bluuebunny/crossref_metadata_2025 huggingface dataset:
FOUR NEW EFFICIENT LOGICAL DISPLAY TECHNIQUES OF ELECTRICITY DISTRIBUTION NETWORKS
Authors: AL-A'ALI MANSOOR
Published: October 2007

Tracing a schematic display of an electricity distribution network is a cumbersome task and does not empower the engineer to take fast decisions to control the dynamic network because of the difficulty in reading the displayed circuits. This paper presents four different new approaches, which achieve an intelligent logical dynamically derived network connections and display for Electrical Distribution Networks. The four approaches were designed and implemented using the Object Oriented approach and programmed using Delphi graphics components. The system developed is dynamically interactive and allows switching operations as well as displays. This paper focuses on the display issues only. The logical display approaches presented in this paper eliminate the well-known difficulties of adding and retiring stations which are awkward operations in the schematic display. The four new approaches are compared in terms of speed, readability and space utilization. To our knowledge there is no similar work done previously.
MULTICELLULAR BIOLOGICAL GROWING SYSTEMS: HYPERBOLIC LIMITS TOWARDS MACROSCOPIC DESCRIPTION
Authors: BELLOMO N. , BELLOUQUID A. , NIETO J. , SOLER J.
Published: October 2007

This paper deals with the analysis of the asymptotic limit towards the derivation of hyperbolic macroscopic equations for a class of equations modeling complex multicellular systems. Cellular interactions generate both modification of biological functions and proliferating destructive events related to growth of tumor cells in competition with the immune system. The asymptotic analysis refers to the hyperbolic limit to show how the macroscopic tissue behavior can be described by linear and nonlinear hyperbolic systems which seem the most natural in this context.
MODELLING SCAFFOLD OCCUPATION BY A GROWING, NUTRIENT-RICH TISSUE
Authors: WILSON DUNCAN J. , KING JOHN R. , BYRNE HELEN M.
Published: October 2007

In this paper we present a simple deterministic model of a biological tissue growing within a porous scaffold. By neglecting the effects of nutrient limitations and intercellular pressure on cell growth, and by using Darcy's law to model the cells' movement through the scaffold, our model is formulated as a moving boundary problem. Due to the difficulty in solving the resulting system, we reformulate it as a linear complementarity problem using the Baiocchi transformation, and give both one-dimensional analytical solutions and two-dimensional numerical ones. We then focus on the behaviour of the moving boundary as the colony approaches confluence, using asymptotic analysis to derive the time of confluence and the shape of the moving boundary; we show in particular that the moving boundary evolves to an ellipse. We also show that pressures increase considerably in the tissue shortly before the scaffold is filled, and identify the potential problem for tissue engineers of a "slit" being left devoid of cells.
MATHEMATICAL ANALYSIS AND CHALLENGES ARISING FROM MODELS OF TUMOR GROWTH
Authors: FRIEDMAN AVNER
Published: October 2007

In the last four decades, various cancer models have been developed in which the evolution of the densities of cells (abnormal, normal, or dead) and the concentrations of biochemical species are described in terms of differential equations. In this paper, we deal with tumor models in which the tumor occupies a well-defined region in space; the boundary of this region is held together by the forces of cell-to-cell adhesion. We shall refer to such tumors as "solid" tumors, although they may sometimes consist of fluid-like tissue, such as in the case of brain tumors (e.g. gliomas) and breast tumors. The most common class of solid tumors is carcinoma: a cancer originating from epithelial cells, that is, from the closely packed cells which align the internal cavities of the body.

Models of solid tumors must take spatial effects into account, and are therefore described in terms of partial differential equations (PDEs). They also need to take into account the fact that the tumor region is changing in time; in fact, the tumor region, say Ω(t), and its boundary Γ(t), are unknown in advance. Thus one needs to determine both the unknown "free boundary" Γ(t) together with the solution of the PDEs in Ω(t). These types of problems are called free boundary problems. The models described in this paper are free boundary problems, and our primary interest is the spatial/geometric features of the free boundary. Some of the basic questions we shall address are: What is the shape of the free boundary? How does the free boundary behave as t → ∞? Does the tumor volume increase or shrink as t → ∞? Under what conditions does the tumor eventually become dormant? Finally, we shall explore the dependence of the free boundary on some biological parameters, and this will give rise to interesting bifurcation phenomena.

The structure of the paper is as follows. In Secs. 1 and 2 we consider models in which all the cells are of one type, they are all proliferating cells. The tissue is modeled either as a porous medium (in Sec. 1) or as a fluid medium (in Sec. 2). The models are extended in Secs. 3 and 4 to include three types of cells: proliferating, quiescent, and dead. Finally, in Sec. 5 we outline a general multiphase model that includes gene mutations.
A HYBRID MODEL FOR TUMOR SPHEROID GROWTH IN VITRO I: THEORETICAL DEVELOPMENT AND EARLY RESULTS
Authors: KIM YANGJIN , STOLARSKA MAGDALENA A. , OTHMER HANS G.
Published: October 2007

