bluuebunny/crossref_metadata_2025 huggingface dataset:
Restoration of Cytoadherence to an Adherence-Deficient Mutant ofMycoplasma arthritidisby Genetic Complementation
Authors: Washburn Leigh R. , Bird Daniel W. , Dybvig Kevin
Published: January 2003

Mycoplasma arthritidiscauses a severe septic arthritis in rats under natural and experimental conditions. An earlier study implicated a membrane lipoprotein designated MAA1 in cytadherence ofM. arthritidis. In addition, a spontaneous adherence-deficient mutant was shown to contain a nonsense mutation in the gene encoding MAA1, resulting in production of a truncated product, MAA1Δ. In the present study, a wild-typemaa1gene carried on transposon Tn4001Twas introduced into the low-adherence mutant by polyethylene glycol-mediated transformation. The presence of the tranposon and the wild-typemaa1gene in the chromosome of transformants was confirmed by PCR and Southern hybridization. The latter procedure also confirmed that each transformant contained a single copy of the transposon. Western immunoblotting showed that transformants produced both wild-type MAA1 and MAA1Δ, indicating that the introduced wild-typemaa1gene was functional. This phenotype was stably maintained after multiple subcultures even in the absence of antibiotic selection. Finally, transformants were shown to adhere to rat L-2 lung cells in culture at wild-type levels, providing confirmation for an important role for MAA1 in adherence.
Roles of Sortase in Surface Expression of the Major Protein Adhesin P1, Saliva-Induced Aggregation and Adherence, and Cariogenicity of
Streptococcus mutans
Authors: Lee Song F. , Boran Thomas L.
Published: January 2003

Sortase is a newly discovered transpeptidase that covalently links LPXTGX-containing surface proteins to the gram-positive bacterial cell wall. In this study, the sortase gene (
srtA
) was isolated from
Streptococcus mutans
NG8 by PCR. The gene encoded a 246-amino-acid protein, including a 40-amino-acid signal peptide. The
srtA
gene was insertionally inactivated by a tetracycline resistance cassette. P1, a major surface protein adhesin previously shown to anchor to the peptidoglycan by the LPXTGX motif, was secreted into the culture medium by the
srtA
mutant. In contrast, the wild-type P1 remained cell wall associated. Complementation of the mutant with
srtA
restored the P1 surface expression phenotype. P1 produced by the mutant, but not that produced by the wild type and the
srtA
-complemented mutant, was recognized by an antibody raised against the hydrophobic domain and charged tail C terminal to the LPXTGX motif. These results suggest that the failure to anchor P1 to the cell wall is due to the lack of cleavage of P1 at the LPXTGX motif. The
srtA
mutant was markedly less hydrophobic than the wild type and the complemented mutant. The
srtA
mutant failed to aggregate in the presence of saliva or salivary agglutinin and adhered poorly to saliva- or salivary agglutinin-coated hydroxylapatite. In rats, the
srtA
mutant colonized the teeth poorly when sucrose was absent. When sucrose was present, the
srtA
mutant colonized the teeth but less effectively and induced significantly less caries (
P
< 0.05) than the wild-type strain. In conclusion, the sortase enzyme in
S. mutans
is responsible for anchoring P1 to the cell surface and plays a role in modulating the surface properties and cariogenicity of
S. mutans
.
Different Innate Ability of I/St and A/Sn Mice To Combat VirulentMycobacterium tuberculosis: Phenotypes Expressed in Lung and Extrapulmonary Macrophages
Authors: Majorov Konstantin B. , Lyadova Irina V. , Kondratieva Tatiana K. , Eruslanov Eugeny B. , Rubakova Elvira I. , Orlova Marianna O. , Mischenko Vladimir V. , Apt Alexander S.
Published: January 2003

Mice of the I/St and A/Sn inbred strains display a severe and moderate course, respectively, of disease caused byMycobacterium tuberculosis. Earlier, we showed that the response to mycobacterial antigens in I/St mice compared to that in A/Sn mice is shifted toward Th2-like reactivity and a higher proliferative activity and turnover of T cells. However, the physiologic basis for different expressions of tuberculosis severity in these mice remains largely unknown. Here, we extend our previous observations with evidence that I/St interstitial lung macrophages are defective in the ability to inhibit mycobacterial growth and to survive following in vitro infection withM. tuberculosisH37Rv. A unique feature of this phenotype is its exclusive expression in freshly isolated lung macrophages. The defect is not displayed in ex vivo macrophages obtained from the peritoneal cavity nor in macrophages developed in vitro from progenitors extracted from various organs, including the lung itself. In addition, we show that, in sharp contrast to peritoneal macrophages, the mycobactericidal capacity of lung macrophages is not elevated in the presence of exogenous gamma interferon. Our data suggest that the in vivo differentiation in a particular anatomical microenvironment determines the pattern of macrophage-mycobacterium interaction. Thus, caution should be exercised when conclusions based upon the results obtained in a particular in vitro system are generalized to the functions of all phagocytes duringM. tuberculosisinfection.
Elevated Immunoglobulin E against RecombinantBrugia malayiγ-Glutamyl Transpeptidase in Patients with Bancroftian Filariasis: Association with Tropical Pulmonary Eosinophilia or Putative Immunity
Authors: Lobos Edgar , Nutman Thomas B. , Hothersall John S. , Moncada Salvador
Published: January 2003

