledge of the underlying principles that govern the formulation process and also time, since a number of measurements of process conditions are usually required. The case-based reasoning (CBR) methodology can support polyurethane formulation tasks by providing a framework for collecting, structuring, and representing historical formulating knowledge. To date, most CBR retrieval algorithms employ a modified version of the nearest neighbour rule that uses a distance function as similarity measure, which in turn depends upon the attribute type. The application of moment-based retrieval used in image recognition for CBR retrieval is studied in this paper. Comparison with the classical retrieval algorithms that use standard distance measures showed that low-order geometric, central, and Legendre moments retrieve the same cases as the Euclidean distance does, whereas high-order geometric, central, and Legendre moments retrieved different cases. It is suggested that there is not a single distinguished approach to similarity in CBR, rather CBR systems should allow the integration of different approaches to similarity and the selection of different concepts.
Laminar flamelet model prediction of NOx formation in a turbulent bluff-body combustor
Authors: Ravikanti M , Hossain M , Malalasekera W
Published: November 2008

A bluff-body combustor, with recirculation zone and simple boundary conditions, is ideal as a compromise for an industrial combustor for validating combustion models. This combustor, however, has proved to be very challenging to the combustion modellers in a number of previous studies. In the present study, an improved prediction has been reported through better representation of turbulence effect by Reynolds stress transport model and extended upstream computational domain. Thermo-chemical properties of the flame have been represented by a laminar flamelet model. A comparison among reduced chemical kinetic mechanism of Peters and detailed mechanisms of GRI 2.11, GRI 3.0, and San Diego has been studied under the laminar flamelet modelling framework. Computed results have been compared against the well-known experimental data of Sydney University bluff-body CH4/H2 flame. Results show that the laminar flamelet model yields very good agreement with measurements for temperature and major species with all the reaction mechanisms. The GRI 2.11 performs better than the other reaction mechanisms in predicting minor species such as OH and pollutant NO. The agreement achieved for NO is particularly encouraging considering the simplified modelling formulation utilized for the kinetically controlled NO formation.
The effectiveness of multi-stage dehumidification—humidification for improving the cooling ability of evaporative air conditioning
Authors: Saleh A , Al-Nimr M A
Published: November 2008

Evaporative cooling systems are commonly used because of their low initial and running cost. These systems have a great potential to provide thermal comfort in places where humidity is low; however, they are less efficient where air humidity is high. The present work proposes a system that can be used either in dry or humid climates by introducing a new concept: multi-dehumidification—humidification processes that can be coupled with evaporative cooling systems. The effect of this modification on the production of low temperature is investigated. To validate the model, the improvement carried out is quantified by comparing the performance of a classical evaporative cooling system and with the proposed single-step dehumidification—humidification system. It is found that increasing the number of dehumidification—humidification processes greatly reduces the air temperature and improves the performance of the system. In some cases, the reduction in the air temperature exceeds 20 °C in humid climates, a result that is comparable with those obtained by vapour-compression cooling systems. In conclusion, the proposed system delivers the low cost benefits of evaporative cooling systems with the high performance of conventional compression cooling systems.
Postmenopausal vulval disease
Authors: Olsson Ann , Selva-Nayagam Priya , Oehler Martin K
Published: November 2008

Vulval disease in the postmenopausal age group is relatively common. Some vulval conditions such as lichen sclerosus are more prevalent in the postmenopausal years. Often more than one condition is present at the same time. Accurate diagnosis is essential for effective treatment. The risk of progression to malignancy associated with some of these diseases dictates long-term surveillance.
Mechanism of ATP turnover inhibition in the EJC
Authors: Nielsen Klaus H. , Chamieh Hala , Andersen Christian B.F. , Fredslund Folmer , Hamborg Kristiane , Le Hir Hervé , Andersen Gregers R.
Published: November 2008

