bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA damage and anti-tumor activity induced by Zn, Ag and Co containing meso- tetra(4-N-oxyethylpyridyl)porphyrins in vivo
Authors: Karapetyan Nelli H. , Torosyan Lusya V. , Ananyan Gayane V. , Muradyan Rafael E.
Published: June 2010

In the present study, the activity of the new water-soluble cationic meso-tetra(4-N-oxyethylpyridyl)porphyrin and its Zn , Ag and Co metal derivatives as anti-tumor agents was explored. The tumor was induced by 7,12-dimethylbenz[a]antracene (DMBA) on rats of Wistar strain. The levels of DNA damage induced by porphyrins T4OEPyP , AgT4OEPyP , ZnT4OEPyP and CoT4OEPyP in tumor tissue were analyzed. Thermodynamic parameters of DNA were investigated by thermal melting method and differential scanning microcalorimetry to understand the differences in DNA structure of three types of rat: normal, dieseased with tumor, and treated by porphyrins. Agarose gel electrophoresis method was used to detect porphyrin-induced apoptosis or necroses. Based on the data obtained, we concluded that the investigated ZnTOEPyP and AgTOEPyP porphyrins have more anti-tumor activity than CoTOEPyP and TOEPyP .
Effects of methoxy-substituted metalloporphyrins in catalytic alkene epoxidation by n-Bu4NHSO5
Authors: Aghabali Amineh , Safari Nasser
Published: June 2010

TPPMnOAc and four different kinds of manganese tetraphenylporphyrin acetates were synthesized using different numbers of methoxy substituents in various positions of the phenyl rings. These porphyrins were used as catalysts in the epoxidation of various alkenes with tetra-n-butylammonium hydrogen monopersulfate (n- Bu 4 NHSO 5) as the oxidant and imidazole as the axial base. The following order of catalytic activity was obtained: TPPMnOAc ≥ T (2,3- OMeP ) PMnOAc > T (4- OMeP ) PMnOAc > T (3,4- OMeP ) PMnOAc > T (2,4,6- OMeP ) PMnOAc . By studying the UV-vis spectra in the reaction solution, the stability of the applied methoxy porphyrins and the effect of this factor on obtained yields were investigated. Lower catalytic activity in some of the methoxy porphyrins emphasized steric effects and special hydrogen bonding among the reaction elements. However, the stability of T (2,3- OMeP ) PMnOAc under our reaction condition was considerable and high activity was observed. By adding small amounts of alcohol to the reaction solution, the effect of the solvent mixture was previewed and steps were taken to identify the active intermediate of the catalyst in these conditions.
Halo-Wittig- and zirconium-promoted synthesis of conjugated metalloporphyrin dimers
Authors: Yaseen Muhammad , Ali Mukhtar , Munawar Munawar Ali , Salim Muhammad , NajeebUllah Muhammad , Khokhar Irshad , Sayyad Muhammad H.
Published: June 2010

The synthesis and spectroscopic studies of metalloporphyrin dimers having 1,3-butadiyne linker attached to the beta pyrrolic positions of the linked porphyrins are reported. Bromoethenyl metalloporphyrins were synthesized by zirconocene-promoted bromomethylenation of beta formyl metalloporphyrins. Bromoethenyl metalloporphyrins were dehydrohalogenated by potassium tert-butoxide to give beta ethynyl or 2-ethynyl metalloporphyrins. It is the first documented example of zirconocene-promoted bromomethylenation of beta formyl metalloporphyrins. Bromoethenyl metalloporphyrins were also synthesized by halo-Wittig route. 2-ethynyl metalloporphyrins were self dimerized to give metalloporphyrin dimers having 1,3-butadiyne linking bridge. FTIR, Raman spectroscopy, UV-visible, elemental analysis, 1H NMR and mass spectrometry were used to characterize the compounds.
STATISTICAL MEASURES AS MEASURES OF DIVERSITY
Authors: PARKASH OM , THUKRAL A. K.
Published: June 2010

Two fields of research have found tremendous applicability in the analysis of biological data-statistics and information theory. Statistics is extensively used for the measurement of central tendency, dispersion, comparison and covariation. Measures of information are used to study diversity and equitability. These two fields have been used independent of each other for data analysis. In this communication, we develop the link between the two and prove that statistical measures can be used as information measures. Our study will be a new interdisciplinary field of research and it will be possible to describe information content of a system from its statistics.
STABILITY ANALYSIS OF A RATIO-DEPENDENT CHEMOSTAT MODEL WITH TIME DELAY AND VARIABLE YIELD
Authors: LI ZHE , XU RUI
Published: June 2010

A chemostat model with time delay, variable yield and ratio-dependent functional response is investigated. By analyzing the corresponding characteristic equations, the local stability of a boundary equilibrium and a positive equilibrium is discussed and the existence of Hopf bifurcation is established. By using the comparison arguments, sufficient conditions are obtained for the global stability of the boundary equilibrium. By constructing a suitable Lyapunov functional, sufficient conditions are derived for the global asymptotic stability of the positive equilibrium. Finally, numerical simulations are carried out to illustrate the theoretical results.
A SINGLE SPECIES POPULATION IN A POLLUTED ENVIRONMENT
Authors: PAL A. K. , SAMANTA G. P.
Published: June 2010

