bluuebunny/crossref_metadata_2025 huggingface dataset:
Confidence from uncertainty - A multi-target drug screening method from robust control theory
Authors: Luni Camilla , Shoemaker Jason E , Sanft Kevin R , Petzold Linda R , Doyle Francis J
Published: November 2010

Background

Robustness is a recognized feature of biological systems that evolved as a defence to environmental variability. Complex diseases such as diabetes, cancer, bacterial and viral infections, exploit the same mechanisms that allow for robust behaviour in healthy conditions to ensure their own continuance. Single drug therapies, while generally potent regulators of their specific protein/gene targets, often fail to counter the robustness of the disease in question. Multi-drug therapies offer a powerful means to restore disrupted biological networks, by targeting the subsystem of interest while preventing the diseased network from reconciling through available, redundant mechanisms. Modelling techniques are needed to manage the high number of combinatorial possibilities arising in multi-drug therapeutic design, and identify synergistic targets that are robust to system uncertainty.

Results

We present the application of a method from robust control theory, Structured Singular Value or μ- analysis, to identify highly effective multi-drug therapies by using robustness in the face of uncertainty as a new means of target discrimination. We illustrate the method by means of a case study of a negative feedback network motif subject to parametric uncertainty.

Conclusions

The paper contributes to the development of effective methods for drug screening in the context of network modelling affected by parametric uncertainty. The results have wide applicability for the analysis of different sources of uncertainty like noise experienced in the data, neglected dynamics, or intrinsic biological variability.
Toll-like receptor 2 agonists inhibit human fibrocyte differentiation
Authors: Maharjan Anu S , Pilling Darrell , Gomer Richard H
Published: November 2010

Background

In healing wounds, some monocytes enter the wound and differentiate into fibroblast-like cells called fibrocytes. Since Toll-like receptors (TLRs) are present on monocytes, and pathogens that can infect a wound have and/or release TLR agonists, we examined whether TLR agonists affect fibrocyte differentiation.

Results

When human peripheral blood mononuclear cells (PBMCs) were cultured with TLR3, TLR4, TLR5, TLR7, TLR8 or TLR9 agonists, there was no significant effect on fibrocyte differentiation, even though enhanced extracellular tumor necrosis factor (TNF)-α accumulation and/or increased cell surface CD86 or major histocompatibility complex (MHC) class II levels were observed. However, all TLR2 agonists tested inhibited fibrocyte differentiation without any significant effect on cell survival. Adding TLR2 agonists to purified monocytes had no effect on fibrocyte differentiation. However, some TLR2 agonists caused PBMCs to secrete a factor that inhibits the differentiation of purified monocytes into fibrocytes. This factor is not interferon (IFN)-α, IFN-γ, interleukin (IL)-12, aggregated immunoglobulin G (IgG) or serum amyloid P (SAP), factors known to inhibit fibrocyte differentiation. TLR2 agonist-treated PBMCs secrete low levels of IL-6, TNF-α, IFN-γ, granulocyte colony-stimulating factor and tumor growth factor β1, but combinations of these factors had no effect on fibrocyte differentiation from purified monocytes.

Conclusions

Our results indicate that TLR2 agonists indirectly inhibit fibrocyte differentiation and that, for some TLR2 agonists, this inhibition involves other cell types in the PBMC population secreting an unknown factor that inhibits fibrocyte differentiation. Together, these data suggest that the presence of some bacterial signals can inhibit fibrocyte differentiation and may thus slow wound closure.
Diagnostic accuracy of existing methods for identifying diabetic foot ulcers from inpatient and outpatient datasets
Authors: Sohn Min‐Woong , Budiman‐Mak Elly , Stuck Rodney M , Siddiqui Farah , Lee Todd A
Published: November 2010

Background

As the number of persons with diabetes is projected to double in the next 25 years in the US, an accurate method of identifying diabetic foot ulcers in population‐based data sources are ever more important for disease surveillance and public health purposes. The objectives of this study are to evaluate the accuracy of existing methods and to propose a new method.

Methods

Four existing methods were used to identify all patients diagnosed with a foot ulcer in a Department of Veterans Affairs (VA) hospital from the inpatient and outpatient datasets for 2003. Their electronic medical records were reviewed to verify whether the medical records positively indicate presence of a diabetic foot ulcer in diagnoses, medical assessments, or consults. For each method, five measures of accuracy and agreement were evaluated using data from medical records as the gold standard.

Results

Our medical record reviews show that all methods had sensitivity > 92% but their specificity varied substantially between 74% and 91%. A method used in Harrington et al. (2004) was the most accurate with 94% sensitivity and 91% specificity and produced an annual prevalence of 3.3% among VA users with diabetes nationwide. A new and simpler method consisting of two codes (707.1× and 707.9) shows an equally good accuracy with 93% sensitivity and 91% specificity and 3.1% prevalence.

Conclusions

Our results indicate that the Harrington and New methods are highly comparable and accurate. We recommend the Harrington method for its accuracy and the New method for its simplicity and comparable accuracy.
Efficacy and safety of peginterferon alfa‐2a + RBV in cHCV/HIV‐ vs cHCV‐infected patients: interim analysis of a multicenter German cohort
Authors: Baumgarten A , Lutz T , Kreckel P , Wellmann E , Alshuth U , Mauss S , Rockstroh J
Published: November 2010

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK
Lersivirine: a new NNRTI active across HIV‐1 subtypes with a unique resistance profile
Authors: Mori J , Westby M , Tawadrous M , van der Ryst E , Charles C
Published: November 2010

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK
Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients
Authors: Krishnan Anand , Ochola Judith , Mundy Julie , Jones Mark , Kruger Peter , Duncan Emma , Venkatesh Bala
Published: November 2010

Introduction

Recent reports have highlighted the prevalence of vitamin D deficiency and suggested an association with excess mortality in critically ill patients. Serum vitamin D concentrations in these studies were measured following resuscitation. It is unclear whether aggressive fluid resuscitation independently influences serum vitamin D.

