bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Orbital Calculations for Polyhedral Water Clusters Including Gas Molecules
Authors: HORI AKIRA , HONDOH TAKEO
Published: July 2010

Abstract:Semiempirical molecular orbital calculations were performed for several types of polyhedral water clusters (12‐, 14‐, and 16‐hedra) including a gas molecule. The stabilities of the polyhedral water clusters were evaluated from the differences in the cohesive energy between the clusters including a gas molecule and the corresponding vacant clusters. It was found that there is a correlation between the structure type of the hydrate crystal and the type of polyhedral water cluster that is energetically favored; a gas molecule for which the 14‐hedral cluster is energetically more favorable than the 16‐hedral one tends to form a structure I hydrate crystal. The vibrational frequencies of the guest molecules shifted due to the interaction between the gas molecule and the surrounding water molecules. Optical absorption spectra in the ultraviolet range were also calculated for polyhedral water clusters, including a gas molecule.
Optimizing Thermodynamic Parameters to Match Methane and Ethane Structural Transition in Natural Gas Hydrate Equilibria
Authors: BALLARD ADAM L. , SLOAN E. D.
Published: July 2010

Abstract: A simple natural gas mixture (methane and ethane) when mixed with water to form natural gas hydrates can exhibit complex phase equilibria. In this case, two structure I hydrate formers when combined form a structure II hydrate under certain conditions. Optimized Kihara parameters were derived from experimental data using the statistical thermodynamics model based on the van der Waals and Platteeuw theory and using the Kihara spherical core potential for the guest‐water interactions. The parameters were based upon both pure component data and the structural transition point, with the intent of better predictions over the remainder of the phase diagram.
Feasibility of Storing Natural Gas in Hydrates Commercially
Authors: ROGERS R. E. , ZHONG YU
Published: July 2010

Abstract: A study to determine the feasibility of using gas hydrates to store natural gas for peak‐load use in electric power plants and other commercial applications gives new impetus for practical utilization of unique gas‐hydrate storage properties. Laboratory apparatus was constructed to evaluate storage capacity attainable with hydrates and to achieve formation/decomposition rates of the hydrates at a level allowing commercial use. A fiber optics‐camera system was installed to view the action inside the hydrate test cell; photographs are presented that give insight into hydrate formation at the gas/liquid interface, as well as the formation mechanism and packing density. From a quiescent water solution in a cell that contained 286 ppm sodium dodecyl sulfate, storage capacity of 155 vol/vol of natural gas in hydrates was achieved at a constant pressure of 3.89 MPa (550 psig) and a temperature of 276 K (37°F); 86% of the theoretical maximum storage capacity was achieved within 2.5 hours of hydrate initiation; hydrate particles were adsorbed on the vessel walls; interstitial water of the particles formed hydrates to give high‐density packing. Formation rates and process simplification were such that a complete formation/decomposition cycle of commercial scale could be achieved within a 24‐hour period. The work suggests the possibility of storing gas in hydrates industrially by means of a simple, quiescent system that rapidly forms the hydrates and packs the mass for storage.
NMR Imaging Study of Hydrates in Sediments
Authors: MORK MARIT , SCHEI GRETHE , LARSEN ROAR
Published: July 2010

Abstract: In this study, hydrates were generated in synthetic sediments in a laboratory cell. After hydrate formation took place and the sediment solidified, the samples were investigated both visually and by the use of nuclear magnetic resonance (NMR) imaging. The hydrates in this initial study were formed from model systems at low pressure. The results show hydrates distribution effects. Scans in the NMR apparatus were also made of the unfrozen samples to serve as a basis for comparison. NMR here maps the mobility of hydrogen atoms and their distribution in a sample. The relevant factor is the density of mobile H‐atoms, and this is shown to be about five times smaller for a volume of (for example) tetrahydrofuran (THF, C4H8O) hydrate than for the fluids of water and/or THF. This correlates very well with an observed signal decrease by a factor of six in an NMR‐studied sample after hydrate formation had taken place.
Rheological Characterization of Hydrate Suspensions in Oil Dominated Systems
Authors: CAMARGO R. , PALERMO T. , SINQUIN A. , GLENAT P.
Published: July 2010

Abstract: In the work described in this paper, the rheological behavior of hydrate suspensions in an asphaltic crude oil was studied. A P‐T cell adapted to operate as a double cylinder configuration rheometer was used. The results obtained show that the hydrate suspensions studied exhibit shear thinning behavior and thixotropy. This behavior is more visible in suspensions with higher particle content and seems to be related to colloidal interactions between the crystals, which causes aggregation between crystals at low shear rates.
Crystal Growth, Structure Characterization, and Schemes for Economic Transport: An Integrated Approach to the Study of Natural Gas Hydrates
Authors: MAHAJAN D. , KOETZLE T. F. , KLOOSTER W. T. , BRAMMER L. , McMULLAN R. K. , GOLAND A. N.
Published: July 2010