The effect of toxicants on ecological systems is an important and urgent issue from mathematical and experimental point of view. In this paper, we have studied the dynamical behavior of a single species population affected by environmental toxicant and population toxicant. Boundedness, local and global stabilities, bifurcation are addressed. We have also studied the effect of discrete delay of the environmental toxicant on the instantaneous growth rates of the population biomass and population toxicant due to incubation period. The length of delay preserving the stability is also estimated. Computer simulations are carried out to illustrate our analytical findings.
Bone modeling in bromocriptine-treated pregnant and lactating rats: possible osteoregulatory role of prolactin in lactation
Authors: Suntornsaratoon Panan , Wongdee Kannikar , Goswami Suchandra , Krishnamra Nateetip , Charoenphandhu Narattaphol
Published: June 2010

The lactogenic hormone prolactin (PRL) directly regulates osteoblast functions in vitro and modulates bone remodeling in nulliparous rats, but its osteoregulatory roles in pregnant and lactating rats with physiological hyperprolactinemia remained unclear. Herein, bone changes were investigated in rats treated with bromocriptine (Bromo), an inhibitor of pituitary PRL release, or Bromo+PRL at different reproductive phases, from mid-pregnancy to late lactation. PRL receptors were strongly expressed in osteoblasts lining bone trabeculae, indicating bone as a target of PRL actions. By using dual energy X-ray absorptiometry, we found a significant increase in bone mineral density in the femora and vertebrae of pregnant rats. Such pregnancy-induced bone gain was, however, PRL independent and may have resulted from the increased cortical thickness. Bone trabeculae were modestly changed during pregnancy as evaluated by bone histomorphometry. On the other hand, lactating rats, especially in late lactation, showed massive bone loss in bone trabeculae but not in cortical shells. Further study in Bromo- and Bromo+PRL-treated rats suggested that PRL contributed to decreases in trabecular bone volume and number and increases in trabecular separation and eroded surface, as well as a paradoxical increase in bone formation rate in late lactation. Uncoupling of trabecular bone formation and resorption was evident in lactating rats, with the latter being predominant. In conclusion, pregnancy mainly induced cortical bone gain, whereas lactation led to trabecular bone loss in both long bones and vertebrae. Although PRL was not responsible for the pregnancy-induced bone gain, it was an important regulator of bone modeling during lactation.
Phosphorylation of the CREB-specific coactivator TORC2 at Ser307 regulates its intracellular localization in COS-7 cells and in the mouse liver
Authors: Uebi Tatsuya , Tamura Mitsuhiro , Horike Nanao , Hashimoto Yoshiko Katoh , Takemori Hiroshi
Published: June 2010

The CREB-specific coactivator TORC2 (also known as CRTC2) upregulates gluconeogenic gene expression in the liver. Salt-inducible kinase (SIK) family enzymes inactivate TORC2 through phosphorylation and localize it in the cytoplasm. Ser171 and Ser275 were found to be phosphorylated in pancreatic β-cells. Calcineurin (Cn) is proposed as the Ser275 phosphatase, because its inhibitor cyclosporin A (CsA) stabilizes phospho-Ser275 and retains TORC2 in the cytoplasm. Because the regulation of dephosphorylation at Ser171 has not been fully clarified, we performed experiments with a range of doses of okadaic acid (OA), an inhibitor of PP2A/PP1, and with overexpression of various phosphatases and found that PP1 functions as an activator for TORC2, whereas PP2A acts as an inhibitor. In further studies using TORC2 mutants, we detected a disassociation between the intracellular distribution and the transcription activity of TORC2. Additional mutant analyses suggested the presence of a third phosphorylation site, Ser307. The Ser307-disrupted TORC2 was constitutively localized in the nucleus, but its coactivator activity was normally suppressed by SIK1 in COS-7 cells. CsA, but not OA, stabilized the phosphogroup at Ser307, suggesting that differential dephosphorylation at Ser171 and Ser307 cooperatively regulate TORC2 activity and that the nuclear localization of TORC2 is insufficient to function as a coactivator. Because the COS-7 cell line may not possess signaling cascades for gluconeogenic programs, we next examined the importance of Ser307 and Ser171 for TORC2's function in mouse liver. Levels of phosphorylation at Ser171 and Ser307 changed in response to fasting or fed conditions and insulin resistance of the mouse liver, which were modified by treatment with CsA/OA and by overexpression of PP1/PP2A/Cn. These results suggest that multiple phosphorylation sites and their phosphatases may play important roles in regulating TORC2/CREB-mediated gluconeogenic programs in the liver.
Learning-based recovery from perceptual impairment in salt discrimination after permanently altered peripheral gustatory input
Authors: Blonde Ginger , Jiang Enshe , Garcea Mircea , Spector Alan C.
Published: June 2010

Rats lacking input to the chorda tympani (CT) nerve, a facial nerve branch innervating anterior tongue taste buds, show robust impairments in salt discrimination demonstrating its necessity. We tested the sufficiency of the CT for salt taste discrimination and whether the remaining input provided by the greater superficial petrosal (GSP) nerve, a facial nerve branch innervating palatal taste buds, or by the glossopharyngeal (GL) nerve, innervating posterior tongue taste buds, could support performance after extended postsurgical testing. Rats presurgically trained and tested in a two-response operant task to discriminate NaCl from KCl were subjected to sham surgery or transection of the CT (CTx), GL (GLx), or GSP (GSPx), alone or in combination. While initially reduced postsurgically, performance by rats with an intact GSP after CTx + GLx increased to normal over 6 wk of testing. Rats with CTx + GSPx consistently performed near chance levels. In contrast, rats with GSPx + GLx were behaviorally normal. A subset of rats subjected to sham surgery and exposed to lower concentrations during postsurgical testing emulating decreased stimulus intensity after neurotomy showed no significant impairment. These results demonstrate that CTx changes the perceptual nature of NaCl and/or KCl, leading to severe initial postsurgical impairments in discriminability, but a “new” discrimination can be relearned based on the input of the GSP. Despite losing ∼75% of their taste buds, rats are unaffected after GSPx + GLx, demonstrating that the CT is not only necessary, but also sufficient, for maintaining salt taste discrimination, notwithstanding the unlikely contribution of the small percentage of taste receptors innervated by the superior laryngeal nerve.
Role of the Zebra Finch Auditory Thalamus in Generating Complex Representations for Natural Sounds
Authors: Amin Noopur , Gill Patrick , Theunissen Frédéric E.
Published: June 2010