Methods

Nineteen patients undergoing cardiopulmonary bypass were studied. Serum 25(OH)D3, 1α,25(OH)2D3, parathyroid hormone, C-reactive protein (CRP), and ionised calcium were measured at five defined timepoints: T1 - baseline, T2 - 5 minutes after onset of cardiopulmonary bypass (CPB) (time of maximal fluid effect), T3 - on return to the intensive care unit, T4 - 24 hrs after surgery and T5 - 5 days after surgery. Linear mixed models were used to compare measures at T2-T5 with baseline measures.

Results

Acute fluid loading resulted in a 35% reduction in 25(OH)D3 (59 ± 16 to 38 ± 14 nmol/L, P < 0.0001) and a 45% reduction in 1α,25(OH)2D3 (99 ± 40 to 54 ± 22 pmol/L P < 0.0001) and i(Ca) (P < 0.01), with elevation in parathyroid hormone (P < 0.0001). Serum 25(OH)D3 returned to baseline only at T5 while 1α,25(OH)2D3 demonstrated an overshoot above baseline at T5 (P < 0.0001). There was a delayed rise in CRP at T4 and T5; this was not associated with a reduction in vitamin D levels at these time points.

Conclusions

Hemodilution significantly lowers serum 25(OH)D3 and 1α,25(OH)2D3, which may take up to 24 hours to resolve. Moreover, delayed overshoot of 1α,25(OH)2D3 needs consideration. We urge caution in interpreting serum vitamin D in critically ill patients in the context of major resuscitation, and would advocate repeating the measurement once the effects of the resuscitation have abated.
The Rho kinase Rock2b establishes anteroposterior asymmetry of the ciliated Kupffer's vesicle in zebrafish
Authors: Wang Guangliang , Cadwallader Adam B. , Jang Duck Soo , Tsang Michael , Yost H. Joseph , Amack Jeffrey D.
Published: November 2010

The vertebrate body plan features a consistent left-right (LR) asymmetry of internal organs. In several vertebrate embryos, motile cilia generate an asymmetric fluid flow that is necessary for normal LR development. However, the mechanisms involved in orienting LR asymmetric flow with previously established anteroposterior (AP) and dorsoventral (DV) axes remain poorly understood. In zebrafish, asymmetric flow is generated in Kupffer's vesicle (KV). The cellular architecture of KV is asymmetric along the AP axis, with more ciliated cells densely packed into the anterior region. Here, we identify a Rho kinase gene, rock2b, which is required for normal AP patterning of KV and subsequent LR development in the embryo. Antisense depletion of rock2b in the whole embryo or specifically in the KV cell lineage perturbed asymmetric gene expression in lateral plate mesoderm and disrupted organ LR asymmetries. Analyses of KV architecture demonstrated that rock2b knockdown altered the AP placement of ciliated cells without affecting cilia number or length. In control embryos, leftward flow across the anterior pole of KV was stronger than rightward flow at the posterior end, correlating with the normal AP asymmetric distribution of ciliated cells. By contrast, rock2b knockdown embryos with AP patterning defects in KV exhibited randomized flow direction and equal flow velocities in the anterior and posterior regions. Live imaging of Tg(dusp6:memGFP)pt19 transgenic embryos that express GFP in KV cells revealed that rock2b regulates KV cell morphology. Our results suggest a link between AP patterning of the ciliated Kupffer's vesicle and LR patterning of the zebrafish embryo.
Shared molecular mechanisms regulate multiple catenin proteins: canonical Wnt signals and components modulate p120-catenin isoform-1 and additional p120 subfamily members
Authors: Hong Ji Yeon , Park Jae-il , Cho Kyucheol , Gu Dongmin , Ji Hong , Artandi Steven E. , McCrea Pierre D.
Published: November 2010

Wnt signaling pathways have fundamental roles in animal development and tumor progression. Here, employing Xenopus embryos and mammalian cell lines, we report that the degradation machinery of the canonical Wnt pathway modulates p120-catenin protein stability through mechanisms shared with those regulating β-catenin. For example, in common with β-catenin, exogenous expression of destruction complex components, such as GSK3β and axin, promotes degradation of p120-catenin. Again in parallel with β-catenin, reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-catenin degradation. At the primary sequence level, we resolved conserved GSK3β phosphorylation sites in the amino-terminal region of p120-catenin present exclusively in isoform-1. Point-mutagenesis of these residues inhibited the association of destruction complex components, such as those involved in ubiquitylation, resulting in stabilization of p120-catenin. Functionally, in line with predictions, p120 stabilization increased its signaling activity in the context of the p120–Kaiso pathway. Importantly, we found that two additional p120-catenin family members, ARVCF-catenin and δ-catenin, associate with axin and are degraded in its presence. Thus, as supported using gain- and loss-of-function approaches in embryo and cell line systems, canonical Wnt signals appear poised to have an impact upon a breadth of catenin biology in vertebrate development and, possibly, human cancers.
RAGE–TXNIP axis is required for S100B-promoted Schwann cell migration, fibronectin expression and cytokine secretion
Authors: Sbai Oualid , Devi Takhellambam S. , Melone Mariarosa A. B. , Feron Francois , Khrestchatisky Michel , Singh Lalit P. , Perrone Lorena
Published: November 2010

