bluuebunny/crossref_metadata_2025 huggingface dataset:
MULTIMODAL PHYLOGENY FOR TAXONOMY: INTEGRATING INFORMATION FROM NUCLEOTIDE AND AMINO ACID SEQUENCES
Authors: BICEGO MANUELE , DELLAGLIO FRANCO , FELIS GIOVANNA E.
Published: October 2007

The crucial role played by the analysis of microbial diversity in biotechnology-based innovations has increased the interest in the microbial taxonomy research area. Phylogenetic sequence analyses have contributed significantly to the advances in this field, also in the view of the large amount of sequence data collected in recent years. Phylogenetic analyses could be realized on the basis of protein-encoding nucleotide sequences or encoded amino acid molecules: these two mechanisms present different peculiarities, still starting from two alternative representations of the same information. This complementarity could be exploited to achieve a multimodal phylogenetic scheme that is able to integrate gene and protein information in order to realize a single final tree. This aspect has been poorly addressed in the literature. In this paper, we propose to integrate the two phylogenetic analyses using basic schemes derived from the multimodality fusion theory (or multiclassifier systems theory), a well-founded and rigorous branch for which its powerfulness has already been demonstrated in other pattern recognition contexts. The proposed approach could be applied to distance matrix–based phylogenetic techniques (like neighbor joining), resulting in a smart and fast method. The proposed methodology has been tested in a real case involving sequences of some species of lactic acid bacteria. With this dataset, both nucleotide sequence– and amino acid sequence–based phylogenetic analyses present some drawbacks, which are overcome with the multimodal analysis.
DISEASE-RELATED CONCEPT MINING BY KNOWLEDGE-BASED TWO-DIMENSIONAL GENE MAPPING
Authors: MATSUNAGA TSUTOMU , MURAMATSU MASAAKI
Published: October 2007

There is a strong need to systematically organize and comprehend the rapidly expanding stores of biomedical knowledge to formulate hypotheses on disease mechanisms. However, no method is available that automatically structuralizes fragmentary knowledge along with domain-specific expressions for a large-scale integration. A method presented here, cross-subspace analysis (CSA), produces a holistic view of over 3,000 human genes with a two-dimensional (2D) arrangement. The genes are plotted in relation to functions determined by machine learning from the occurrence patterns of various biomedical terms in MEDLINE abstracts. By focusing on the 2D distributions of gene plots that share the same biomedical concepts, as defined by databases such as Gene Ontology, relevant biomedical concepts can be computationally extracted. In an analysis where myocardial infarction and ischemic stroke were taken as examples, we found valid relations with lifestyle, diet-related metabolism, and host immune responses, all of which are known risk factors for the diseases. These results demonstrate that systematizing accumulated gene knowledge can lead to hypothesis generation and knowledge discovery, regardless of the area of inquiry or discipline.
OVERLAPPING ALTERNATIVE DONOR SPLICE SITES IN THE HUMAN GENOME
Authors: ERMAKOVA EKATERINA O. , NURTDINOV RAMIL N. , GELFAND MIKHAIL S.
Published: October 2007

Over 50% of donor splice sites in the human genome have a potential alternative donor site at a distance of three to six nucleotides. Conservation of these potential sites is determined by the consensus requirements and by its exonic or intronic location. Several hundred pairs of overlapping sites are confirmed to be alternatively spliced as both sites in a pair are supported by a protein, by a full-length mRNA, or by expressed sequence tags (ESTs) from at least two independent clone libraries. Overlapping sites may clash with consensus requirements. Pairs with a site shift of four nucleotides are the most abundant, despite the frameshift in the protein-coding region that they introduce. The site usage in pairs is usually uneven, and the major site is more frequently conserved in other mammalian genomes. Overlapping alternative donor sites and acceptor sites may have different functional roles: alternative splicing of overlapping acceptor sites leads mainly to microvariations in protein sequences; whereas alternative donor sites often lead to frameshifts and thus either yield major differences in the protein sequence and structure, or generate nonsense-mediated decay-inducing mRNA isoforms likely involved in regulated unproductive splicing pathways.
A GENTLE INTRODUCTION TO SNP ANALYSIS: RESOURCES AND TOOLS
Authors: MAH JAMES T. L. , CHIA K. S.
Published: October 2007

Bioinformatics is the use of informatics tools and techniques in the study of molecular biology, genetic, or clinical data. The field of bioinformatics has expanded tremendously to cope with the large expansion of information generated by the mouse and human genome projects, as newer generations of computers that are much more powerful have emerged in the commercial market. It is now possible to employ the computing hardware and software at hand to generate novel methodologies in order to link data across the different databanks generated by these international projects and derive clinical and biological relevance from all of the information gathered. The ultimate goal would be to develop a computer program that can provide information correlating genes, their single nucleotide polymorphisms (SNPs), and the possible structural and functional effects on the encoded proteins with relation to known information on complex diseases with great ease and speed. Here, the recent developments of available software methods to analyze SNPs in relation to complex diseases are reviewed with emphasis on the type of predictions on protein structure and functions that can be made. The need for further development of comprehensive bioinformatics tools that can cope with information generated by the genomics communities is emphasized.
COMPUTING THE BREAKPOINT DISTANCE BETWEEN PARTIALLY ORDERED GENOMES
Authors: FU ZHENG , JIANG TAO
Published: October 2007