We estimated the spectrotemporal receptive fields of neurons in the songbird auditory thalamus, nucleus ovoidalis, and compared the neural representation of complex sounds in the auditory thalamus to those found in the upstream auditory midbrain nucleus, mesencephalicus lateralis dorsalis (MLd), and the downstream auditory pallial region, field L. Our data refute the idea that the primary sensory thalamus acts as a simple, relay nucleus: we find that the auditory thalamic receptive fields obtained in response to song are more complex than the ones found in the midbrain. Moreover, we find that linear tuning diversity and complexity in ovoidalis (Ov) are closer to those found in field L than in MLd. We also find prevalent tuning to intermediate spectral and temporal modulations, a feature that is unique to Ov. Thus even a feed-forward model of the sensory processing chain, where neural responses in the sensory thalamus reveals intermediate response properties between those in the sensory periphery and those in the primary sensory cortex, is inadequate in describing the tuning found in Ov. Based on these results, we believe that the auditory thalamic circuitry plays an important role in generating novel complex representations for specific features found in natural sounds.
NMDA Channels Together With L-Type Calcium Currents and Calcium-Activated Nonspecific Cationic Currents Are Sufficient to Generate Windup in WDR Neurons
Authors: Aguiar P. , Sousa M. , Lima D.
Published: June 2010

Windup is characterized as a frequency-dependent increase in the number of evoked action potentials in dorsal horn neurons in response to electrical stimulation of afferent C-fibers. This phenomenon was first described in the mid-60s, but the core mechanisms behind it still remain elusive. Several factors affecting its dynamics have been identified, but the distinction between modulating mechanisms from generating mechanisms is not always clear. Several mechanisms contribute to the excitation of dorsal horn neurons exhibiting windup, and one of our main aims was to help making this distinction. The approach presented here relies on mathematical and computational analysis to study the mechanism(s) underlying windup. From experimentally obtained windup profiles, we extract the time scale of the facilitation mechanisms that may support the characteristics of windup. Guided by these values and using simulations of a biologically realistic compartmental model of a wide dynamic range (WDR) neuron, we are able to assess the contribution of each mechanism for the generation of action potentials windup. We show that the key mechanisms giving rise to windup is the temporal summation of N-methyl-d-aspartate (NMDA) long-lasting postsynaptic responses taking place on top of a membrane potential cumulative depolarization. Calcium-activated nonspecific cationic currents driven by calcium influx from L-type calcium channels and synaptic currents support this cumulative depolarization and plateau formation in WDR neuron membrane potential. The effects of different nonhomogeneous stimulation protocols are explored, and their important role in clarifying many aspects of the windup generation is shown. The models are used to produce several predictions that can be tested experimentally.
Prostaglandin E2receptor subtype EP2- and EP4-regulated gene expression profiling in human ciliary smooth muscle cells
Authors: Reitmair Armin , Lambrecht Nils W. G. , Yakubov Iskandar , Nieves Amelia , Old David , Donde Yariv , Dinh Danny , Burk Robert , Sachs George , Im Wha Bin , Wheeler Larry
Published: June 2010

Prostanoids are an important class of intraocular pressure (IOP)-lowering antiglaucoma agents that act primarily via increased uveo-scleral aqueous humor outflow through the ciliary body. We have developed two novel PGE2analogs that are specific agonists for the PGE2receptor subtypes EP2 and EP4, respectively. To identify gene regulatory networks and key players that mediate the physiological effects observed in vivo, we performed genomewide expression studies using human ciliary smooth muscle cells. Quantitative real-time RT-PCR confirmed a largely overlapping gene expression profile subsequent to EP2 and EP4 agonist treatment, with 65 significantly regulated genes identified overall, 5 being specific for the EP2 agonist and 6 specific for the EP4 agonist. We found predicted functional cAMP-response elements in promoter regions of a large fraction of the predominantly upregulated genes, which suggests that the cAMP signaling pathway is the most important intracellular signaling pathway for these agonists in these cells. Several target genes were identified that, as part of complex regulatory networks, are implicated in tissue remodeling processes and osmoregulation (e.g., AREG, LOXL3, BMP2, AQP3) and thus may help elucidate the mechanism of action of these IOP-lowering drugs involving the uveo-scleral outflow path.
Strain-dependent variation in collateral circulatory function in mouse hindlimb
Authors: Chalothorn Dan , Faber James E.
Published: June 2010