Abstract: In this paper, two themes are specifically targeted for developing a cost‐effective option to transport methane hydrates from distant locations. Under the first theme, data are presented on crystal growth techniques, sample preparation and neutron diffraction studies of 3.5Xe · 8CCl4· 136D2O, xCH4· 8CCl4· 136D2O, xH2S · 8CS2· 136 H2O, and 20Br2· 172D2O. Under the second theme, the GTL option is selected wherein methanol is the product of choice for transport. For GTL, the processing of aqueous CH4 by steam reforming is the preferred route to synthesis gas. Subsequent conversion of synthesis gas into methanol will require the formulation of advanced catalysts.
High‐Pressure Optical Cell for Hydrate Measurements Using Raman Spectroscopy
Authors: THIEU V. , SUBRAMANIAN S. , COLGATE S. O. , SLOAN E. D.
Published: July 2010

Abstract: A high‐pressure optical cell was designed and fabricated for the measurement of hydrate phase equilibria. These measurements were carried out using Raman spectroscopy, which provided molecular microscopic evidence of hydrate dissociation, along with macroscopic temperature and pressure evidence. Initial measurements were made of hydrates formed from methane (CH4) dissolved in deionized water. Distinct signatures of CH4 in different phases (aqueous and sI hydrate) were the basis for this study. Time resolved Raman spectra monitored the dissociation of hydrate as cell temperature was increased. The spectra depicted the transition of CH4 in the two cavities of sI hydrate to CH4 dissolved in water. A pressure trace of the experiment indicated a slight jump in pressure of about 30 psi (0.2 MPa) at the hydrate dissociation point, which agreed with the Raman spectroscopic data. Experimental data obtained using this method agreed well with literature data for the simple methane system. The technique demonstrated that the optical cell is suitable for Raman measurements of hydrate phase equilibria at high pressures. Ultimately, this procedure will be used to measure thermodynamic conditions for more complex systems.
Use of Oligonucleotide Arrays to Analyze Drug Toxicity
Authors: KAMINSKI NAFTALI , ALLARD JOHN , HELLER RENU A.
Published: July 2010

Abstract:The advent of oligonucleotide arrays allows the simultaneous analysis of the expression of thousands of genes. This powerful technology, highly dependent on advanced analysis tools, can transform the level of information currently available on the mechanisms underlying drug‐related toxicity. It is now possible to analyze the global transcriptional response to a drug and determine the global pathways associated with the effects of this agent. This analysis can be performed on samples from patients that developed a toxic effect, on cells exposed to the toxic agent, and in animal models of toxicity. Especially useful is the comparison of transcriptional responses in animals susceptible to drug‐induced disease with those of genetically modified animals that are resistant to this effect. This analytic strategy allows the delineation of specific mechanisms relevant and specific to drug‐induced toxicity and thus might lead to novel therapeutic interventions in these toxic reactions.
Analysis of Drug Pharmacology towards Predicting Drug Behavior by Expression Profiling Using High‐Density Oligonucleotide Arrays
Authors: HU JING‐SHAN , DURST MARK , KERB REINHOLD , TRUONG VIVI , MA JING‐TYAN , KHURGIN ELINA , BALABAN DAVID , GINGERAS THOMAS R. , HOFFMAN BRIAN B.
Published: July 2010

Abstract: An important aspect of the drug development process is prediction of efficacious and toxic side effects. Profiling of mRNA expression is a powerful approach to analyze the molecular phenotype of cells under various conditions, for example, in response to stimulation by compounds. We attempt to explore the approach of using expression profiling to identify patterns or fingerprints that are correlated with specific drug properties or behaviors. Identification of such expression patterns may also lead to revelation of the potential action mechanism of drugs and fingerprints indicative of certain drug efficacy or side effects. We describe here a strategy that was used to identify a set of genes whose differential expression pattern correlates with activation mode and target specificity of a specific group of drug compounds.
In Silico Toxicology
Authors: HOLTZMAN SAMUEL
Published: July 2010

Abstract: It is toxicology's job to discover a new substance's harmful effects and suggest ways to prevent or mitigate those harmful effects. This paper offers a new possibility‐in silico toxicology‐to help address this multifaceted challenge.
Transgenic Zebrafish as Sentinels for Aquatic Pollution
Authors: CARVAN MICHAEL J. , DALTON TIMOTHY P. , STUART GARY W. , NEBERT DANIEL W.
Published: July 2010