The total order of genes or markers on a chromosome is crucial for most comparative genomics studies. However, current gene mapping efforts might only suffice to provide a partial order of the genes on a chromosome. Several different genes or markers might be mapped at the same position due to the low resolution of gene mapping or missing data. Moreover, conflicting datasets might give rise to the ambiguity of gene order. In this paper, we consider the reversal distance and breakpoint distance problems for partially ordered genomes. We first prove that these problems are nondeterministic polynomial-time (NP)-hard, and then give an efficient heuristic algorithm to compute the breakpoint distance between partially ordered genomes. The algorithm is based on an efficient approximation algorithm for a natural generalization of the well-known feedback vertex set problem, and has been tested on both simulated and real biological datasets. The experimental results demonstrate that our algorithm is quite effective for estimating the breakpoint distance between partially ordered genomes and for inferring the gene (total) order.
Histamine enhances the production of human β-defensin-2 in human keratinocytes
Authors: Kanda Naoko , Watanabe Shinichi
Published: October 2007

The anti-microbial peptide human β-defensin-2 (hBD-2), produced by epidermal keratinocytes, plays pivotal roles in anti-microbial defense, inflammatory dermatoses, and wound repair. hBD-2 induces histamine release from mast cells. We examined the in vitro effects of histamine on hBD-2 production in normal human keratinocytes. Histamine enhanced TNF-α- or IFN-γ-induced hBD-2 secretion and mRNA expression. Histamine alone enhanced transcriptional activities of NF-κB and activator protein-1 (AP-1) and potentiated TNF-α-induced NF-κB and AP-1 activities or IFN-γ-induced NF-κB and STAT1 activities. Antisense oligonucleotides against NF-κB components p50 and p65, AP-1 components c-Jun and c-Fos, or H1 antagonist pyrilamine suppressed hBD-2 production induced by histamine plus TNF-α or IFN-γ. Antisense oligonucleotide against STAT1 only suppressed hBD-2 production induced by histamine plus IFN-γ. Histamine induced serine phosphorylation of inhibitory NF-κBα (IκBα) alone or together with TNF-α or IFN-γ. Histamine induced c-Fos mRNA expression alone or together with TNF-α, whereas it did not further increase c-Jun mRNA levels enhanced by TNF-α. Histamine induced serine phosphorylation of STAT1 alone or together with IFN-γ, whereas it did not further enhance IFN-γ-induced tyrosine phosphorylation of STAT1. The histamine-induced serine phosphorylation of STAT1 was suppressed by MAPKK (MEK) inhibitor PD98059. These results suggest that histamine stimulates H1 receptor and potentiates TNF-α- or IFN-γ-induced hBD-2 production dependent on NF-κB, AP-1, or STAT1 in human keratinocytes. Histamine may potentiate anti-microbial defense, skin inflammation, and wound repair via the induction of hBD-2.
Relative resistance to slow inactivation of human cardiac Na+channel hNav1.5 is reversed by lysine or glutamine substitution at V930 in D2-S6
Authors: Chancey Jessica Hotard , Shockett Penny E. , O'Reilly John P.
Published: October 2007

Transmembrane segment 6 is implicated in slow inactivation (SI) of voltage-gated Na+channels (Navs). To further study its role and understand differences between SI phenotypes of different Navisoforms, we analyzed several domain 2-segment 6 (D2-S6) mutants of the human cardiac hNav1.5, which is relatively resistant to SI. Mutants were examined by transient HEK cell transfection and patch-clamp recording of whole cell Na+currents. Substitutions with lysine (K) included N927K, V930K, and L931K. We show recovery from short (100 ms) depolarization to 0 mV in N927K and L931K is comparable to wild type, whereas recovery in V930K is delayed and biexponential, suggesting rapid entry into a slow-inactivated state. SI protocols confirm enhanced SI phenotype (rapid development, hyperpolarized steady state, slowed recovery) for V930K, contrasting with the resistant phenotype of wild-type hNav1.5. This enhancement, not found in N927K or L931K, suggests that the effect in V930K is site specific. Glutamine (Q) substituted at V930 also exhibits an enhanced SI phenotype similar to that of V930K. Therefore, K or Q substitution eliminates hNav1.5 resistance to SI. Alanine (A) or cysteine (C) substitution at V930 shows no enhancement of SI, and in fact, V930A and V930C, as well as L931K, exhibit a resistance to SI, demonstrating that characteristics of specific amino acids (e.g., size, hydrophobicity) differentially affect SI gating. Thus V930 in D2-S6 appears to be an important structural determinant of SI gating in hNav1.5. We suggest that conformational change involving D2-S6 is a critical component of SI in Navs, which may be differentially regulated between isoforms by other isoform-specific determinants of SI phenotype.
Mechanism of nicotinic acid transport in human liver cells: experiments with HepG2 cells and primary hepatocytes
Authors: Said Hamid M. , Nabokina Svetlana M. , Balamurugan Krishnaswamy , Mohammed Zainab M. , Urbina Cecilia , Kashyap Moti L.
Published: October 2007