The extent (density and diameter) of the native (preexisting) collateral circulation in healthy tissues and the capacity of collaterals to enlarge/remodel in obstructive arterial disease are important determinants of ischemic injury. Evidence suggests that these parameters vary widely from yet-to-be-identified genetic and environmental factors. Recently, a locus on chromosome 7 was linked to less recovery of perfusion after femoral artery ligation in BALB/c and A/J versus C57BL/6 mouse strains. Moreover, evidence suggested that BALB/c and A/J share an allele(s) at this locus that is different from C57BL/6 mice. Here we tested the hypothesis that differences in collateral extent and/or remodeling underlie these findings. Compared with C57BL/6, BALB/c and A/J strains have fewer native collaterals in hindlimb (also confirmed in brain)—associated with greater reduction in perfusion immediately after femoral ligation, slower recovery of perfusion, greater hindlimb use impairment, and worse ischemia. However, A/J also differed from BALB/c in a number of these parameters, including having more robust collateral remodeling. Analysis of A/J → C57BL/6 chromosome substitution strains confirmed that a difference in an allele(s) on chromosome 7 conferred most, but not all, of the magnitude of the differences in collateral function. Additional studies of C57BL/6 × BALB/c F1 mice demonstrated that alleles of the C57BL/6 strain exert dominance for collateral traits. Finally, negative results were obtained from studies examining a previously identified candidate gene potentially responsible for these differences—Bcl2-associated athanogene-3. These findings emphasize the major contribution of genetic background to variation in the collateral circulation and its capacity to lessen ischemia in obstructive disease.
Multiplexed quantitative real-time PCR to detect 22q11.2 deletion in patients with congenital heart disease
Authors: Tomita-Mitchell Aoy , Mahnke Donna K. , Larson Joshua M. , Ghanta Sujana , Feng Ying , Simpson Pippa M. , Broeckel Ulrich , Duffy Kelly , Tweddell James S. , Grossman William J. , Routes John M. , Mitchell Michael E.
Published: June 2010

22q11.2 Deletion syndrome (22q11.2 DS) [DiGeorge syndrome type 1 (DGS1)] occurs in ∼1:3,000 live births; 75% of children with DGS1 have severe congenital heart disease requiring early intervention. The gold standard for detection of DGS1 is fluorescence in situ hybridization (FISH) with a probe at the TUPLE1 gene. However, FISH is costly and is typically ordered in conjunction with a karyotype analysis that takes several days. Therefore, FISH is underutilized and the diagnosis of 22q11.2 DS is frequently delayed, often resulting in profound clinical consequences. Our goal was to determine whether multiplexed, quantitative real-time PCR (MQPCR) could be used to detect the haploinsufficiency characteristic of 22q11.2 DS. A retrospective blinded study was performed on 382 subjects who had undergone congenital heart surgery. MQPCR was performed with a probe localized to the TBX1 gene on human chromosome 22, a gene typically deleted in 22q11.2 DS. Cycle threshold (Ct) was used to calculate the relative gene copy number (rGCN). Confirmation analysis was performed with the Affymetrix 6.0 Genome-Wide SNP Array. With MQPCR, 361 subjects were identified as nondeleted with an rGCN near 1.0 and 21 subjects were identified as deleted with an rGCN near 0.5, indicative of a hemizygous deletion. The sensitivity (21/21) and specificity (361/361) of MQPCR to detect 22q11.2 deletions was 100% at an rGCN value drawn at 0.7. One of 21 subjects with a prior clinical (not genetically confirmed) DGS1 diagnosis was found not to carry the deletion, while another subject, not previously identified as DGS1, was detected as deleted and subsequently confirmed via microarray. The MQPCR assay is a rapid, inexpensive, sensitive, and specific assay that can be used to screen for 22q11.2 deletion syndrome. The assay is readily adaptable to high throughput.
Sex-specific gene expression in the BXD mouse liver
Authors: Gatti Daniel M. , Zhao Ni , Chesler Elissa J. , Bradford Blair U. , Shabalin Andrey A. , Yordanova Roumyana , Lu Lu , Rusyn Ivan
Published: June 2010

Differences in clinical phenotypes between the sexes are well documented and have their roots in differential gene expression. While sex has a major effect on gene expression, transcription is also influenced by complex interactions between individual genetic variation and environmental stimuli. In this study, we sought to understand how genetic variation affects sex-related differences in liver gene expression by performing genetic mapping of genomewide liver mRNA expression data in a genetically defined population of naive male and female mice from C57BL/6J, DBA/2J, B6D2F1, and 37 C57BL/6J × DBA/2J (BXD) recombinant inbred strains. As expected, we found that many genes important to xenobiotic metabolism and other important pathways exhibit sexually dimorphic expression. We also performed gene expression quantitative trait locus mapping in this panel and report that the most significant loci that appear to regulate a larger number of genes than expected by chance are largely sex independent. Importantly, we found that the degree of correlation within gene expression networks differs substantially between the sexes. Finally, we compare our results to a recently released human liver gene expression data set and report on important similarities in sexually dimorphic liver gene expression between mouse and human. This study enhances our understanding of sex differences at the genome level and between species, as well as increasing our knowledge of the molecular underpinnings of sex differences in responses to xenobiotics.
Barium Staminate as Semiconductor Working Electrodes for Dye-Sensitized Solar Cells
Authors: Guo Fu-an , Li Guoqiang , Zhang Weifeng
Published: June 2010

Dye-sensitized solar cells (DSSCs) are fabricated with perovskite-typeBaSnO3as the photoelectrode materials. Different preparation methods including coprecipitation, hydrothermal, and solid state reaction are employed to synthesizeBaSnO3particles to optimize the photoelectric activities of electrode materials. The photoelectric properties ofBaSnO3particles and the performances of DSSCs are investigated by surface photovoltage spectroscopy and current-voltage measurements. The light-to-electricity conversion of 1.1% is preliminarily reached on the DSSC made of the coprecipitation-derivedBaSnO3particles. Large current density of hole injection into the HOMO level of N719 dye from the valence band ofBaSnO3and reduced photogenerated charge recombination inBaSnO3could be responsible for the observed solar cell performance of the DSSC fabricated from the coprecipitation-derivedBaSnO3particles.
Outer Planet Missions with Electric Propulsion Systems—Part I
Authors: Solórzano Carlos Renato Huaura , de Almeida Prado Antonio Fernando Bertachini , Sukhanov Alexander Alexandrovich
Published: June 2010