The exon junction complex (EJC) is deposited onto spliced mRNAs and is involved in many aspects of mRNA function. We have recently reconstituted and solved the crystal structure of the EJC core made of MAGOH, Y14, the most conserved portion of MLN51, and the DEAD-box ATPase eIF4AIII bound to RNA in the presence of an ATP analog. The heterodimer MAGOH/Y14 inhibits ATP turnover by eIF4AIII, thereby trapping the EJC core onto RNA, but the exact mechanism behind this remains unclear. Here, we present the crystal structure of the EJC core bound to ADP-AIF3, the first structure of a DEAD-box helicase in the transition-mimicking state during ATP hydrolysis. It reveals a dissociative transition state geometry and suggests that the locking of the EJC onto the RNA by MAGOH/Y14 is not caused by preventing ATP hydrolysis. We further show that ATP can be hydrolyzed inside the EJC, demonstrating that MAGOH/Y14 acts by locking the conformation of the EJC, so that the release of inorganic phosphate, ADP, and RNA is prevented. Unifying features of ATP hydrolysis are revealed by comparison of our structure with the EJC–ADPNP structure and other helicases. The reconstitution of a transition state mimicking complex is not limited to the EJC and eIF4AIII as we were also able to reconstitute the complex Dbp5–RNA–ADP–AlF3, suggesting that the use of ADP–AlF3 may be a valuable tool for examining DEAD-box ATPases in general.
Molecular basis of TRAP–5′SL RNA interaction in the Bacillus subtilis trp operon transcription attenuation mechanism
Authors: McGraw Adam P. , Mokdad Ali , Major François , Bevilacqua Philip C. , Babitzke Paul
Published: November 2008

Expression of the Bacillus subtilis trpEDCFBA operon is regulated by the interaction of tryptophan-activated TRAP with 11 (G/U)AG trinucleotide repeats that lie in the leader region of the nascent trp transcript. Bound TRAP prevents folding of an antiterminator structure and favors formation of an overlapping intrinsic terminator hairpin upstream of the trp operon structural genes. A 5′-stem–loop (5′SL) structure that forms just upstream of the triplet repeat region increases the affinity of TRAP–trp RNA interaction, thereby increasing the efficiency of transcription termination. Single-stranded nucleotides in the internal loop and in the hairpin loop of the 5′SL are important for TRAP binding. We show here that altering the distance between these two loops suggests that G7, A8, and A9 from the internal loop and A19 and G20 from the hairpin loop constitute two structurally discrete TRAP-binding regions. Photochemical cross-linking experiments also show that the hairpin loop of the 5′SL is in close proximity to the flexible loop region of TRAP during TRAP–5′SL interaction. The dimensions of B. subtilis TRAP and of a three-dimensional model of the 5′SL generated using the MC-Sym and MC-Fold pipeline imply that the 5′SL binds the protein in an orientation where the helical axis of the 5′SL is perpendicular to the plane of TRAP. This interaction not only increases the affinity of TRAP–trp leader RNA interaction, but also orients the downstream triplet repeats for interaction with the 11 KKR motifs that lie on TRAP's perimeter, increasing the likelihood that TRAP will bind in time to promote termination.
Combining the Opinions of Experts Who Partition Events Differently
Authors: Bordley Robert F.
Published: November 2008

This paper focuses on updating a client's beliefs about an event based on information about the different probabilities that various experts assess for that event. A substantial literature solves this problem when all experts assess their probabilities over the same partitioning of the possible outcomes of an event. But different experts often think about the same problem in quite different ways. This can lead to differences in how experts prefer to partition the possible outcomes of an event. Forcing the experts to use a common partition could lead to less informative probability assessments. Thus, this paper presents a new approach for combining probability assessments from different experts, which allows experts to assess their probability assessments across different partitionings.
Ambidexterity in Technology Sourcing: The Moderating Role of Absorptive Capacity
Authors: Rothaermel Frank T. , Alexandre Maria Tereza
Published: November 2008

A firm's organizational and technological boundaries are two important demarcation lines when sourcing for technology. Based on this theoretical lens, four possible combinations of exploration and exploitation emerge. Applying an ambidexterity perspective to a firm's technology sourcing strategy, we hypothesize that a curvilinear relationship exists between a firm's technology sourcing mix and its performance. We further introduce a contingency element by proposing that a firm's absorptive capacity exerts a positive moderating effect on this relationship. We empirically test these hypotheses on a random, multi-industry sample of U.S. manufacturing companies. We find support for the notion that the relationship between technology sourcing mix and firm performance is an inverted U-shape. Moreover, higher levels of absorptive capacity allow a firm to more fully capture the benefits resulting from ambidexterity in technology sourcing.
Novel Algorithm for More Accurate Calculation of Renal Function in Adults with Cancer
Authors: Holweger Karin , Lipp Hans-Peter , Dietz Klaus , Hartmann Joerg Thomas , Bokemeyer Carsten
Published: November 2008

Background:

Cytotoxic agents have a narrow therapeutic window. A high percentage of some of them is renally excreted in unchanged form. Accurate assessment of an individual's glomerular filtration rate (GFR) helps to predict the pharmacokinetic behavior of those drugs more precisely. GFR calculations, however, have their limitations.