A major allergen of the lymphatic filarial nematodeBrugia malayi, a homologue of γ-glutamyl transpeptidase (γ-GT), is involved in the pathology of tropical pulmonary eosinophilia (TPE) through its potent allergenicity and the induction of antibodies against the host pulmonary epithelium. To investigate the immunoglobulin G (IgG) subclass and IgE responses to recombinantB. malayiγ-GT, we analyzed the results obtained from 51 patients with differing clinical manifestations of bancroftian filariasis. γ-GT-specific IgG1, rather than IgG4, was the predominant IgG subclass, particularly in patients with TPE (geomean, 6,321 ng/ml; range, 78 to 354,867 ng/ml) and was 75 times higher than in patients with elephantiasis (CP) (P< 0.003) and 185 times higher than in endemic normal individuals (ENL) (P< 0.010). IgG2 responses were low and IgG3 was almost absent, with no significant differences among the groups. γ-GT-specific IgG4 responses were significantly elevated in those with subclinical microfilaremia (MF) compared to the CP and ENL groups and correlated with the presence of circulating filarial antigen (CAg). More significantly, γ-GT-specific IgE antibody levels were strikingly elevated in patients with TPE (geomean, 681 ng/ml; range, 61 to 23,841 ng/ml) and in the ENL group (geomean, 106 ng/ml; range, 13 to 1,405 ng/ml) whereas the γ-GT-specific IgE level was 44 and 61 times lower in those with MF and CP, respectively (P< 0.001). Elevated γ-GT-specific IgE/IgG4 ratios were demonstrated in patients with TPE (ratio, 45) and ENL (ratio, 107). Because expression of γ-GT inBrugiainfective third-stage larvae (L3) was demonstrated by immunoblot analysis, the elevated γ-GT-specific IgE antibodies appear to be associated not only with pulmonary pathology but also with possible resistance to infection in lymphatic filariasis.
Characterization of the Conformational Epitope of Guy's 13, a Monoclonal Antibody That Prevents
Streptococcus mutans
Colonization in Humans
Authors: van Dolleweerd Craig J. , Chargelegue Daniel , Ma Julian K.-C.
Published: January 2003

Guy's 13 is a mouse monoclonal antibody which recognizes streptococcal antigen I/II (SA I/II), a major cell surface glycoprotein of
Streptococcus mutans
. In a number of clinical trials, this antibody has been shown to prevent colonization in the human oral cavity. The aim of this study was to identify the SA I/II epitope recognized by Guy's 13. The data suggest that the epitope is conformational, delimited by two noncontiguous regions of the antigen: residues 45 to 457, within the N-terminal half of SA I/II, and residues 816 to 983, within the C-terminal half. In fluid-phase immunoassays a strict requirement for the simultaneous presence of both regions was demonstrated for antibody binding. Furthermore, these two regions of SA I/II were shown to have the ability to interact with each other in the absence of Guy's 13 antibody, suggesting that the normal conformation of SA I/II might be determined by the interaction of these two regions.
Colonization of C57BL/6J and BALB/c Wild-Type and Knockout Mice withHelicobacter pylori: Effect of Vaccination and Implications for Innate and Acquired Immunity
Authors: Panthel Klaus , Faller Gerhard , Haas Rainer
Published: January 2003

The gram-negative bacterial pathogenHelicobacter pyloriis a major cause of peptic ulcer disease and a risk factor for gastric cancer in humans. AdaptedH. pyloristrains, such as strain SS1, are able to infect mice and are a useful model for gastric colonization and vaccination studies. In this study we used a streptomycin-resistant derivative ofH. pyloriSS1 to analyze the colonization behavior and the success of vaccination in wild-type (wt) and various knockout mice of the BALB/c and C57BL/6J genetic backgrounds. We here report that BALB/c interleukin-4 knockout (IL-4−/−) mice are weakly overcolonized compared to the wt strain but that the IL-12−/−knockout results in a strong overcolonization (500%). Unexpectedly, in the C57BL/6J background the same knockouts behaved in diametrically opposed manners. The IL-4−/−mutation caused a 50% reduction and the IL-12−/−knockout caused a 95% reduction compared to the wt colonization rate. For C57BL/6J mice we further analyzed the IL-18−/−and Toll-like receptor 2 knockout mutations, which showed reductions to 66 and 57%, respectively, whereas mice with the IL-10−/−phenotype were hardly infected at all (5%). In contrast, the tumor necrosis factor receptor knockout (p55−/−and p55/75−/−) mice showed an overcolonization compared to the C57BL/6J wt strain. With exception of the low-level infected C57BL/6J IL-10−/−and IL-12−/−knockout mice, all knockout mutants were accessible to a prophylactic vaccination and their vaccination behavior was comparable to that of the wt strains.
Does Host Complement KillBorrelia burgdorferiwithin Ticks?
Authors: Rathinavelu Sivaprakash , Broadwater Anne , de Silva Aravinda M.
Published: January 2003

The Lyme disease spirochete,Borrelia burgdorferi, inhabits the gut lumen of the tick vector. At this location the spirochete is exposed to host blood when a tick feeds. We report here on studies that were done with normal and complement-deficient (C3-knockout) mice to determine if the host complement system killed spirochetes within the vector. We found that spirochete numbers within feeding nymphs were not influenced by complement, most likely because host complement was inactivated within the vector. The Lyme disease outer surface protein A (OspA) vaccine is a transmission-blocking vaccine that targets spirochetes in the vector. In experiments with mice hyperimmunized with OspA, complement was not required to kill spirochetes within nymphs and to block transmission from nymphs to the vaccinated host. However, host complement did enhance the ability of OspA antibody to block larvae from acquiring spirochetes. Thus, the effects of OspA antibody on nymphal transmission and larval acquisition appear to be based on different mechanisms.
Effect of Inhibition of Extracellular Signal-Regulated Kinase 1 and 2 Pathway on Apoptosis andbcl-2Expression inHelicobacter pylori-Infected AGS Cells
Authors: Choi Il Ju , Kim Joo Sung , Kim Jung Mogg , Jung Hyun Chae , Song In Sung
Published: January 2003