For interplanetary missions, efficient electric propulsion systems can be used to increase the mass delivered to the destination. Outer planet exploration has experienced new interest with the launch of the Cassini and
New Horizons Missions. At the present, new technologies are studied for better use of electric propulsion systems in missions to the outer planets. This paper presents low‐thrust trajectories using the method of the transporting trajectory to Uranus, Neptune, and Pluto. They use nuclear and radio isotopic electric propulsion. These direct transfers have continuous electric propulsion of low power along the entire trajectory. The main goal of the paper is to optimize the transfers, that is, to provide maximum mass to be delivered to the outer planets.
Nigella sativaL. Seed Extract Modulates the Neurotransmitter Amino Acids Release in Cultured NeuronsIn Vitro
Authors: El-Naggar Tarek , Gómez-Serranillos María Pilar , Palomino Olga María , Arce Carmen , Carretero María Emilia
Published: June 2010

Nigella sativaL. (NS) has been used for medicinal purposes since ancient times. This study aimed to investigate the cytotoxicity of NS dry methanolic extract on cultured cortical neurons and its influence on neurotransmitter release, as well as the presence of excitatory (glutamate and aspartate) and inhibitory amino acids (gamma-aminobutyric acid—GABA—and glycine) in NS extract. Cultured rat cortical neurons were exposed to different times and concentrations of NS dry methanolic extract and cell viability was then determined by a quantitative colorimetric method. NS did not induce any toxicity. The secretion of different amino acids was studied in primary cultured cortical neurons by high-performance liquid chromatography (HPLC) using a derivation before injection with dansyl chloride. NS modulated amino acid release in cultured neurons; GABA was significantly increased whereas secretion of glutamate, aspartate, and glycine were decreased. Thein vitrofindings support the hypothesis that the sedative and depressive effects of NS observedin vivocould be based on changes of inhibitory/excitatory amino acids levels.
Detection of Soot Using a Resistivity Sensor Device Employing Thermophoretic Particle Deposition
Authors: Lutic Doina , Pagels Joakim , Bjorklund Robert , Josza Peter , Visser Jacobus H. , Grant Ann W. , Johansson Mats L. , Paaso Jaska , Fägerman Per-Erik , Sanati Mehri , Spetz Anita Lloyd
Published: June 2010

Results are reported for thermophoretic deposition of soot particles on resistivity sensors as a monitoring technique for diesel exhaust particles with the potential of improved detection limit and sensitivity. Soot with similar characteristics as from diesel exhausts was generated by a propane flame and diluted in stages. The soot in a gas flow at 240–270C∘was collected on an interdigitated electrode structure held at a considerably lower temperature, 105–125C∘. The time delay for reaching measurable resistance values, the subsequent rate, and magnitude of resistance decrease were a function of the distance between the fingers in the electrodes and the degree of dilution of the soot containing flow. Soot deposition and subsequent removal by heating the sensor support was also performed in a real diesel exhaust. Good similarities between the behavior in our laboratory system and the real diesel exhaust were noticed.
Pulsatile Flow of a Two‐Fluid Model for Blood Flow through Arterial Stenosis
Authors: Sankar D. S.
Published: June 2010

Pulsatile flow of a two‐fluid model for blood flow through stenosed narrow arteries is studied through a mathematical analysis. Blood is treated as two‐phase fluid model with the suspension of all the erythrocytes in the as Herschel‐Bulkley fluid and the plasma in the peripheral layer as a Newtonian fluid. Perturbation method is used to solve the system of nonlinear partial differential equations. The expressions for velocity, wall shear stress, plug core radius, flow rate and resistance to flow are obtained. The variations of these flow quantities with stenosis size, yield stress, axial distance, pulsatility and amplitude are analyzed. It is found that pressure drop, plug core radius, wall shear stress and resistance to flow increase as the yield stress or stenosis size increases while all other parameters held constant. It is observed that the percentage of increase in the magnitudes of the wall shear stress and resistance to flow over the uniform diameter tube is considerably very low for the present two‐fluid model compared with that of the single‐fluid model of the Herschel‐Bulkley fluid. Thus, the presence of the peripheral layer helps in the functioning of the diseased arterial system.
Proinflammatory Mediators of Toxic Shock and Their Correlation to Lethality
Authors: Krakauer Teresa , Buckley Marilyn J. , Fisher Diana
Published: June 2010

Bacterial exotoxins and endotoxins both stimulate proinflammatory mediators but the contribution of each individual toxin in the release of mediators causing lethal shock is incompletely understood. This study examines the cytokine response and lethality of mice exposed to varying doses of staphylococcal enterotoxin B (SEB) or lipopolysaccharide (LPS) and their combinations. In vivo, SEB alone induced moderate levels of IL-2 and MCP-1 and all mice survived even with a high dose of SEB (100μg/mouse). LPS (80μg/mouse) caused 48% lethality and induced high levels of IL-6 and MCP-1. SEB induced low levels of TNFα, IL-1, IFNγ, MIP-2, and LPS synergized with SEB in the expression of these cytokines and that of IL-6 and MCP-1. Importantly, the synergistic action of SEB and LPS resulted in lethal shock and hypothermia. ANOVA of cytokine levels by survival status of SEB-plus-LPS groups revealed significantly higher levels of TNFα, IL-6, MIP-2, and MCP-1 in nonsurvivors measured at 8 hours. Significantly higher levels of IFNγand IL-2 were observed at 21 hours in nonsurvivors of toxic shock compared to those in survivors. Overall, synergistic action of SEB and LPS resulted in higher and prolonged levels of these key cytokines leading to toxic shock.
Upregulation of TLR2/4 Expression in Mononuclear Cells in Postoperative Systemic Inflammatory Response Syndrome after Liver Transplantation
Authors: Hei Ziqing , Chi Xinjin , Cheng Nan , Luo Gangjian , Li Shangrong
Published: June 2010