Tumor spheroids grown in vitro have been widely used as models of in vivo tumor growth because they display many of the characteristics of in vivo growth, including the effects of nutrient limitations and perhaps the effect of stress on growth. In either case there are numerous biochemical and biophysical processes involved whose interactions can only be understood via a detailed mathematical model. Previous models have focused on either a continuum description or a cell-based description, but both have limitations. In this paper we propose a new mathematical model of tumor spheroid growth that incorporates both continuum and cell-level descriptions, and thereby retains the advantages of each while circumventing some of their disadvantages. In this model the cell-based description is used in the region where the majority of growth and cell division occurs, at the periphery of a tumor, while a continuum description is used for the quiescent and necrotic zones of the tumor and for the extracellular matrix. Reaction-diffusion equations describe the transport and consumption of two important nutrients, oxygen and glucose, throughout the entire domain. The cell-based component of this hybrid model allows us to examine the effects of cell–cell adhesion and variable growth rates at the cellular level rather than at the continuum level. We show that the model can predict a number of cellular behaviors that have been observed experimentally.
POROUS MEDIUM FLOW IN A TUBE: TRAVELING WAVES AND KPP BEHAVIOR
Authors: VÁZQUEZ JUAN LUIS
Published: October 2007

We study the long-time behavior of the solutions of the Porous Medium Equation ut = Δ um, m > 1, posed in a tube Ω = ℝ × D, where D is a bounded domain in ℝn, and with homogeneous Dirichlet conditions on the lateral boundary. We show that the asymptotic behavior of general nonnegative solutions follows the KPP pattern in suitable rescaled variables. We proceed as follows: we pass to the renormalized problem and show that this problem admits a wave solution that travels along the tube with constant speed with respect to the new time (which is logarithmic in the old time scale). This solution has a bounded free boundary as a forward front.

We also show that the universal asymptotic pattern for solutions with compactly supported data is described in the renormalized form by two of these traveling waves going out in different directions, joined by a stationary profile in the middle region.

We compare this situation with the heat equation case ut = Δu that behaves quite differently.
RATIONAL BLOW-DOWNS AND NONSYMPLECTIC 4-MANIFOLDS WITH ONE BASIC CLASS
Authors: PARK JONGIL , YUN KI-HEON
Published: October 2007

We present a simple way to construct an infinite family of simply connected, nonspin, smooth 4-manifolds with one basic class which do not admit a symplectic structure with either orientation.
A SMASH PRODUCT CONSTRUCTION OF NONLOCAL VERTEX ALGEBRAS
Authors: LI HAISHENG
Published: October 2007

A notion of vertex bialgebra and a notion of nonlocal vertex module-algebra for a vertex bialgebra are studied and then a smash product construction of nonlocal vertex algebras is presented. For every nonlocal vertex algebra V satisfying a suitable condition, a canonical bialgebra B(V) is constructed such that primitive elements of B(V) are essentially pseudo-derivations and group-like elements are essentially pseudo-endomorphisms. As an application, vertex algebras associated with the Heisenberg Lie algebras as well as those associated with the nondegenerate even lattices are reconstructed through smash products, and furthermore, a different approach to the construction of modules for the lattice vertex algebras is given.
STEM KERNELS FOR RNA SEQUENCE ANALYSES
Authors: SAKAKIBARA YASUBUMI , POPENDORF KRIS , OGAWA NANA , ASAI KIYOSHI , SATO KENGO
Published: October 2007

Several computational methods based on stochastic context-free grammars have been developed for modeling and analyzing functional RNA sequences. These grammatical methods have succeeded in modeling typical secondary structures of RNA, and are used for structural alignment of RNA sequences. However, such stochastic models cannot sufficiently discriminate member sequences of an RNA family from nonmembers and hence detect noncoding RNA regions from genome sequences. A novel kernel function, stem kernel, for the discrimination and detection of functional RNA sequences using support vector machines (SVMs) is proposed. The stem kernel is a natural extension of the string kernel, specifically the all-subsequences kernel, and is tailored to measure the similarity of two RNA sequences from the viewpoint of secondary structures. The stem kernel examines all possible common base pairs and stem structures of arbitrary lengths, including pseudoknots between two RNA sequences, and calculates the inner product of common stem structure counts. An efficient algorithm is developed to calculate the stem kernels based on dynamic programming. The stem kernels are then applied to discriminate members of an RNA family from nonmembers using SVMs. The study indicates that the discrimination ability of the stem kernel is strong compared with conventional methods. Furthermore, the potential application of the stem kernel is demonstrated by the detection of remotely homologous RNA families in terms of secondary structures. This is because the string kernel is proven to work for the remote homology detection of protein sequences. These experimental results have convinced us to apply the stem kernel in order to find novel RNA families from genome sequences.
A ROBUST BIOMARKER DISCOVERY PIPELINE FOR HIGH-PERFORMANCE MASS SPECTROMETRY DATA
Authors: FISHER WAYNE G. , ROSENBLATT KEVIN P. , FISHMAN DAVID A. , WHITELEY GORDON R. , MIKULSKIS ALVYDAS , KUZDZAL SCOTT A. , LOPEZ MARY F. , TAN NICLAS CHIANG , GERMAN DWIGHT C. , GARNER HAROLD R.
Published: October 2007