During peripheral nerve injury, Schwann cells (SCs) adopt a migratory phenotype and remodel the extracellular matrix and provide a supportive activity for neuron regeneration. SCs synthesize neurotrophic factors and cytokines that are crucial for the repair of the injured nerve. The receptor for advanced glycation end products (RAGE) and its ligand S100B, which are secreted by SCs, are required for the repair of the injured peripheral nerve in vivo. However, the precise intracellular pathways involved have not been completely elucidated. Here, we show that RAGE-induced S100B secretion involves the recruitment of S100B in lipid rafts and caveolae. Moreover, we demonstrate for the first time that RAGE induces the expression of thioredoxin interacting protein (TXNIP) in SCs and the injured sciatic nerve in vivo. TXNIP is involved in the activation of p38 MAPK, CREB and NFκB in SCs. TXNIP silencing partially inhibits RAGE-induced SC migration and completely abolishes RAGE-induced fibronectin and IL-1β expression. Our results support a model in which TXNIP mediates in part RAGE-induced SC migration and is required for the expression of provisional ECM and pro-inflammatory IL-1β. We provide new insight on the role of the SC RAGE–TXNIP axis in the repair of injured peripheral nerves.
S-RNase disrupts tip-localized reactive oxygen species and induces nuclear DNA degradation in incompatible pollen tubes of Pyrus pyrifolia
Authors: Wang Chun-Lei , Wu Jun , Xu Guo-Hua , Gao Yong-bin , Chen Gong , Wu Ju-You , Wu Hua-qing , Zhang Shao-Ling
Published: November 2010

Pear (Pyrus pyrifolia L.) has an S-RNase-based gametophytic self-incompatibility (SI) mechanism, and S-RNase has also been implicated in the rejection of self-pollen and genetically identical pollen. However, RNA degradation might be only the beginning of the SI response, not the end. Recent in vitro studies suggest that S-RNase triggers mitochondrial alteration and DNA degradation in the incompatible pollen tube of Pyrus pyrifolia, and it seems that a relationship exists between self S-RNase, actin depolymerization and DNA degradation. To further uncover the SI response in pear, the relationship between self S-RNase and tip-localized reactive oxygen species (ROS) was evaluated. Our results show that S-RNase specifically disrupted tip-localized ROS of incompatible pollen tubes via arrest of ROS formation in mitochondria and cell walls. The mitochondrial ROS disruption was related to mitochondrial alteration, whereas cell wall ROS disruption was related to a decrease in NADPH. Tip-localized ROS disruption not only decreased the Ca2+ current and depolymerized the actin cytoskeleton, but it also induced nuclear DNA degradation. These results indicate that tip-localized ROS disruption occurs in Pyrus pyrifolia SI. Importantly, we demonstrated nuclear DNA degradation in the incompatible pollen tube after pollination in vivo. This result validates our in vitro system in vivo.
Mechanics and energetics of step-to-step transitions isolated from human walking
Authors: Soo Caroline H. , Donelan J. Maxwell
Published: November 2010

We isolated step-to-step transitions from other contributors to walking mechanics using a cyclical rocking task and then examined the contribution of individual joints to the total work required to redirect the velocity of the center of mass (COM). Nine participants were instructed to rock backward and forward in the sagittal plane, eliminating the need to swing the legs and progress forward. To systematically increase the required work, we increased step length from 60 to 100% of leg length, keeping rocking frequency constant. The individual limbs method quantified the COM work and the joint power method apportioned the COM work among its various sources. As predicted by a physics-based model, we found that work in rocking was performed mainly during the step-to-step transitions and increased strongly with step length. We also found that increases in the average COM work rate exacted a proportional metabolic cost. The similar patterns of COM work and COM work rate during rocking and walking support the use of rocking to isolate the mechanics of step-to-step transitions. We found that the ankle was the main joint contributing to the positive work required to redirect the COM velocity during forward rocking. At the longest length, it accounted for 88% of the work performed by the trailing leg joints. Interestingly, the summed contribution of ankle, knee and hip joint work accounted for only 39% of the front leg negative COM work during the forward transition, suggesting that most of the collision work is performed by passive tissue.
Presynaptic Ca2+ stores contribute to odor-induced responses in Drosophila olfactory receptor neurons
Authors: Murmu Meena Sriti , Stinnakre Jacques , Martin Jean-René
Published: November 2010