Objective:

To establish a more accurate calculation of renal function over a broad range of constitutive GFR values.

Methods:

Patients with cancer were included in the analysis. Serum levels of cystatin C, creatinine, urea, albumin, and β-trace protein were measured, and GFR was calculated by 8 mathematical formulas. The results were compared with creatinine clearance (CrCI) calculated from timed urine specimens.

Results:

One hundred two patients were evaluated: median age, 57.5 years (range 20–91); females, 52; males, 50; and mean urinary CrCI, 77.0 mL/min. The bias (mean percentage error) was -2% and the precision (mean absolute percentage error) was 23% for the Modification of Diet in Renal Disease (MDRD) estimation of GFR. All equations significantly overestimated CrCI in patients with measured clearance less than 50 mL/min (p <0.05), with the exception of the modified Salazar-Corcoran formula. All equations underestimated CrCI in patients with measured clearance greater than 100 mL/min. The Wright formula was the least biased and most precise (–5%, 16%, respectively). In patients with measured CrCI 50–100 mL/min, the MDRD calculation had a bias of -4% and a precision of 17%. The Jelliffe and Larsson equations were associated with significant sex bias (p <0.05).

Conclusions:

These observations suggest that individual GFR values over a broad range cannot be calculated accurately enough with only one selected formula. It may be useful to classify renal function of patients with cancer according to the novel algorithm by using MDRD first and then to subsequently calculate GFR in higher and lower ranges with the Wright and modified Salazar-Corcoran formulas, respectively. This algorithm should be validated using larger numbers of patients.
Discordant Results from “Real-World” Patient Samples Assayed for Digoxin
Authors: Jones Terry E , Morris Raymond G
Published: November 2008

Background:

Digoxin has a narrow therapeutic index and is primarily renally eliminated. To optimize dosing of digoxin, therapeutic drug monitoring has been important since assays became available in the 1970s. Immunoassays are not specific, and cross-reactivity with endogenous and exogenous compounds has been reported for more than 20 years. Interassay concordance has not been investigated in recent years in “real-world” patient samples.

Objective:

To identify whether different digoxin immunoassays produce clinically different results in real-world situations, estimate the frequency of discordance, and determine whether an equation-based estimate compares well with digoxin immunoassays.

Methods:

Plasma samples were sent to 2 accredited laboratories simultaneously and the digoxin results were compared. Results of immunoassays conducted using the Cedia DRI Digoxin Assay and the DGNA Digoxin Assay were compared with an equation-based estimate of plasma digoxin concentration.

Results:

Thirty-six digoxin samples were assayed; in 39% of these, digoxin concentrations were discordant and different dosage adjustments would have followed. The presence of digoxin-like immunoreactive substances may explain some of this discordance. The mean of the equation-based result was similar to the Immunoassay results, but marked variability was evident. The DGNA assay produced higher results on 24 samples; 9 higher values occurred with the DRI method.

Conclusions:

Commercial digoxin immunoassays frequently produce clinically significant discordant results. The equation-based estimate does not appear to be an acceptable alternative to therapeutic drug monitoring. Immunoassay manufacturers should be required to improve assay performance by including real-world blood samples in development and clinicians should consider digoxin assay results warily.
Agomelatine Treatment of Major Depressive Disorder
Authors: Dolder Christian R , Nelson Michael , Snider Morgan
Published: November 2008

Objective:

To review the efficacy, safety, pharmacologic, and pharmacokinetic data of agomelatine to better understand its potential role in the treatment of patients with major depressive disorder.

Data:

A MEDLINE search (1966–October 2008) was conducted using the following terms: agomelatine, antidepressant, S20098, melatonin, serotonin, 5-HT2C, MT, efficacy, safety, adverse effect, pharmacology, pharmacokinetic, receptor binding, depression, major depressive disorder, and mood disorder.