A high-throughput software pipeline for analyzing high-performance mass spectral data sets has been developed to facilitate rapid and accurate biomarker determination. The software exploits the mass precision and resolution of high-performance instrumentation, bypasses peak-finding steps, and instead uses discrete m/z data points to identify putative biomarkers. The technique is insensitive to peak shape, and works on overlapping and non-Gaussian peaks which can confound peak-finding algorithms. Methods are presented to assess data set quality and the suitability of groups of m/z values that map to peaks as potential biomarkers. The algorithm is demonstrated with serum mass spectra from patients with and without ovarian cancer. Biomarker candidates are identified and ranked by their ability to discriminate between cancer and noncancer conditions. Their discriminating power is tested by classifying unknowns using a simple distance calculation, and a sensitivity of 95.6% and a specificity of 97.1% are obtained. In contrast, the sensitivity of the ovarian cancer blood marker CA125 is ~50% for stage I/II and ~80% for stage III/IV cancers. While the generalizability of these markers is currently unknown, we have demonstrated the ability of our analytical package to extract biomarker candidates from high-performance mass spectral data.
A MULTIVARIATE EXTENSION OF THE GENE SET ENRICHMENT ANALYSIS
Authors: KLEBANOV LEV , GLAZKO GALINA , SALZMAN PETER , YAKOVLEV ANDREI , XIAO YUANHUI
Published: October 2007

A test-statistic typically employed in the gene set enrichment analysis (GSEA) prevents this method from being genuinely multivariate. In particular, this statistic is insensitive to changes in the correlation structure of the gene sets of interest. The present paper considers the utility of an alternative test-statistic in designing the confirmatory component of the GSEA. This statistic is based on a pertinent distance between joint distributions of expression levels of genes included in the set of interest. The null distribution of the proposed test-statistic, known as the multivariate N-statistic, is obtained by permuting group labels. Our simulation studies and analysis of biological data confirm the conjecture that the N-statistic is a much better choice for multivariate significance testing within the framework of the GSEA. We also discuss some other aspects of the GSEA paradigm and suggest new avenues for future research.
TWO-PASS IMPUTATION ALGORITHM FOR MISSING VALUE ESTIMATION IN GENE EXPRESSION TIME SERIES
Authors: TSIPORKOVA ELENA , BOEVA VESELKA
Published: October 2007

Gene expression microarray experiments frequently generate datasets with multiple values missing. However, most of the analysis, mining, and classification methods for gene expression data require a complete matrix of gene array values. Therefore, the accurate estimation of missing values in such datasets has been recognized as an important issue, and several imputation algorithms have already been proposed to the biological community. Most of these approaches, however, are not particularly suitable for time series expression profiles. In view of this, we propose a novel imputation algorithm, which is specially suited for the estimation of missing values in gene expression time series data. The algorithm utilizes Dynamic Time Warping (DTW) distance in order to measure the similarity between time expression profiles, and subsequently selects for each gene expression profile with missing values a dedicated set of candidate profiles for estimation. Three different DTW-based imputation (DTWimpute) algorithms have been considered: position-wise, neighborhood-wise, and two-pass imputation. These have initially been prototyped in Perl, and their accuracy has been evaluated on yeast expression time series data using several different parameter settings. The experiments have shown that the two-pass algorithm consistently outperforms, in particular for datasets with a higher level of missing entries, the neighborhood-wise and the position-wise algorithms. The performance of the two-pass DTWimpute algorithm has further been benchmarked against the weighted K-Nearest Neighbors algorithm, which is widely used in the biological community; the former algorithm has appeared superior to the latter one. Motivated by these findings, indicating clearly the added value of the DTW techniques for missing value estimation in time series data, we have built an optimized C++ implementation of the two-pass DTWimpute algorithm. The software also provides for a choice between three different initial rough imputation methods.
Fibronectin-dependent collagen I deposition modulates the cell response to fibronectin
Authors: Sottile Jane , Shi Feng , Rublyevska Inna , Chiang Hou-Yu , Lust Joseph , Chandler Jennifer
Published: October 2007

Communication between cells and the extracellular matrix (ECM) is critical for regulation of cell growth, survival, migration, and differentiation. Remodeling of the ECM can occur under normal physiological conditions, as a result of tissue injury, and in certain pathological conditions. ECM remodeling leads to alterations in ECM composition and organization that can alter many aspects of cell behavior, including cell migration. The cell migratory response varies depending on the type, amount, and organization of ECM molecules present, as well as the integrin and proteoglycan repertoire of the cells. We and others have shown that the deposition of several ECM molecules, including collagen types I and III, depends on the presence and stability of ECM fibronectin. Hence, the effect of fibronectin and fibronectin matrix on cell function may partially depend on its ability to direct the deposition of collagen in the ECM. In this study, we used collagen-binding fibronectin mutants and recombinant peptides that interfere with fibronectin-collagen binding to show that fibronectin-dependent collagen I deposition regulates the cell migratory response to fibronectin. These data show that the ability of fibronectin to organize other proteins in the ECM is an important aspect of fibronectin function and highlight the importance of understanding how interactions between ECM proteins influence cell behavior.
The origin of passive force enhancement in skeletal muscle
Authors: Joumaa V. , Rassier D. E. , Leonard T. R. , Herzog W.
Published: October 2007