In both vertebrates and invertebrates, olfactory receptor neurons (ORNs) respond to several odors. They also adapt to stimulus variations, and this is considered to be a simple form of non-associative learning and neuronal plasticity. Different mechanisms have been described to support neuronal and/or synaptic plasticity. For example in vertebrates, presynaptic Ca2+ stores relying on either the ryanodine receptor (RyR) or the inositol (1,4,5)-trisphosphate receptor (InsP3R) have been reported to participate in synaptic transmission, in hippocampal pyramidal neurons, and in basket cell–Purkinje cell synapses. However, in invertebrates, especially in sensory neurons such as ORNs, similar mechanisms have not yet been detected. In this study, using Drosophila and taking advantage of an in vivo bioluminescence Ca2+-imaging technique in combination with genetic and pharmacological tools, first we show that the GFP–aequorin Ca2+ sensor is sensitive enough to detect odor-induced responses of various durations. Second, we show that for a relatively long (5 s) odor application, odor-induced Ca2+ responses occurring in the axon terminals of ORNs involve intracellular Ca2+ stores. This response is decreased by specifically targeting InsP3R or RyR by RNAi, or application of the specific blockers thapsigargin or ryanodine, suggesting that Ca2+ stores serve to amplify the presynaptic signal. Furthermore, we show that disrupting the intracellular Ca2+ stores in the ORNs has functional consequences since InsP3R- or RyR-RNAi expressing flies were defective in olfactory behavior. Altogether, our results indicate that for long odor applications in Drosophila, the olfactory response depends on intracellular Ca2+ stores within the axon terminals of the ORNs.
Particle size of apoB-48 carrying lipoproteins in remnant lipoproteins isolated from postprandial plasma
Authors: Nakano Takamitsu , Tanaka Akira , Okazaki Mitsuyo , Tokita Yoshiharu , Nagamine Takeaki , Nakajima Katsuyuki
Published: November 2010

Background

Particle size of apoB-48 carrying lipoproteins in remnant-like lipoprotein particles (RLP) in postprandial plasma has not been well characterized.

Methods

Plasma lipids, lipoproteins and apolipoproteins in 12 healthy subjects were analysed after an oral fat load. RLP isolated by immunoaffinity gel from plasma of a normolipidaemic and a hyperlipidaemic subject in four hours after an oral fat load was fractionated by high-performance liquid chromatography (HPLC) and monitored by total cholesterol (TC), triglycerides (TG), apoB-48 and apoB-100.

Results

TC, low-density lipoprotein (LDL)-C and apoB did not change after an oral fat load, while TG, RLP-C, RLP-TG and apoB-48 increased significantly in postprandial plasma. HPLC profiles monitored by TC and TG revealed that major lipoproteins increased in RLP after an oral fat load was VLDL size particles. The percentage of RLP-TG in total TG and the ratio of RLP-TG/RLP-C were significantly increased in four hours after an oral fat load compared with the fasting state ( P < 0.01). RLP in four hours after an oral fat load fractionated by HPLC and monitored by TC, TG, apoB-48 and apoB-100 revealed that VLDL size or smaller particles were the major lipoproteins.

Conclusions

ApoB-48 carrying lipoproteins in RLP isolated from a normolipidaemic and a hyperlipidaemic subject after an oral fat load showed a similar particle size with apoB-100 carrying VLDL remnants. Therefore, the most apoB-48 carrying particles found in postprandial RLP can be classified as CM remnants. The majority of remnants in the postprandial state were not CM remnants, but VLDL remnants.
Analysis of Pharmaceutical Safety-Related Regulatory Actions in Japan: Do Tradeoffs Exist Between Safer Drugs and Launch Delay?
Authors: Yamada Toru , Kusama Makiko , Hirai Yuka , Arnold Frank , Sugiyama Yuichi , Ono Shunsuke
Published: November 2010

Background:

Prediction and management of drug safety is a global regulatory issue. Safety-related regulatory actions (SRRAs) are taken mostly when unexpected adverse drug reactions occur. Currently, Japan is reconciled to delayed access to new drugs (ie, launch delay compared to Western countries), but may have been benefiting by free-riding on safety data accumulated in other countries prior to Japanese launch.

Objective:

To identify factors that are significantly associated with SRRAs, and to discuss the challenges that Japan might have to face with increasing access to new drugs.

Methods:

The SRRAs of 135 new drugs approved from January 2000 to December 2005 were analyzed to investigate association with launch lag, company and drug characteristics, market size, submission data, and regulatory status. SRRAs were measured in terms of the number of emergency safety information notifications and official safety instructions issued by the Japanese regulatory agency within 3 years after approval. A negative binomial distribution model was used for regression analysis.

Results:

Longer launch lags and presence of drugs with similar modes of action were associated with fewer SRRAs. Bridging strategy showed increased SRRAs. No significant association was observed between SRRAs and the subject number in clinical data packages. Occurrence of SRRAs was varied among development strategy, preceding products, and regional regulations.

Conclusions:

The occurrence of SRRAs was associated with the accumulation of both foreign and domestic postmarketing evidence rather than with clinical trial data upon launch. Considering the paradigm shift to simultaneous global drug development and filing for regulatory approval, this study indicates the importance of intensive data collection in the early postmarketing phase and use of safety information in early markets. However, even if we would be sufficiently cautious about safety risks of new drugs, a population that enjoys first-in-class drugs probably has to bear the risks.
First Report of Lamotrigine-Induced Drug Rash with Eosinophilia and Systemic Symptoms Syndrome with Pancreatitis
Authors: Roquin Guillaume , Peres Marine , Lerolle Nicolas , Dib Nina , Mercat Alain , Croue Anne , Augusto Jean-François
Published: November 2010

Objective:

To report a case of lamotrigine-induced drug rash with eosinophilia and systemic symptoms (DRESS) syndrome with pancreatitis as the initial visceral involvement.

Case Summary:

A 75-year-old man was admitted to the local hospital for generalized tonic-clonic seizures. Results of the clinical examination and neurologic investigations were unremarkable. Lamotrigine treatment was initiated and the patient was discharged a few days later. Forty days after lamotrigine initiation, he developed an exanthematous maculopapular rash with fever, peripheral lymphadenopathies, and hypereosinophilia. Lamotrigine hypersensitivity was suspected and the drug was suspended on day 45. On day 47, the patient presented with acute abdominal pain with an elevated lipase level. Acute pancreatitis was confirmed on computed tomography scan. The patient's condition worsened and he was transferred to the intensive care unit with multiorgan failure. The diagnosis of lamotrigine-induced DRESS syndrome was confirmed by a compatible skin histology and concomitant human herpesvirus-6 infection.

