bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alphavirus Replicon Particles as Candidate HIV Vaccines
Authors: Davis Nancy L. , West Ande , Reap Elizabeth , MacDonald Gene , Collier Martha , Dryga Sergey , Maughan Maureen , Connell Mary , Walker Chris , McGrath Kathryn , Cecil Chad , Ping Li‐Hua , Frelinger Jeff , Olmsted Robert , Keith Paula , Swanstrom Ronald , Williamson Carolyn , Johnson Philip , Montefiori David , Johnston Robert E. 
Published: September 2003

AbstractReplicon particles based on Venezuelan equine encephalitis virus (VEE) contain a self‐replicating RNA encoding the VEE replicase proteins and expressing a gene of interest in place of the viral structural protein genes. Structural proteins for packaging of replicon RNA into VEE replicon particles (VRPs) are expressed from separate helper RNAs. Aspects of the biology of VEE that are exploited in VRP vaccines include 1) expression of very high levels of immunogen, 2) expression of immunizing proteins in cells in the draining lymph node, and 3) the ability to induce mucosal immunity from a parental inoculation. Results of experiments with VRPs expressing green fluorescent protein or influenza virus hemagglutinin (HA) demonstrated that specific mutations in the VRP envelope glycoproteins affect both targeting in the draining lymph node and efficiency of the immune response in mice. VRPs expressing either the matrix‐capsid portion of Gag, the full‐length envelope gp160, or the secreted gp140 of cloned SIVsm H‐4i were mixed in a cocktail and used to immunize macaques at 0, 1, and 4 months. Neutralizing antibodies against SIVsm H‐4 were induced in 6 of 6 vaccinates and CTL in 4 of 6. An intrarectal challenge with the highly pathogenic SIVsm E660 was given at 5 months. A vaccine effect was seen in reduced peak virus loads, reduced virus loads both at set point and at 41 weeks postchallenge, and preserved or increased CD4 counts compared to controls. A candidate VRP HIV vaccine expressing Clade C Gag contains a sequence that is very close to the South African Clade C consensus and was selected from a recent seroconverter in the Durban cohort to represent currently circulating genotypes in South Africa. A GMP lot of this vaccine has been manufactured and tested for a phase I trial in the first months of 2002.
Medicinal Chemistry and Chemical Biology of New Generation Taxane Antitumor Agents
Authors: Ojima Iwao , Geney Raphaël , Ungureanu Ioana Maria , Li Dansu 
Published: September 2003

AbstractP‐glycoprotein (P‐GP)‐based multidrug resistance (MDR) and undesirable side effects are significant drawbacks to the clinical use of paclitaxel and docetaxel. Extensive SAR studies of taxanes in these laboratories led to the discovery of new generation taxanes that are highly active against not only drug‐sensitive but also drug‐resistant human cancer cell lines as well as tumor xenografts in mice. One of these second generation taxanes, SB‐T‐110131 (IDN5109), exhibited excellent pharmacological profile in the preclinical studies and has been selected for clinical development (re‐coded as Bay 59‐8862), which is currently in the phase II clinical trials. Bay 59‐8862 is orally active with high bioavailability, showing excellent activity against a variety of drug‐resistant tumors. “Advanced second generation taxanes” show essentially no difference in cytotoxicity against drug‐resistant and drug‐sensitive cell lines, virtually overcoming MDR. Photoaffinity labeling of P‐GP using photoreactive radiolabeled paclitaxel analogs has disclosed the paclitaxel‐binding domain of P‐GP. Highly efficient taxane‐based MDR reversal agents (TRAs) have also been developed, which can recover the cytotoxicity of paclitaxel to practically the original level against paclitaxel‐resistant MDR expressing cancer cells. Highly promising results have emerged from the study of taxane‐monoclonal antibody (MAb) immunoconjugates, which have been proved to specifically deliver extremely cytotoxic agents to tumor in an animal model.
Suppression of Gastric Mucosal Inflammatory Responses to Helicobacter pylori Lipopolysaccharide by Peroxisome Proliferator‐Activated Receptor γ Activation
Authors: Slomiany Bronislaw L. , Slomiany Amalia 
Published: September 2003