Abstract: Using the golden mutant zebrafish having a decrease in interfering pigmentation, we are developing transgenic lines in which DNA motifs that respond to selected environmental pollutants are capable of activating a reporter gene that can be easily assayed. We have begun with three response elements that recognize three important classes of foreign chemicals. Aromatic hydrocarbon response elements (AHREs) respond to numerous polycyclic hydrocarbons and halogenated coplanar molecules such as 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD; dioxin) and polychlorinated biphenyls. Electrophile response elements (EPREs) respond to quinones and numerous other potent electrophilic oxidants. Metal response elements (MREs) respond to heavy metal cations such as mercury, copper, nickel, cadmium, and zinc. Soon, we will include estrogen response elements (EREs) to detect the effects of environmental endocrine disruptors, and retinoic acid response elements (RARE, RXRE) to detect the effects of retinoids in the environment. Each of these substances is known to be bioconcentrated in fish to varying degrees; for example, 10−17 M TCDD in a body of water becomes concentrated to approximately 10−12 M TCDD in a fish, where it would act upon the AHRE motif and turn on the luciferase (LUC) reporter gene. The living fish as a sentinel will not only be assayed intact in the luminometer, but‐upon several days or weeks of depuration‐would be usable again. To date, we have established that zebrafish transcription factors are able to recognize both mammalian and trout AHRE, EPRE, and MRE sequences in a dose‐dependent and chemical‐class‐specific manner, and that expression of both the LUC and jellyfish green fluorescent protein (GFP) reporter genes is easily detected in zebrafish cell cultures and in the intact live zebrafish. Variations in sensitivity of this model system can be achieved by increasing the copy number of response elements and perhaps by altering the sequence of each core consensus response element and flanking regions. This transgenic technology should allow for a simple, exquisitely sensitive, and inexpensive assay for monitoring aquatic pollution. We have already initiated studies using sentinel zebrafish to monitor a public drinking water source.
The Use of Explant Lens Culture to Assess Cataractogenic Potential
Authors: ALEO MICHAEL D. , AVERY MICHAEL J. , BEIERSCHMITT WILLIAM P. , DRUPA CYNTHIA A. , FORTNER JAY H. , KAPLAN ADAM H. , NAVETTA KIMBERLY A. , SHEPARD RICHARD M. , WALSH COLLEEN M.
Published: July 2010

Abstract:Explanted cultures of crystalline lenses have been used to investigate mechanisms of xenobiotic‐induced cataract formation. However, very few studies have utilized mechanistic information to predict the cataractogenic potential of structurally diverse xenobiotics. The present investigation outlines how visual assessment of lens clarity, biochemical endpoints of toxicity, and mechanisms of lenticular opacity formation can be used to select compounds with a lower probability of causing cataract formationin vivo. The rat lens explant culture system has been used to screen thiazolidinediones against ciglitazone for their direct cataractogenic potentialin vitro. The two compounds that were selected as development candidates (englitazone and darglitazone) did not produce cataracts in rats exposed daily for 3 months. The culture system has also been used to illustrate that the lens is capable of metabolizing compounds to reactive intermediates. In this example, the toxicity ofS‐(1,2‐dichlorovinyl)‐L‐cysteine (DCVC), a model cataractogen, was attenuated by inhibiting lenticular cysteine conjugate β‐lyase metabolism using aminooxyacetic acid. Finally, this model was used retrospectively to investigate the cataractogenic potential of CJ‐12,918 and CJ‐13,454 in rats. These compounds showed differences in the incidence of cataract formationin vivobased on differences in hepatic metabolism and penetration of parent drug and metabolites into the lens. The rank order of cataractogenic potentialin vitrocorrelated better within vivoresults when an induced S9 microsomal fraction was added to the culture media. However, the model did not correctly predict the cataractogenic potential of ZD2138, a structurally similar compound. These studies illustrate the use of explant culture to assess mechanisms of cataract formation and outline its use and limitations for predicting cataractogenic potentialin vivo.
Molecular Genetic Control of Axis Patterning during Early Embryogenesis of Vertebrates
Authors: SCHOENWOLF GARY C.
Published: July 2010

Abstract: Formation of the axis and its subsequent patterning to establish the tube‐within‐a‐tube body plan characteristic of vertebrates are initiated during gastrulation. In higher vertebrates (i.e., birds and mammals), gastrulation involves six key events: establishment of the rostrocaudal/mediolateral axis; formation and progression of the primitive streak and organizer; epiboly of the epiblast, ingression of prospective mesodermal and endodermal cells through the primitive streak, and migration of cells away from the primitive streak; regression of the primitive streak; establishment of the right‐left axis; and formation of the tail bud. Over 50 years of study of these processes have provided a morphological framework for understanding how these events occur, and recent advances in imaging, microsurgical intervention, and cell tracking are beginning to elucidate the underlying cell behaviors that drive morphogenetic movements. Moreover, homotopic transplantation and dye microinjection studies are being used to generate high‐resolution fate maps, and heterotopic transplantation studies are revealing the cell‐cell interactions that are sufficient as well as required for mesodermal and ectodermal commitment. Additionally, the roles of the organizer and secondary signaling centers in establishing the body plan are being defined. With the advent of the molecular/genetic age, the molecular basis for axis formation is beginning to become understood. Thus, it is becoming clear that secreted growth factors/signaling molecules produced by localized signaling centers induce and pattern the axis, presumably through downstream activation of signal‐transduction proteins and cascades of transcription factors.
Classification and Description of Frontotemporal Dementias
Authors: NEARY D. , SNOWDEN J. S. , MANN D. M.A.
Published: July 2010