Discussion:

This observation has 2 points of interest. First, pancreatic toxicity of lamotrigine has been rarely reported in the literature. Secondly, pancreatitis is uncommon at the early stage of DRESS syndrome. Only 1 other case of DRESS syndrome, secondary to allopurinol, reports pancreatitis along with an Epstein-Barr virus infection. The Naranjo probability scale indicated a probable causality between lamotrigine and DRESS syndrome in this patient.

Conclusions:

This is the first reported case of lamotrigine-induced DRESS syndrome with pancreatitis as the initial visceral involvement. Clinicians should be aware of this mode of presentation of DRESS syndrome.
EphrinBs Regulate d-Serine Synthesis and Release in Astrocytes
Authors: Zhuang Zhiye , Yang Bing , Theus Michelle H. , Sick Justin T. , Bethea John R. , Sick Thomas J. , Liebl Daniel J.
Published: November 2010

There is growing evidence that astrocytes play critical roles in neuron-glial interactions at the synapse. Astrocytes are believed to regulate presynaptic and postsynaptic structures and functions, in part, by the release of gliotransmitters such as glutamate, ATP, andd-serine; however, little is known of how neurons and astrocytes communicate to regulate these processes. Here, we investigated a family of transmembrane proteins called ephrinBs and Eph receptors that are expressed in the synapse and are known to regulate synaptic transmission and plasticity. In addition to their presence on CA1 hippocampal neurons, we determined that ephrins and Eph receptors are also expressed on hippocampal astrocytes. Stimulation of hippocampal astrocytes with soluble ephrinB3, known to be expressed on CA1 postsynaptic dendrites, enhancedd-serine synthesis and release in culture. Conversely, ephrinB3 had no effect ond-serine release from astrocytes deficient in EphB3 and EphA4, which are the primary receptors for ephrinB3. Eph receptors mediate this response through interactions with PICK1 (protein interacting with C-kinase) and by dephosphorylating protein kinase C α to activate the conversion ofl-serine tod-serine by serine racemase. These findings are supportedin vivo, where reducedd-serine levels and synaptic transmissions are observed in the absence of EphB3 and EphA4. These data support a role for ephrins and Eph receptors in regulating astrocyte gliotransmitters, which may have important implications on synaptic transmission and plasticity.
Selective Ablations Reveal That Orbital and Lateral Prefrontal Cortex Play Different Roles in Estimating Predicted Reward Value
Authors: Simmons Janine M. , Minamimoto Takafumi , Murray Elisabeth A. , Richmond Barry J.
Published: November 2010

Subregions of prefrontal cortex are important for estimating reward values and using these values to guide behavior. The present studies directly tested whether orbital prefrontal cortex (O-PFC) and lateral prefrontal cortex (L-PFC) are necessary for evaluating trial-to-trial changes in the reward values predicted by visual cues. We have compared intact rhesus monkeys, those with bilateral O-PFC lesions (n= 3), and those with bilateral L-PFC lesions (n= 3). We used three versions of a visually cued color discrimination task: we varied reward size, delay to reward, or both. O-PFC lesions altered estimations of predicted reward value in all versions of the task. L-PFC lesions disrupted performance only when both reward size and delay to reward were varied together. Neither lesion directly affected basic internal drive states (satiation curves). Our results suggest that O-PFC is essential for establishing independent, context-specific scales with which predicted reward values are measured. L-PFC appears necessary for integration of predicted reward value across these different scales.
Implication of Kir4.1 Channel in Excess Potassium Clearance: AnIn VivoStudy on Anesthetized Glial-Conditional Kir4.1 Knock-Out Mice
Authors: Chever Oana , Djukic Biljana , McCarthy Ken D. , Amzica Florin
Published: November 2010

The Kir4.1 channel is crucial for the maintenance of the resting membrane potential of glial cells, and it is believed to play a main role in the homeostasis of extracellular potassium. To understand its importance in these two phenomena, we have measuredin vivothe variations of extracellular potassium concentration ([K+]o) (with potassium-sensitive microelectrodes) and membrane potential of glial cells (with sharp electrodes) during stimulations in wild-type (WT) mice and glial-conditional knock-out (cKO) Kir4.1 mice. The conditional knockout was driven by the human glial fibrillary acidic protein promoter,gfa2. Experiments were performed in the hippocampus of anesthetized mice (postnatal days 17–24). Low level stimulation (<20 stimuli, 10 Hz) induced a moderated increase of [K+]o(<2 mmincrease) in both WT and cKO mice. However, cKO mice exhibited slower recovery of [K+]olevels. With long-lasting stimulation (300 stimuli, 10 Hz), [K+]oin WT and cKO mice displayed characteristic ceiling level (>2 mmincrease) and recovery undershoot, with a more pronounced and prolonged undershoot in cKO mice. In addition, cKO glial cells were more depolarized, and, in contrast to those from WT mice, their membrane potential did not follow the stimulation-induced [K+]ochanges, reflecting the loss of their high potassium permeability. Ourin vivoresults support the role of Kir4.1 in setting the membrane potential of glial cells and its contribution to the glial potassium permeability. In addition, our data confirm the necessity of the Kir4.1 channel for an efficient uptake of K+by glial cells.
Retrieval of Associative Information Congruent with Prior Knowledge Is Related to Increased Medial Prefrontal Activity and Connectivity
Authors: van Kesteren Marlieke T. R. , Rijpkema Mark , Ruiter Dirk J. , Fernández Guillén
Published: November 2010