Study Selection and Data Extraction:

All articles in English identified from the data sources were evaluated. Randomized, controlled trials involving humans were prioritized in the review. The references of published articles identified in the initial search process were also examined for any additional studies appropriate for the review.

Data Synthesis:

Agomelatine, a potent agonist at type 1 and 2 melatonin receptors, selectively inhibits serotonin. It is extensively metabolized via cytochrome P450 isoenyzmes 1A1, 1A2, and 2C9 to metabolites with less activity than the parent drug. Five randomized controlled studies were identified that examined the efficacy and safety of agomelatine in major depressive disorder. In general, agomelatine was found to produce significant improvements in depressive symptoms compared with placebo on many, but not all, rating scales. Three of the trials had active comparator arms (le, venlafaxine, paroxetine). In these 3 investigations, agomelatine produced effects on depressive symptoms similar to those of the comparator drugs. A small number of studies have demonstrated sleep benefits with the use of agomelatine in depressed patients. Positive findings also exist for the use of agomelatine in seasonal affective disorder and bipolar depression. The most common adverse effects reported with agomelatine use were headache, nasopharyngitis, and gastrointestinal complaints. The magnitude of agomelatine-related adverse effects appears to be at least similar to some currently marketed antidepressants.

Conclusions:

Overall, agomelatine is a promising and well-tolerated medication for the treatment of major depressive disorder. More large-scale controlled trials are needed to gain a better understanding of the relative efficacy and safety of agomelatine.
Cephalosporin-Induced Neurotoxicity: Clinical Manifestations, Potential Pathogenic Mechanisms, and the Role of Electroencephalographic Monitoring
Authors: Grill Marie Francisca , Maganti Rama
Published: November 2008

Objective:

To review the clinical manifestations of cephalosporin-induced neurotoxicity, underlying potential mechanisms, role of electroencephalographic (EEG) monitoring, and management of neurotoxicity.

Data:

A PubMed search (1970–May 2006) was conducted using search terms such as cephalosporins, neurotoxicity, seizures, and status epilepticus. The search was not limited to the English language and yielded approximately 187 articles.

Study Selection and Data Extraction:

Several case reports and case series were included to outline the salient clinical features of cephalosporin neurotoxicity. Laboratory studies investigating the potential mechanisms were also included. Reports outlining the EEG features of cephalosporin neurotoxicity were included and the role of continuous EEG monitoring was extracted. Finally, management strategies of such neurotoxicity are discussed.

Data Synthesis:

Cephalosporin-induced neurotoxicity may manifest in a variety of clinical presentations, ranging from simple encephalopathy or mental status changes to myoclonus, asterixis, seizures, nonconvulsive status epilepticus, as well as coma. Patients who are elderly, those with renal insufficiency, and those with prior neurologic disease may be particularly prone to the neurotoxic effects. The main mechanism of neurotoxicity appears to involve γ-aminobutyric acid A receptor inhibition, although other mechanisms may be possible. Cephalosporin neurotoxicity may be associated with a variety of EEG manifestations. Treatment mainly involves withdrawal of the offending drug, in addition to hemodialysis in patients with renal failure, and use of benzodiazepines or other anticonvulsants in patients who develop frank status epilepticus. Neurotoxicity can be prevented in high-risk cases with dosage adjustments and monitoring of serum concentrations.

Conclusions:

Knowledge and awareness of the neurotoxic clinical manifestations, EEG findings, and underlying mechanisms are essential for clinicians in identifying and treating this potentially lethal but reversible complication of cephalosporin therapy. Further studies are needed to determine the most appropriate treatment paradigms for patients who develop status epilepticus as a result of cephalosporins.
Email Medication Counseling Services Provided by Finnish Community Pharmacies
Authors: Pohjanoksa-Mäntylä Marika K , Kulovaara Heidi , Bell J Simon , Enäkoski Marianne , Airaksinen Marja S
Published: November 2008

Background:

The importance of email as a mode of communication between medication users and pharmacists is likely to increase. However, little is known about the email medication counseling practices of community pharmacies.

Objective:

To determine the prevalence of email medication counseling services in Finland and to assess the accuracy and comprehensiveness of responses by pharmacies providing the opportunity for email medication counseling to inquiries related to use of antidepressants.