Helicobacter pyloriinduces activation of mitogen-activated protein kinases (MAPKs). However, its effect onH. pylori-induced apoptosis has not been evaluated. Thus, we examined whetherH. pylori-induced extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 MAPK activation affects gastric epithelial cell apoptosis andbcl-2family gene expression, especially in relation to thecagAstatus of anH. pyloristrain. In flow cytometric and oligonucleosome-bound DNA enzyme-linked immunosorbent assay analyses, infection withcagA+H. pyloristrains induced gastric cancer cell apoptosis in AGS cells more prominently than infection withcagAmutants. Activation of ERK1/2 and p38 MAPKs was also more prominent incagA+strains. Pretreatment with a MEK inhibitor (PD98059) inhibited ERK1/2 activation and increasedH. pylori-induced apoptosis significantly. This increased apoptosis was accompanied by decreased antiapoptoticbcl-2mRNA expression amongbcl-2-related genes (bcl-2,bax,bak,mcl-1, andbcl-XL/S), and the effect was also more prominent in thecagA+strains. However, the alteration ofbcl-2gene expression was not accompanied by protein level changes. Inhibition of p38 using specific inhibitor SB203580 decreasedH. pylori-induced apoptosis but resulted in little alteration ofbcl-2-related gene expression. In conclusion,H. pylori-induced ERK1/2 activation, especially by thecagA+H. pyloristrain, may play a protective role against gastric epithelial cell apoptosis partially through maintenance ofbcl-2gene expression.
Entamoeba histolytica
Cysteine Proteinases Disrupt the Polymeric Structure of Colonic Mucin and Alter Its Protective Function
Authors: Moncada Darcy , Keller Kathy , Chadee Kris
Published: January 2003

The adherent mucous gel layer lining the colonic epithelium is the first line of host defense against invasive pathogens, such as
Entamoeba histolytica
. The mucous layer prevents the attachment of amoeba to the colonic epithelium by trapping and aiding in the expulsion of the parasite. Disruption of the mucous layer is thought to occur in invasive amebiasis, and the mechanism by which the parasite overcomes this barrier is not known. The aim of this study was to characterize the specific interactions occurring between
E. histolytica
secreted cysteine proteinases and colonic mucin as a model to examine the initial events of invasive amebiasis.
E. histolytica
secreted products were examined for mucinase activity utilizing mucin metabolically labeled with [
35
S]cysteine as a substrate. Cysteine proteinases degraded mucin in a time- and dose-dependent manner. A significant reduction (>50%) in high-molecular-weight mucin with altered buoyant density was observed when degraded mucin was analyzed by Sepharose 4B column chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography, and CsCl density gradient centrifugation. Mucinase activity was eliminated by the specific cysteine protease inhibitor
trans
-epoxysuccinyl-
l
-leucylamido-(4-guanidino)butane and was independent of glycosidase activity. Moreover, the degraded mucin was 38% less effective than native mucin at inhibiting amebic adherence to target epithelial cells. These results are the first to show that
E. histolytica
cysteine proteinases alter the protective function of the mucous barrier by disrupting the structure of the MUC2 polymer. Mechanistically, the parasite achieves this via proteolytic degradation of the terminal cysteine-rich domains.
DNA from Periodontopathogenic Bacteria Is Immunostimulatory for Mouse and Human Immune Cells
Authors: Nonnenmacher Claudia , Dalpke Alexander , Zimmermann Stefan , Flores-de-Jacoby Lavin , Mutters Reinier , Heeg Klaus
Published: January 2003

Although bacterial DNA (bDNA) containing unmethylated CpG motifs stimulates innate immune cells through Toll-like receptor 9 (TLR-9), its precise role in the pathophysiology of diseases is still equivocal. Here we examined the immunostimulatory effects of DNA extracted from periodontopathogenic bacteria. A major role in the etiology of periodontal diseases has been attributed toActinobacillus actinomycetemcomitans,Porphyromonas gingivalis, andPeptostreptococcus micros.We therefore isolated DNA from these bacteria and stimulated murine macrophages and human gingival fibroblasts (HGF) in vitro. Furthermore, HEK 293 cells transfected with human TLR-9 were also stimulated with these DNA preparations. We observed that DNA from these pathogens stimulates macrophages and gingival fibroblasts to produce tumor necrosis factor alpha and interleukin-6 in a dose-dependent manner. Methylation of the CpG motifs abolished the observed effects. Activation of HEK 293 cells expressing TLR-9 which were responsive to bDNA but not to lipopolysaccharide confirmed that immunostimulation was achieved by bDNA. In addition, the examined bDNA differed in the ability to stimulate murine macrophages, HGF, and TLR-9-transfected cells. DNA fromA. actinomycetemcomitanselicited a potent cytokine response, while DNA fromP. gingivalisandP. microsshowed lower immunostimulatory activity. Taken together, the results strongly suggest that DNA fromA. actinomycetemcomitans,P. gingivalis, andP. microspossesses immunostimulatory properties in regard to cytokine secretion by macrophages and fibroblasts. These stimulatory effects are due to unmethylated CpG motifs within bDNA and differ between distinct periodontopathogenic bacteria strains. Hence, immunostimulation by DNA fromA. actinomycetemcomitans,P. gingivalis, andP. microscould contribute to the pathogenesis of periodontal diseases.
Immunopathogenesis of Pulmonary Granulomas in the Guinea Pig after Infection withMycobacterium tuberculosis
Authors: Turner Oliver C. , Basaraba Randall J. , Orme Ian M.
Published: January 2003