Background. To explore the relationship between Toll-like rpheral blood mononuclear cells (PBMC) and systemic inflammatory response syndrome (SIRS) in postoperative patients of liver transplantation (LT).Methods. Blood samples of 27 patients receiving LT were collected at T1 (after induction of anaesthesia), T2 (25 minutes after the beginning of anhepatic phase), T3 (3 hours after graft reperfusion), and T4 (24 hours after graft reperfusion). The expression of TLR2/4 on PBMC and serum concentration of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-8 were measured. The patients were divided into SIRS group (n=12) and non-SIRS group (n=15) for analysis.Results. Blood loss and transfusion were higher in the SIRS group than in the non-SIRS group. Both the preanhepatic and anhepatic phase were significantly longer in the SIRS group. The TLR2/4 expression on PBMC as well as serum TNF-α, IL-1β, and IL-8 were significantly higher at T3 and T4 than that at T1 and T2 in the SIRS patients. The expression of TLR4 on PBMC is positively correlated to serum TNF-α, IL-8. Expression of TLR2/4 on PBMC and serum concentrations of TNF-α, IL-1β, did not differ among the 4-time points in non-SIRS patients.Conclusions. Upregulation of TLR2/4 expression on PBMC may contribute to the development of postoperative SIRS during perioperative period of LT.
Is There a Biological Basis for Treatment of Fibrodysplasia Ossificans Progressiva with Rosiglitazone? Potential Benefits and Undesired Effects
Authors: Bocciardi Renata , Ravazzolo Roberto
Published: June 2010

Thiazolidinediones (TZDs), among which Rosiglitazone, are known agonists of the peroxisome-proliferator-activated receptorγ(PPARγ) commonly used for treatment of hyperglycemia. A recently published article describing a case report on a patient affected by Fibrodysplasia Ossificans Progressiva (FOP) treated with Rosiglitazone has prompted interest for careful analysis of the rational basis of such treatment. This article reviews the effects of PPARγagonists in relationship with various pathogenic steps that occur during the course of FOP by reviewing the particularly rich literature on the effects of Rosiglitazone, to underscore their relevance to FOP and to consider possible adverse effects.
Osteogenic Activity of Locally Applied Small Molecule Drugs in a Rat Femur Defect Model
Authors: Cottrell Jessica A. , Vales Francis M. , Schachter Deborah , Wadsworth Scott , Gundlapalli Rama , Kapadia Rasesh , O'Connor J. Patrick
Published: June 2010

The long-term success of arthroplastic joints is dependent on the stabilization of the implant within the skeletal site. Movement of the arthroplastic implant within the bone can stimulate osteolysis, and therefore methods which promote rigid fixation or bone growth are expected to enhance implant stability and the long-term success of joint arthroplasty. In the present study, we used a simple bilateral bone defect model to analyze the osteogenic activity of three small-molecule drug implants via microcomputerized tomography (micro-CT) and histomorphometry. In this study, we show that local delivery of alendronate, but not lovastatin or omeprazole, led to significant new bone formation at the defect site. Since alendronate impedes osteoclast-development, it is theorized that alendronate treatment results in a net increase in bone formation by preventing osteoclast mediated remodeling of the newly formed bone and upregulating osteoblasts.
Isolated Gastrointestinal Metastasis of Breast Carcinoma: A Case Report
Authors: Titi M. A. , Anabtawi A. , Newland A. D.
Published: June 2010

Purpose. Gastrointestinal tract is one of the rare locations for breast cancer metastasis. This paper shows such metastasis may occur even in the absence of breast metastasis in other more common locations.Case Report. A 64-year old female was admitted to the hospital with abdominal discomfort and diarrhea. She had breast carcinoma treated 7 years previously with normal follow-up since. Colonoscopy showed hepatic flexure thickening that was confirmed to be breast metastasis. Staging investigations showed upper and lower gastrointestinal tract metastasis with negative findings elsewhere.Conclusion. Although more common causes for gastrointestinal symptoms should be excluded, however, a high index of suspicion of metastatic breast cancer is needed when such patients develop gastrointestinal symptoms.
Controversies in the Management of Endometrial Cancer
Authors: Masciullo V. , Amadio G. , Lo Russo D. , Raimondo I. , Giordano A. , Scambia G.
Published: June 2010

Endometrial cancer (EC) remains the most common malignancy of the female genital tract. The median age at diagnosis is the sixth decade, with abnormal uterine bleeding at the presentation in 90% of the patients. Surgical treatment, including complete hysterectomy, removal of remaining adnexal structures, and an appropriate surgical staging, represents the milestone of curative therapy for patients with EC. Adjuvant therapy is necessary in patients at high risk of recurrence. Conservative treatment approaches should be used in selected cases for women with a desire of fertility preservation. This review summarizes the management of EC and discusses current controversies regarding the role of lymphadenectomy and radiotherapy in patients with intermediate‐risk tumors confined to the uterus.
The TLR4/TRIF-Mediated Activation of NLRP3 Inflammasome Underlies Endotoxin-Induced Liver Injury in Mice
Authors: Tsutsui Hiroko , Imamura Michiko , Fujimoto Jiro , Nakanishi Kenji
Published: June 2010