Methods:

An inventory was made of all Finnish community pharmacies that provided the opportunity for email medication counseling. Data related to the accuracy and comprehensiveness of responses were collected, using a virtual pseudo-customer method with 3 scenarios related to common concerns of patients on antidepressants. Two inquiries were emailed to each pharmacy that provided the opportunity for email medication counseling in January and February 2005. The responses were content analyzed by 2 researchers, using a prestructured scoring system.

Results:

Almost one-third (30%, n = 182) of Finnish community pharmacies maintained a working Web site, and 94% of those provided the opportunity for email medication counseling. An online “ask-the-pharmacist” service was offered by 13% (n = 23) of the pharmacies with a Web site. Pharmacies responded to 54% of the email inquiries sent by the virtual pseudo-customers. The response rate and the content score ratio between mean and maximum scores varied among the scenarios. The content score ratio was highest for the scenarios concerning the adverse effects of fluoxetine (0.53, n = 55) and interactions with mirtazapine (0.52, n = 63) and lowest for the scenario related to sexual dysfunction and weight gain associated with citalopram (0.38, n = 52).

Conclusions:

Community pharmacies are potential providers of email medication counseling services. However, more attention should be directed to responding to consumer inquiries and to the content of these responses.
A Crucial Role for Primary Cilia in Cortical Morphogenesis
Authors: Willaredt Marc A. , Hasenpusch-Theil Kerstin , Gardner Humphrey A. R. , Kitanovic Igor , Hirschfeld-Warneken Vera C. , Gojak Christian P. , Gorgas Karin , Bradford C. Lulu , Spatz Joachim , Wölfl Stefan , Theil Thomas , Tucker Kerry L.
Published: November 2008

Primary cilia are important sites of signal transduction involved in a wide range of developmental and postnatal functions. Proteolytic processing of the transcription factor Gli3, for example, occurs in primary cilia, and defects in intraflagellar transport (IFT), which is crucial for the maintenance of primary cilia, can lead to severe developmental defects and diseases. Here we report an essential role of primary cilia in forebrain development. Uncovered byN-ethyl-N-nitrosourea-mutagenesis,cobblestoneis a hypomorphic allele of the IFT geneIft88,in which Ift88 mRNA and protein levels are reduced by 70–80%.cobblestonemutants are distinguished by subpial heterotopias in the forebrain. Mutants show both severe defects in the formation of dorsomedial telencephalic structures, such as the choroid plexus, cortical hem and hippocampus, and also a relaxation of both dorsal-ventral and rostral-caudal compartmental boundaries. These defects phenocopy many of the abnormalities seen in theGli3mutant forebrain, and we show that Gli3 proteolytic processing is reduced, leading to an accumulation of the full-length activator isoform. In addition, we observe an upregulation of canonical Wnt signaling in the neocortex and in the caudal forebrain. Interestingly, the ultrastructure and morphology of ventricular cilia in thecobblestonemutants remains intact. Together, these results indicate a critical role for ciliary function in the developing forebrain.
Type 1 Adenylyl Cyclase Is Essential for Maintenance of Remote Contextual Fear Memory
Authors: Shan Qiang , Chan Guy C.-K. , Storm Daniel R.
Published: November 2008

Although molecular mechanisms for hippocampus-dependent memory have been extensively studied, much less is known about signaling events important for remote memory. Here we report that mice lacking type 1 adenylyl cyclase (AC1) are able to establish and retrieve remote contextual memory but unable to sustain it as long as wild-type mice. Interestingly, mice overexpressing AC1 show superior remote contextual memory even though they exhibit normal hippocampus-dependent contextual memory. These data illustrate that calcium coupling to cAMP contributes to the stability of remote memory and identifies AC1 as a potential drug target site to improve long-term remote memory.
Direct Binding with Histone Deacetylase 6 Mediates the Reversible Recruitment of Parkin to the Centrosome
Authors: Jiang Qian , Ren Yong , Feng Jian
Published: November 2008