Pulmonary tuberculosis in guinea pigs is similar to the disease in humans and is accordingly widely used as a model to test tuberculosis vaccines. The primary site of expression of acquired immunity and the hallmark of tuberculosis is the granuloma. Granuloma morphology is well described, but there is limited information regarding T-cell subset influx. We monitored the course of pulmonary tuberculosis in guinea pigs and observed four distinct immunohistopathological stages. In all stages there were similar numbers and arrangement of CD4 and CD8 T cells. There were only small numbers of apoptotic lymphocytes, scattered around and within the necrotic core, and acid-fast bacilli were visible both within macrophages and free within airway debris. A key finding of the study was the observation that the development of the necrotic core was an early event and almost certainly preceded the emergence of the acquired immune response. This in turn suggests that innate mechanisms are the basis of the early lesions and that subsequent acquired responses are unable to moderate them. This hypothesis differs from the current dogma that excessive activity of T cells mediates delayed-type hypersensitivity and that cellular cytolysis is the root cause of the necrosis.
Phagocytosis and Intracellular Fate ofAspergillus fumigatusConidia in Alveolar Macrophages
Authors: Ibrahim-Granet O. , Philippe B. , Boleti H. , Boisvieux-Ulrich E. , Grenet D. , Stern M. , Latgé J. P.
Published: January 2003

Aspergillus fumigatusis the most prevalent airborne fungal pathogen responsible for fatal invasive aspergillosis in immunocompromised patients. Upon arrival in the lung alveolus, conidia ofA. fumigatusare phagocytosed by alveolar macrophages, the major phagocytic cells of the lung. Engulfment and intracellular trafficking ofA. fumigatusconidia in alveolar macrophages of two different origins, the murine cell line MH-S and human pulmonary alveolar macrophages, were analyzed by electron microscopy and immunofluorescence. Phagocytosis ofA. fumigatusconidia required actin polymerization and phosphatidylinositol 3-kinase activity. Fusion ofA. fumigatusphagosomes with early and late endosomes was shown by immunolabeling with specific markers for the transferrin receptor, early endosome antigen, and Rab7. Maturation ofA. fumigatusphagolysosomes was monitored by using a fixable acidotropic probe, LysoTracker Red DND-99, and an anti-cathepsin D antibody. Bafilomycin A-induced inhibition of lysosomal acidification abolished the conidial killing by the macrophages. These data suggest that the maturation ofA. fumigatusphagosomes results from fusion with the compartments of the endocytic pathway and that the killing of conidia depends on phagolysosome acidification. A model for the phagocytosis ofA. fumigatusconidia by alveolar macrophages is proposed on the basis of these results.
Transposon Mutagenesis ofMycobacterium marinumIdentifies a Locus Linking Pigmentation and Intracellular Survival
Authors: Gao Lian-Yong , Groger Richard , Cox Jeffery S. , Beverley Stephen M. , Lawson Elise H. , Brown Eric J.
Published: January 2003

Pathogenic mycobacteria survive and replicate within host macrophages, but the molecular mechanisms involved in this necessary step in the pathogenesis of infection are not completely understood.Mycobacterium marinumhas recently been used as a model for aspects of the pathogenesis of tuberculosis because of its close genetic relationship toMycobacterium tuberculosisand because of similarities in the pathology and course of infection caused by this organism in its natural hosts, fish and frogs, with tuberculosis in humans. In order to advance the utility of theM. marinummodel, we have developed efficient transposon mutagenesis of the organism by using aDrosophila melanogaster mariner-based transposon. To determine the efficiency of transposition, we have analyzed pigmentation mutants from the transposon mutant library. In addition to insertions in four known genes in the pathway of pigment biosynthesis, two insertions in novel genes were identified in our mutant library. One of these is in a putative inhibitor of the carotenoid biosynthesis pathway. The second unexpected insertion is in an intergenic region between two genes homologous toRv2603candRv2604cofM. tuberculosis. In addition to a pigmentation defect, this mutant showed increased susceptibility to singlet oxygen and grew poorly in murine macrophages. Complementation withM. tuberculosisgenomic DNA encompassingRv2603ctoRv2606ccorrected the pigmentation and growth defects of the mutant. These data demonstrate the utility ofmariner-based transposon mutagenesis ofM. marinumand thatM. marinumcan be used to study the function ofM. tuberculosisgenes involved in intracellular survival and replication.
Restricted Expression of Shiga Toxin Binding Sites on Mucosal Epithelium of Mouse Distal Colon
Authors: Imai Yasuyuki , Fukui Takashi , Kurohane Kohta , Miyamoto Daisei , Suzuki Yasuo , Ishikawa Tomoyuki , Ono Yousuke , Miyake Masaki
Published: January 2003

