bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein phosphatase 2A negatively regulates aPKC signaling by modulating phosphorylation of Par-6 inDrosophilaneuroblast asymmetric divisions
Authors: Ogawa Hironori , Ohta Nao , Moon Woongjoon , Matsuzaki Fumio
Published: August 2009

Drosophila neural stem cells or neuroblasts undergo typical asymmetric cell division. An evolutionally conserved protein complex, comprising atypical protein kinase C (aPKC), Bazooka (Par-3) and Par-6, organizes cell polarity to direct these asymmetric divisions. Aurora-A (AurA) is a key molecule that links the divisions to the cell cycle. Upon its activation in metaphase, AurA phosphorylates Par-6 and activates aPKC signaling, triggering the asymmetric organization of neuroblasts. Little is known, however, about how such a positive regulatory cue is counteracted to coordinate aPKC signaling with other cellular processes. During a mutational screen using the Drosophila compound eye, we identified microtubule star (mts), which encodes a catalytic subunit of protein phosphatase 2A (PP2A), as a negative regulator for aPKC signaling. Impairment of mts function causes defects in neuroblast divisions, as observed in lethal (2) giant larvae (lgl) mutants. mts genetically interacts with par-6 and lgl in a cooperative manner in asymmetric neuroblast division. Furthermore, Mts tightly associates with Par-6 and dephosphorylates AurA-phosphorylated Par-6. Our genetic and biochemical evidence indicates that PP2A suppresses aPKC signaling by promoting Par-6 dephosphorylation in neuroblasts, which uncovers a novel balancing mechanism for aPKC signaling in the regulation of asymmetric cell division.
An N-terminal addressing sequence targets NLRX1 to the mitochondrial matrix
Authors: Arnoult Damien , Soares Fraser , Tattoli Ivan , Castanier Céline , Philpott Dana J. , Girardin Stephen E.
Published: August 2009

NLRX1 is the only member of the Nod-like receptor (NLR) family that is targeted to the mitochondria, and its overexpression induces the generation of reactive oxygen species (ROS), thus impacting on NFκB- and JNK-dependent signaling cascades. In addition, NLRX1 has been shown to interact with MAVS (also known as IPS-1, VISA and Cardif) at the mitochondrial outer membrane and to modulate antiviral responses. Here we report that NLRX1 has a functional leader sequence and fully translocates to the mitochondrial matrix via a mechanism requiring the mitochondrial inner-membrane potential, ΔΨm. Importantly, we failed to detect NLRX1 at the mitochondrial outer membrane. We also show that the leader sequence of NLRX1 is removed, which generates a mature protein lacking the first 39 amino acids through a maturation process that is common for mitochondrial-matrix proteins. Finally, we identified UQCRC2, a matrix-facing protein of the respiratory chain complex III, as an NLRX1-interacting molecule, thus providing a molecular basis for the role of NLRX1 in ROS generation. These results provide the first identification of a protein belonging to the NLR family that is targeted to the mitochondrial matrix.
Actin machinery and mechanosensitivity in invadopodia, podosomes and focal adhesions
Authors: Albiges-Rizo Corinne , Destaing Olivier , Fourcade Bertrand , Planus Emmanuelle , Block Marc R.
Published: August 2009

The invasiveness of cells is correlated with the presence of dynamic actin-rich membrane structures called invadopodia, which are membrane protrusions that are associated with localized polymerization of sub-membrane actin filaments. Similar to focal adhesions and podosomes, invadopodia are cell-matrix adhesion sites. Indeed, invadopodia share several features with podosomes, but whether they are distinct structures is still a matter of debate. Invadopodia are built upon an N-WASP-dependent branched actin network, and the Rho GTPase Cdc42 is involved in inducing invadopodial-membrane protrusion, which is mediated by actin filaments that are organized in bundles to form an actin core. Actin-core formation is thought to be an early step in invadopodium assembly, and the actin core is perpendicular to the extracellular matrix and the plasma membrane; this contrasts with the tangential orientation of actin stress fibers anchored to focal adhesions. In this Commentary, we attempt to summarize recent insights into the actin dynamics of invadopodia and podosomes, and the forces that are transmitted through these invasive structures. Although the mechanisms underlying force-dependent regulation of invadopodia and podosomes are largely unknown compared with those of focal adhesions, these structures do exhibit mechanosensitivity. Actin dynamics and associated forces might be key elements in discriminating between invadopodia, podosomes and focal adhesions. Targeting actin-regulatory molecules that specifically promote invadopodium formation is an attractive strategy against cancer-cell invasion.
Liprin-α1 promotes cell spreading on the extracellular matrix by affecting the distribution of activated integrins
Authors: Asperti Claudia , Astro Veronica , Totaro Antonio , Paris Simona , de Curtis Ivan
Published: August 2009