The aim of the present study was to test whether titin is a calcium-dependent spring and whether it is the source of the passive force enhancement observed in muscle and single fiber preparations. We measured passive force enhancement in troponin C (TnC)-depleted myofibrils in which active force production was completely eliminated. The TnC-depleted construct allowed for the investigation of the effect of calcium concentration on passive force, without the confounding effects of actin-myosin cross-bridge formation and active force production. Passive forces in TnC-depleted myofibrils ( n = 6) were 35.0 ± 2.9 nN/ μm2 when stretched to an average sarcomere length of 3.4 μm in a solution with low calcium concentration (pCa 8.0). Passive forces in the same myofibrils increased by 25% to 30% when stretches were performed in a solution with high calcium concentration (pCa 3.5). Since it is well accepted that titin is the primary source for passive force in rabbit psoas myofibrils and since the increase in passive force in TnC-depleted myofibrils was abolished after trypsin treatment, our results suggest that increasing calcium concentration is associated with increased titin stiffness. However, this calcium-induced titin stiffness accounted for only ∼25% of the passive force enhancement observed in intact myofibrils. Therefore, ∼75% of the normally occurring passive force enhancement remains unexplained. The findings of the present study suggest that passive force enhancement is partly caused by a calcium-induced increase in titin stiffness but also requires cross-bridge formation and/or active force production for full manifestation.
SR Ca2+ refilling upon depletion and SR Ca2+ uptake rates during development in rabbit ventricular myocytes
Authors: Huang Jingbo , Hove-Madsen Leif , Tibbits Glen F.
Published: October 2007

While it has been reported that a sparse sarcoplasmic reticulum (SR) and a low SR Ca2+ pump density exist at birth, we and others have recently shown that significant amounts of Ca2+ are stored in the neonatal rabbit heart SR. Here we try to determine developmental changes in SR Ca2+ loading mechanisms and Ca2+ pump efficacy in rabbit ventricular myocytes. SR Ca2+ loading (loadSR) and k0.5 (Ca2+ concentration at half-maximal SR Ca2+ uptake) were higher and lower, respectively, in younger age groups. Inhibition of the L-type calcium current ( ICa) with 15 μM nifedipine dramatically reduced loadSR in older but not in younger age groups. In contrast, subsequent inhibition of the Na+/Ca2+ exchanger (NCX) with 10 μM KB-R7943 strongly reduced loadSR in the younger but not the older age groups. Accordingly, the time integral of the inward NCX current (tail INCX) elicited on repolarization was highly sensitive to nifedipine in the older groups and sensitive to KB-R7943 in the younger groups. Interestingly, slow SR loading took place in the presence of both nifedipine and KB-R7943 in all age groups, although it was less prominent in the older groups. We conclude that the SR loading capacity at the earliest postnatal stages is at least as large as that of adult myocytes. However, reverse-mode NCX plays a prominent role in SR Ca2+ loading at early postnatal stages while ICa is the main source of SR Ca2+ loading at late postnatal and adult stages.
IFN-γ does not mimic the catabolic effects of TNF-α
Authors: Smith Melissa A. , Moylan Jennifer S. , Smith Jeffrey D. , Li Wei , Reid Michael B.
Published: October 2007

Cachexia is common in chronic inflammatory diseases and is attributed, in part, to an elevation of circulating proinflammatory cytokines. TNF-α is the prototype in this category. IFN-γ is also thought to play a role, but the evidence supporting this model is primarily indirect. To determine the direct effects of IFN-γ stimulation on muscle cells, we selected key components of the procatabolic signaling pathways by which TNF-α stimulates protein loss. We tested two hypotheses: 1) IFN-γ mimics TNF-α signaling by increasing intracellular oxidant activity and activating MAPKs and NF-κB and 2) IFN-γ increases the expression of the ubiquitin ligases atrogin1/MAFbx and muscle-specific ring finger protein 1 (MuRF1). Results showed that treatment with IFN-γ at 60 ng/ml increased Stat1 phosphorylation after 15 min, indicating receptor activation. IFN-γ had no effect on cytosolic oxidant activity, as measured by 2′,7′-dichlorofluorescein oxidation. Nor did IFN-γ activate JNK, ERK1/2, or p38 MAPK, as assessed by Western blot. Treatment for up to 60 min did not decrease IκB-α protein levels, as measured by Western blot analysis, or the DNA binding activity of NF-κB, as measured by EMSA. After 6 h, IFN-γ decreased Akt phosphorylation and increased atrogin1/MAFbx and MuRF1 mRNA. Daily treatment for up to 72 h did not alter adult fast-type myosin heavy chain content or the total protein-to-DNA ratio. These data show that responses of myotubes to IFN-γ and TNF-α differ markedly and provide little evidence for a direct catabolic effect of IFN-γ on muscle.
WISE-2005: adrenergic responses of women following 56-days, 6° head-down bed rest with or without exercise countermeasures
Authors: Edgell Heather , Zuj Kathryn A. , Greaves Danielle K. , Shoemaker J. Kevin , Custaud Marc-Antoine , Kerbeci Pascaline , Arbeille Phillipe , Hughson Richard L.
Published: October 2007