Shiga toxins (Stx) are some of the major virulence factors of enterohemorrhagicEscherichia colistrains such as serotype O157:H7. To explore how Stx might initially gain access to the bloodstream from sites of infection, frozen sections of mouse colon were immunohistochemically examined for binding sites for recombinant binding subunits (Stx1B). Binding sites were selectively expressed on the epithelium in the distal half of the mouse colon, whereas the proximal half did not exhibit any binding sites. In agreement with this observation, we also demonstrated the distal-part-restricted distribution of glycolipids that bind to Stx1B in the mouse colon. For comparison, the binding sites of several control lectins were also examined. Selective binding to the distal part of the colon was not seen with any other control lectins, includingGriffonia simplicifolialectin-I isolectin B4 (GS-I-B4), which shares α-galactose specificity with Stx1B. Partial overlapping of the specificities of Stx1B and GS-I-B4 was seen by assay with globotriose-conjugated multivalent ligands. The results indicate that Stx1B is stricter in the recognition of carbohydrate determinants than GS-I-B4 when examined with biological ligands.
Epithelial Cell Surface Sites Involved in the Polyvalent Adherence of
Porphyromonas gingivalis
: a Convincing Role for Neuraminic Acid and Glucuronic Acid
Authors: Agnani G. , Tricot-Doleux S. , Houalet S. , Bonnaure-Mallet M.
Published: January 2003

We investigated the target structures of the epithelial cells responsible for the attachment of
Porphyromonas gingivalis
by immunocytofluorimetry, enzyme-linked immunosorbent assay, and confocal microscopy. Integrins (β1, β3, and αV) and E-cadherin played no significant role. Carbohydrates (such as α
-d-
methylglucoside,
l-
fucose,
d-
and
l-
mannose,
N-
acetylglucosamine, and
N-
acetylgalactosamine) had little inhibitory effect on bacterial binding. Enzymatic treatments of the epithelial membranes and sugar competition studies showed that
N-
acetylneuraminic acid and glucuronic acid were involved in binding.
ON THE CLIQUE–WIDTH OF GRAPH WITH FEW P4'S
Authors: MAKOWSKY J. A. , ROTICS U.
Published: January 2003

Babel and Olariu (1995) introduced the class of (q, t) graphs in which every set of q vertices has at most t distinct induced P4s. Graphs of clique-width at most k were introduced by Courcelle, Engelfriet and Rozenberg (1993) as graphs which can be defined by k-expressions based on graph operations which use k vertex labels. In this paper we study the clique–width of the (q, t) graphs, for almost all possible combinations of q and t. On one hand we show that every (q, q - 3) graph for q ≥ 7, has clique–width ≤ q and a q–expression defining it can be obtained in linear time. On the other hand we show that the class of (q, q - 3) graphs for 4 ≤ q ≤ 6 and the class of (q, q - 1) graphs for q ≥ 4 are not of bounded clique-width.
A NEW ROBUST TWO DIMENSIONAL SPECTRAL ESTIMATION BASED ON AN AR MODEL EXCITED BY A t DISTRIBUTION PROCESS AND ITS QR-DECOMPOSITION RECURSIVE ALGORITHM
Authors: SANUBARI JUNIBAKTI , TOKUDA KEIICHI
Published: January 2003

In this paper a novel robust two dimensional spectral estimation based on an AR model is proposed. The robustness of the method is obtained by assuming that the output or the residual signals are independently and identically distributed (IID) t-processes with small; α degrees of freedom. By doing so, the effect of large amplitude residuals is reduced. To reduce the calculation burden, the optimal solution is recursively calculated by incorporating the QR-decomposition method. The optimal solution is updated each time the number of input samples grows. Simulation results show that when the excitation is Gaussian, the obtained estimate by using large and small α are comparable. On the other hand, when the excitation is impulsive, the obtained estimate after 100 by 100 pixels iterations by using small α ; i.e.  α = 3; is more accurate than that obtained by using α = ∞ which is applied in the conventional least square approach. The plots of the mean square error (MSE) show that by using small α we can achieve smaller MSE's than that by using large α.
EXOR DECOMPOSITION WITH COMMON VARIABLES AND ITS APPLICATION TO MULTIPLE-OUTPUT NETWORKS
Authors: ISHIKAWA RYOJI , KODA GORO , SHIMIZU KENSUKE , HIRAYAMA TAKASHI
Published: January 2003

This paper presents an EXOR decomposition with common variable sets, which is an attempt to decompose an n-variable logic function f into two (n - 1)-variable subfunctions g0 and g1 by using exclusive-or (EXOR) operation. We present the conditions and formulas for the decomposition. We also consider the subfunction-sharing method for multiple-output networks as n application of the EXOR decomposition. Experimental results show that the area of networks is often reduced effectively by sharing the subfunctions obtained by the decomposition.
CONVERGENCE IMPROVEMENT OF ADAPTIVE LATTICE ALGORITHM WITH FUZZY BASED ADAPTIVE GAIN
Authors: RYU GEUN-TAEK , KIM DAE-SUNG , LEE DAE-YOUNG , HAN SUNG-HWAN , BAE HYEON-DEOK
Published: January 2003

The choice of the adaptive gain is important to the performance of LMS-based adaptive filters. Depending on application areas, the realization structure of the filters is also important. This letter presents an adaptive lattice algorithm which adjusts the adaptive gain of LMS using fuzzy if-then rules determined by matching input and output variables during adaptation procedure. In each lattice filter stage, this filter adjusts the adaptive gain as the output of the fuzzy logic which has two input variables, normalized squared forward prediction error and one step previous adaptive gain. The proposed algorithm is applied to echo canceling problem of long distance communication channel. The simulation results are compared with NLMS on TDL and lattice structures.
EFFICIENT DESIGN OF BINARY TO RNS CONVERTERS
Authors: ANANDA MOHAN P. V.
Published: January 2003