We remember information that is congruent instead of incongruent with prior knowledge better, but the underlying neural mechanisms related to this enhancement are still relatively unknown. Recently, this memory enhancement due to a prior schema has been suggested to be based on rapid neocortical assimilation of new information, related to optimized encoding and consolidation processes. The medial prefrontal cortex (mPFC) is thought to be important in mediating this process, but its role in retrieval of schema-consistent information is still unclear. In this study, we regarded multisensory congruency with prior knowledge as a schema and used this factor to probe retrieval of consolidated memories either consistent or inconsistent with prior knowledge. We conducted a visuotactile learning paradigm in which participants studied visual motifs randomly associated with word–fabric combinations that were either congruent or incongruent with common knowledge. The next day, participants were scanned using functional magnetic resonance imaging while their memory was tested. Congruent associations were remembered better than incongruent ones. This behavioral finding was parallelized by stronger retrieval-related activity in and connectivity between medial prefrontal and left somatosensory cortex. Moreover, we found a positive across-subject correlation between the connectivity enhancement and the behavioral congruency effect. These results show that successful retrieval of congruent compared to incongruent visuotactile associations is related to enhanced processing in an mPFC–somatosensory network, and support the hypothesis that new information that fits a preexisting schema is more rapidly assimilated in neocortical networks, a process that may be mediated, at least in part, by the mPFC.
Calcium Regulates Vesicle Replenishment at the Cone Ribbon Synapse
Authors: Babai Norbert , Bartoletti Theodore M. , Thoreson Wallace B.
Published: November 2010

Cones release glutamate-filled vesicles continuously in darkness, and changing illumination modulates this release. Because sustained release in darkness is governed by vesicle replenishment rates, we analyzed how cone membrane potential regulates replenishment. Synaptic release from cones was measured by recording postsynaptic currents inAmbystoma tigrinumhorizontal or OFF bipolar cells evoked by depolarization of simultaneously voltage-clamped cones. We measured replenishment after attaining a steady state between vesicle release and replenishment using trains of test pulses. Increasing Ca2+currents (ICa) by changing the test step from −30 to −10 mV increased replenishment. Lengthening −30 mV test pulses to match the Ca2+influx during 25 ms test pulses to −10 mV produced similar replenishment rates. Reducing Ca2+driving force by using test steps to +30 mV slowed replenishment. Using UV flashes to reverse inhibition ofICaby nifedipine accelerated replenishment. Increasing [Ca2+]iby flash photolysis of caged Ca2+also accelerated replenishment. Replenishment, but not the initial burst of release, was enhanced by using an intracellular Ca2+buffer of 0.5 mmEGTA rather than 5 mmEGTA, and diminished by 1 mmBAPTA. This suggests that although release and replenishment exhibited similar Ca2+dependencies, release sites are <200 nm from Ca2+channels but replenishment sites are >200 nm away. Membrane potential thus regulates replenishment by controlling Ca2+influx, principally by effects on replenishment mechanisms but also by altering releasable pool size. This in turn provides a mechanism for converting changes in light intensity into changes in sustained release at the cone ribbon synapse.
Activation of Extrasynaptic, But Not Synaptic, NMDA Receptors Modifies Amyloid Precursor Protein Expression Pattern and Increases Amyloid-β Production
Authors: Bordji Karim , Becerril-Ortega Javier , Nicole Olivier , Buisson Alain
Published: November 2010

Calcium is a key mediator controlling essential neuronal functions depending on electrical activity. Altered neuronal calcium homeostasis affects metabolism of amyloid precursor protein (APP), leading to increased production of β-amyloid (Aβ), and contributing to the initiation of Alzheimer's disease (AD). A linkage between excessive glutamate receptor activation and neuronal Aβ release was established, and recent reports suggest that synaptic and extrasynaptic NMDA receptor (NMDAR) activation may have distinct consequences in plasticity, gene regulation, and neuronal death. Here, we report for the first time that prolonged activation of extrasynaptic NMDAR, but not synaptic NMDAR, dramatically increased the neuronal production of Aβ. This effect was preceded by a shift from APP695 to Kunitz protease inhibitory domain (KPI) containing APPs (KPI-APPs), isoforms exhibiting an important amyloidogenic potential. Conversely, after synaptic NMDAR activation, we failed to detect any KPI-APP expression and neuronal Aβ production was not modified. Calcium imaging data showed that intracellular calcium concentration after extrasynaptic NMDAR stimulation was lower than after synaptic activation. This suggests distinct signaling pathways for each pool of receptors. We found that modification of neuronal APP expression pattern triggered by extrasynaptic NMDAR activation was regulated at an alternative splicing level involving calcium-/calmodulin-dependent protein kinase IV, but overall APP expression remained identical. Finally, memantine dose-dependently inhibited extrasynaptic NMDAR-induced KPI-APPs expression as well as neuronal Aβ release. Altogether, these data suggest that a chronic activation of extrasynaptic NMDAR promotes amyloidogenic KPI-APP expression leading to neuronal Aβ release, representing a causal risk factor for developing AD.
Pyramidal Neuron Conductance State Gates Spike-Timing-Dependent Plasticity
Authors: Delgado Jary Y. , Gómez-González José F. , Desai Niraj S.
Published: November 2010