Abstract: A number of distinct clinical syndromes have been described that are associated with focal degeneration of the frontal and temporal lobes and have a non‐Alzheimer pathology. The nosological status of frontotemporal lobar degeneration (FTLD) has been a matter of controversy, in view of the diversity of clinical manifestations and distribution and nature of histopathological change. This paper describes the major clinical syndromes of frontotemporal dementia, progressive aphasia, and semantic dementia; it discusses their underlying pathologies and considers their molecular status. Common histopathological changes are demonstrated across the three clinical syndromes, highlighting the link between these clinical disorders. It has been suggested that these disorders should be regarded as tauopathies on the basis of the tau pathology seen in a number of cases and the mutations in the tau gene in some familial cases. However, in a series of 47 consecutive autopsy series of FTLD, only 36% had tau pathology and 10% mutations in the tau gene, suggesting that FTLD does not constitute a unitary etiological disorder and that its characterization as a tauopathy may be potentially misleading.
Coexistent Tau and Amyloid Pathology in Hereditary Frontotemporal Dementia with Tau Mutations
Authors: ROSSO S. M. , KAMPHORST W. , RAVID R. , Van SWIETEN J. C.
Published: July 2010

Abstract: Hereditary frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP‐17) is associated with different mutations in the microtubule‐associated protein (MAP) tau gene. Pathological changes consist of accumulation of hyperphosphorylated tau protein in frontal and temporal cortex, hippocampus, and some subcortical nuclei. We describe the neuropathological findings in five patients with P301L mutation, and in two affected sibs with R406W mutation. The P301L brains all showed a pretangle‐type tauopathy of the frontal and temporal cortices. One of these patients, however, also showed an Alzheimer‐type tauopathy with neurofibrillary tangles (NFT), neuritic plaques, and amyloid angiopathy of the temporoparietal cortex. Three tau bands (64, 68, and 72 kDa) were seen in the frontal cortex, while the temporal cortex revealed four bands (60, 64, 68, and 72 kDa), containing all six tau isoforms. The first R406W brain showed many NFT in affected regions with only a few diffuse amyloid plaques. The second R406W brain contained a much higher density of NFT in affected regions, and an extensive amyloid deposition consisting of both diffuse and neuritic plaques with dense cores. An intriguing question is whether the FTD and Alzheimer disease changes are concomitant, or whether there is an interaction between tau and amyloid pathology. An acceleration of NFT formation due to amyloid deposition has been observed in nondemented aging and preclinical AD. The question whether this mechanism occurs in FTD with tau mutations remains to be elucidated.
In Vivo Analysis of Wild‐type and FTDP‐17 Tau Transgenic Mice
Authors: GÖTZ J. , BARMETTLER R. , FERRARI A. , GOEDERT M. , PROBST A. , NITSCH R. M.
Published: July 2010

Abstract: Mutations in the coding and intronic regions of the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17). Some of these mutations lead to an overproduction of tau isoforms with four microtubule‐binding repeats, followed by the development of fibrillary lesions and selective cell death. In order to analyze the development of these neurofibrillary lesions in transgenic mice, the longest four‐repeat human brain tau isoform was expressed under control of two different neuron‐specific promoters. In a first model, utilizing the human Thy1 promoter, transgenic tau was hyperphosphorylated and abnormally localized to cell bodies and dendrites. In a second model, which made use of a human Thy1.2 expression vector, transgenic expression levels were much higher, and an additional phenotype was observed: Large numbers of pathologically enlarged axons containing neurofilament‐ and tau‐immunoreactive spheroids were present, especially in spinal cord. Signs of Wallerian degeneration and neurogenic muscle atrophy were observed. Behaviorally, transgenic mice showed signs of muscle weakness. Our data show that overexpression of human four‐repeat tau in itself is sufficient to lead to nerve cell dysfunction and amyotrophy. We have now extended our initial studies by introducing exonic mutations including G2t 2V and PS01L into the tau gene in order to achieve a more advanced FTDP‐17 associated phenotype.
Presenilin Function in APP Processing
Authors: ANNAERT WIM , CUPERS PHILIPPE , SAFTIG PAUL , DE STROOPER BART
Published: July 2010

Abstract: Familial Alzheimer's disease (FAD) is now linked to at least three genes encoding the amyloid precursor protein (APP) on chromosome 21, and presenilin 1 and 2 on chromosome 14 and 1, respectively. FAD cases in whom presenilin mutations occur are more frequent than those with APP mutations. However, altogether they only account for approximately 0.1% of all the people suffering from Alzheimer's disease (AD),1 and the causes of the remaining 99.9% of the sporadic form of AD or senile dementia remain unknown. Since FAD presents with the same neuropathological features as sporadic AD, i.e., cognitive impairments and the amyloid plaques and tangles in the brain, our working hypothesis is that similar molecular pathogenic mechanisms underly both sporadic and familial AD. It follows that APP and the presenilins must be key players in the disease. Detailed knowledge about the cell biology of these proteins will be a rich source of insight into the pathology of AD, but will also shed light on the fundamental neurobiology of these proteins.
Role of Presenilin‐1 in Murine Neural Development
Authors: YANG XUDONG , HANDLER MELISSA , SHEN JIE
Published: July 2010