Integrin activation is needed to link the extracellular matrix with the actin cytoskeleton during cell motility. Protrusion requires coordination of actin dynamics with focal-adhesion turnover. We report that the adaptor protein liprin-α1 is stably associated with the cell membrane. Lipin-α1 shows a localization that is distinct from that of activated β1 integrins at the edge of spreading cells. Depletion of liprin-α1 inhibits the spreading of COS7 cells on fibronectin by affecting lamellipodia formation, whereas its overexpression enhances spreading, and lamellipodia and focal-adhesion formation at the cell edge. Cooperation between liprin-α1 and talin is needed, because either talin or liprin depletion prevents spreading in the presence of the other protein. The effects of liprin on spreading, but not its effects in the reorganization of the cell edge, are dependent on its interaction with leukocyte common antigen-related tyrosine phosphatase receptors. Therefore, liprin is an essential regulator of cell motility that contributes to the effectiveness of cell-edge protrusion.
Methodological obstacles in knocking down small noncoding RNAs
Authors: Ploner Andreas , Ploner Christian , Lukasser Melanie , Niederegger Harald , Hüttenhofer Alexander
Published: August 2009

In the recent past, several thousand noncoding RNA (ncRNA) genes have been predicted within eukaryal genomes. However, for their functional analysis only a few high-throughput methods are currently available to knock down selected ncRNA species, such as microRNAs, which are targeted by antisense probes, termed antagomirs. We thus compared the efficiencies of four knockdown strategies, previously mainly employed for the analysis of protein-coding genes, to study the function of ncRNAs, in particular, small nucleolar RNAs (snoRNAs). Thereby, the class of snoRNAs represents one of the most abundant ncRNA species. The majority of snoRNAs has been shown to mediate nucleotide modifications by targeting ribosomal RNAs (rRNAs) through complementary antisense elements. However, some snoRNAs, termed “orphan snoRNAs,” lack telltale complementarities to rRNAs and thus their function remains elusive. We therefore applied RNA interference (RNAi), locked nucleic acid (LNA), or peptide nucleic acid antisense approaches, as well as a ribozyme-based strategy to knock down a snoRNA. As a proof of principle, we targeted the canonical U81 snoRNA, which has been shown to mediate modification of nucleotide A391 within eukaryal 28S rRNA. Our results demonstrate that while RNAi is an unsuitable tool for snoRNA knockdown, a ribozyme-based strategy, as well as an LNA-antisense oligonucleotide approach, resulted in a decrease of U81 snoRNA expression levels up to 60%. However, no concomitant decrease in enzymatic activity of U81 snoRNA was observed, indicating that improvement of more efficient knockdown techniques for ncRNAs will be required in the future.
An Algorithm for Fast Generation of Bivariate Poisson Random Vectors
Authors: Shin Kaeyoung , Pasupathy Raghu
Published: August 2009

We present the “trivariate reduction extension” (TREx)—an exact algorithm for the fast generation of bivariate Poisson random vectors. Like the normal-to-anything (NORTA) procedure, TREx has two phases: a preprocessing phase when the required algorithm parameters are identified, and a generation phase when the parameters identified during the preprocessing phase are used to generate the desired Poisson vector. We prove that the proposed algorithm covers the entire range of theoretically feasible correlations, and we provide efficient-computation directives and rigorous bounds for truncation error control. We demonstrate through extensive numerical tests that TREx, being a specialized algorithm for Poisson vectors, has a preprocessing phase that is uniformly a hundred to a thousand times faster than a fast implementation of NORTA. The generation phases of TREx and NORTA are comparable in speed, with that of TREx being marginally faster. All code is publicly available.
Approximate Dynamic Programming for Ambulance Redeployment
Authors: Maxwell Matthew S. , Restrepo Mateo , Henderson Shane G. , Topaloglu Huseyin
Published: August 2009

We present an approximate dynamic programming approach for making ambulance redeployment decisions in an emergency medical service system. The primary decision is where we should redeploy idle ambulances so as to maximize the number of calls reached within a delay threshold. We begin by formulating this problem as a dynamic program. To deal with the high-dimensional and uncountable state space in the dynamic program, we construct approximations to the value function that are parameterized by a small number of parameters. We tune the parameters using simulated cost trajectories of the system. Computational experiments demonstrate the performance of the approach on emergency medical service systems in two metropolitan areas. We report practically significant improvements in performance relative to benchmark static policies.
Spontaneous Hemothorax Following Anticoagulation with Low-Molecular-Weight Heparin
Authors: Ganguli Amitava , Walker Lauren , FitzGerald Richard Joaquim , Pirmohamed Munir
Published: August 2009

Objective:

To report a case of spontaneous hemothorax following anticoagulation with low-molecular-weight heparin (LMWH) for the management of suspected pulmonary embolism.

Case Summary:

A 66-year-old man with a background history of breast carcinoma was admitted with pleuritic chest pain. He was initially managed as a suspected case of pulmonary embolism. Dalteparin, an LMWH, was started at a maximum dose of 18,000 units subcutaneously once daily, according to British national prescribing guidelines. On day 4, following 3 doses of dalteparin, the patient developed acute respiratory distress attributable to a massive right hemothorax confirmed by computed tomography pulmonary angiography (CTPA) and intercostal drainage of 1500 mL of frank blood. CTPA identified no pulmonary embolus or vascular abnormalities. Reaccumulation of hemothorax occurred over the 48 hours following drain removal, necessitating insertion of a second drain, which removed 1400 mL of blood-stained fluid. The patient's hemoglobin decreased from 12.7 to 8.5 g/dL and he received a 3-unit blood transfusion. Histologic assessment of pleural fluid revealed no malignancy and results of video-assisted thoracoscopic surgery were normal. Discontinuation of dalteparin on day 4 led to resolution of symptoms.