AbstractPeroxisome proliferator‐activated receptor‐ γ(PPAR γ) is a nuclear transcription factor that regulates the expression of genes associated with inflammation. We applied the animal model of H. pylori lipopolysaccharide(LPS)‐induced gastritis to assess the effect of a specific PPAR γligand, ciglitazone, on the apoptotic processes and the mucosal activity of inducible nitric oxide synthase (NOS‐2), and the expression of COX‐1 and ‐2 cyclooxygenases. In the absence of ciglitazone, the LPS‐elicited mucosal inflammatory responses were accompanied by a massive epithelial cell apoptosis, upregulation of NOS‐2 and COX‐2 protein expression, and a marked increase in the mucosal PGE 2 generation and NOS‐2 activity. The expression of COX‐1 protein, however, remained unchanged. Administration of ciglitazone led to dose‐dependent reduction (up to 48%) in the severity of mucosal inflammatory involvement elicited by the LPS and this effect of the agent was reflected in a 72.5% reduction in apoptosis, a 58.7% decline in the mucosal PGE 2 generation and a 75.6% drop in NOS‐2 activity, and produced a marked decrease inCOX‐2 and NOS‐2 protein expression. Our findings demonstrate that PPAR γactivation suppresses gastric mucosal inflammatory responses to H. pylori LPS, and suggest that pharmacological manipulation of PPAR γactivation may provide therapeutic benefits in the resolution of inflammation associated with H. pylori infection.
The Complex Nature of Protein Phosphatases
Authors: Sim Alistair T. R. , Ludowyke Russell I. 
Published: September 2003

AbstractProtein phosphatases are integrally associated with the regulation of cellular signaling. The mechanisms underlying the specific regulatory roles are likely to be unique to each cell system. Nevertheless, analysis of phosphatase regulation in a number of systems has identified phosphatase targeting through association with a wide range of binding partners to be a fundamental mechanism of regulation. Using protein phosphatase 2A (PP2A) as an example, this snapshot summarizes these fundamental mechanisms of protein phosphatase regulation.
E2F1 Activates the Human p53 Promoter and Overcomes the Repressive Effect of Hepatitis B Viral X Protein (HBx) on the p53 Promoter
Authors: Choi Murim , Lee Hyeon , Rho Hyune Mo 
Published: September 2003

AbstractThe functional effect of the interaction of E2F1 and hepatitis B virus X protein (HBx) on the promoter of human p53 gene was studied using chloramphenicol acetyl transferase (CAT) assay. E2F1 activated the p53 promoter through E2F1 binding site. As previously reported, HBx repressed the p53 promoter through E‐box. When E2F1 was cotransfected with HBx, E2F1 overcame the repressive effect of HBx on the p53 promoter through the E2F1 site. However, in the thymidine kinase ( tk ) heterologous promoter system with the E2F1 binding sites, cotransfection of E2F1 and HBx showed a strong synergistic activation. An in vitro interaction assay showed that E2F1 and HBx physically bind with each other. Analyses of the interaction domain with the GAL4 fusion protein showed that the pRb‐binding domain of E2F1 was necessary for the functional interaction of these two proteins. Taken together, these results imply the functional inhibitory action of E2F1 on the HBV life cycle and HBV‐mediated hepatocellular carcinogenesis (HCC). Therefore, the normal or enhanced function of E2F1 gene would be important in controlling the HBx function in HCC.
Do Hemoglobin and Hemocyanin Impair Schistosoma Killing by NO?
Authors: Ascenzi Paolo , Fasano Mauro , Gradoni Luigi 
Published: September 2003

AbstractNitric oxide (NO) possesses antiparasitic effects on both Protozoa and Metazoa in definitive and intermediate hosts as well as in vectors. Here, we postulate that hemoglobin and hemocyanin may impair Schistosoma killing by NO in the definitive and intermediate hosts. Interestingly, hemoglobin, myoglobin, and neuroglobin may protect Plasmodium and Trypanosoma from the antiparasitic effects of NO.
Biochemical and Cytochemical Characterization of Extracellular Proteoglycans in the Inner Circular Smooth Muscle Layer of Dog Small Intestine
Authors: de Toledo Olga Maria Szymanski , Marquezini Mônica Valéria , Jia Kaio Bin , Pinheiro Mônica de Campos , Mora Oswaldo Alves 
Published: September 2003