We tested the hypotheses that women completing 56 days, 6° head-down bed-rest (HDBR) would have changes in sensitivity of cardiovascular responses to adrenergic receptor stimulation and that frequent aerobic and resistive exercise would prevent these changes. Twenty-four women, eight controls, eight exercisers (lower body negative pressure treadmill and flywheel resistance exercise), and eight receiving nutritional supplement but no exercise were studied in baseline and during administration of the β-agonist isoproterenol (ISO) and the α- and β-agonist norepinephrine (NOR). In the control and nutrition groups, HDBR increased heart rate (HR) and reduced stroke volume (SV), and there was a significantly greater increase in HR with ISO after HDBR. In contrast, the HR and SV of the exercise group were unchanged from pre-HDBR. After HDBR, leg vascular resistance (LVR) was greater than pre-HDBR in the exercise group but reduced in control and nutrition. LVR was reduced with ISO and increased with NOR. Changes in total peripheral resistance were similar to those of LVR but of smaller magnitude, perhaps because changes in cerebrovascular resistance index were directionally opposite to those of LVR. There were no changes in sensitivity of the vascular resistance responses to adrenergic stimulation. The HR response might reflect a change in sensitivity or a necessary response to the reduction in SV after HDBR in control and nutrition groups. The reduced peripheral vascular resistance after HDBR might help to explain orthostatic intolerance in women. Exercise was an effective countermeasure to the HDBR effects.
Adenosine triphosphate increases the reactivity of the afferent arteriole to low concentrations of norepinephrine
Authors: Hultström Michael , Lai En Yin , Ma Zufu , Källskog Örjan , Patzak Andreas , Persson A. Erik G.
Published: October 2007

Adenosine triphosphate (ATP) and norepinephrine (NE) interact in the control of blood flow in the kidney. A combined effect of NE and ATP has not been previously investigated at the level of the afferent arteriole (Af). We studied the effects of ATP on the contractile response of the Af to NE. Vascular reactivity to ATP, NE, and their combination was investigated in isolated perfused Af from mice. The roles of α-adrenoceptors and P2-ATP-receptors were investigated by use of specific agonists and antagonists. Cytosolic calcium was measured using the fluorescent calcium dye fura-2. ATP in concentrations from 10−12to 10−4mol/l induced transient contractions. NE constricted the Af in a dose-dependent manner and induced significant contractions at > 10−7mol/l. Treatment with ATP (10−8and 10−6mol/l) increased the NE response. Diameters were reduced by 20% already at 10−11mol/l NE during ATP treatment of 10−6mol/l. ATP increased the calcium response to NE significantly at 10−8and 10−7mol/l NE. The P2-type ATP receptor blocker pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) (10−5mol/l) abolished the sensitization of the NE response by ATP. The α1-blocker prazosin (10−7mol/l) inhibited the ATP effect, as did the α2-blocker yohimbine (10−7mol/l). Neither the phenylephrine- nor clonidine-induced concentration response curves was affected by ATP in the bath solution. Costimulation with ATP enhances the response of the Af to NE. This effect is mediated by increased cytosolic calcium. The enhancing effect involves P2-type ATP receptors and both α1- and α2-adrenoceptors.
Effects ofl-arginine andl-NAME on chronic partial bladder outlet obstruction in rabbit
Authors: Lin Wei-Yu , Levin Robert M. , Chichester Paul , Leggett Robert , Juan Yung-Shun , Johnson Arnold , Neumann Paul , Whitbeck Catherine , Guven Ahmet , Kogan Barry , Mannikarottu Anita
Published: October 2007

Nitric oxide (NO) is synthesized from l-arginine by nitric oxide synthase (NOS). NOS can be inhibited by NG-nitro-l-arginine methyl ester (l-NAME) and stimulated by supplementing the diet with l-arginine. The aim of this study was to investigate the influence of NOS activity on the response of rabbits to chronic partial bladder outlet obstruction (PBOO). Surgical PBOOs (2 and 8 wk) were performed on male New Zealand White rabbits. Before obstruction, one-third of the animals were premedicated for 7 days with l-NAME and another third with l-arginine. The results are summarized as follows. First, bladder weight after 8-wk PBOO was significantly lower in animals treated with l-arginine compared with both untreated and rabbits treated with l-NAME. Second, contractile function decreased progressively with PBOO duration. However, after 8 wk of PBOO, the l-arginine group had significantly greater contractile function compared with the no-treatment group, and the l-NAME group had significantly lower contractile function compared with the no-treatment group. Third, at 8 wk following PBOO, the level of protein oxidation and nitration was lowest for the l-arginine group and highest in the l-NAME group. These studies clearly demonstrated that increasing blood flow by stimulating NOS significantly protected the bladder from PBOO dysfunctions, whereas inhibiting blood flow by l-NAME enhanced the dysfunctions mediated by PBOO.
Kinetics of ATP release and cell volume regulation of hyposmotically challenged goldfish hepatocytes
Authors: Pafundo Diego E. , Chara Osvaldo , Faillace María P. , Krumschnabel Gerhard , Schwarzbaum Pablo J.
Published: October 2007