Discussion:

The causal association between anticoagulant therapy and spontaneous hemothorax remains relatively uncommon. The striking temporal relationship between commencing dalteparin on day 1 and subsequent development of effusion on day 4, following 3 doses of LMWH, led us to believe that the bleed occurred as a result of the therapy. Exclusion of other causes strengthened this conclusion. Application of the Naranjo probability scale categorized this adverse reaction as being probably due to LMWH.

Conclusions:

Spontaneous hemothorax is a rare phenomenon in conjunction with LMWH but should be considered in cases of acute respiratory distress following commencement of LMWH.
Measuring the Assessment and Counseling Provided with the Supply of Nonprescription Asthma Reliever Medication: A Simulated Patient Study
Authors: Schneider Carl R , Everett Alan W , Geelhoed Elizabeth , Kendall Peter A , Clifford Rhonda M
Published: August 2009

Background:

Over one quarter of asthma reliever medications are provided without prescription by community pharmacies in Australia. Evidence that community pharmacies provide these medications with sufficient patient assessment and medication counseling to ensure compliance with the government's Quality Use of Medicines principles is currently tacking.

Objective:

To assess current practice when asthma reliever medication is provided in the community pharmacy setting and to identify factors that correlate with assessment of asthma control.

Methods:

Researchers posing as patients visited a sample of Perth metropolitan community pharmacies in May 2007. During the visit, the simulated patient enacted a standardized scenario of someone with moderately controlled asthma who wished to purchase a salbutamol (albuterol) inhaler without prescription. Results of the encounter were recorded immediately after the visit. Regression analysis was performed, with medication use frequency (a marker of asthma control) as the dependent variable.

Results:

One hundred sixty community pharmacies in the Perth metropolitan area were visited in May 2007. Pharmacists and/or pharmacy assistants provided some form of assessment in 84% of the visits. Counseling was provided to the simulated patients in 24% of the visits. Only 4 pharmacy staff members asked whether the simulated patient knew how to use the inhaler. Significant correlation was found between assessment and/or counseling of reliever use frequency and 3 independent variables: visit length (p < 0.001), number of assessment questions asked (p < 0.001), and the simulated patient who conducted the visit (p < 0.02).

Conclusions:

Both patient assessment and medication counseling were suboptimal compared with recommended practice when nonprescription asthma reliever medication was supplied in the community pharmacy setting. Pharmacy and pharmacist demographic variables do not appear to affect assessment of asthma control. This research indicates the need for substantial improvements in practice in order to provide reliever medication in line with Quality Use of Medication principles of ensuring safe and effective use of medication.
An Exploratory Retrospective Evaluation of Ropinirole-Associated Psychotic Symptoms in an Outpatient Population Treated for Restless Legs Syndrome or Parkinson's Disease
Authors: Stoner Steven C , Dahmen Megan M , Makos Mignon , Lea Jessica W , Carver Lora J , Rasu Rafia S
Published: August 2009

Background:

Traditional treatment approaches for the management of restless legs syndrome (RLS) and Parkinson's disease (PD) include the use of medications that either directly or indirectly increase dopamine levels. In turn, a potential adverse event that could be expected is the development or exacerbation of psychiatric-related symptoms.

Objective:

To evaluate and describe the incidence of psychosis and associated behavioral features in patients taking ropinirole for RLS or PD.

Methods:

Patients were identified from a computerized database search of outpatients being treated with ropinirole for 1 of 2 medical conditions: PD or RLS. Data were collected in a retrospective manner from 95 patients who were tracked over the course of their therapy to determine whether psychosis or associated behavioral symptoms developed as a result and whether an intervention was needed to adjust ropinirole dosing or if additional medications had to be added to control features associated with psychosis.

Results:

A total of 284 patients being treated for RLS or PD were identified; of this group, 95 patients were identified as being treated for PD or RLS with ropinirole. Of the 95 patients being treated with ropinirole, 13 developed psychotic features that required therapeutic intervention with either the use of an antipsychotic or dose adjustment of ropinirole. PD patients included in this study were numerically more likely to develop psychotic features compared with RLS patients; however, the difference was not statistically significant (p = 0.122). The results do suggest that this risk is increased when ropinirole is used as part of a dual therapy approach with dopamine agonists in the treatment of either PD or RLS (p = 0.003).

Discussion:

Dopamine agonists have long been used as preferred treatment in the management of PD and RLS. When treating either PD or RLS in the psychiatric population, the concern arises that increased activity at dopamine receptors may induce or exacerbate psychiatric features. A potential clinical concern with the use of ropinirole is the potential for patients to develop psychiatric features, although there are few data available to demonstrate whether stimulation of targeted individual dopamine receptors is linked to the development or exacerbation of psychotic features. It is also undetermined whether concurrent antipsychotic treatment provides any protective benefit against psychosis, especially in patients already being treated for psychotic symptoms.