In this paper, the choice of composite moduli for realising a large dynamic range RNS is considered. The objective is to reduce the hardware as well as conversion time for Binary to RNS conversion. The proposed designs use two stages of conversion, the first using Periodicity properties of 2x mod mi and second using Binary to RNS conversion architectures proposed in literature due to Alia–Martinelli,1 Capocelli–Giancarlo2 and Stouraits et al.7 Detailed comparison regarding the area requirements and conversion time are presented. The proposed architectures do not need any ROMs for binary to RNS conversion. The results have been extended to the case of even moduli as well due to the recent interest in using one even modulus in certain RNSs.
A CHARGE RECYCLING TECHNIQUE FOR THE DESIGN OF LOW POWER CMOS CLOCK DRIVERS
Authors: NIKOLAIDIS S. , KYRIAKIS-BITZAROS E. D.
Published: January 2003

The design of low power CMOS clock drivers using a charge recycling technique is introduced in this paper. Considering a clock signal and its complement, the half of the charge stored in the load capacitances is reused in every clock edge. The proposed circuit exploits the inherent input-output delay of the driver for the generation of all necessary control signals, using fully digital logic and conventional technology. Extensive simulations of the circuit have been performed and the influence of various design parameters on its response has been studied. Compared to traditional taper buffers, power savings over 45% are obtained for the output load transitions whereas the total power reduction decreases by 10% to 35% due to control overhead. Moreover, no speed degradation is observed but almost a duplication of the silicon area is required.
ORDERED BINARY DECISION DIAGRAMS AND THEIR SIGNIFICANCE IN COMPUTER-AIDED DESIGN OF VLSI CIRCUITS
Authors: MEINEL CHRISTOPH , THEOBALD THORSTEN
Published: January 2003

Many problems in computer-aided design of highly integrated circuits (CAD for VLSI) can be transformed to the task of manipulating objects over finite domains. The efficiency of these operations depends substantially on the chosen data structures. In the last years, ordered binary decision diagrams (OBDDs) have proven to be a very efficient data structure in this context. Here, we give a survey on these developments and stress the deep interactions between basic research and practically relevant applied research with its immediate impact on the performance improvement of modern CAD design and verification tools.
ANALYSIS AND SIMULATION OF BUFFERED B-NETWORKS
Authors: LAU F. C. M. , CHAN J.
Published: January 2003

The B-network was first studied by Lee and Yoon. The systematic imbalance of the internal link traffic, which was overlooked, was rectified by Lau & Poon. The rectified model was then simulated with buffer added at the input and/or output stage. In this paper, the performance of buffered B-network is fully investigated. The packet arrival rates in each link, throughput and average delay of the network are derived mathematically. They are then compared with the simulation results. Finally, comparisons are made on the throughput and average delay performance between buffered B-networks, unbuffered B-networks, gamma networks and crossbar networks.
CHAOTIC OSCILLATOR CONFIGURATION USING A FREQUENCY DEPENDENT NEGATIVE RESISTOR
Authors: ELWAKIL A. S. , KENNEDY M. P.
Published: January 2003

Chaos is observed from a fourth-order autonomous circuit inspired by Chua's circuit and obtained by replacing the active symmetric nonlinear resistor (Chua's diode) with a parallel combination of a frequency dependent negative resistor (FDNR) and a general-purpose signal diode. Accordingly, nonlinearity is introduced by a passive device with antisymmetric current-voltage characteristics whereas activity is transferred to the FDNR. The observed chaotic attractor has similar dynamics to the Colpitts chaotic attractor and we show its topological equivalence to the well-known Rossler attractor. Experimental results, PSpice simulations and numerical simulations of the derived mathematical models are included.
APPLICATION OF THE SENSITIVITY THEORY IN MICROWAVE MEASUREMENTS
Authors: LADVÁNSZKY J.
Published: January 2003

In the measurement of reflection coefficient, inaccuracy of the calibration standards may result in the measurement inaccuracy. It is shown that circuit theoretical methods6 are applicable for the reduction of this kind of measurement inaccuracy. Two methods for the reduction of such measurement inaccuracy are introduced and verified in examples.
SIMILARITY-BASED SUBSEQUENCE SEARCH IN IMAGE SEQUENCE DATABASES
Authors: PARK SANGHYUN , CHU WESLEY W.
Published: January 2003

This paper proposes an indexing technique for fast retrieval of similar image subsequences using the multi-dimensional time warping distance. The time warping distance is a more suitable similarity measure as compared to the Lp distance in many applications where sequences may be of different lengths and/or different sampling rates. Our indexing scheme employs a disk-based suffix tree as an index structure and uses a lower-bound distance function to filter out dissimilar subsequence without false dismissals. It applies the normalization for an easier control of relative weighting of feature dimensions and the discretization to compress the index tree. Experiments on medical and synthetic image sequences verified that the proposed method significantly outperforms the naïve method and scales well in a large volume of image sequence databases.
FACE ANNOTATION FOR FAMILY PHOTO ALBUM MANAGEMENT
Authors: CHEN LONGBIN , HU BAOGANG , ZHANG LEI , LI MINGJING , ZHANG HONGJIANG
Published: January 2003

In this paper, we propose a framework to semi-automatically annotate faces in family photo albums. The core of the framework is the features used to define face similarity and this results in the learning algorithm used to refine automatic face annotation. We have adopted similarity based search and relevance feedback ideas developed for content-based image retrieval and a set of simple yet effective color and texture based features, in addition to the traditional face recognition features, in performing candidate annotation search. The experimental evaluation of the proposed approach has been conducted with a family album of 1707 photos and the results show that the proposed approach is an effective and efficient one for semi-automatic family photo album annotation.
SEMANTIC VIDEO TRANSCODING USING CLASSES OF RELEVANCE
Authors: CUCCHIARA RITA , GRANA COSTANTINO , PRATI ANDREA
Published: January 2003