This study reports on the functional expression of a specific, high-affinity carrier-mediated mechanism for the transport of niacin (nicotinic acid) in human liver cells. Both human-derived liver HepG2 cells and human primary hepatocytes were used as models in these investigations. The initial rate of transport of nicotinic acid into HepG2 cells was found to be acidic pH, temperature, and energy dependent; it was, however, Na+ independent in nature. Evidence for the existence of a carrier-mediated system that is specific for [3H]nicotinic acid transport was found and included the following: 1) saturability as a function of concentration with an apparent Km of 0.73 ± 0.16 μM and Vmax of 25.02 ± 1.45 pmol·mg protein−1·3 min−1, 2) cis-inhibition by unlabeled nicotinic acid and nicotinamide but not by unrelated organic anions (lactate, acetate, butyrate, succinate, citrate, and valproate), and 3) trans-stimulation of [3H]nicotinic acid efflux by unlabeled nicotinic acid. Transport of the vitamin into human primary hepatocytes occurs similarly via an acidic pH-dependent and specific carrier-mediated process. Inhibitors of the Ca2+-calmodulin-mediated pathway (but not modulators of the PKC-, PKA-, and protein tyrosine kinase-mediated pathways) inhibited nicotinic acid transport into both HepG2 cells and human primary hepatocytes. Maintenance of HepG2 cells (for 48 h) in growth medium oversupplemented with nicotinic acid (or nicotinamide) did not affect the subsequent transport of [3H]nicotinic acid into HepG2 cells. These results show, for the first time, the existence of a specific and regulated membrane carrier-mediated system for nicotinic acid transport in human liver cells.
Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic β-cell: a computational approach
Authors: Fridlyand Leonid E. , Harbeck Mark C. , Roe Michael W. , Philipson Louis H.
Published: October 2007

In this report we describe a mathematical model for the regulation of cAMP dynamics in pancreatic β-cells. Incretin hormones such as glucagon-like peptide 1 (GLP-1) increase cAMP and augment insulin secretion in pancreatic β-cells. Imaging experiments performed in MIN6 insulinoma cells expressing a genetically encoded cAMP biosensor and loaded with fura-2, a calcium indicator, showed that cAMP oscillations are differentially regulated by periodic changes in membrane potential and GLP-1. We modeled the interplay of intracellular calcium (Ca2+) and its interaction with calmodulin, G protein-coupled receptor activation, adenylyl cyclases (AC), and phosphodiesterases (PDE). Simulations with the model demonstrate that cAMP oscillations are coupled to cytoplasmic Ca2+ oscillations in the β-cell. Slow Ca2+ oscillations (<1 min−1) produce low-frequency cAMP oscillations, and faster Ca2+ oscillations (>3–4 min−1) entrain high-frequency, low-amplitude cAMP oscillations. The model predicts that GLP-1 receptor agonists induce cAMP oscillations in phase with cytoplasmic Ca2+ oscillations. In contrast, observed antiphasic Ca2+ and cAMP oscillations can be simulated following combined glucose and tetraethylammonium-induced changes in membrane potential. The model provides additional evidence for a pivotal role for Ca2+-dependent AC and PDE activation in coupling of Ca2+ and cAMP signals. Our results reveal important differences in the effects of glucose/TEA and GLP-1 on cAMP dynamics in MIN6 β-cells.
Airway responses to esophageal acidification
Authors: Lang Ivan M. , Haworth Steven T. , Medda Bidyut K. , Roerig David L. , Forster Hubert V. , Shaker Reza
Published: October 2007

The effects of esophageal acidification on airway function are unclear. Some have found that the esophageal acidification causes a small increase in airway resistance, but this change is too small to cause significant symptoms. The aims of this study were to investigate the effects of esophageal acidification on multiple measures of airway function in chloralose-anesthetized cats. The esophagus was cannulated and perfused with either 0.1 M PBS or 0.1 N HCl at 1 ml/min as the following parameters were quantified in separate experiments: diameter of bronchi ( n = 5), tracheal mucociliary transport rate ( n = 4), tracheobronchial mucus secretion ( n = 7), and lung function ( n = 6). We found that esophageal acidification for 10–30 min decreased bronchial diameters primarily of the smaller low-resistance airways (10–22%, P < 0.05), decreased tracheal mucociliary transport (53%, 8.7 ± 2.4 vs. 4.1 ± 1.3 mm/min, P < 0.05), increased tracheobronchial mucus secretion (147%, 3.4 ± 0.7 vs. 8.4 ± 2.6 mg/10 min, P < 0.05), and caused no change in total lung resistance or dynamic compliance ( P > 0.05). Considering that tracheal mucociliary transport rate is governed in part by mucus secretion, we concluded that the primary airway response to esophageal acidification observed is increased mucus secretion. Airway constriction may act to assist in rapid secretion of mucus and to increase the effectiveness of coughing while not affecting lung resistance or compliance. Given the buffering capabilities of mucus, esophageal acidification activates appropriate physiological responses that may act to neutralize gastroesophageal reflux that reaches the larynx, pharynx, or lower airways.
The roles of mast cells and Kupffer cells in rat systemic anaphylaxis
Authors: Shibamoto Toshishige , Shimo Tomohiro , Cui Sen , Zhang Wei , Takano Hiromichi , Kurata Yasutaka , Tsuchida Hideaki
Published: October 2007