Conclusions:

Our findings suggest that ropinirole may play a role in inducing or exacerbating psychosis and its associated features, although a number of confounding variables prevent the determination of a clear association and suggest that further investigation is warranted in controlled clinical trials.
Assessing the Usefulness of Health-Related Quality-of-Life Trials: A Clinician's Perspective Using Two COPD Examples
Authors: Phung Olivia J , White C Michael , Baker William L , Coleman Craig I
Published: August 2009

Objective:

To empower clinicians to discern when health-related quality-of-life (HRQoL) evidence from a single trial, or from constituent trials within a systematic review or meta-analysis, is compelling enough to after clinical practice.

Data Sources:

To determine the criteria that would be most useful in assessing the quality of HRQoL data, recommendation statements or consensus guidelines that offer guidance to those conducting HRQoL trials were located through a MEDLINE search (1950–April 2009) using the search terms health-related quality of life and recommendations or guidelines.

Study Selection and Data Extraction:

Recommendation statements or consensus guidelines that offer guidance to investigators conducting HRQoL trials were evaluated to determine what criteria would be the most useful in assessing the quality of HRQoL data.

Data Synthesis:

We discuss how quality of HRQoL data may be assessed by evaluating the following broad questions: (1) Is the HRQoL analysis hypothesis-driven? (2) How is HRQoL being measured? (3) Are the HRQoL data being collected adequately and analyzed correctly? and (4) To what extent do investigators discuss the results of HRQoL analyses? Using select examples from the literature on chronic obstructive pulmonary disease, we applied the 4 broad questions in the assessment of their quality. Also, the use of scoring systems for quality rating for HRQoL data is discussed and applied to the example cases.

Conclusions:

HRQoL data are an important outcome because they capture treatment impact on physical, social, and psychological well-being. Assessing the quality and usefulness of HRQoL data requires an understanding of the advantages, limitations, and caveats of their use. Because of the potential lack of quality in HRQoL outcomes, clinicians should thoroughly assess the validity and usefulness of the evaluation. Tools are available to aid clinicians and decisionmakers in the assessment of HRQoL outcomes, but additional research needs to be conducted on the topic of quality assessment of HRQoL studies to improve the usefulness of these evaluations to clinicians.
Drug Information Rounds Levetiracetam Use in Pregnancy
Authors: Longo Brian , Forinash Alicia B , Murphy Julie A
Published: August 2009

Objective:

To review data evaluating levetiracetam management of epilepsy during pregnancy.

Data Sources:

A literature search of PubMed (1966–June 2009) was performed using the terms pregnancy, epilepsy, levetiracetam, and anticonvulsants. Bibliographies of all articles retrieved were reviewed to identify additional relevant articles.

Study Selection and Data Extraction:

All studies including humans and published in English with data describing levetiracetam management during pregnancy were included.

Data Synthesis:

The pharmacokinetic studies included in this review demonstrate that the clearance of levetiracetam increases during pregnancy, particularly during the third trimester, which subsequently leads to decreased serum levetiracetam concentrations. The increase in clearance is most likely due to an increase in renal blood flow. The teratogenic studies included in this review included a total of 147 patients. Of these patients, 2% experienced a major congenital malformation (MCM) and 4.8% experienced a minor anomaly. All of the patients who had either an MCM or a minor anomaly were receiving antiepileptic drug (AED) polytherapy. It was unknown whether 10.9% of the 147 patients discussed were receiving levetiracetam monotherapy or AED polytherapy. None of the published literature assessed adherence to AED therapy. Folic acid supplementation was addressed in only one of the case series presented.

Conclusions:

If levetiracetam is used during pregnancy, women should receive adequate amounts of folic acid (0.4–5 mg/day) and serum concentrations of levetiracetam should be determined before conception if possible and during each trimester, especially during the middle of the third trimester, to assess therapeutic concentrations. The dose may need to be increased during the third trimester to provide concentrations consistent with those before conception. Patients should be informed that there appears to be a small chance of malformations with levetiracetam, but that the data are limited.
A Benchmark for Platelet Count Monitoring with Low-Molecular-Weight Heparin: Expanding Implementation of National Patient Safety Goals
Authors: Spinler Sarah A
Published: August 2009

Practitioners in US hospitals are implementing anticoagulation dosing and monitoring protocols to improve the safety of anticoagulation, consistent with National Patient Safety Goal 03.05.01. An audit of the Utrecht Patient Oriented Database of patients treated with low-molecular-weight heparin (LMWH) at the University Medical Center Utrecht revealed low compliance with platelet count monitoring as well as initial management of suspected heparin-induced thrombocytopenia (HIT). Limitations to this work included the inability to exclude other drug-induced causes of thrombocytopenia and their definition of the frequency of platelet count monitoring for compliance in patients given venous thromboembolism prophylaxis. Despite these limitations, the authors’ work represents the first published report on extending the quality of heparin anticoagulation management to platelet count monitoring and evaluation for HIT in a large patient population. Clinicians should include evaluations of compliance with platelet count monitoring with unfractionated heparin and LMWH, as well as appropriateness of the initial management strategies for HIT, and direct thrombin inhibitor protocols in their patient safety practice assessments.
The glass cliff: When and why women are selected as leaders in crisis contexts
Authors: Bruckmüller Susanne , Branscombe Nyla R.
Published: August 2009