In this work we present a framework for on-the-fly video transcoding that exploits computer vision-based techniques to adapt the Web access to the user requirements. The proposed transcoding approach aims at coping with both user bandwidth and resources capabilities, and with user interests in the video's content. We propose an object-based semantic transcoding that, according to the user-defined classes of relevance, applies different transcoding techniques to the objects segmented in a scene. Object extraction is provided by on-the-fly video processing, without manual annotation. Multiple transcoding policies are reviewed and a performance evaluation metric based on the Weighted Mean Square Error (and corresponding PSNR), that takes into account the perceptual user requirements by means of classes of relevance, is defined. Results are analyzed by varying transcoding techniques, bandwidth requirements and video types (with indoor and outdoor scenes), showing that the use of semantics can dramatically improve the bandwidth to distortion ratio.
Innate Immune Responses to Microbial Poisons: Discovery and Function of the Toll-Like Receptors
Authors: Beutler Bruce
Published: January 2003

There are many circumstances under which a toxin exploits an endogenous receptor or another protein of host origin to work its untoward effects. In most instances, the receptor normally fulfills a function that has nothing to do with the toxin per se; that is, the toxin is not the “natural” ligand. The situation with endotoxin, however, is a remarkable one. The endotoxin receptor evolved to detect endotoxin. Why have mammals maintained a gene that can undermine their survival? The search for the endotoxin receptor answered this question and also revealed the essential function and biological strategy of the Toll-like receptors: principal sensors of the innate immune system.
Telomere Inhibition and Telomere Disruption as Processes for Drug Targeting
Authors: Rezler Evonne M. , Bearss David J. , Hurley Laurence H.
Published: January 2003

The components and cofactors of the holoenzyme telomerase and its substrate telomeric DNA are attractive targets for anticancer agents that act by inhibiting the activity of telomerase. This review outlines recent advances in telomerase inhibition that have been achieved using antisense oligonucleotides and ribozymes that target the telomerase mRNA or its hTR RNA template. Although these are potent catalytic inhibitors of telomerase, they are challenging to implement in the clinic due to their delayed effectiveness. Drugs that directly bind to the telomeres, the complex structures that are associated at the telomeric ends, and stabilize secondary DNA structures such as G-quadruplexes are also potent inhibitors of telomerase. Special focus is given here to the telomeres, the biological machinery that works in tandem with telomerase to elongate telomeres, the causes of telomere disruption or dysfunction, and the consequences of disruption/dysfunction on the activity and design of anticancer agents.
Induction of Drug-Metabolizing Enzymes: A Path to the Discovery of Multiple Cytochromes P450
Authors: Conney Allan H.
Published: January 2003

This article provides a personal account of the discovery of the induced synthesis of drug-metabolizing enzymes and of subsequent research that led to the discovery of multiple cytochromes P450 with different catalytic activities. The manuscript also emphasizes the role of environmental factors (in addition to genetic polymorphisms) in explaining person-to-person and day-to-day differences in rates and pathways of drug metabolism that occur in the human population.
Trafficking of NMDA Receptors
Authors: Wenthold Robert J. , Prybylowski Kate , Standley Steve , Sans Nathalie , Petralia Ronald S.
Published: January 2003

The NMDA receptor (NMDAR) plays a central role in the function of excitatory synapses. Recent studies have provided interesting insights into several aspects of the trafficking of this receptor in neurons. The NMDAR is not a static resident of the synapse. Rather, the number and composition of synaptic NMDARs can be modulated by several factors. The interaction of PDZ proteins, generally thought to occur at the synapse, appears to occur early in the secretory pathway; this interaction may play a role in the assembly of the receptor complex and its exit from the endoplasmic reticulum. This review addresses recent advances in our understanding of NMDAR trafficking and its synaptic delivery and maintenance.
Signal Transduction–Directed Cancer Treatments
Authors: Sausville Edward A. , Elsayed Yusri , Monga Manish , Kim George
Published: January 2003

The pathogenic mechanisms giving rise to cancer frequently involve altered signal transduction pathways. Therefore therapeutic agents that directly address signal transduction molecules are being explored as cancer treatments. Inhibitors of protein tyrosine and threonine kinases including STI-571, ZD-1839, OSI-774, and flavopiridol are ATP-site antagonists that have completed initial phase I and phase II evaluations. Herceptin and C225 are monoclonal antibodies also directed against signaling targets. Numerous other kinase antagonists are in clinical evaluation, including UCN-01 and PD184352. Alternative strategies to downmodulate kinase-driven signaling include 17-allyl-amino-17-demethoxygeldanamycin and rapamycin derivatives, and phospholipase-directed signaling may be modulated by alkylphospholipids. Farnesyltransferase inhibitors were originally developed as inhibitors of ras-driven signals but may have activity by affecting other or additional targets. Signal transduction will remain a fertile basis for suggesting cancer treatments of the future, the evaluation of which should include monitoring effects of the drugs on their intended target signaling molecules in preclinical and early clinical studies.
Pharmacology and Physiology of Human Adrenergic Receptor polymorphisms
Authors: Small Kersten M. , McGraw Dennis W. , Liggett Stephen B.
Published: January 2003