AbstractCurrent literature concerning smooth muscle blood vessels has shown versican as the main proteoglycan (PG) component of the matrix. To show whether smooth muscle matrix has the same PG distribution when present in organs, other than the blood vessels, the inner circular smooth muscle layer of the small intestine was obtained by dissection as a highly purified tissue and analyzed by biochemical and cytochemical methods. The smooth muscle layer PGs were extracted from dog small intestine with 4 M guanidine‐HCl in the presence of proteinase inhibitors, purified by charge equilibrium, isolated by equilibrium CsCl density gradients, and analyzed in terms of anion exchange, size, and glycosaminoglycan (GAG) distribution. Proteoheparan sulfate itself represented 91.5% of the PGs present in this tissue. The remainder was proteodermatan sulfate. Cytochemical analyses using the cationic dye cuprolinic blue associated with enzymatic treatments with chondroitinases ABC and heparitinase III showed the arrangement and identification of PGs in basal lamina and intramuscular connective tissues. The PGs in the basal lamina were proteoheparan sulfate, and those associated with collagen fibrils in the endomysium and perimysium were rich in dermatan sulfate. In contrast to the blood vessels, inner circular muscle smooth tissue in intestine has, as the main PG, perlecan.
The Effects of Protein Hydrophobic Exposure on the Slope of the Line in the Δπ vs πi Plot
Authors: Zhang Fan , Lu Ying‐Jie , Wang Shao‐Xiong , Sui Sen‐Fang 
Published: September 2003

AbstractThe Δπvs πi curve from monolayer surface pressure detection is a powerful method to characterize the membrane insertion. The Δπvs πi curve is fixed by two parameters, the πc and the slope. The intersected point ( πc ) of Δπvs πi curve with abscissa is generally used as a quantitative measure of the membrane insertion ability of a protein. In the current work we demonstrate a correlation between the variation in the slope of the Δπvs πi curve with protein hydrophobic exposure by performing monolayer experiments on three different proteins, human apolipoprotein H, trichosanthin, and mutant trichosanthin. The value of |slope| increases gradually following the degree of hydrophobic exposure. These findings suggest that the two parameters, the πc and the slope, will complement each other to interpret the lipid/protein interaction involved in membrane insertion.
Swapping of Three‐Dimensional Domains as a Molecular Mechanism of Dimerization of Aminoacyl‐tRNA Synthetases
Authors: Deniziak Marzanna A. , Barciszewski Jan 
Published: September 2003

AbstractIt has been shown recently that many proteins undergo oligomerization through exchange of structural elements. That process, termed a 3D domain swapping, is the replacement of a portion of the tertiary structure of a protein with an identical piece from a second polypeptide chain. When the exchange is reciprocated, domain‐swapped dimers embrace with the exchange of elements of secondary structure or domains; however, if the exchange is not reciprocated but propagated along multiple polynucleotide chains, higher‐order assemblies may form. In this paper we discuss swapping as a general mechanism of aminoacyl‐tRNA synthetases dimerization, specifically plant methionyl‐tRNA synthetase.
Regulation of Mitochondrial Gene Expression by Retinoids
Authors: Everts Helen B. , Berdanier Carolyn D. 
Published: September 2003

AbstractSeveral nuclear hormone receptors have been localized to the mitochondrial compartment. Evidence supports the hypothesis that these receptors directly regulate mitochondrial transcription. Retinoic acid has also been shown to regulate mitochondrial transcription and function. This review discusses mechanisms of mitochondrial transcription and how retinoic acid may either indirectly or directly regulate mitochondrial transcription. How retinoic acid may affect individual nutrient requirements is also discussed.
Thymocyte Apoptosis Induced by Phosphorylation of Histones is Associated with the Change in Chromatin Structure to Allow Easy Accessibility of DNase
Authors: Enomoto Riyo , Tatsuoka Hiroyuki , Yoshida Yukari , Komai Tomoe , Node Kaori , Nogami Rieko , Yamauchi Aiko , Lee Eibai 
Published: September 2003

AbstractThe inhibitors of protein phosphatase such as calyculin A and okadaic acid induce the apoptotic cell death in rat thymocytes. To clarify the molecular mechanism of these inhibitor‐induced apoptosis, the effect of calyculin A on DNA fragmentation in the isolated nuclei were studied. A significant increase in DNA fragmentation was observed in the nuclei prepared from the cells treated with calyculin A that caused histone hyperphosphorylation. No changes of the activities of caspase‐8 and ‐3 were observed in the extract from the cells treated with calyculin A. The circular dichroism analysis of soluble chromatin from calyculin A‐treated thymocyte nuclei indicated that phosphorylation of histones decreased its α‐helical content. Thus, the change in the chromatin structure may be due to the chemical modification of histones. Moreover, the structural change in chromatin preceded DNA fragmentation in the nuclei. Therefore, these results suggest that the change of chromatin structure allow easy accessibility of nuclear DNase to chromosomal DNA.
In Vitro Selection of Self‐Interacting Transmembrane Segments‐‐Membrane Proteins Approached from a Different Perspective
Authors: Langosch Dieter , Lindner Eric , Gurezka Rolf 
Published: September 2003