The glass cliff refers to women being more likely to rise to positions of organizational leadership in times of crisis than in times of success, and men being more likely to achieve those positions in prosperous times. We examine the role that (a) a gendered history of leadership and (b) stereotypes about gender and leadership play in creating the glass cliff. In Expt 1, participants who read about a company with a male history of leadership selected a male future leader for a successful organization, but chose a female future leader in times of crisis. This interaction – between company performance and gender of the preferred future leader – was eliminated for a counter‐stereotypic history of female leadership. In Expt 2, stereotypically male attributes were most predictive of leader selection in a successful organization, while stereotypically female attributes were most predictive in times of crisis. Differences in the endorsement of these stereotypes, in particular with regard to the ascription of lower stereotypically female attributes to the male candidate mediated the glass cliff effect. Overall, results suggest that stereotypes about male leadership may be more important for the glass cliff effect than stereotypes about women and leadership.
Surface complexation and proton-promoted dissolution in aqueous apatite systems
Authors: Bengtsson Åsa , Sjöberg Staffan
Published: August 2009

The dissolution of hydroxyapatite (HAP) and fluorapatite (FAP) has been studied (25 °C, 0.1 M NaCl medium) within the pH ranges 2–11 (FAP) and 4–10 (HAP). A range of techniques has been utilized to achieve understanding in how these two abundant minerals may interact with their natural surroundings (e.g., body fluids and soil environments). Synthetic crystalline HAP and FAP were prepared, and both minerals were found to undergo a phase transformation generated during a dialysis step of the synthetic routes. Surface-deficient layers with the nonstoichiometric compositions Ca8.4(HPO4)1.6(PO4)4.4(OH)0.4 and Ca9(HPO4)2(PO4)4F2 were identified. The equilibrium analysis of experimental solubility data of the two apatite systems was based upon potentiometric titration data, batch experiments, and zeta-potential measurements in combination with information provided by X-ray photoelectron spectroscopy (XPS) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The analysis required, besides the two solubility equilibria, the formation of surface protonation/deprotonation reactions, re-adsorption processes involving phosphate and fluoride ions as well as an ion exchange reaction (≡F + H2O ⇋ ≡OH + H+ + F–) to fully describe the dissolution characteristics of the two apatite systems. The resulting model also agrees with observations from XPS and solubility data, claiming the formation of CaF2(s) in the most acidic pH range of the FAP system. In addition, calculated isoelectric points (pHiep) are in agreement with values from surface charge measurements showing pHiep (HAP) = 8.1 and pHiep (FAP) = 5.7.
Recent advances in organometallic alkane and noble gas complexes
Authors: Calladine James A. , Vuong Khuong Q. , Sun Xue Z. , George Michael W.
Published: August 2009

Fast time-resolved infrared (TRIR) spectroscopy has been useful for studying the reactions of a wide range of organometallic alkane and noble gas complexes at ambient temperature following irradiation of metal carbonyl precursor complexes. The reactivity of organometallic alkane and xenon complexes decreases both across and down groups V, VI, and VII, and for a given metal/ligand combination the alkane and xenon complexes have similar reactivities. Systematic studies of reactivity have produced long-lived Re complexes which have allowed such complexes to be characterized using NMR spectroscopy. A new approach using liquid propane at low temperature as a solvent to monitor the interaction of such weakly coordinating ligands with transition-metal centers is outlined. TRIR studies monitoring the coordination and activation of methane and ethane in supercritical methane and liquid ethane solvents at room temperature are also reviewed.
Solubility and critical phenomena in reactive liquid–liquid systems
Authors: Toikka Alexander , Toikka Maria
Published: August 2009

The goal of this work is to consider solubility phenomena in reactive fluid mixtures with liquid-phase splitting. One of the main tasks is to analyze peculiarities of liquid–liquid (LL) systems with equilibrium and nonequilibrium chemical reaction. The special aim is to consider the critical states in these systems. The reactive liquid–liquid equilibrium (LLE) is treated on the base of phase rule. The topology of diagrams of reactive LLE is discussed for some types of binary and ternary systems. Examples are presented of a possible transformation of phase diagrams caused by the shifting of chemical equilibrium and by changes in the shape of the binodal. The transformations resulting in the reactive critical phase formation are considered. Quaternary mixtures are also discussed with the use of experimental data on the solubility in the system with n-propyl acetate synthesis reaction. The mutual crossing of the chemical equilibrium surface and binodal in the composition tetrahedron leads to the origin of the area of simultaneous chemical and LLE with two critical points (reactive critical phases). The shape of the curve of simultaneous chemical and phase equilibrium is also presented in the square of transformed composition variables.
The Way an Odor Is Experienced during Aversive Conditioning Determines the Extent of the Network Recruited during Retrieval: A Multisite Electrophysiological Study in Rats
Authors: Chapuis Julie , Garcia Samuel , Messaoudi Belkacem , Thevenet Marc , Ferreira Guillaume , Gervais Remi , Ravel Nadine
Published: August 2009