Administration of heat-killedPropionibacterium acnesrenders mice highly susceptible to LPS. After LPS challengeP. acnes-primed mice promptly show hypothermia, hypercoagulation (disseminated intravascular coagulation), elevation of serum proinflammatory cytokine levels, and high mortality. The surviving mice develop liver injury. As previously reported, IL-18 plays a pivotal role in the development of this liver injury. Many cell types including macrophages constitutively store IL-18 as biologically inactive precursor (pro) form. Upon appropriate stimulation exemplified by TLR4 engagement, the cells secrete biologically active IL-18 by cleaving pro-IL-18 with caspase-1. Caspase-1 is also constitutively produced as a zymogen in macrophages. Recently, NLRP3, a cytoplasmic pathogen sensor, has been demonstrated to be involved in the activation of caspase-1. Here, we review the molecular mechanisms for the liver injuries, particularly focusing on the TLR4/NLRP3-mediated caspase-1 activation process, with a brief introduction of the mechanism underlyingP. acnes-induced sensitization to LPS.
Massive Myocardial Infarction in a Full-Term Newborn: A Case Report
Authors: Fesslova Vlasta , Lucci Gina , Brankovic Jelena , Cordaro Stefania , Caselli Emilio , Moro Guido
Published: June 2010

A full-term female newborn with neonatal asphyxia and severe anemia (Hb 2.5 g/dL) with normal heart developed a massive myocardial infarction. No examinations were performed during pregnancy for parental nomadism. The baby had immediate external cardiac massage, ventilatory assistance, and blood transfusion. Cardiomegaly was evident at chest X-ray and marked signs of ischemia-lesion at ECG. Echocardiography showed dilated, hypertrophic, and hypocontractile left ventricle (LV), mitral and tricuspid regurgitation, and moderate pericardial effusion. Rh isoimmunization and infective agents were excluded at laboratory tests. Despite the treatment with inotropes, hydrocortisone, and furosemide, the baby worsened and died at 45 hours of life. Postmortem examination showed diffuse subendocardial infarction of LV and diffuse parenchymal hemorrhages and myocardial hypertrophy, increase of eosinophilia, and polymorphonucleated cells at histology. Our patient suffered apparently from longstanding fetal anemia of unknown etiology that led to perinatal distress, severe hypoxia, and massive myocardial infarction, unresponsive to the therapy.
Williams Syndrome with a “Twist”
Authors: Maritsi Despoina , Kossiva Lydia , Vartzelis George
Published: June 2010

Williams syndrome is a rare genetic condition with multisystemic involvement, caused by a microscopic deletion in the chromosome band 7q11.23. We describe the first case of a toddler with Williams syndrome who developed Benign Paroxysmal Torticollis (BPT), a benign dystonic disorder of unknown aetiology.
An Observing System Simulation Experiment (OSSE) to Assess the Impact of Doppler Wind Lidar (DWL) Measurements on the Numerical Simulation of a Tropical Cyclone
Authors: Zhang Lei , Pu Zhaoxia
Published: June 2010

The importance of wind observations has been recognized for many years. However, wind observations—especially three‐dimensional global wind measurements—are very limited. A satellite‐based Doppler Wind Lidar (DWL) is proposed to measure three‐dimensional wind profiles using remote sensing techniques. Assimilating these observations into a mesoscale model is expected to improve the performance of the numerical weather prediction (NWP) models. In order to examine the potential impact of the DWL three‐dimensional wind profile observations on the numerical simulation and prediction of tropical cyclones, a set of observing simulation system experiments (OSSEs) is performed using the advanced research version of the Weather Research and Forecasting (WRF) model and its three‐dimensional variational (3DVAR) data assimilation system. Results indicate that assimilating the DWL wind observations into the mesoscale numerical model has significant potential for improving tropical cyclone track and intensity forecasts.
In Vitro Inhibition of Neutrophil Elastase Activity by Inhaled Anti-Pseudomonas Antibiotics Used in Cystic Fibrosis Patients
Authors: Hector Andreas , Kappler Matthias , Griese Matthias
Published: June 2010

Background. Inhaled antibiotics are commonly used in the treatment of cystic fibrosis lung disease. A previous study suggested neutrophil elastase activation by colistin in vitro. Here, we investigated direct effects of the commonly used antibiotics colistin and tobramycin on neutrophil elastase activity.Methods. Neutrophil elastase was measured spectrophotometrically. The antibiotics colistin and tobramycin were added in different concentrations with or without the addition of albumin.Results. Generally, neutrophil elastase activity was lower in the absence of albumin compared to its presence. Both antibiotics, colistin and tobramycin, had inhibitory effects on neutrophil elastase activity except for high concentrations of colistin when albumin was absent.Conclusions. Our results suggest inhibitory effects of colistin and tobramycin in vitro. There was a clear dependency of neutrophil elastase measurements on the presence of albumin. Clinical studies are needed to investigate potential direct effects of inhaled antibiotics on neutrophil elastase activity in cystic fibrosis airways.
Essential Requirement for PP2A Inhibition by the Oncogenic Receptor c-KIT Suggests PP2A Reactivation as a Strategy to Treat c-KIT+ Cancers
Authors: Roberts Kathryn G. , Smith Amanda M. , McDougall Fiona , Carpenter Helen , Horan Martin , Neviani Paolo , Powell Jason A. , Thomas Daniel , Guthridge Mark A. , Perrotti Danilo , Sim Alistair T.R. , Ashman Leonie K. , Verrills Nicole M.
Published: June 2010