Adrenergic receptors are expressed on virtually every cell type in the body and are the receptors for epinephrine and norepinephrine within the sympathetic nervous system. They serve critical roles in maintaining homeostasis in normal physiologic settings as well as pathologic states. These receptors are also targets for therapeutically administered agonists and antagonists. Recent studies have shown that at least seven adrenergic receptor subtypes display variation in amino acid sequence in the human population due to common genetic polymorphisms. Variations in potential regulatory domains in noncoding sequence are also present. Here, we review the consequences of these polymorphisms in terms of signaling, human physiology and disease, and response to therapy.
Progress Toward Clinical Application of the Nitric Oxide–Releasing Diazeniumdiolates
Authors: Keefer Larry K.
Published: January 2003

Diazeniumdiolates, compounds of structure R1R2NN(O)=NOR3, which have also been called NONOates, have proven useful for treating an increasing diversity of medical disorders in relevant animal models. Here, I review the chemical features that make them such excellent starting points for designing materials capable of targeting reliable and controllable fluxes of bioactive NO for in vitro and in vivo applications. This is followed by a consideration of recent proof-of-concept studies that underscore what I believe to be the substantial clinical promise of such materials. Examples covered include progress toward inhibiting restenosis after angioplasty, preparing thromboresistant medical devices, reversing vasospasm, and relieving pulmonary hypertension. Together with a very recent report describing the beneficial effects of diazeniumdiolate therapy in a patient with acute respiratory distress syndrome, the results of the animal experiments support the prediction that a broad selection of problems in clinical medicine can be solved by judiciously mining the enormous variety of possible R1R2NN(O)=NOR3 structures.
TheCaenorhabditis elegansDopaminergic System: Opportunities for Insights into Dopamine Transport and Neurodegeneration
Authors: Nass Richard , Blakely Randy D.
Published: January 2003

The neurotransmitter dopamine (DA) plays a central role in the coordination of movement, attention, and the recognition of reward. Loss of DA from the basal ganglia, as a consequence of degeneration of neurons in the substantia nigra, triggers postural instability and Parkinson's disease (PD). DA transporters (DATs) regulate synaptic DA availability and provide a conduit for the uptake of DA mimetic neurotoxins, which can be used to evoke neuronal death and Parkinson-like syndrome. Recently, we have explored the sensitivity of DA neurons in the nematode Caenorhabditis elegans to the Parkinsonian-inducing neurotoxin 6-hydroxydopamine (6-OHDA) and found striking similarities, including DAT dependence, to neurodegeneration observed in mammalian models. In this review, we present our findings in the context of molecular and behavioral dimensions of DA signaling in C. elegans with an eye toward opportunities for uncovering DAT mutants, DAT regulators, and components of toxin-mediated cell death.
The Role of Drug Transporters at the Blood-Brain Barrier
Authors: de Boer A.G. , van der Sandt I.C.J. , Gaillard P.J.
Published: January 2003

The blood-brain barrier (BBB) is a dynamic interface between the blood and the brain. It eliminates (toxic) substances from the endothelial compartment and supplies the brain with nutrients and other (endogenous) compounds. It can be considered as an organ protecting the brain and regulating its homeostasis. Until now, many transport systems have been discovered that play an important role in maintaining BBB integrity and brain homeostasis. In this review, we focus on the role of carrier- and receptor-mediated transport systems (CMT, RMT) at the BBB. These include CMT systems, such as P-glycoprotein, multidrug-resistance proteins 1–7, nucleoside transporters, organic anion transporters, and large amino-acid transporters; RMT systems, such as the transferrin-1 and -2 receptors; and the scavenger receptors SB-AI and SB-BI.
Protein Flexibility and Computer-Aided Drug Design
Authors: Wong Chung F. , McCammon J. Andrew
Published: January 2003

Although computational techniques are increasingly being used in computer-aided drug design, the effects due to protein flexibility are still ignored in many applications. This review revisits rigorous statistical mechanical methods for predicting binding affinity, discusses some recent developments for improving their speed and reliability, and examines faster approximate models for facilitating virtual screening and lead optimization.
Challenging Dogma: Thresholds for Genotoxic Carcinogens? The Case of Vinyl Acetate
Authors: Hengstler J.G. , Bogdanffy M.S. , Bolt H.M. , Oesch F.
Published: January 2003

Although many questions remain unanswered, the general principle of the sequence of events leading to cancer after exposure to genotoxic carcinogens has become increasingly clear. This helps to understand the parameters that influence the shape of the dose-effect curve for carcinogenesis, including metabolic activation and inactivation of carcinogens, DNA repair, cell cycle control, apoptosis, and control by the immune system. A linear dose-response relationship with no observable threshold seems to be a conservative but adequate description for the carcinogenic activity of many genotoxic carcinogens, such as aflatoxin B1, the tobacco-specific nitrosoketone NNK, and probably N,N-diethylnitrosamine. However, extrapolation models connecting the high-level risk to the zero intercept have clearly resulted in overestimations of risk. Vinyl acetate is an example that is discussed extensively in this review. At extremely high and toxic doses, vinyl acetate is carcinogenic in rats and mice and causes chromosomal aberrations. In tissues of contact, vinyl acetate is converted to acetic acid and acetaldehyde. Only when threshold levels are achieved do critical steps in the mechanism ultimately leading to cancer become active, namely pH reduction in exposed cells of more than 0.15 units leading to cytotoxicity, damage to DNA, and regenerative proliferation. Consistent with the known exposure to endogenous acetic acid and acetaldehyde, tissues sustain a certain level of exposure without adverse effects. Physiological modeling shows that the conditions necessary for carcinogenesis are in place only when threshold levels of vinyl acetate are exceeded. The example of vinyl acetate underlines the importance of toxicological research that unequivocally identifies genotoxic carcinogens acting through a threshold process.