Recent findings have revealed the importance of orthonasal and retronasal olfaction in food memory, especially in conditioned odor aversion (COA); however, little is known about the dynamics of the cerebral circuit involved in the recognition of an odor as a toxic food signal and whether the activated network depends on the way (orthonasal vs retronasal) the odor was first experienced. In this study, we mapped the modulations of odor-induced oscillatory activities through COA learning using multisite recordings of local field potentials in behaving rats. During conditioning, orthonasal odor alone or associated with ingested odor was paired with immediate illness. For all animals, COA retrieval was assessed by orthonasal smelling only. Both types of conditioning induced similarly strong COA. Results pointed out (1) a predictive correlation between the emergence of powerful beta (15–40 Hz) activity and the behavioral expression of COA and (2) a differential network distribution of this beta activity according to the way the animals were exposed to the odor during conditioning. Indeed, for both types of conditioning, the aversive behavior was predicted by the emergence of a strong beta oscillatory activity in response to the odor in the olfactory bulb, piriform cortex, orbitofrontal cortex, and basolateral amygdala. This network was selectively extended to the infralimbic and insular cortices when the odor was ingested during acquisition. These differential networks could participate in different food odor memory; these results are discussed in line with recent behavioral results that indicate that COA can be formed over long odor-illness delays only if the odor is ingested.
How Connectivity, Background Activity, and Synaptic Properties Shape the Cross-Correlation between Spike Trains
Authors: Ostojic Srdjan , Brunel Nicolas , Hakim Vincent
Published: August 2009

Functional interactions between neuronsin vivoare often quantified by cross-correlation functions (CCFs) between their spike trains. It is therefore essential to understand quantitatively how CCFs are shaped by different factors, such as connectivity, synaptic parameters, and background activity. Here, we study the CCF between two neurons using analytical calculations and numerical simulations. We quantify the role of synaptic parameters, such as peak conductance, decay time, and reversal potential, and analyze how various patterns of connectivity influence CCF shapes. In particular, we find that the symmetry of the CCF distinguishes in general, but not always, the case of shared inputs between two neurons from the case in which they are directly synaptically connected. We systematically examine the influence of background synaptic inputs from the surrounding network that set the baseline firing statistics of the neurons and modulate their response properties. We find that variations in the background noise modify the amplitude of the cross-correlation function as strongly as variations of synaptic strength. In particular, we show that the postsynaptic neuron spiking regularity has a pronounced influence on CCF amplitude. This suggests an efficient and flexible mechanism for modulating functional interactions.
Dual Adaptation Supports a Parallel Architecture of Motor Memory
Authors: Lee Jeong-Yoon , Schweighofer Nicolas
Published: August 2009

Although our understanding of the mechanisms underlying motor adaptation has greatly benefited from previous computational models, the architecture of motor memory is still uncertain. On one hand, two-state models that contain both a fast-learning–fast-forgetting process and a slow-learning–slow-forgetting process explain a wide range of data on motor adaptation, but cannot differentiate whether the fast and slow processes are arranged serially or in parallel and cannot account for learning multiple tasks simultaneously. On the other hand, multiple parallel-state models learn multiple tasks simultaneously but cannot account for a number of motor adaptation data. Here, we investigated the architecture of human motor memory by systematically testing possible architectures via a combination of simulations and a dual visuomotor adaptation experimental paradigm. We found that only one parsimonious model can account for both previous motor adaptation data and our dual-task adaptation data: a fast process that contains a single state is arranged in parallel with a slow process that contains multiple states switched via contextual cues. Our result suggests that during motor adaptation, fast and slow processes are updated simultaneously from the same motor learning errors.
Formation of Long-Term Memory Representation in Human Temporal Cortex Related to Pictorial Paired Associates
Authors: Yamashita Ken-ichiro , Hirose Satoshi , Kunimatsu Akira , Aoki Shigeki , Chikazoe Junichi , Jimura Koji , Masutani Yoshitaka , Abe Osamu , Ohtomo Kuni , Miyashita Yasushi , Konishi Seiki
Published: August 2009

It is widely held that long-term memory gradually develops in the temporal neocortex after initial memory encoding into the hippocampus. However, little is known as to whether and where long-term memory can be newly created in the human temporal neocortex. In this functional magnetic resonance imaging study, we detected brain activity in the temporal neocortex that was developed ∼8 weeks after study of unfamiliar pictorial paired associates. Two sets of paired Fourier figures were studied, one ∼8 weeks before test and the other immediately before test, keeping the correct performance during the tests balanced across the two sets of stimuli. Significant signal increase was observed in the right hippocampus during retrieval of newly studied pairs relative to initially studied pairs. In contrast, significant signal increase was observed in the anterior temporal cortex during retrieval of initially studied pairs relative to newly studied pairs. The greater activity during retrieval of older memory developed in the temporal neocortex provides direct evidence of formation of temporal neocortical representation for stable long-term memory.
PKC Differentially Translocates during Spaced and Massed Training inAplysia
Authors: Farah Carole A. , Weatherill Daniel , Dunn Tyler W. , Sossin Wayne S.
Published: August 2009