Abstract: Our previous studies showed that presenilin‐1 (PS1) is required for murine neural and skeletal development. Here we report that the reduction in the neural progenitor cells observed in the PS1−/− mouse brain is due to premature differentiation of progenitor cells, rather than to increased apoptotic cell death or decreased cell proliferation. In the ventricular zone of PS1−/− mice, expression of the Notch1 downstream effector gene Hes5 is reduced, and expression of the Notch1 ligand Dll1 is elevated, indicating reduced Notch signaling. These results provide direct evidence that PS1 is involved in the regulation of neurogenesis and Notch signaling during development.
The Value of Transgenic Models for the Study of Neurodegenerative Diseases
Authors: PRICE DONALD L. , WONG PHILIP C. , MARKOWSKA ALICJA L. , LEE MICHAEL K. , THINAKAREN GOPAL , CLEVELAND DONALD W. , SISODIA SANGRAM S. , BORCHELT DAVID R.
Published: July 2010

Abstract: Transgenic animal models are useful in studying the features of APP‐ and PS1‐linked FAD and SOD1‐linked FALS. These models help to investigate the nature of the cellular/biochemical/molecular alterations in neural tissue; the character and evolution of neuronal and/or glial abnormalities; the ways mutant proteins cause damage to neurons; and the biochemical pathways associated with cell death. New technologies will help to define changes in a variety of genes/gene products and the events and conformational changes in mutant proteins that are implicated in pathogenic cascades. It is hoped such study will result in novel treatments for testing in transgenic models that can then be translated into new treatments for human neurodegenerative diseases.
α‐Secretase Activity of the Disintegrin Metalloprotease ADAM 10: Influences of Domain Structure
Authors: FAHRENHOLZ FALK , GILBERT SANDRA , KOJRO ELZBIETA , LAMMICH SVEN , POSTINA ROLF
Published: July 2010

Abstract: Disintegrin metalloproteases from different organisms form the ADAM (adisintegrin and metalloprotease) family. All members display a common domain organization and possess four potential functions: proteolysis, cell adhesion, cell fusion, and cell signaling. Members of the ADAM family are responsible for the proteolytic cleavage of transmembrane proteins and release of their extracellular domain. The proteolytic process is referred to as ectodomain shedding, which is activated by phorbol esters and inhibited by hydroxamic acid‐based inhibitors. We have shown that the disintegrin metalloprotease ADAM 10 has both constitutive and regulated α‐secretase activity. Expression of a dominant negative mutant of ADAM 10 in HEK cells decreases the secretion of APPsα. In order to investigate the influence of distinct protein domains of ADAM 10 on α‐secretase activity, several deletion mutants of ADAM 10 were constructed. Our findings demonstrate that the deletion of the disintegrin domain results in a mutant ADAM 10 with remaining α‐secretase activity, whereas the deletion of the prodomain destroys the proteolytic activity of ADAM 10.
GSK3β Forms a Tetrameric Complex with Endogenous PS1‐CTF/NTF and β‐Catenin: Effects of the D257/D385A and FAD‐linked Mutations
Authors: TESCO G. , TANZI R. E.
Published: July 2010

Abstract: We have previously shown that the endogenous C‐terminal fragment of presenilin 1 coimmunoprecipitates with endogenous β‐catenin. Since PS1 has been suggested to be involved in β‐catenin stabilization, we further investigated whether GSK3β, responsible for β‐catenin phosphorylation and degradation, is part of the PS1/β‐catenin complex. In naïve H4 and CHO cells, PS1 co‐immunoprecipitated with both endogenous β‐catenin and GSK3β. In addition, GSK3β endogenously binds to the PS1‐CTF/NTF complex and β‐catenin in naïve CHO cells. GSK3β also co‐immunoprecipitated with PS1 full length in CHO cell lines overexpressing PS1 wild type. Given that it has been recently shown that PS1 mutations of aspartate 257 or 385 result in prevention of PS1 endoproteolysis and inhibition of γ‐secretase activity, we also tested whether PS1 endoproteolysis is required for β‐catenin/GSK3β/PS1 binding and whether PS1 FAD‐linked mutations affect GSK3β recruitment in the PS1/β‐catenin complex. GSK3β was detected in PS1 immunoprecipitates from H4 cell lines overexpressing PS1 wild type, ΔE10, A286E, L246V and in CHO cell lines overexpressing aspartate or M146L mutations. The latter data show that the absence of PS1 endoproteolysis (D257A/D385A and ΔE10) or the presence of PS1‐FAD mutations does not interfere with β‐catenin/GSK3β/PS1 complex formation.
Inhibition of the Neuronal Insulin Receptor An in Vivo Model for Sporadic Alzheimer Disease?
Authors: HOYER SIEGFRIED , LEE SAE KYUNG , LÖFFLER THOMAS , SCHLIEBS REINHARD
Published: July 2010