Mast cells and other cells such as macrophages have been shown to mediate systemic anaphylaxis. We determined the roles of mast cells and Kupffer cells in hepatic and systemic anaphylaxis of rats. Roles of mast cells were examined by using the mast cell-deficient white spotting (Ws/Ws) rat; the Ws/Ws and wild type (+/+) rats were sensitized with ovalbumin (1 mg). Roles of Kupffer cells were examined by depleting Kupffer cells using gadolinium chloride or liposome-encapsulated dichloromethylene diphosphonate in the Ws/Ws and Sprague-Dawley rats. An intravenous injection of 0.6 mg ovalbumin caused substantial anaphylactic hypotension in both the Ws/Ws and +/+ rats; however, the occurrence was delayed in the Ws/Ws rats. After antigen, portal venous pressure increased by 13.1 cmH2O in the +/+ rats, while it increased only by 5.7 cmH2O in the Ws/Ws rats. In response to antigen, the isolated perfused liver of the Ws/Ws rats also showed weak venoconstriction, the magnitude of which was one tenth as large as that of the +/+ rats, indicating that hepatic anaphylaxis was primarily due to mast cells. In contrast, Kupffer cell depletion did not attenuate anaphylactic hepatic venoconstriction in isolated perfused livers. In conclusion, mast cells are involved mainly in anaphylactic hepatic presinusoidal portal venoconstriction but only in the early stage of anaphylactic systemic hypotension in rats. Macrophages, including Kupffer cells, do not participate in rat hepatic anaphylactic venoconstriction.
Mapping mechanisms and charting the time course of premature cell senescence and apoptosis: lysosomal dysfunction and ganglioside accumulation in endothelial cells
Authors: Patschan Susann , Chen Jun , Gealekman Olga , Krupincza Katrina , Wang Maureen , Shu Liming , Shayman James A. , Goligorsky Michael S.
Published: October 2007

Endothelial cells subjected to glycated collagen I develop premature senescence within 3–5 days, as revealed by increased senescence-associated β-galactosidase activity, decreased proliferation, and an increase in cell size. Here, we analyzed the time course and possible mechanisms of this process. Lysosomal integrity studies revealed a rapid collapse of pH gradient and lysosomal permeabilization, detectable after 30 min, and preceded by the increased production of reactive oxygen species. Measurement of mitochondrial membrane potential after application of glycated collagen demonstrated that depolarization was delayed by 4 h compared with changes in lysosomal pH and permeability. Based on the above findings of lysosomal permeabilization, we hypothesized that the reduced activity of senescence-associated β-galactosidase could be responsible for the cellular accumulation of gangliosides, previously shown to induce cell senescence. After 5 days of exposure to glycated collagen, there was an increase in the levels of gangliosides GM3, GD1b, and GT1b, coincident with development of cell senescence. Treatment of endothelial cells with d- threo-EtDOP4, an inhibitor of glucosylceramide synthase, inhibited apoptosis, but not the development of senescence. In conclusion, collagen I modified by advanced glycation initially induces apoptosis of human umbilical vein endothelial cells. This process is initiated by the collapse of lysosomal pH and an increase in lysosomal permeability, with the subsequent mitochondrial depolarization and accumulation of gangliosides. Blockade of ganglioside synthesis suppresses apoptosis, but not senescence, which develops after 3 days of exposure to glycated collagen. These data imply a critical role for lysosomal permeabilization in triggering apoptosis of endothelial cells exposed to the diabetic milieu.
Acute and delayed renal protection against renal ischemia and reperfusion injury with A1adenosine receptors
Authors: Joo Jin Deok , Kim Mihwa , Horst Patrick , Kim Jeehee , D'Agati Vivette D. , Emala Charles W. , Lee H. Thomas
Published: October 2007

We showed previously that activation of A1adenosine receptors (AR) protects against renal ischemia-reperfusion (IR) injury in rats and mice. In the heart, transient A1AR activation produces biphasic protective effects: acute protection wanes after several hours but protective effects return 24–72 h later (second window of protection). In this study, we determined whether A1AR activation produces delayed renal protection and elucidated the mechanisms of acute and delayed renal protection. A1AR wild-type mice were subjected to 30-min renal ischemia and 24 h of reperfusion to produce acute renal failure. Pretreatment with a selective A1AR agonist 2-chloro- N6-cyclopentyladenosine (CCPA; 0.1 mg/kg bolus ip) either 15 min or 24 h before renal ischemia protected against renal IR injury and reduced renal corticomedullary necrosis, apoptosis, and inflammation. Transient A1AR activation led to phosphorylation of extracellular signal-regulated protein kinase mitogen-activated protein kinase (ERK MAPK), Akt, and heat shock protein 27 (HSP27). Moreover, induction of HSP27 and Akt occurred with CCPA treatment. Inhibition of PKC with chelerythrine prevented acute but not delayed renal protection with A1AR activation. Moreover, deletion of PI3Kγ or inhibition of Akt, but not inhibition of ERK, prevented delayed and acute renal protection with A1AR activation. Inhibition of Gi/owith pertussis toxin obliterated both acute and delayed A1AR-mediated renal protection. In contrast to renal protection with delayed ischemic preconditioning, nitric oxide synthase activity was not induced with delayed A1AR-mediated renal protection. Therefore, transient activation of renal A1AR led to acute as well as delayed protective effects against renal IR injury via distinct signaling pathways.
Pkd1 and Nek8 mutations affect cell-cell adhesion and cilia in cysts formed in kidney organ cultures
Authors: Natoli Thomas A. , Gareski Tiffany C. , Dackowski William R. , Smith Laurie , Bukanov Nikolay O. , Russo Ryan J. , Husson Hervé , Matthews Douglas , Piepenhagen Peter , Ibraghimov-Beskrovnaya Oxana
Published: October 2007