Learning is highly regulated by the pattern of training. InAplysia, an important organism for the development of cellular and molecular models of learning, spaced versus massed application of the same stimulus leads to different forms of memory. A critical molecular step underlying memory is the serotonin (5HT)-mediated activation of the novel PKC Apl II. Here, we demonstrate that activation of PKC Apl II is highly sensitive to the pattern of 5HT application. Spaced applications downregulate PKC translocation through PKA signaling, whereas massed applications lead to persistent translocation of PKC. Differential regulation of PKC translocation is mediated by competing feedback mechanisms that act through protein synthesis. These studies elucidate a fundamental molecular difference between spaced and massed training protocols.
Alterations in Cortical Excitation and Inhibition in Genetic Mouse Models of Huntington's Disease
Authors: Cummings Damian M. , André Véronique M. , Uzgil Besim O. , Gee Steven M. , Fisher Yvette E. , Cepeda Carlos , Levine Michael S.
Published: August 2009

Previously, we identified progressive alterations in spontaneous EPSCs and IPSCs in the striatum of the R6/2 mouse model of Huntington's disease (HD). Medium-sized spiny neurons from these mice displayed a lower frequency of EPSCs, and a population of cells exhibited an increased frequency of IPSCs beginning at ∼40 d, a time point when the overt behavioral phenotype begins. The cortex provides the major excitatory drive to the striatum and is affected during disease progression. We examined spontaneous EPSCs and IPSCs of somatosensory cortical pyramidal neurons in layers II/III in slices from three different mouse models of HD: the R6/2, the YAC128, and the CAG140 knock-in. Results revealed that spontaneous EPSCs occurred at a higher frequency, and evoked EPSCs were larger in behaviorally phenotypic mice whereas spontaneous IPSCs were initially increased in frequency in all models and subsequently decreased in R6/2 mice after they displayed the typical R6/2 overt behavioral phenotype. Changes in miniature IPSCs and evoked IPSC paired-pulse ratios suggested altered probability of GABA release. Also, in R6/2 mice, blockade of GABAAreceptors induced complex discharges in slices and seizuresin vivoat all ages. In conclusion, altered excitatory and inhibitory inputs to pyramidal neurons in the cortex in HD appear to be a prevailing deficit throughout the development of the disease. Furthermore, the differences between synaptic phenotypes in cortex and striatum are important for the development of future therapeutic approaches, which may need to be targeted early in the development of the phenotype.
Associative Conditioning Tunes Transient Dynamics of Early Olfactory Processing
Authors: Fernandez Patricia C. , Locatelli Fernando F. , Person-Rennell Nicole , Deleo Gregory , Smith Brian H.
Published: August 2009

Odors evoke complex spatiotemporal responses in the insect antennal lobe (AL) and mammalian olfactory bulb. However, the behavioral relevance of spatiotemporal coding remains unclear. In the present work we combined behavioral analyses with calcium imaging of odor induced activity in the honeybee AL to evaluate the relevance of this temporal dimension in the olfactory code. We used a new way for evaluation of odor similarity of binary mixtures in behavioral studies, which involved testing whether a match of odor-sampling time is necessary between training and testing conditions for odor recognition during associative learning. Using graded changes in the similarity of the mixture ratios, we found high correlations between the behavioral generalization across those mixtures and a gradient of activation in AL output. Furthermore, short odor stimuli of 500 ms or less affected how well odors were matched with a memory template, and this time corresponded to a shift from a sampling-time-dependent to a sampling-time-independent memory. Accordingly, 375 ms corresponded to the time required for spatiotemporal AL activity patterns to reach maximal separation according to imaging studies. Finally, we compared spatiotemporal representations of binary mixtures in trained and untrained animals. AL activity was modified by conditioning to improve separation of odor representations. These data suggest that one role of reinforcement is to “tune” the AL such that relevant odors become more discriminable.
Transgenic Mice Lacking Serotonin Neurons Have Severe Apnea and High Mortality during Development
Authors: Hodges Matthew R. , Wehner Mackenzie , Aungst Jason , Smith Jeffrey C. , Richerson George B.
Published: August 2009

Central serotonin (5-HT) neurons modulate many vital brain functions, including respiratory control. Whether breathing depends critically on 5-HT neurons, or whether their influence is excitatory or inhibitory, remains controversial. Here we show that neonatalLmx1bflox/flox;ePet-Cre/+mice (also calledLmx1bf/f/pmice), which selectively lack serotonin neurons, display frequent and severe apnea lasting as long as 55 s. This was associated with a marked decrease in ventilation to less than one-half of normal. These respiratory abnormalities were most severe during the postnatal period, markedly improving by the time the pups were 2–4 weeks old. Despite the severe breathing dysfunction, many of these mice survived, but there was a high perinatal mortality, and those that survived had a decrease in growth rate until the age at which the respiratory defects resolved. Consistent with thesein vivoobservations, respiratory output was markedly reduced in isolated brainstem–spinal cord preparations from neonatalLmx1bf/f/pmice and completely blocked in perfused brain preparations from neonatal rats treated with selective antagonists of 5-HT2Aand neurokinin 1 (NK-1) receptors. The ventilatory deficits in neonatalLmx1bf/f/pmice were reversedin vitroandin vivowith agonists of 5-HT2Aand/or NK-1 receptors. These results demonstrate that ventilatory output in the neonatal period is critically dependent on serotonin neurons, which provide excitatory drive to the respiratory network via 5-HT2Aand NK-1 receptor activation. These findings provide insight into the mechanisms of sudden infant death syndrome, which has been associated with abnormalities of 5-HT neurons and of cardiorespiratory control.
Mechanisms of Primary Axonal Damage in a Viral Model of Multiple Sclerosis
Authors: Das Sarma Jayasri , Kenyon Lawrence C. , Hingley Susan T. , Shindler Kenneth S.
Published: August 2009