Neocortical neuronsin vivoprocess each of their individual inputs in the context of ongoing synaptic background activity, produced by the thousands of presynaptic partners a typical neuron has. Previous work has shown that background activity affects multiple aspects of neuronal and network function. However, its effect on the induction of spike-timing dependent plasticity (STDP) is not clear. Here we report that injections of simulated background conductances (produced by a dynamic-clamp system) into pyramidal cells in rat brain slices selectively reduced the magnitude of timing-dependent synaptic potentiation while leaving the magnitude of timing-dependent synaptic depression unchanged. The conductance-dependent suppression also sharpened the STDP curve, with reliable synaptic potentiation induced only when EPSPs and action potentials (APs) were paired within 8 ms of each other. Dual somatic and dendritic patch recordings suggested that the deficit in synaptic potentiation arose from shunting of dendritic EPSPs and APs. Using a biophysically detailed computational model, we were not only able to replicate the conductance-dependent shunting of dendritic potentials, but show that synaptic background can truncate calcium dynamics within dendritic spines in a way that affects potentiation more strongly than depression. This conductance-dependent regulation of synaptic plasticity may constitute a novel homeostatic mechanism that can prevent the runaway synaptic potentiation to which Hebbian networks are vulnerable.
Neural Representations of Relevant and Irrelevant Features in Perceptual Decision Making
Authors: Kayser Andrew S. , Erickson Drew T. , Buchsbaum Bradley R. , D'Esposito Mark
Published: November 2010

Although perceptual decision making activates a network of brain areas involved in sensory, integrative, and motor functions, circuit activity can clearly be modulated by factors beyond the stimulus. Of particular interest is to understand how the network is modulated by top-down factors such as attention. Here, we demonstrate in a motion coherence task that selective attention produces marked changes in the blood oxygen level-dependent (BOLD) response in a subset of regions within a human perceptual decision-making circuit. Specifically, when motion is attended, the BOLD response decreases with increasing motion coherence in many regions, including the motion-sensitive area MT+, the intraparietal sulcus, and the inferior frontal sulcus. However, when motion is ignored, the negative parametric response in a subset of this circuit becomes positive. Through both modeling and connectivity analyses, we demonstrate that this inversion both reflects a top-down influence and segregates attentional from accumulation regions, thereby permitting us to further delineate the contributions of different regions to the perceptual decision.
Orchestration of Stepwise Synaptic Growth by K+and Ca2+Channels inDrosophila
Authors: Lee Jihye , Wu Chun-Fang
Published: November 2010

Synapse formation is tightly associated with neuronal excitability. We found striking synaptic overgrowth caused byDrosophilaK+-channel mutations of theseizureandslowpokegenes, encoding Erg and Ca2+-activated large-conductance (BK) channels, respectively. These mutants display two distinct patterns of “satellite” budding from larval motor terminus synaptic boutons. Double-mutant analysis indicates that BK and Erg K+channels interact with separate sets of synaptic proteins to affect distinct growth steps. Post-synaptic L-type Ca2+channels, Dmca1D, and PSD-95-like scaffold protein, Discs large, are required for satellite budding induced byslowpokeandseizuremutations. Pre-synapticcacophonyCa2+channels and the NCAM-like adhesion molecule, Fasciclin II, take part in a maturation step that is partially arrested byseizuremutations. Importantly,slowpokeandseizuresatellites were both suppressed byrutabagamutations that disrupt Ca2+/CaM-dependent adenylyl cyclase, demonstrating a convergence of K+channels of different functional categories in regulation of excitability-dependent Ca2+influx for triggering cAMP-mediated growth plasticity.
Kinesin I Transports Tetramerized Kv3 Channels through the Axon Initial Segment via Direct Binding
Authors: Xu Mingxuan , Gu Yuanzheng , Barry Joshua , Gu Chen
Published: November 2010

Precise targeting of various voltage-gated ion channels to proper membrane domains is crucial for their distinct roles in neuronal excitability and synaptic transmission. How each channel protein is transported within the cytoplasm is poorly understood. Here, we report that KIF5/kinesin I transports Kv3.1 voltage-gated K+(Kv) channels through the axon initial segment (AIS) via direct binding. First, we have identified a novel interaction between Kv3.1 and KIF5, confirmed by immunoprecipitation from mouse brain lysates and by pull-down assays with exogenously expressed proteins. The interaction is mediated by a direct binding between the Kv3.1 N-terminal T1 domain and a conserved region in KIF5 tail domains, in which proper T1 tetramerization is crucial. Overexpression of this region of KIF5B markedly reduces axonal levels of Kv3.1bHA. In mature hippocampal neurons, endogenous Kv3.1b and KIF5 colocalize. Suppressing the endogenous KIF5B level by RNA interference significantly reduces the Kv3.1b axonal level. Furthermore, mutating the Zn2+-binding site within T1 markedly decreases channel axonal targeting and forward trafficking, likely through disrupting T1 tetramerization and hence eliminating the binding to KIF5 tail. The mutation also alters channel activity. Interestingly, coexpression of the YFP (yellow fluorescent protein)-tagged KIF5B assists dendritic Kv3.1a and even mutants with a faulty axonal targeting motif to penetrate the AIS. Finally, fluorescently tagged Kv3.1 channels colocalize and comove with KIF5B along axons revealed by two-color time-lapse imaging. Our findings suggest that the binding to KIF5 ensures properly assembled and functioning Kv3.1 channels to be transported into axons.
Glutamatergic Neurons of the Mouse Medial Septum and Diagonal Band of Broca Synaptically Drive Hippocampal Pyramidal Cells: Relevance for Hippocampal Theta Rhythm
Authors: Huh Carey Y. L. , Goutagny Romain , Williams Sylvain
Published: November 2010