Histone deacetylase 6 (HDAC6), a microtubule-associated tubulin deacetylase, plays a significant role in the formation of protein aggregates in many neurodegenerative disorders. Parkin, a protein-ubiquitin E3 ligase linked to Parkinson's disease, accumulates at the centrosome in a microtubule-dependent manner in response to proteasome inhibition. Here, we show that the centrosome recruitment of parkin was mediated by its direct binding to HDAC6 through multiple interaction domains. The tubulin deacetylase activity of HDAC6 was required for the accumulation of parkin as well as its dispersion upon the reversal of proteasome inhibition. The bidirectional movements of parkin required intact microtubule network and were dependent on dynein and kinesin 1, respectively. Tubulin deacetylation increases microtubule dynamicity and may thus facilitate microtubule-based trafficking of the parkin-HDAC6 complex. The results suggest that HDAC6 acts as a sensor of proteasome inhibition and directs the trafficking of parkin by using different motor proteins.
Phosphoinositides Regulate P2X4ATP-Gated Channels through Direct Interactions
Authors: Bernier Louis-Philippe , Ase Ariel R. , Chevallier Stéphanie , Blais Dominique , Zhao Qi , Boué-Grabot Éric , Logothetis Diomedes , Séguéla Philippe
Published: November 2008

P2X receptors are ATP-gated nonselective cation channels highly permeable to calcium that contribute to nociception and inflammatory responses. The P2X4subtype, upregulated in activated microglia, is thought to play a critical role in the development of tactile allodynia following peripheral nerve injury. Posttranslational regulation of P2X4function is crucial to the cellular mechanisms of neuropathic pain, however it remains poorly understood. Here, we show that the phosphoinositides PI(4,5)P2(PIP2) and PI(3,4,5)P3(PIP3), products of phosphorylation by wortmannin-sensitive phosphatidylinositol 4-kinases and phosphatidylinositol 3-kinases, can modulate the function of native and recombinant P2X4receptor channels. In BV-2 microglial cells, depleting the intracellular levels of PIP2and PIP3with wortmannin significantly decreased P2X4current amplitude and P2X4-mediated calcium entry measured in patch clamp recordings and ratiometric ion imaging, respectively. Wortmannin-induced depletion of phosphoinositides inXenopusoocytes decreased the current amplitude of P2X4responses by converting ATP into a partial agonist. It also decreased their recovery from desensitization and affected their kinetics. Injection of phosphoinositides in wortmannin-treated oocytes reversed these effects and application of PIP2on excised inside-out macropatches rescued P2X4currents from rundown. Moreover, we report the direct interaction of phospholipids with the proximal C-terminal domain of P2X4subunit (Cys360–Val375) using anin vitrobinding assay. These results demonstrate novel regulatory roles of the major signaling phosphoinositides PIP2and PIP3on P2X4function through direct channel–lipid interactions.
Discharges in Human Muscle Receptor Afferents during Block Grasping
Authors: Dimitriou Michael , Edin Benoni B.
Published: November 2008

Human grasping relies on feedforward control that is monitored and corrected on-line by means of sensory feedback. While much of the sensory mechanisms underpinning hand-object interaction are known, information has been lacking about muscle receptor responses during the phases before and after actual object contact. We therefore let subjects use their thumb and fingers to grasp blocks presented to them while we recorded muscle afferents from the thumb and finger extensor muscles along with wrist and digit kinematics, and electromyographic activity. The kinematics of the task was indistinguishable from “normal” grasping. None of the afferents encoded either object contact or finger apposition. Both primary and secondary afferents were more phase advanced on the parent muscle lengths than expected from previous studies as well as from their responses to imposed length changes of their parent muscles. Thus, the discharges of both primary and secondary afferents were well correlated to the tendon velocity of their parent muscles and that of primary afferents also to acceleration whereas neither appeared to encode muscle length as such. Decoding the velocity of muscle length changes were significantly improved if the discharge of Golgi tendon organ afferents were taken into account along with that of the muscle spindle afferents. We propose that these findings may be explained by the biomechanical properties of contracting muscles. Moreover, we conclude that it seems unlikely that the muscle spindle afferents recorded in this task have any role in providing “proprioceptive” information pertaining to the size of an object grasped.
CO2-Sensitive Preinspiratory Neurons of the Parafacial Respiratory Group Express Phox2b in the Neonatal Rat
Authors: Onimaru Hiroshi , Ikeda Keiko , Kawakami Kiyoshi
Published: November 2008