Development of novel therapies for polycystic kidney disease (PKD) requires assays that adequately reflect disease biology and are adaptable to high-throughput screening. Here we describe an embryonic cystic kidney organ culture model and demonstrate that a new mutant allele of the Pkd1 gene ( Pkd1 tm1Bdgz) modulates cystogenesis in this model. Cyst formation induced by cAMP is influenced by the dosage of the mutant allele: Pkd1 tm1Bdgz −/− cultures develop a larger cystic area compared with +/+ counterparts, while Pkd1 tm1Bdgz +/− cultures show an intermediate phenotype. A similar relationship between the degree of cystogenesis and mutant gene dosage is seen in cystic kidney organ cultures derived from mice with a mutated Nek8 gene ( Nek8 jck). Both Pkd1− and Nek8− cultures display altered cell-cell junctions, with reduced E-cadherin expression and altered desmosomal protein expression, similar to ADPKD epithelia. Additionally, characteristic ciliary abnormalities are identified in cystic kidney cultures, with elevated ciliary polycystin 1 expression in Nek8 homozygous cultures and elevated ciliary Nek8 protein expression in Pkd1 homozygotes. These data suggest that the Nek8 and Pkd1 genes function in a common pathway to regulate cystogenesis. Moreover, compound Pkd1 and Nek8 heterozygous adult mice develop a more aggressive cystic disease than animals with a mutation in either gene alone. Finally, we validate the kidney organ culture cystogenesis assay as a therapeutic testing platform using the CDK inhibitor roscovitine. Therefore, embryonic kidney organ culture represents a relevant model for studying molecular cystogenesis and a rapid tool for the screening for therapies that block cystic growth.
Inferior Colliculus Responses to Multichannel Microstimulation of the Ventral Cochlear Nucleus: Implications for Auditory Brain Stem Implants
Authors: Shivdasani Mohit N. , Mauger Stefan J. , Rathbone Graeme D. , Paolini Antonio G.
Published: October 2007

Multichannel techniques were used to assess the frequency specificity of activation in the central nucleus of the inferior colliculus (CIC) produced by electrical stimulation of localized regions within the ventral cochlear nucleus (VCN). Data were recorded in response to pure tones from 141 and 193 multiunit clusters in the rat VCN and the CIC, respectively. Of 141 VCN sites, 126 were individually stimulated while recording responses in the CIC. A variety of CIC response types were seen with an increase in both electrical and acoustic stimulation levels. The majority of sites exhibited monotonic rate-level types acoustically, whereas spike rate saturation was achieved predominantly with electrical stimulation. In 20.6% of the 364 characteristic frequency aligned VCN–CIC pairs, the CIC sites did not respond to stimulation. In 26% of the 193 CIC sites, a high correlation was observed between acoustic tuning and electrical tuning obtained through VCN stimulation. A high degree of frequency specificity was found in 58% of the 118 lowest threshold VCN–CIC pairs. This was dependent on electrode placement within the VCN because a higher degree of frequency specificity was achieved with stimulation of medial, central, and posterolateral VCN regions than more anterolateral regions. Broadness of acoustic tuning in the CIC played a role in frequency-specific activation. Narrowly tuned CIC sites showed the lowest degree of frequency specificity on stimulation of the anterolateral VCN regions. These data provide significant implications for auditory brain stem implant electrode placement, current localization, power requirements, and facilitation of information transfer to higher brain centers.
Responses to Social Vocalizations in the Inferior Colliculus of the Mustached Bat Are Influenced by Secondary Tuning Curves
Authors: Holmstrom Lars , Roberts Patrick D. , Portfors Christine V.
Published: October 2007

Neurons in the inferior colliculus (IC) of the mustached bat integrate input from multiple frequency bands in a complex fashion. These neurons are important for encoding the bat's echolocation and social vocalizations. The purpose of this study was to quantify the contribution of complex frequency interactions on the responses of IC neurons to social vocalizations. Neural responses to single tones, two-tone pairs, and social vocalizations were recorded in the IC of the mustached bat. Three types of data driven stimulus-response models were designed for each neuron from single tone and tone pair stimuli to predict the responses of individual neurons to social vocalizations. The first model was generated only using the neuron's primary frequency tuning curve, whereas the second model incorporated the entire hearing range of the animal. The extended model often predicted responses to many social vocalizations more accurately for multiply tuned neurons. One class of multiply tuned neuron that likely encodes echolocation information also responded to many of the social vocalizations, suggesting that some neurons in the mustached bat IC have dual functions. The third model included two-tone frequency tunings of the neurons. The responses to vocalizations were better predicted by the two-tone models when the neuron had inhibitory frequency tuning curves that were not near the neuron's primary tuning curve. Our results suggest that complex frequency interactions in the IC determine neural responses to social vocalizations and some neurons in IC have dual functions that encode both echolocation and social vocalization signals.
Activation of 5-Hydroxytryptamine Type 3 Receptor-Expressing C-Fiber Vagal Afferents Inhibits Retrotrapezoid Nucleus Chemoreceptors in Rats
Authors: Moreira Thiago S. , Takakura Ana C. , Colombari Eduardo , Guyenet Patrice G.
Published: October 2007