Neurons of the medial septum and diagonal band of Broca (MS-DBB) provide an important input to the hippocampus and are critically involved in learning and memory. Although cholinergic and GABAergic MS-DBB neurons are known to modulate hippocampal activity, the role of recently described glutamatergic MS-DBB neurons is unknown. Here, we examined the electrophysiological properties of glutamatergic MS-DBB neurons and tested whether they provide a functional synaptic input to the hippocampus. To visualize the glutamatergic neurons, we used MS-DBB slices from transgenic mice in which the green fluorescent protein is expressed specifically by vesicular glutamate transporter 2-positive neurons and characterized their properties using whole-cell patch-clamp technique. For assessing the function of the glutamatergic projection, we used anin vitroseptohippocampal preparation, electrically stimulated the fornix or chemically activated the MS-DBB using NMDA microinfusions and recorded postsynaptic responses in CA3 pyramidal cells. We found that glutamatergic MS-DBB neurons as a population display a highly heterogeneous set of firing patterns including fast-, cluster-, burst-, and slow-firing. Remarkably, a significant proportion exhibited fast-firing properties, prominent Ih, and rhythmic spontaneous firing at theta frequencies similar to those found in GABAergic MS-DBB neurons. Activation of the MS-DBB led to fast, AMPA receptor-mediated glutamatergic responses in CA3 pyramidal cells. These results describe for the first time the electrophysiological signatures of glutamatergic MS-DBB neurons, their rhythmic firing properties, and their capacity to drive hippocampal principal neurons. Our findings suggest that the glutamatergic septohippocampal pathway may play an important role in hippocampal theta oscillations and relevant cognitive functions.
Amputation with Median Nerve Redirection (Targeted Reinnervation) Reactivates Forepaw Barrel Subfield in Rats
Authors: Marasco Paul D. , Kuiken Todd A.
Published: November 2010

Prosthetic limbs are difficult to control and do not provide sensory feedback. Targeted reinnervation was developed as a neural–machine interface for amputees to address these issues. In targeted reinnervation, amputated nerves are redirected to proximal muscles and skin, creating nerve interfaces for prosthesis control and sensory feedback. Touching the reinnervated skin causes sensation to be projected to the missing limb. Here we use electrophysiological brain recording in the Sprague Dawley rat to investigate the changes to somatosensory cortex (S1) following amputation and nerve redirection with the intent to provide insight into the sensory phenomena observed in human targeted reinnervation amputees. Recordings revealed that redirected nerves established an expanded representation in S1, which may help to explain the projected sensations that encompass large areas of the hand in targeted reinnervation amputees. These results also provide evidence that the reinnervated target skin could serve as a line of communication from a prosthesis to cortical hand processing regions. S1 border regions were simultaneously responsive to reinnervated input and also vibrissae, lower lip, and hindfoot, suggesting competition for deactivated cortical territory. Electrically evoked potential latencies from reinnervated skin to cortex suggest direct connection of the redirected afferents to the forepaw processing region of S1. Latencies also provide evidence that the widespread reactivation of S1 cortex may arise from central anatomical interconnectivity. Targeted reinnervation offers the opportunity to examine the cortical plasticity effects when behaviorally important sensory afferents are redirected from their original location to a new skin surface on a different part of the body.
Wnt/Planar Cell Polarity Signaling Controls the Anterior–Posterior Organization of Monoaminergic Axons in the Brainstem
Authors: Fenstermaker Ali G. , Prasad Asheeta A. , Bechara Ahmad , Adolfs Youri , Tissir Fadel , Goffinet Andre , Zou Yimin , Pasterkamp R. Jeroen
Published: November 2010

Monoaminergic neurons [serotonergic (5-HT) and dopaminergic (mdDA)] in the brainstem project axons along the anterior–posterior axis. Despite their important physiological functions and implication in disease, the molecular mechanisms that dictate the formation of these projections along the anterior–posterior axis remain unknown. Here we reveal a novel requirement for Wnt/planar cell polarity signaling in the anterior–posterior organization of the monoaminergic system. We find that 5-HT and mdDA axons express the core planar cell polarity components Frizzled3, Celsr3, and Vangl2. In addition, monoaminergic projections show anterior–posterior guidance defects inFrizzled3,Celsr3, andVangl2mutant mice. The only known ligands for planar cell polarity signaling are Wnt proteins. In culture, Wnt5a attracts 5-HT but repels mdDA axons, and Wnt7b attracts mdDA axons. However, mdDA axons fromFrizzled3mutant mice are unresponsive to Wnt5a and Wnt7b. Both Wnts are expressed in gradients along the anterior–posterior axis, consistent with their role as directional cues. Finally,Wnt5amutants show transient anterior–posterior guidance defects in mdDA projections. Furthermore, we observe during development that the cell bodies of migrating descending 5-HT neurons eventually reorient along the direction of their axons. InFrizzled3mutants, many 5-HT and mdDA neuron cell bodies are oriented abnormally along the direction of their aberrant axon projections. Overall, our data suggest that Wnt/planar cell polarity signaling may be a global anterior–posterior guidance mechanism that controls axonal and cellular organization beyond the spinal cord.