Phox2b protein is a specific marker for neurons in the parafacial region of the ventral medulla, which are proposed to play a role in central chemoreception and postnatal survival. Mutations ofPHOX2Bcause congenital central hypoventilation syndrome. However, there have been no reports concerning electrophysiological characteristics of these Phox2b-expressing neurons in the parafacial region of the neonate immediately after birth. This region overlaps with the parafacial respiratory group (pFRG) composed predominantly of preinspiratory (Pre-I) neurons that are involved in respiratory rhythm generation. We studied (1) whether pFRG neurons are Phox2b immunoreactive or not and (2) whether they show intrinsic CO2chemosensitivity. We found that most pFRG/Pre-I neurons were Phox2b immunoreactive and depolarized upon increase in CO2concentration under condition of action potential-dependent synaptic transmission blockade by tetrodotoxin. We also confirmed that these pFRG neurons expressed neurokinin-1 receptor. They were tyrosine hydroxylase negative and presumed to be glutamatergic. Our findings suggest that Phox2b-expressing parafacial neurons play a role in respiratory rhythm generation as well as central chemoreception and thus are essential for postnatal survival.
Anesthesia-Induced Hyperphosphorylation Detaches 3-Repeat Tau from Microtubules without Affecting Their StabilityIn Vivo
Authors: Planel Emmanuel , Krishnamurthy Pavan , Miyasaka Tomohiro , Liu Li , Herman Mathieu , Kumar Asok , Bretteville Alexis , Figueroa Helen Y. , Haung Yu Wai , Whittington Robert A. , Davies Peter , Takashima Akihiko , Nixon Ralph A. , Duff Karen E.
Published: November 2008

In Alzheimer's disease, tau is hyperphosphorylated, which is thought to detach it from microtubules (MTs), induce MT destabilization, and promote aggregation. Using a previously describedin vivomodel, we investigated whether hyperphosphorylation impacts tau function in wild-type and transgenic mice. We found that after anesthesia-induced hypothermia, MT-free tau was hyperphosphorylated, which impaired its ability to bind MTs and promote MT assembly. MT-bound tau was more resistant to hyperphosphorylation compared with free tau and tau did not dissociate from MTs in wild-type mice. However, 3-repeat tau detached from MT in the transgenic mice. Surprisingly, dissociation of tau from MTs did not lead to overt depolymerization of tubulin, and there was no collapse, or disturbance of axonal MT networks. These results indicate that,in vivo, a subpopulation of tau bound to MTs does not easily dissociate under conditions that extensively phosphorylate tau. Tau remaining on the MTs under these conditions is sufficient to maintain MT network integrity.
A Neonatal Ventral Hippocampal Lesion Causes Functional Deficits in Adult Prefrontal Cortical Interneurons
Authors: Tseng Kuei Y. , Lewis Barbara L. , Hashimoto Takanori , Sesack Susan R. , Kloc Michelle , Lewis David A. , O'Donnell Patricio
Published: November 2008

Animals with a neonatal ventral hippocampal lesion (NVHL) develop abnormal behaviors during or after adolescence, suggesting that early insults can have delayed consequences. Many of these behaviors depend on the prefrontal cortex (PFC), and we have reported that PFC pyramidal neurons of adult rats with an NVHL respond to stimulation of the ventral tegmental area with an increase in firing instead of the characteristic decrease. As the dopamine modulation of cortical interneurons matures during adolescence, these findings raise the possibility that maturation of local inhibitory circuits within the PFC may have been altered in NVHL rats. Here, we assessed the state of PFC interneurons in NVHL rats within situhybridization measures of the mRNAs for the calcium binding protein parvalbumin (PV) and the GABA synthesizing enzyme GAD67, as well as with electrophysiological measures of interneuron function. Although no differences were observed with PV or GAD67, whole-cell recordings in slices revealed abnormal responses to the D2agonist quinpirole in interneurons from NVHL rats. The loss of D2modulation of local inhibition in slices from NVHL rats was also evident in the absence of a lasting component in the D2attenuation of excitatory synaptic responses in pyramidal neurons, which in sham treated rats was picrotoxin sensitive. The results suggest that the neonatal lesion causes improper maturation, but not loss, of PFC interneurons during adolescence, a finding consistent with current interpretations of imaging data in schizophrenia that suggest a hyperactive, “noisy” cortex underlying dysfunction in the PFC and other cortical areas.
δ-Opioid Receptor Expression in the Ventral Tegmental Area Protects Against Elevated Alcohol Consumption
Authors: Margolis Elyssa B. , Fields Howard L. , Hjelmstad Gregory O. , Mitchell Jennifer M.
Published: November 2008