Retrotrapezoid nucleus (RTN) chemoreceptors are regulated by inputs from the carotid bodies (CB) and from pulmonary mechanoreceptors. Here we tested whether RTN neurons are influenced by 5-hydroxytryptamine type 3 receptor-expressing C-fiber vagal afferents. In urethan-anesthetized rats, selective activation of vagal C-fiber afferents by phenylbiguanide (PBG) eliminated the phrenic nerve discharge (PND) and inhibited RTN neurons ( n = 24). PBG had no inhibitory effect in vagotomized rats. Muscimol injection into the solitary tract nucleus, commissural part, reduced inhibition of PND and RTN by PBG (73%), blocked activation of PND and RTN by CB stimulation (cyanide) but had no effect on inhibition of PND and RTN by lung inflation. Bilateral injections of muscimol into interstitial solitary tract nucleus (NTS) reduced the inhibition of PND and RTN by PBG (53%), blocked the inhibitory effects of lung inflation but did not change the activation of PND and RTN neurons by CB stimulation. PBG and lung inflation activated postinspiratory neurons located within the rostral ventral respiratory group (rVRG) and inhibited inspiratory and expiratory neurons. Bilateral injections of muscimol into rVRG eliminated PND and partially decreased RTN neuron inhibition by PBG (32%). In conclusion, activation of cardiopulmonary C-fiber afferents inhibits the activity of RTN chemoreceptors. The pathway relays within a broad medial region of the NTS and involves the rVRG to a limited degree. The apnea triggered by activation of cardiopulmonary C-fiber afferents may be due in part to a reduction of the activity of RTN chemoreceptors.
Head-Unrestrained Gaze Shifts After Muscimol Injection in the Caudal Fastigial Nucleus of the Monkey
Authors: Quinet Julie , Goffart Laurent
Published: October 2007

The effects of unilateral cFN inactivation on horizontal and vertical gaze shifts generated from a central target toward peripheral ones were tested in two head unrestrained monkeys. After muscimol injection, the eye component was hypermetric during ipsilesional gaze shifts, hypometric during contralesional ones and deviated toward the injected side during vertical gaze shifts. The ipsilesional gaze hypermetria increased with target eccentricity until ∼24° after which it diminished and became smaller than the hypermetria of the eye component. Contrary to eye saccades, the amplitude and peak velocity of which were enhanced, the amplitude and peak velocity of head movements were reduced during ipsilesional gaze shifts. These changes in head movement were not correlated with those affecting the eye saccades. Head movements were also delayed relative to the onset of eye saccades. The alterations in head movement and the faster eye saccades likely explained the reduced head contribution to the amplitude of ipsilesional gaze shifts. The contralesional gaze hypometria increased with target eccentricity and was associated with uncorrelated reductions in eye and head peak velocities. When compared with control movements of similar amplitude, contralesional eye saccades had lower peak velocity and longer duration. This slowing likely accounted for the increase in head contribution to the amplitude of contralesional gaze shifts. These data suggest different pathways for the fastigial control of eye and head components during gaze shifts. Saccade dysmetria was not compensated by appropriate changes in head contribution, raising the issue of the feedback control of movement accuracy during combined eye-head gaze shifts.
Variational Problems with Moving Boundaries Using Decomposition Method
Authors: Memarbashi Reza
Published: October 2007

The aim of this paper is to present a numerical method for solving variational problems with moving boundaries. We apply Adomian decomposition method on the Euler-Lagrange equation with boundary conditions that yield from transversality conditions and natural boundary conditions.
Effects of a Combination of Thyme and Oregano Essential Oils on TNBS-Induced Colitis in Mice
Authors: Bukovská Alexandra , Cikoš Štefan , Juhás Štefan , Il’ková Gabriela , Rehák Pavol , Koppel Juraj
Published: October 2007

We examined the anti-inflammatory effects of the combination of thyme and oregano essential oil dietary administered at three concentrations (0.4% thyme and 0.2% oregano oils; 0.2% thyme and 0.1% oregano oils; 0.1% thyme and 0.05% oregano oils) on mice with TNBS-induced colitis. Treatment of colitic animals with the essential oils decreased the mRNA levels of pro-inflammatory cytokines IL-1β, IL-6, GM-CSF, and TNFα, especially after application of the medium dose. The medium dose of the essential oils significantly lowered the amount of IL-1βand IL-6 proteins too. Moreover, administration of the medium dose decreased the mortality rate, accelerated the body weight gain recovery, and reduced the macroscopic damage of the colonic tissue. Our results indicate that combined treatment with appropriate concentrations of thyme and oregano essential oils can reduce the production of proinflammatory cytokines, and thereby attenuate TNBS-induced colitis in mice.
Molecular Image Segmentation Based on Improved Fuzzy Clustering
Authors: Yu Jinhua , Wang Yuanyuan
Published: October 2007

Segmentation of molecular images is a difficult task due to the low signal‐to‐noise ratio of images.
A novel two‐dimensional fuzzy C‐means (2DFCM) algorithm is proposed for the molecular image
segmentation. The 2DFCM algorithm is composed of three stages. The first stage is the noise
suppression by utilizing a method combining a Gaussian noise filter and anisotropic diffusion
techniques. The second stage is the texture energy characterization using a Gabor wavelet method.
The third stage is introducing spatial constraints provided by the denoising data and the textural
information into the two‐dimensional fuzzy clustering. The incorporation of intensity and textural
information allows the 2DFCM algorithm to produce satisfactory segmentation results for images
corrupted by noise (outliers) and intensity variations. The 2DFCM can achieve 0.96 ± 0.03 segmentation accuracy for synthetic images under different imaging conditions. Experimental results on a real molecular image also show the effectiveness of the proposed algorithm.
Vortex Simulation of the Bubbly Flow around a Hydrofoil
Authors: Uchiyama Tomomi , Degawa Tomohiro
Published: October 2007