Abstract: It has been hypothesized that a central event in the early pathogenesis of sporadic Alzheimer disease (SAD) is the dysfunction of the neuronal insulin receptor signal transduction. To prove this, this receptor was inhibited by a triplicate icv application of STZ. Insulin binding sites were upregulated as in SAD. With respect to glucose transport proteins, detailed investigations are necessary.
Receptors and Transcriptional Factors Involved in the Anti‐Inflammatory Activity of VIP and PACAP
Authors: LECETA JAVIER , GOMARIZ ROSA P. , MARTINEZ CARMEN , ABAD CATALINA , GANEA DOINA , DELGADO MARIO
Published: July 2010

Abstract: VIP and PACAP modulate the function of inflammatory cells through specific receptors. VIP/PACAP inhibit the production of TNFα, IL‐6, IL‐12, and nitric oxide (NO), and stimulate IL‐10 in peritoneal macrophages and Raw 264.7 cells. Here we report on the specific VIP/PACAP receptors, transduction pathways, and transcriptional factors involved in the regulation of these macrophage factors by VIP and PACAP. Both neuropeptides inhibit IL‐6 production mainly through PAC1 binding, PKC activation, and the subsequent shedding of the LPS receptor CD14 in macrophages. However, the effects on TNFα, IL‐10, IL‐12, and NO are mostly mediated through the constitutively expressed VPAC1 receptor, although the inducible expressed VPAC2 may also participate. VIP/PACAP binding to VPAC1 induces both a cAMP‐dependent and a cAMP‐independent pathways that regulate cytokine and NO production at the transcriptional level. VIP/PACAP inhibit TNFα through reduction in NFkB binding and changes in the composition of CRE‐binding complexes; they inhibit IL‐12 through reduction in NFkB binding and changes in the composition of the ets‐2 complexes. VIP/PACAP inhibit iNOS expression through reduction in NFkB and IRF‐1 binding, and augment IL‐10 by increasing CREB‐binding. Whereas the inhibition of IRF‐1 and CRE‐binding complexes seems to be mediated through the cAMP‐dependent pathway, VIP/PACAP inhibition of NFkB nuclear translocation is mediated through a reduction in IkBα degradation mediated by the cAMP‐independent pathway. This study provides new evidence for the understanding of the molecular mechanism by means of which VIP and PACAP attenuate the inflammatory response.
Functional Significance of Colocalization of PACAP and Catecholamine in Nerve Terminals
Authors: SHIODA SEIJI , YADA TOSHIHIKO , MUROYA SHINJI , URAMURA SHIGEAKI , NAKAJO SHIGEO , OHTAKI HIROKAZU , HORI TOSHIKO , SHIMODA YOSHIMI , FUNAHASHI HISAYUKI
Published: July 2010

Abstract: Medullary neurons containing pituitary adenylate cyclase‐activating polypeptide (PACAP) and noradrenalin (NA) project to the hypothalamus and they are involved in the regulation of arginine vasopressin (AVP) neurons. At the ultrastructural level, PACAP immunoreactivity was detected in the granular vesicles in catecholaminergic nerve terminals that made synaptic contact with AVP neurons. Both PACAP (at least 1 nM) and NA (at least 1 μmM) induced large increases in the cytosolic Ca2+ concentration ([Ca2+]i) in isolated AVP cells. PACAP at 0.1 nM and NA at 0.1 μmM had little effects, if any, on [Ca2+]i. However, when 0.1 nM PACAP and 0.1 μM NA were combined, they evoked large increase in [Ca2+]i in AVP neurons. An inhibitor of protein kinase A (PKA) completely inhibited the PACAP‐induced increase in [Ca2+]i, but only partly inhibited the NA‐induced increase in [Ca2+]i. In AVP cells that were prelabeled with quinacrine, PACAP and NA acted synergistically to induce a loss of quinacrine fluorescence, indicating secretion of neurosecretory granules in AVP neurons. The results suggest that PACAP and NA, coreleased from the same nerve terminals, act in synergy to evoke calcium signaling and secretion in AVP neurons, and that the synergism is mediated by the interaction between cAMP‐PKA pathway an as yet unidentified factor “X” linked to L‐type Ca2+ channels. The synergism between PACAP and NA may contribute to the regulation of AVP secretion under physiological conditions.
The Effects of PACAP on Insulin Secretion and Glucose Disposal Are Altered by Adrenalectomy in Mice
Authors: AHRÉN BO , FILIPSSON KARIN
Published: July 2010

Abstract:We previously showed that pituitary adenylate cyclase‐activating polypeptide (PACAP) potently stimulates insulin secretionin vivoin mice without altering glucose disposal. Such a combination of results would be explained if epinephrine released by PACAP counteracts the action of insulin and, therefore, that the glucose disposal after PACAP administration is altered by adrenalectomy. In the study reported in this paper, we examined the influence of PACAP27 (1.3 nmol/kg i.v.) on insulin secretion and glucose disposal during an intravenous glucose (1 g/kg) tolerance test in mice subjected to bilateral adrenalectomy 48 h prior to the tolerance test. We found that in control mice, PACAP potentiated glucose‐stimulated insulin secretion threefold without affecting glucose disposal. Adrenalectomy potentiated the augmentation by PACAP27 of glucose‐stimulated insulin secretion, and in adrenalectomized mice, PACAP27 simultaneously augmented glucose disposal (elimination rate 2.30 ± 0.07%/min vs. 2.56 ± 0.05%/min;p=0.011). Furthermore, PACAP27 augmented glucose elimination stimulated by i.v. insulin administration only in adrenalectomized, but not in control mice. We, therefore, conclude that under in vivo conditions, epinephrine released by PACAP from the adrenals prevents the marked insulinotropic action of the peptide from augmenting glucose disposal.
PACAP Acts as a Neurotrophic Factor During Histogenesis of the Rat Cerebellar Cortex
Authors: VAUDRY D. , GONZALEZ B. J. , BASILLE M. , PAMANTUNG T. F. , FOURNIER A. , VAUDRY H.
Published: July 2010