In most animal cells, hypotonic swelling is followed by a regulatory volume decrease (RVD) thought to prevent cell death. In contrast, goldfish hepatocytes challenged with hypotonic medium (180 mosM, HYPO) increase their volume 1.7 times but remain swollen and viable for at least 5 h. Incubation with ATPγS (an ATP analog) in HYPO triggers a 42% volume decrease. This effect is concentration dependent ( K1/2= 760 nM) and partially abolished by P2 receptor antagonists (64% inhibition). A similar induction of RVD is observed with ATP, UTP, and UDP, whereas adenosine inhibits RVD. Goldfish hepatocytes release more than 500 nM ATP during the first minutes of HYPO with no induction of RVD. The fact that similar concentrations of ATPγS did trigger RVD could be explained by showing that ATPγS induced ATP release. Finally, we observed that in a very small extracellular volume, hepatocytes do show a 56% RVD. This response was diminished by P2 receptor antagonists (73%) and increased (73%) when the extracellular ATP hydrolysis was inhibited 72%. Using a mathematical model, we predict that during the first 2 min of HYPO exposure the extracellular [ATP] is mainly governed by ATP diffusion and by both nonlytic and lytic ATP release, with almost no contribution from ecto-ATPase activity. We show that goldfish hepatocytes under standard HYPO (large volume) do not display RVD unless this is triggered by the addition of micromolar concentrations of nucleotides. However, under very low assay volumes, sufficient endogenous extracellular [ATP] can build up to induce RVD.
Intracellular targeting of copper-transporting ATPase ATP7A in a normal andAtp7b−/−kidney
Authors: Linz Rachel , Barnes Natalie L. , Zimnicka Adriana M. , Kaplan Jack H. , Eipper Betty , Lutsenko Svetlana
Published: October 2007

Kidneys regulate their copper content more effectively than many other organs in diseases of copper deficiency or excess. We demonstrate that two copper-transporting ATPases, ATP7A and ATP7B, contribute to this regulation. ATP7A is expressed, to a variable degree, throughout the kidney and shows age-dependent intracellular localization. In 2-wk-old mice, ATP7A is located in the vicinity of the basolateral membrane, whereas in 20-wk-old mice, ATP7A is predominantly in intracellular vesicles. Acute elevation of serum copper, via intraperitoneal injection, results in the in vivo redistribution of ATP7A from intracellular compartments toward the basolateral membrane, illustrating a role for ATP7A in renal response to changes in copper load. Renal copper homeostasis also requires functional ATP7B, which is coexpressed with ATP7A in renal cells of proximal and distal origin. The kidneys of Atp7b−/−mice, an animal model of Wilson disease, show metabolic alterations manifested by the appearance of highly fluorescent deposits; however, in marked contrast to the liver, renal copper is not significantly elevated. The lack of notable copper accumulation in the Atp7b−/−kidney is likely due to the compensatory export of copper by ATP7A. This interpretation is supported by the predominant localization of ATP7A at the basolateral membrane of Atp7b−/−cortical tubules. Our results suggest that both Cu-ATPases regulate renal copper, with ATP7A playing a major role in exporting copper via basolateral membranes and protecting renal tissue against copper overload.
Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo
Authors: Edison Erica E. , Brosnan Margaret E. , Meyer Christian , Brosnan John T.
Published: October 2007

A fraction of the body's creatine and creatine phosphate spontaneously degrades to creatinine, which is excreted by the kidneys. In humans, this amounts to ∼1–2 g/day and demands a comparable rate of de novo creatine synthesis. This is a two-step process in which l-arginine:glycine amidinotransferase (AGAT) catalyzes the conversion of glycine and arginine to ornithine and guanidinoacetate (GAA); guanidinoacetate methyltransferase (GAMT) then catalyzes the S-adenosylmethionine-dependent methylation of GAA to creatine. AGAT is found in the kidney and GAMT in the liver, which implies an interorgan movement of GAA from the kidney to the liver. We studied the renal production of this metabolite in both rats and humans. In control rats, [GAA] was 5.9 μM in arterial plasma and 10.9 μM in renal venous plasma for a renal arteriovenous (A-V) difference of −5.0 μM. In the rat, infusion of arginine or citrulline markedly increased renal GAA production but infusion of glycine did not. Rats fed 0.4% creatine in their diet had decreased renal AGAT activity and mRNA, an arterial plasma [GAA] of 1.5 μM, and a decreased renal A-V difference for GAA of −0.9 μM. In humans, [GAA] was 2.4 μM in arterial plasma, with a renal A-V difference of −1.1 μM. These studies show, for the first time, that GAA is produced by both rat and human kidneys in vivo.
Complex roles of PIP2in the regulation of ion channels and transporters
Authors: Huang Chou-Long
Published: October 2007

The regulation of ion channels and transporters by phosphoinositides has received much attention over the past 10 years. There are multiple potential mechanisms for regulation of ion channels and transporters by PIP2, including a direct binding of PIP2to the target proteins, alterations of membrane insertion, and retrieval. Added to the complexities of multiple potential mechanisms is how cells use PIP2to regulate so many different processes. Here, I briefly review several past and recent studies to illustrate the complexities and raise outstanding questions for future studies.
Nitric oxide deficiency in chronic kidney disease
Authors: Baylis Chris
Published: October 2007

The overall production of nitric oxide (NO) is decreased in chronic kidney disease (CKD) which contributes to cardiovascular events and further progression of kidney damage. There are many likely causes of NO deficiency in CKD and the areas surveyed in this review are: 1. Limitations on substrate (l-Arginine) availability, probably due to impaired renal l-Arginine biosynthesis, decreased transport of l-Arginine into endothelial cells and possible competition between NOS and competing metabolic pathways, such as arginase. 2. Increased circulating levels of endogenous NO synthase (NOS) inhibitors, in particular asymmetric dimethylarginine (ADMA). Increased methylation of proteins and their subsequent breakdown to release free ADMA may contribute but the major culprit is probably reduced ADMA catabolism by the enzymes dimethylarginine dimethylaminohydrolases. 3. Reduced renal cortex abundance of the neuronal NOS (nNOS)α protein correlates with injury while increasing nNOSβ abundance may provide a compensatory, protective response. Interventions that can restore NO production by targeting these various pathways are likely to reduce the cardiovascular complications of CKD as well as slowing the rate of progression.
Reinforcement Learning With Modulated Spike Timing–Dependent Synaptic Plasticity
Authors: Farries Michael A. , Fairhall Adrienne L.
Published: October 2007