AbstractThe principles underlying the folding of integral membrane proteins are uncovered in an increasingly detailed way. Experimental determination of high‐resolution structures followed by analysis of packing reveal structural similarities as well as differences to soluble globular proteins. At the same time, protein/protein interactions at the level of membrane‐embedded domains have been investigated for different model proteins. More recently, self‐interacting transmembrane helices have been selected from combinatorial libraries in vitro to study the mechanistic basis of protein/protein interaction in membranes in a systematic way. With an emphasis on the latter approach, this review discusses insights emerging from an integrated view on the recent advances.
Biosynthesis of Chondroitin/Dermatan Sulfate
Authors: Silbert Jeremiah E. , Sugumaran Geetha 
Published: September 2003

AbstractChondroitin sulfate and dermatan sulfate are synthesized as galactosaminoglycan polymers containing N ‐acetylgalactosmine alternating with glucuronic acid. The sugar residues are sulfated to varying degrees and positions depending upon the tissue sources and varying conditions of formation. Epimerization of any of the glucuronic acid residues to iduronic acid at the polymer level constitutes the formation of dermatan sulfate. Chondroitin/dermatan glycosaminoglycans are covalently attached by a common tetrasaccharide sequence to the serine residues of core proteins while they are adherent to the inner surface of endoplasmic reticulum/Golgi vesicles. Addition of the first sugar residue, xylose, to core proteins begins in the endoplasmic reticulum, followed by the addition of two galactose residues by two distinct glycosyl transferases in the early cis/medial regions of the Golgi. The linkage tetrasaccharide is completed in the medial/trans Golgi by the addition of the first glucuronic acid residue, followed by transfer of N ‐acetylgalactosamine to initiate the formation of a galactosaminoglycan rather than a glucosaminoglycan. This specific N ‐acetylgalactosaminyl transferase is different from the chondroitin synthase involved in generation of the repeating disaccharide units to form the chondroitin polymer. Sulfation of the chondroitin polymer by specific sulfotransferases occurs as the polymer is being formed. All the enzymes in the pathway for synthesis have been cloned, with the exception of the glucuronyl to iduronyl epimerase involved in the formation of dermatan residues.
Functional Characteristics and Catalytic Mechanisms of the Bacterial Hyaluronan Synthases
Authors: Weigel Paul H. 
Published: September 2003

AbstractThe first gene for a glycosaminoglycan synthase to be cloned was the hyaluronan (HA) synthase from S. pyogenes, which we reported in 1993. Since then, at least 20 bacterial, viral, or eukaryotic HA synthase gene or cDNA sequences and two bacterial chondroitin synthase genes have been reported. During the last decade a great deal has been elucidated about the structure, function, and mechanisms of action of the bacterial HA synthases, which are the focus of this review. Very rapid progress has been made in elucidating the mechanism of HA synthesis by the HA synthase from Pasteurella multocida . Although little of this information is applicable to understanding the mechanism of action of streptococcal HA synthases, good progress has also been made in understanding how these latter enzymes work.
Keratan Sulfate Biosynthesis
Authors: Funderburgh James L. 
Published: September 2003

AbstractKeratan sulfate was originally identified as the major glycosaminoglycan of cornea but is now known to modify at least a dozen different proteins in a wide variety of tissues. Despite a large body of research documenting keratan sulfate structure, and an increasing interest in the biological functions of keratan sulfate, until recently little was known of the specific enzymes involved in keratan sulfate biosynthesis or of the molecular mechanisms that control keratan sulfate expression. In the last 2 years, however, marked progress has been achieved in identification of genes involved in keratan sulfate biosynthesis and in development of experimental conditions to study keratan sulfate secretion and control in vitro. This review summarizes current understanding of keratan sulfate structure and recent developments in understanding keratan sulfate biosynthesis.
Novel Mechanisms for Feedback Regulation of Phospholipase C‐β Activity
Authors: Litosch Irene 
Published: September 2003