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Recent studies have demonstrated that significant axonal injury also occurs in MS patients and correlates with neurological dysfunction, but it is not known whether this neuronal damage is a primary disease process, or occurs only secondary to demyelination. In the current studies, neurotropic strains of mouse hepatitis virus (MHV) that induce meningitis, encephalitis, and demyelination in the CNS, an animal model of MS, were used to evaluate mechanisms of axonal injury. The pathogenic properties of genetically engineered isogenic spike protein recombinant demyelinating and nondemyelinating strains of MHV were compared. Studies demonstrate that a demyelinating strain of MHV causes concomitant axonal loss and macrophage-mediated demyelination. The mechanism of axonal loss and demyelination in MHV infection is dependent on successful transport of virus from gray matter to white matter using the MHV host attachment spike glycoprotein. Our data show that axonal loss and demyelination can be independent direct viral cytopathic events, and suggest that similar direct axonal damage may occur in MS. These results have important implications for the design of neuroprotective strategies for CNS demyelinating disease, and our model identifies the spike protein as a therapeutic target to prevent axonal transport of neurotropic viruses.
Serotonergic Modulation of Locomotion in Zebrafish—Endogenous Release and Synaptic Mechanisms
Authors: Gabriel Jens Peter , Mahmood Riyadh , Kyriakatos Alexandros , Söll Iris , Hauptmann Giselbert , Calabrese Ronald L. , El Manira Abdeljabbar
Published: August 2009

Serotonin (5-HT) plays an important role in shaping the activity of the spinal networks underlying locomotion in many vertebrate preparations. At larval stages in zebrafish, 5-HT does not change the frequency of spontaneous swimming; and it only decreases the quiescent period between consecutive swimming episodes. However, it is not known whether 5-HT exerts similar actions on the locomotor network at later developmental stages. For this, the effect of 5-HT on the fictive locomotor pattern of juvenile and adult zebrafish was analyzed. Bath-application of 5-HT (1–20 μm) reduced the frequency of the NMDA-induced locomotor rhythm. Blocking removal from the synaptic cleft with the reuptake inhibitor citalopram had similar effects, suggesting that endogenous serotonin is modulating the locomotor pattern. One target for this modulation was the mid-cycle inhibition during locomotion because the IPSPs recorded in spinal neurons during the hyperpolarized phase were increased both in amplitude and occurrence by 5-HT. Similar results were obtained for IPSCs recorded in spinal neurons clamped at the reversal potential of excitatory currents (0 mV). 5-HT also slows down the rising phase of the excitatory drive recorded in spinal cord neurons when glycinergic inhibition is blocked. These results suggest that the decrease in the locomotor burst frequency induced by 5-HT is mediated by a potentiation of mid-cycle inhibition combined with a delayed onset of the subsequent depolarization.
The Bed Nucleus of the Stria Terminalis Mediates Inter-individual Variations in Anxiety and Fear
Authors: Duvarci Sevil , Bauer Elizabeth P. , Paré Denis
Published: August 2009

While learning to fear stimuli that predict danger promotes survival, the inability to inhibit fear to inappropriate cues leads to a pernicious cycle of avoidance behaviors. Previous studies have revealed large inter-individual variations in fear responding with clinically anxious humans exhibiting a tendency to generalize learned fear to safe stimuli or situations. To shed light on the origin of these inter-individual variations, we subjected rats to a differential auditory fear conditioning paradigm in which one conditioned auditory stimulus (CS+) was paired to footshocks whereas a second (CS−) was not. We compared the behavior of rats that received pretraining excitotoxic lesions of the bed nucleus of the stria terminalis (BNST) to that of sham rats. Sham rats exhibit a continuum of anxious/fearful behaviors. At one end of the continuum were rats that displayed a poor ability to discriminate between the CS+ and CS−, high contextual freezing, and an anxiety-like trait in the elevated plus maze (EPM). At the other end were rats that display less fear generalization to the CS−, lower freezing to context, and a nonanxious trait in the EPM. Although BNST-lesioned rats acquired similarly high levels of conditioned fear to the CS+, they froze less than sham rats to the CS−. In fact, BNST-lesioned rats behaved like sham rats with high discriminative abilities in that they exhibited low contextual fear and a nonanxious phenotype in the EPM. Overall, this suggests that inter-individual variations in fear generalization and anxiety phenotype are determined by BNST influences on the amygdala and/or its targets.