Abstract:During development of the rat cerebellum, PAC1receptors are transiently expressed by neuroblasts of the external granule cell layer (EGL). We have previously shown that PACAP is a potent stimulator of granule cell survivalin vitro. In the study reported in this paper, we have investigated the effect of PACAP on the development of the rat cerebellar cortexin vivo. PACAP induces a transient increase in the volume of the cerebellar cortex, with a maximum effect at postnatal day 12, which can be accounted for by an increase in the number of granule cells in the EGL, the molecular layer, and the internal granule cell layer (IGL). The effect of PACAP on the number of granule cells is blocked by the antagonist PACAP(6–38), which, by itself, produces a slight inhibition of the number of granule cells in the IGL. These data indicate that PACAP activates proliferation and/or inhibits programmed cell death of granule cells in the developing rat cerebellum. PACAP also stimulates neuronal migration from the EGL to the IGL. Thus, it appears that PACAP can actin vivoas a neurotrophic factor controlling histogenesis of the cerebellar cortex.
Occurrence and Effect of PACAP in the Human Fetal Adrenal Gland
Authors: BREAULT LYNE , YON LAURENT , MONTÉRO MAÏTÉ , CHOUINARD LUCIE , CONTESSE VINCENT , DELARUE CATHERINE , FOURNIER ALAIN , LEHOUX JEAN‐GUY , VAUDRY HUBERT , GALLO‐PAYET NICOLE
Published: July 2010

Abstract: In the study reported in this paper, we characterized PACAP in the human fetal adrenal gland and we investigated the effect of PACAP on steroid secretion from cultured fetal adrenal cells. The adrenal gland from 20‐week‐old fetuses contained substantial concentrations of PACAP‐immunoreactive material (88.6 ng/g wet tissue). HPLC analysis of adrenal extracts revealed the presence of both PACAP27 and PACAP38, the latter being the predominant form. Incubation of cultured fetal adrenal cells with PACAP38 (10−7 M) significantly increased cortisol and DHEAS secretion. Administration of the β‐adrenoreceptor agonist isoproterenol mimicked the stimulatory effect of PACAP on both steroid secretion whereas preincubation of fetal cells with the β‐adrenoreceptor antagonist propranolol suppressed the steroidogenic effect of PACAP. These data, together with the observation that PACAP receptors are exclusively located on chromaffin cells, suggest that, in the fetal human adrenal gland, the effect of PACAP on steroid secretion is mediated via the local release of catecholamines.
Campthotecin Design and Delivery Approaches for Elevating Anti‐Topoisomerase I Activities in Vivo
Authors: BURKE THOMAS G. , BOM DAVID
Published: July 2010

Abstract: The camptothecins as a class have exhibited unique dynamics and reactivity in vivo, with respect to both drug hydrolysis and blood protein interactions. These factors have confounded their pharmaceutical development and clinical implementation. Recent bench and clinical research alike indicates that the combination of medicinal chemical and drug delivery approaches has been and will continue to be highly valuable in improving the overall therapeutic indices of camptothecin‐based anti‐topoisomerase I therapies. In the future the development of camptothecin analogues that exhibit highly specific human albumin interactions will likely be avoided, and agents such as the highly lipophilic DB‐67 analogue with improved tissue stability will be evaluated. Drug delivery scientists will also devise better ways of targeting camptothecin therapies to solid tumors by using carriers such as tumor‐targeted long‐circulating liposomes.
Camptothecins as Probes of the Microenvironments of Topoisomerase I ‐ DNA Complexes
Authors: HECHT SIDNEY M.
Published: July 2010

Abstract: By uncoupling the cleavage and ligation reactions of DNA oligonucleotides mediated by topoisomerase I, it has been possible to demonstrate modification of DNA oligonucleotide structure by the enzyme. These modifications indicate an unusual flexibility inherent in the behavior of topoisomerase I and may reflect some of the cellular roles played by the enzyme. The ability of individual camptothecin analogues to inhibit these modification processes differentially provides insight into the relative nature of the microenvironments present. To the extent that these enzyme‐mediated structural modifications do constitute models of cellular roles for the enzyme, the observed differential inhibition also provides a potential strategy for assessing the function and importance of such modifications.
Conjugation of Camptothecins to Poly‐(l‐Glutamic Acid)
Authors: SINGER JACK W. , DE VRIES PETER , BHATT RAMA , TULINSKY JOHN , KLEIN PETER , LI CHUN , MILAS LUKA , LEWIS ROBERT A. , WALLACE SIDNEY
Published: July 2010