This study is concerned with the two-dimensional simulation for an air-water bubbly flow around a hydrofoil. The vortex method, proposed by the authors for gas-liquid two-phase free turbulent flow in a prior paper, is applied for the simulation. The liquid vorticity field is discrerized by vortex elements, and the behavior of vortex element and the bubble motion are simultaneously computed by the Lagrangian approach. The effect of bubble motion on the liquid flow is taken into account through the change in the strength of vortex element. The bubbly flow around a hydrofoil of NACA4412 with a chord length 100 mm is simulated. The Reynolds number is2.5×105, the bubble diameter is 1 mm, and the volumetric flow ratio of bubble to whole fluid is 0.048. It is confirmed that the simulated distributions of air volume fraction and pressure agree well with the trend of the measurement and that the effect of angle of attack on the flow is favorably analyzed. These demonstrate that the vortex method is applicable to the bubbly flow analysis around a hydrofoil.
Permanence and Periodic Solution of Predator-Prey System with Holling Type Functional Response and Impulses
Authors: Wang Weibing , Shen Jianhua , Nieto Juan J.
Published: October 2007

We considered a nonautonomous two dimensional predator-prey system with impulsive effect. Conditions for the permanence of the system and for the existence of a unique stable periodic solution are obtained.
Solution Estimates for Semilinear Difference-Delay Equations with Continuous Time
Authors: Gil' Michael , Cheng Sui Sun
Published: October 2007

We consider semilinear difference-delay equations with continuous time in a Euclidean space. Estimates are found for the solutions. Such estimates are then applied to obtain the stability and boundedness criteria for solutions.
Fourier-Domain Analysis of Hydriding Kinetics Using Pneumato-Chemical Impedance Spectroscopy
Authors: Millet P. , Decaux C. , Ngameni R. , Guymont M.
Published: October 2007

Analysis of phase transformation processes observed in hydrogen absorbing materials
(pure metals, alloys, or compounds) is still a matter of active research. Using pneumato-chemical
impedance spectroscopy (PIS), it is now possible to analyze the mechanism of hydriding
reactions induced by the gas phase. Experimental impedance diagrams, measured on activated
LaNi5 in single- and two-phase domains, are reported in this paper. It is shown that their shape is
mostly affected by the slope of the isotherm at the measurement point. By considering the details
of the multistep reaction paths involved in the hydriding reaction, model impedance equations
have been derived for single- and two-phase domains, and fitted to experimental impedance
diagrams. The possibility of separately measuring surface and phase transformation resistances,
hydrogen diffusion coefficient, and hydrogen solubility in each composition domain is discussed.
Mutagen Sensitivity and Genetic Variants in Nucleotide Excision Repair Pathway: Genotype-Phenotype Correlation
Authors: Lin Jie , Swan Gary E. , Shields Peter G. , Benowitz Neal L. , Gu Jian , Amos Christopher I. , de Andrade Mariza , Spitz Margaret R. , Wu Xifeng
Published: October 2007

The rationale behind gene-disease association studies is that genetic variants (polymorphisms) result in alterations in intermediate phenotypes. However, genotype-phenotype correlations have not been established for most polymorphisms. In this study, we correlated genotype data of genes involved in the nucleotide excision repair pathway with mutagen sensitivity phenotype, quantified by benzo(a)pyrene diol epoxide (BPDE)-induced chromatid breaks in peripheral blood lymphocytes in 422 healthy subjects recruited into a twin study that included 138 pairs of monozygotic twins, 51 pairs of dizygotic twins, and 44 siblings. Among a panel of single nucleotide polymorphisms examined, we found that BPDE sensitivity was modified by individual polymorphisms in XPC, RAD23B, and XPA genes. Specific haplotypes and diplotypes of XPC also modified BPDE sensitivity profiles. In addition, a more consistent and stronger correlation was observed between mutagen sensitivity phenotype and the combination of multiple polymorphisms in the nucleotide excision repair pathway. Specifically, when XPC-PAT, XPC Lys939Gln, XPA A23G, and RAD23B Val249Ala were analyzed together, we observed a significant dose-response relationship between increasing mutagen sensitivity with increasing number of adverse alleles: mutagen sensitivity for those carrying zero to two, three to five, and six or more adverse alleles were 0.64, 0.68, and 1.06, respectively (P for trend = 0.008), and the results remained significant after adjusting for multiple comparisons. Using individuals carrying zero to two adverse alleles as the reference group, the risks of being mutagen sensitive (mutagen sensitivity values greater than the median) were 1.05 (95% confidence interval, 0.68-1.64) and 4.48 (95% confidence interval, 1.21-16.61) for those carrying three to five and six or more adverse alleles, respectively. Analyses of the effects of genotype combinations yielded similar results. These findings underscore the importance of assessing the collective effects of a panel of polymorphisms in the same pathway in modulating mutagen sensitivity. As risk assessment for cancer risk is moving toward a multigenic pathway-based approach, future genotype-phenotype correlation studies should also investigate the combined effects of multiple genetic variants. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2065–71)
Frequency of TP53 Mutations in Relation to Arg72Pro Genotypes in Non–Small Cell Lung Cancer
Authors: Lind Helge , Ekstrøm Per Olaf , Ryberg David , Skaug Vidar , Andreassen Tove , Stangeland Lodve , Haugen Aage , Zienolddiny Shanbeh
Published: October 2007