Spike timing–dependent synaptic plasticity (STDP) has emerged as the preferred framework linking patterns of pre- and postsynaptic activity to changes in synaptic strength. Although synaptic plasticity is widely believed to be a major component of learning, it is unclear how STDP itself could serve as a mechanism for general purpose learning. On the other hand, algorithms for reinforcement learning work on a wide variety of problems, but lack an experimentally established neural implementation. Here, we combine these paradigms in a novel model in which a modified version of STDP achieves reinforcement learning. We build this model in stages, identifying a minimal set of conditions needed to make it work. Using a performance-modulated modification of STDP in a two-layer feedforward network, we can train output neurons to generate arbitrarily selected spike trains or population responses. Furthermore, a given network can learn distinct responses to several different input patterns. We also describe in detail how this model might be implemented biologically. Thus our model offers a novel and biologically plausible implementation of reinforcement learning that is capable of training a neural population to produce a very wide range of possible mappings between synaptic input and spiking output.
Nitric Oxide Activates Leak K+ Currents in the Presumed Cholinergic Neuron of Basal Forebrain
Authors: Kang Youngnam , Dempo Yoshie , Ohashi Atsuko , Saito Mitsuru , Toyoda Hiroki , Sato Hajime , Koshino Hisashi , Maeda Yoshinobu , Hirai Toshihiro
Published: October 2007

Learning and memory are critically dependent on basal forebrain cholinergic (BFC) neuron excitability, which is modulated profoundly by leak K+ channels. Many neuromodulators closing leak K+ channels have been reported, whereas their endogenous opener remained unknown. We here demonstrate that nitric oxide (NO) can be the endogenous opener of leak K+ channels in the presumed BFC neurons. Bath application of 1 mM S-nitroso- N-acetylpenicillamine (SNAP), an NO donor, induced a long-lasting hyperpolarization, which was often interrupted by a transient depolarization. Soluble guanylyl cyclase inhibitors prevented SNAP from inducing hyperpolarization but allowed SNAP to cause depolarization, whereas bath application of 0.2 mM 8-bromoguanosine-3′,5′-cyclomonophosphate (8-Br-cGMP) induced a similar long-lasting hyperpolarization alone. These observations indicate that the SNAP-induced hyperpolarization and depolarization are mediated by the cGMP-dependent and -independent processes, respectively. When examined with the ramp command pulse applied at –70 mV under the voltage-clamp condition, 8-Br-cGMP application induced the outward current that reversed at K+ equilibrium potential ( EK) and displayed Goldman-Hodgkin-Katz rectification, indicating the involvement of voltage-independent K+ current. By contrast, SNAP application in the presumed BFC neurons either dialyzed with the GTP-free internal solution or in the presence of 10 μM Rp-8-bromo-β-phenyl-1,N2-ethenoguanosine 3′,5′-cyclic monophosphorothioate sodium salt, a protein kinase G (PKG) inhibitor, induced the inward current that reversed at potentials much more negative than EK and close to the reversal potential of Na+-K+ pump current. These observations strongly suggest that NO activates leak K+ channels through cGMP-PKG-dependent pathway to markedly decrease the excitability in BFC neurons, while NO simultaneously causes depolarization by the inhibition of Na+-K+ pump through ATP depletion.
Optimal Time Scale for Spike-Time Reliability: Theory, Simulations, and Experiments
Authors: Galán Roberto F. , Ermentrout G. Bard , Urban Nathaniel N.
Published: October 2007

Use of spike timing to encode information requires that neurons respond with high temporal precision and with high reliability. Fast fluctuating stimuli are known to result in highly reproducible spike times across trials, whereas constant stimuli result in variable spike times. Here, we first studied mathematically how spike-time reliability depends on the rapidness of aperiodic stimuli. Then, we tested our theoretical predictions in computer simulations of neuron models (Hodgkin-Huxley and modified quadratic integrate-and-fire), as well as in patch-clamp experiments with real neurons (mitral cells in the olfactory bulb and pyramidal cells in the neocortex). As predicted by our theory, we found that for firing frequencies in the beta/gamma range, spike-time reliability is maximal when the time scale of the input fluctuations (autocorrelation time) is in the range of a few milliseconds (2–5 ms), coinciding with the time scale of fast synapses, and decreases substantially for faster and slower inputs. Finally, we comment how these findings relate to mechanisms causing neuronal synchronization.
Modifiability of Generalization in Dynamics Learning
Authors: Mattar Andrew A. G. , Ostry David J.
Published: October 2007