AbstractThe receptor‐regulated phospholipase C‐ β(PLC‐ β) signaling pathway is an important component in a network of signaling cascades that regulate cell function. PLC‐ βsignaling has been implicated in the regulation of cardiovascular function and neuronal plasticity. The G q family of G proteins mediate receptor stimulation of PLC‐ βactivity at the plasma membrane. Mitogens stimulate the activity of a nuclear pool of PLC‐ β. Stimulation of PLC‐ βactivity results in the rapid hydrolysis of phosphatidylinositol‐4,5‐bisphosphate, with production of inositol‐1,4,5‐trisphosphate and diacylglycerol, intracellular mediators that increase intracellular Ca 2+ levels and activate protein kinase C activity, respectively. Diacylglycerol kinase converts diacylglycerol to phosphatidic acid, a newly emerging intracellular mediator of hormone action that targets a number of signaling proteins. Activation of the G q linked PLC‐ βsignaling pathway can also generate additional signaling lipids, including phosphatidylinositol‐3‐phosphate and phosphatidylinositol‐3,4,5‐trisphosphate, which regulate the activity and/or localization of a number of proteins. Novel feedback mechanisms, directed at the level of G q and PLC‐ β, have been identified. PLC‐ βand regulators of G protein signaling (RGS) function as GTPase‐activating proteins on G q to control the amplitude and duration of stimulation. Protein kinases phosphorylate and regulate the activation of specific PLC‐ βisoforms. Phosphatidic acid regulates PLC‐ β1 activity and stimulation of PLC‐ β1 activity by G proteins. These feedback mechanisms coordinate receptor signaling and cell activation. Feedback mechanisms constitute possible targets for pharmacological intervention in the treatment of disease.
p38 Kinase and c‐Jun N‐Terminal Kinase Oppositely Regulates Tumor Necrosis Factor α‐Induced Vascular Cell Adhesion Molecule‐1 Expression and Cell Adhesion in Chondrosarcoma Cells
Authors: Ju Jung‐Won , Kim Song‐Ja , Jun Chang‐Duk , Chun Jang‐Soo 
Published: September 2003

AbstractWe investigated signaling pathways leading to tumor necrosis factor (TNF) α‐induced intercellular adhesion molecule (ICAM)‐1 and vascular cell adhesion molecule (VCAM)‐1 expression in chondrosarcoma cells, and determined the functional significance of their expression by examining Jurkat T cell adhesion. TNF αinduced VCAM‐1 and ICAM‐1 expression and Jurkat T cell binding. Antibody blocking assay indicated that VCAM‐1 mediates TNF α‐induced Jurkat T cell adhesion. TNF αcaused activation of mitogen‐activated protein (MAP) kinase subtypes, extracellular signal‐regulated protein kinase, p38 kinase, and c‐jun N‐terminal kinase (JNK). ICAM‐1 expression was not altered by the inhibition of MAP kinases. However, VCAM‐1 expression and Jurkat T cell adhesion was blocked by the inhibition of p38 kinase, whereas inhibition of JNK enhanced VCAM‐1 expression and cell adhesion without any modulation of NF κB activation. Our results, therefore, indicate that p38 kinase mediates TNF α‐induced VCAM‐1 expression and cell adhesion, whereas JNK suppresses VCAM‐1 expression that is independent to NF κB activation.
The Overexpression Catalase Reduces NO‐Mediated Inhibition of Endothelial NO Synthase
Authors: Brennan Lisa A. , Wedgwood Stephen , Black Stephen M. 
Published: September 2003

AbstractPreviously, we have demonstrated that increased superoxide generation plays a role in the nitric oxide (NO)‐mediated inhibition of endothelial NO synthase (eNOS) in endothelial cells (ECs) and that the overexpression of SOD1 could reduce the inhibitory effect of NO. However, SOD1 overexpression did not completely abolish the inhibition of eNOS by NO, indicating the presence of other inhibitory mechanisms. Because superoxide can be dismutated into hydrogen peroxide (H 2 O 2 ), in this study we determined whether exposure of ECs to NO resulted in increased generation of H 2 O 2 and the potential role of H 2 O 2 in eNOS inhibition. Our results indicated that H 2 O 2 levels were increased in response to NO. Using adenoviral‐mediated infection, we demonstrated that catalase overexpression both increased basal eNOS activity in the absence of NO and provided a significant protective effect on eNOS activity in the presence of NO. This protective effect was associated with a significant decrease in H 2 O 2 levels in the presence of NO. In conclusion, our results indicate that increased levels of H 2 O 2 may be involved in the inhibition of eNOS by NO and that the scavenging of H 2 O 2 may be useful to prevent eNOS inhibition during treatments that involve inhaled NO or NO donors.