Oncogenic mutations of the receptor tyrosine kinase c-KIT play an important role in the pathogenesis of gastrointestinal stromal tumors, systemic mastocytosis, and some acute myeloid leukemias (AML). Although juxtamembrane mutations commonly detected in gastrointestinal stromal tumor are sensitive to tyrosine kinase inhibitors, the kinase domain mutations frequently encountered in systemic mastocytosis and AML confer resistance and are largely unresponsive to targeted inhibition by the existing agent imatinib. In this study, we show that myeloid cells expressing activated c-KIT mutants that are imatinib sensitive (V560G) or imatinib resistant (D816V) can inhibit the tumor suppressor activity of protein phosphatase 2A (PP2A). This effect was associated with the reduced expression of PP2A structural (A) and regulatory subunits (B55α, B56α, B56γ, and B56δ). Overexpression of PP2A-Aα in D816V c-KIT cells induced apoptosis and inhibited proliferation. In addition, pharmacologic activation of PP2A by FTY720 reduced proliferation, inhibited clonogenic potential, and induced apoptosis of mutant c-KIT+ cells, while having no effect on wild-type c-KIT cells or empty vector controls. FTY720 treatment caused the dephosphorylation of the D816V c-KIT receptor and its downstream signaling targets pAkt, pSTAT5, and pERK1/2. Additionally, in vivo administration of FTY720 delayed the growth of V560G and D816V c-KIT tumors, inhibited splenic and bone marrow infiltration, and prolonged survival. Our findings show that PP2A inhibition is essential for c-KIT–mediated tumorigenesis, and that reactivating PP2A may offer an attractive strategy to treat drug-resistant c-KIT+ cancers. Cancer Res; 70(13); 5438–47. ©2010 AACR.
pp60c-Src Phosphorylates and Activates Vacuolar Protein Sorting 34 to Mediate Cellular Transformation
Authors: Hirsch Dianne S. , Shen Yi , Dokmanovic Milos , Wu Wen Jin
Published: June 2010

Vacuolar protein sorting 34 (VPS34) contributes to the regulation of the mammalian target of rapamycin complex 1/S6 kinase 1 pathway downstream of nutrient signaling. However, intracellular mechanisms leading to VPS34 activation remain unclear. Here, we report that Src directly phosphorylates VPS34, and that this phosphorylation activates VPS34 lipid kinase activity, leading to Src-Y527F–mediated cellular transformation. Silencing endogenous VPS34 specifically inhibits Src-Y527F–induced colony formation in soft agar, but not Ras-G12V–induced colony formation. We have identified two novel hVPS34 mutations, which either eliminate lipid kinase activity (kinase-dead mutant) or reduce tyrosine phosphorylation by Src-Y527F. When kinase-dead mutant of hVPS34 is stably expressed in Src-Y527F–transformed cells, transformation activities are blocked, indicating that the lipid kinase activity of hVPS34 is essential for Src-mediated cellular transformation. Furthermore, stable expression of this hVPS34 kinase-dead mutant causes an increased number of binucleate and multinucleate cells, suggesting that the kinase activity of hVPS34 is also required for cytokinesis. Moreover, when the hVPS34 mutant that has reduced tyrosine phosphorylation by Src is stably expressed in Src-Y527F–transformed cells, Src-Y527F–stimulated colony formation is also reduced. Data presented here provide important evidence that VPS34 lipid kinase activity could be positively regulated by Src-mediated tyrosine phosphorylation in mammalian cells. This finding highlights a previously unappreciated relationship between VPS34, a class III phosphatidylinositol-3-kinase, and Src non–receptor tyrosine kinase. Additionally, we find that the levels of VPS34 expression and tyrosine phosphorylation are correlated with the tumorigenic activity of human breast cancer cells, indicating that Src to VPS34 signaling warrants further investigation as a pathway contributing to the development and progression of human cancers. Cancer Res; 70(14); 5974–83. ©2010 AACR.
Cyclic AMP Suppression Is Sufficient to Induce Gliomagenesis in a Mouse Model of Neurofibromatosis-1
Authors: Warrington Nicole M. , Gianino Scott M. , Jackson Erin , Goldhoff Patricia , Garbow Joel R. , Piwnica-Worms David , Gutmann David H. , Rubin Joshua B.
Published: June 2010

Current models of oncogenesis incorporate the contributions of chronic inflammation and aging to the patterns of tumor formation. These oncogenic pathways, involving leukocytes and fibroblasts, are not readily applicable to brain tumors (glioma), and other mechanisms must account for microenvironmental influences on central nervous system tumorigenesis. Previous studies from our laboratories have used neurofibromatosis-1 (NF1) genetically engineered mouse (GEM) models to understand the spatial restriction of glioma formation to the optic pathway of young children. Based on our initial findings, we hypothesize that brain region–specific differences in cAMP levels account for the pattern of NF1 gliomagenesis. To provide evidence that low levels of cAMP promote glioma formation in NF1, we generated foci of decreased cAMP in brain regions where gliomas rarely form in children with NF1. Focal cAMP reduction was achieved by forced expression of phosphodiesterase 4A1 (PDE4A1) in the cortex of Nf1 GEM strains. Ectopic PDE4A1 expression produced hypercellular lesions with features of human NF1-associated glioma. Conversely, pharmacologic elevation of cAMP with the PDE4 inhibitor rolipram dramatically inhibited optic glioma growth and tumor size in Nf1 GEM in vivo. Together, these results indicate that low levels of cAMP in a susceptible Nf1 mouse strain are sufficient to promote gliomagenesis, and justify the implementation of cAMP-based stroma-targeted therapies for glioma. Cancer Res; 70(14); 5717–27. ©2010 AACR.