Studies on plasticity in motor function have shown that motor learning generalizes, such that movements in novel situations are affected by previous training. It has been shown that the pattern of generalization for visuomotor rotation learning changes when training movements are made to a wide distribution of directions. Here we have found that for dynamics learning, the shape of the generalization gradient is not similarly modifiable by the extent of training within the workspace. Subjects learned to control a robotic device during training and we measured how subsequent movements in a reference direction were affected. Our results show that as the angular separation between training and test directions increased, the extent of generalization was reduced. When training involved multiple targets throughout the workspace, the extent of generalization was no greater than following training to the nearest target alone. Thus a wide range of experience compensating for a dynamics perturbation provided no greater benefit than localized training. Instead, generalization was complete when training involved targets that bounded the reference direction. This suggests that broad generalization of dynamics learning to movements in novel directions depends on interpolation between instances of localized learning.
Differential Effects of Estradiol on Encoding Properties of TMJ Units in Laminae I and V at the Spinomedullary Junction in Female Rats
Authors: Tashiro A. , Okamoto K. , Milam S. B. , Bereiter D. A.
Published: October 2007

To determine whether estrogen status modulated dorsal horn neural activity relevant to temporomandibular joint (TMJ) processing single units were recorded in superficial and deep laminae at the trigeminal subnucleus caudalis/upper cervical cord (Vc/C1–2) junction of ovariectomized (OvX) female rats under barbiturate anesthesia after 17β-estradiol (E2) treatment for 2 days. E2 dose-dependently enhanced the response to intra-TMJ stimulation by adenosine triphosphate (ATP) of neurons classified as nociceptive specific (NS), but not wide dynamic range (WDR), in superficial laminae. ATP caused similar responses among NS and WDR neurons from deep laminae in all groups. By contrast, the cutaneous receptive field areas of WDR, but not NS, units in superficial and deep laminae were enlarged in high E2-treated (HE2) compared with low E2-treated (LE2) females. Units from untreated or vehicle-treated male rats displayed responses similar to those of LE2 females. TMJ units in superficial laminae from females were more likely to receive convergent cutaneous input and respond to jaw movement than males, independent of E2 treatment. Western blot analysis revealed similar levels of P2X2 and P2X3 receptor protein in Vc/C1–2 or trigeminal ganglion samples in all groups. Immunohistochemistry revealed dense terminal labeling for P2X3 receptors in superficial laminae and moderate labeling in deep laminae at the Vc/C1–2 junction. These data indicated a significant linkage between estrogen status and the magnitude of articular input evoked by ATP from TMJ neurons in the superficial laminae at the Vc/C1–2 junction, whereas estrogenic modulation of TMJ neurons in deep laminae affected only the convergent input from overlying facial skin.
History- and Current Instruction-Based Coding of Forthcoming Behavioral Outcomes in the Striatum
Authors: Yamada Hiroshi , Matsumoto Naoyuki , Kimura Minoru
Published: October 2007

Animals optimize behaviors by predicting future critical events based on histories of actions and their outcomes. When behavioral outcomes like reward and aversion are signaled by current external cues, actions are directed to acquire the reward and avoid the aversion. The basal ganglia are thought to be the brain locus for reward-based adaptive action planning and learning. To understand the role of striatum in coding outcomes of forthcoming behavioral responses, we addressed two specific questions. First, how are the histories of reward and aversion used for encoding forthcoming outcomes in the striatum during a series of instructed behavioral responses? Second, how are the behavioral responses and their instructed outcomes represented in the striatum? We recorded discharges of 163 presumed projection neurons in the striatum while monkeys performed a visually instructed lever-release task for reward, aversion, and sound outcomes, whose occurrences could be estimated by their histories. Before outcome instruction, discharge rates of a subset of neurons activated in this epoch showed positive or negative regression slopes with reward history (24/44), that is, to the number of trials since the last reward trial, which changed in parallel with reward probability of current trials. The history effect was also observed for the aversion outcome but in far fewer neurons (3/44). Once outcomes were instructed in the same task, neurons selectively encoded the outcomes before and after behavioral responses (reward, 46/70; aversion, 6/70; sound, 6/70). The history- and current instruction–based coding of forthcoming behavioral outcomes in the striatum might underlie outcome-oriented behavioral modulation.
Ocular Motor Behavior in Macaques With Surgical Exotropia
Authors: Economides John R. , Adams Daniel L. , Jocson Cristina M. , Horton Jonathan C.
Published: October 2007

To provide an animal model of human exotropia, a free tenotomy of the medial recti was performed in two infant macaques. When the animals were old enough to record eye movements with video eye trackers, we measured their ductions, ocular alignment, comitance, smooth pursuit, fixation preference, and gaze stability. Partial recovery of adduction occurred in each monkey from spontaneous re-attachment of the medial rectus muscle to the eye. However, each animal was left with a relatively comitant, large angle exotropia. The magnitude of the exotropia was not affected by covering one eye. There was no dissociated vertical deviation or any significant “A” or “V” pattern to the horizontal misalignment. Smooth pursuit was more accurate when tracking nasally compared with temporally in both animals. Compensatory catch-up saccades in the tracking eye were always accompanied by conjugate movements in the deviated eye. Despite tenotomy of the medial recti, the velocity of adducting saccades was normal. Both monkeys alternated fixation, preferring to use the left eye for targets on the left side and the right eye for targets on the right. Each animal was capable of switching fixation while making accurate saccades. One of the monkeys developed a vertical pendular nystagmus, which was most prominent in the deviated eye. Macaques with ocular misalignment from medial rectus tenotomy exhibit features that are present in humans with alternating exotropia. These animals will be valuable for probing the cortical mechanisms that underlie visual suppression in strabismus.