Alcoholism is a complex and debilitating syndrome affecting ∼140 million people worldwide. However, not everyone who consumes ethanol develops abuse, raising the possibility that some individuals have a protective mechanism that inhibits elevated alcohol consumption. We tested the hypothesis that the δ-opioid receptor (DOR) plays such a protective role. Here we show that DOR activity in the ventral tegmental area (VTA) robustly decreases ethanol consumption in rats and that these effects depend on baseline ethanol consumption. Intra-VTA microinjection of the DOR agonist DPDPE decreases drinking, particularly in low-drinking animals. Furthermore, VTA microinjection of the DOR selective antagonist TIPP-Ψ increases drinking in low, but not high, drinkers and this increase is blocked by comicroinjection of the GABAAantagonist bicuculline. Using electrophysiological techniques we found that in VTA brain slices from drinking rats DPDPE presynaptically inhibits GABAAreceptor mediated IPSCs in low drinkers, but not in high drinkers or naive animals, most likely through activation of DORs on GABA terminals. This DOR-mediated inhibition of IPSCs also correlates inversely with behavioral correlates of anxiety measured in the elevated plus maze. In contrast, presynaptic inhibition of VTA GABAAIPSCs by the μ- opioid receptor agonist DAMGO is significantly reduced in both high- and low-drinking rats (<30%) compared with age-matched nondrinking controls (>70%). Together, our findings demonstrate the protective nature of VTA DORs and identify an important new target for therapeutic intervention for alcoholism.
Loss of LR11/SORLA Enhances Early Pathology in a Mouse Model of Amyloidosis: Evidence for a Proximal Role in Alzheimer's Disease
Authors: Dodson Sara E. , Andersen Olav M. , Karmali Vinit , Fritz Jason J. , Cheng Dongmei , Peng Junmin , Levey Allan I. , Willnow Thomas E. , Lah James J.
Published: November 2008

Alzheimer's disease (AD) is the most prevalent form of dementia, resulting in progressive neuronal death and debilitating damage to brain loci that mediate memory and higher cognitive function. While pathogenic genetic mutations have been implicated in ∼2% of AD cases, the proximal events that underlie the common, sporadic form of the disease are incompletely understood. Converging lines of evidence from human neuropathology, basic biology, and genetics have implicated loss of the multifunctional receptor LR11 (also known as SORLA and SORL1) in AD pathogenesis. Cell-based studies suggest that LR11 reduces the formation of β-amyloid (Aβ), the molecule believed to be a primary toxic species in AD. Recently, mutant mice deficient in LR11 were shown to upregulate murine Aβ in mouse brain. In the current study, LR11-deficient mice were crossed with transgenic mice expressing autosomal-dominant human AD genes, presenilin-1 (PS1ΔE9) and amyloid precursor protein (APPswe). Here, we show that LR11 deficiency in this AD mouse model significantly increases Aβ levels and exacerbates early amyloid pathology in brain, causing a forward shift in disease onset that is LR11 gene dose-dependent. Loss of LR11 increases the processing of the APP holo-molecule into α-, β-, and γ-secretase derived metabolites. We propose that LR11 regulates APP processing and Aβ accumulationin vivoand is of proximal importance to the cascade of pathological amyloidosis. The results of the current study support the hypothesis that control of LR11 expression may exert critical effects on Alzheimer's disease susceptibility in humans.
Free Jazz and the French Critic
Authors: Drott Eric
Published: November 2008

From the mid-1960s to the early 1970s, free jazz was the subject of considerable public interest in France. The present article examines the conditions that fueled enthusiasm for American avant-garde jazz, focusing on the politicization of discourse surrounding the ‘new thing.’ Critics hostile to the movement felt that it undermined jazz's claim to universality, a cornerstone of postwar attempts to valorize the genre in the French cultural sphere. Yet the tendency to identify free jazz with various forms of African American political radicalism presented no less of a challenge for the movement's advocates. By constructing an image of free jazz that stressed its irremediable difference from the norms and values of European culture, writers were compelled to find alternative ways of relating it to contemporary French concerns. A reading of Philippe Carles and Jean-Louis Comolli's text Free Jazz Black Power shows how the authors' attempt to reinscribe African American cultural nationalism as an expression of transnational anticolonial struggle not only helped bring free jazz closer to the French experience, but also served as a way of working through the unresolved legacies of colonialism.