Mutations in the TP53 gene are important events during human lung carcinogenesis. The TP53 gene harbors several polymorphisms, and functional studies have shown that the Arg72Pro polymorphism alters both wild-type and mutant p53 protein activity. Thus, we hypothesized that certain Arg72Pro genotypes may influence the frequency and pattern of somatic mutations in TP53. We therefore examined the status of the Arg72Pro polymorphism and TP53 mutations in 260 non–small-cell lung cancer cases. Here we report a significant trend toward lower frequency of TP53 mutations with increasing number of Pro72 alleles (P = 0.02). Overall, Pro72 allele carriers had significantly lower frequency of TP53 mutations compared with Arg72 homozygotes (P = 0.02). In addition, carriage of the Pro72 variant was related to a lower frequency of mutations affecting the hotspot codon 273. Mutations at codon 273 accounted for 10.6% of the mutations in Arg72 homozygotes and 1.7% of the mutations in Pro72 allele carriers. Our results suggest that the genotype of the Arg72Pro polymorphism may modulate the frequency of TP53 mutations in non–small-cell lung cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2077–81)
Prognostic Relevance of Carbohydrate Antigen 19-9 Levels in Patients with Advanced Biliary Tract Cancer
Authors: Harder Jan , Kummer Oliver , Olschewski Manfred , Otto Florian , Blum Hubert Erich , Opitz Oliver
Published: October 2007

Serum carbohydrate antigen 19-9 (CA 19-9) has been identified as biochemical marker for biliary tract cancer (BTC). The purpose of this study was to evaluate its value as a treatment response marker and its value as a prognostic parameter in patients with unresectable BTC. We analyzed 70 patients with BTC treated with chemotherapy. CA 19-9 levels before and after two treatment courses were analyzed with respect to their effect on treatment response. Patients were categorized into two subgroups according to biliary stenting: patients without endoscopic intervention or biliary drainage (non-stent subgroup) and patients with endoluminal stenting (stent subgroup). Pretreatment CA 19-9 levels were prognostic with respect to overall survival for the entire study population. Patients with CA 19-9 levels above the median of 300 units/mL had a nearly 3-fold risk for early death (hazard ratio, 2.92; 95% confidence interval, 1.51-5.64; adjusted P = 0.002) as compared with patients with CA 19-9 levels ≤300 units/mL. An association between CA 19-9 and therapeutic response was observed in the non-stent subgroup (P = 0.001) only. Furthermore, the decrease of CA 19-9 levels after treatment was predictive for improved survival in the non-stent subgroup (adjusted P = 0.018) but not in the stent subgroup. Our results indicate that pretreatment CA 19-9 levels and CA 19-9 decrease after chemotherapy are of prognostic relevance in patients with BTC. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2097–100)
Factors Associated with Human Small Aggressive Non–Small Cell Lung Cancer
Authors: Tammemagi C. Martin , Freedman Matthew T. , Church Timothy R. , Oken Martin M. , Hocking William G. , Kvale Paul A. , Hu Ping , Riley Thomas L. , Ragard Lawrence R. , Prorok Philip C. , Berg Christine D.
Published: October 2007

Background: Some non–small cell lung cancers (NSCLC) progress to distant lymph nodes or metastasize while relatively small. Such small aggressive NSCLCs (SA-NSCLC) are no longer resectable with curative intent, carry a grave prognosis, and may involve unique biological pathways. This is a study of factors associated with SA-NSCLC.

Methods: A nested case-case study was embedded in the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. SA-NSCLC cases had stage T1, N3, and/or M1 NSCLC (n = 48) and non–SA-NSCLC cases had T2 to T3, N0 to N2, and M0 NSCLC (n = 329). Associations were assessed by multiple logistic regression.

Results: SA-NSCLCs were associated with younger age at diagnosis [odds ratio (OR)≥65 versus <65, 0.44; 95% confidence interval (95% CI), 0.22-0.88], female gender, family history of lung cancer, and the interaction gender*family history of lung cancer and were inversely associated with ibuprofen use (ORyes versus no, 0.29; 95% CI, 0.11-0.76). The ORs for associating gender (women versus men) with SA-NSCLC in those with and without a family history of lung cancer were 11.76 (95% CI, 2.00-69.22) and 1.86 (95% CI, 0.88-3.96), respectively. These associations held adjusted for histology and time from screening to diagnosis and when alternative controls were assessed.

Conclusion: SA-NSCLC was associated with female gender, especially in those with a family history of lung cancer. If these exploratory findings, which are subject to bias, are validated as causal, elucidation of the genetic and female factors involved may improve understanding of cancer progression and lead to preventions and therapies. Ibuprofen may inhibit lung cancer progression. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2082–9)
Can Language-Concordant Prevention Care Managers Improve Cancer Screening Rates?
Authors: Beach Michael L. , Flood Ann Barry , Robinson Christina M. , Cassells Andrea N. , Tobin Jonathan N. , Greene Mary Ann , Dietrich Allen J.
Published: October 2007

Objective: There is evidence that non-English speakers in the United States receive lower quality health care and preventive services than English speakers. We tested the hypothesis that Spanish-speaking women would respond differently to an intervention to increase up-to-date status for cancer screening.

Study Design and Setting: A multisite randomized controlled trial showed that scripted telephone support, provided by a Prevention Care Manager (PCM), increased up-to-date rates for breast, cervical, and colorectal cancer screening. This subgroup analysis investigated the relative efficacy of the PCM among women who chose to communicate with the PCM in Spanish versus English.

Results: Of 1,346 women in this analysis, 63% were Spanish speakers. Whereas the PCM intervention increased cancer screening rates generally, Spanish-speaking women seemed to benefit disproportionately more than English-speaking women for cervical cancer screening (unadjusted odds ratio, 1.77; 95% confidence interval, 1.03-3.05). In addition, in this exploratory analysis, there was a trend toward Spanish-speaking women receiving more benefit than English-speaking women from the intervention in increased breast and colorectal cancer screening rates.

Conclusion: Spanish-speaking women seemed to benefit more than did English-speaking women from a bilingual telephone support intervention aimed at increasing cancer screening rates. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2058–64)