Abstract: Conjugation of water‐insoluble cancer chemotherapeutic drugs to macromolecular polymers can lead to improved pharmaceutical properties and improved therapeutic ratios due to accumulation of the polymer‐drug conjugate in tumor tissue through the enhanced permeability and retention (EPR) to macromolecules associated with tumor vasculature. Pharmaceutical shortcomings of certain active camptothecins including difficulty in formulation and instability of the active lactone form due to interactions with human albumin might be improved by conjugation to polymers. In this report, conjugations of camptothecin (CPT), 10‐hydroxy‐CPT, and 9‐amino‐CPT to poly‐(l‐glutamic acid) (PG) are described; coupling was accomplished either through the 20(S)‐hydroxyl or 9 and 10 substituents with and without the use of a glycine linker. Studies using a PG paclitaxel conjugate (PG‐TXL), which is currently in Phase I testing, demonstrated that PG enhanced aqueous solubility, prolonged plasma residence time, and greatly increased the distribution of paclitaxel to tumor tissue in a murine model. In this report, we describe the use of similar conjugation technology for CPT derivatives and demonstrate that these difficult to formulate compounds can be rendered water soluble, that their maximum tolerated doses are increased, and that they retain substantial anti‐tumor activity in syngeneic and xenogeneic tumor models. Preliminary data suggest that PG with molecular weights between 37 and 50 kDa with CPT loading between 14% and 37% with or without glycine linkers display enhanced efficacy compared with nonconjugated camptothecins administered at their maximum tolerated dose.
Transport of Topoisomerase I Inhibitors by the Breast Cancer Resistance Protein: Potential Clinical Implications
Authors: SCHELLENS JAN H.M. , MALIEPAARD MARC , SCHEPER RIK J. , SCHEFFER GEORGE L. , JONKER JOHAN W. , SMIT JOHAN W. , BEIJNEN JOS H. , SCHINKEL ALFRED H.
Published: July 2010

Abstract: The multidrug resistance protein BCRP (breast cancer resistance protein) is a member of the ATP‐binding cassette family of drug transporters. Overexpression of BCRP caused by exposure of cells to mitoxantrone (MX) or doxorubicin/verapamil resulted in a resistance pattern that is different from what is generally seen in the case of P‐glycoprotein and MRP1 overexpression. Recently, the BCRP gene has been described in ovarian, breast, colon,and gastric cancer and fibrosarcoma cell lines. Our human tumor cells T8 and MX3, derived from the ovarian cancer cell line IGROV1 by stepwise increased exposure to topotecan and MX, are resistant to topotecan, CPT11, SN38, and 9‐aminocamptothecin as well as MX. Increased energy‐dependent efflux of affected drugs was noted. BCRP is a very efficient transporter of topotecan. Our recent studies, using the monoclonal antibody (mAb) BXP34, revealed that BCRP is located in the plasma membrane of the T8 and MX3 cell lines. Preliminary results of staining of human tumor cells showed low or absent levels of BCRP in a panel of solid tumors and acute myeloid leukemia cells.
The Big Bang as Scientific Fact
Authors: FABER S. M.
Published: July 2010

Abstract: In the year 1900, humanity had barely a notion of our place on the cosmic stage, and no inkling at all of how we got here. The one hundred short years of the twentieth century sufficed to unravel 14 billion years of cosmic history and how those grand events, after 9 billions of years or so, set the stage for the birth of our own home, the Solar System. The key events in this history are not hard to comprehend; they can be sketched in a few brief pages. This precious knowledge is part of our shared heritage as human beings and is fundamental to the future prospects of our species. Without it, we are ignorant of the powerful forces that have shaped our past and that will shape our destiny in the future. Read here the cosmic history of humanity, beginning with the Big Bang.
Eternal Inflation
Authors: GUTH ALAN H.
Published: July 2010

Abstract: The basic workings of inflationary models are summarized, along with the arguments that strongly suggest that our universe is the product of inflation. It is argued that essentially all inflationary models lead to (future‐)eternal inflation, which implies that an infinite number of pocket universes are produced. Although the other pocket universes are unobservable, their existence nonetheless has consequences for the way that we evaluate theories and extract consequences from them. The question of whether the universe had a beginning is discussed but not definitively answered. It appears likely, however, that eternally inflating universes do require a beginning.
Inflation and the Beginning of the Universe
Authors: TUROK NEIL
Published: July 2010

Abstract: The question of whether there was a Beginning of the Universe is a truly challenging puzzle for physics and for philosophy. Classical general relativity implies that our observable universe originated in a singularity fifteen billion years ago, but this may be merely a reflection of the incompleteness of the theory. Inflationary theory and quantum cosmology provide our best current attempt to describe these early moments. It has been claimed that the inflationary mechanism renders moot the question of exactly how the universe began. I argue that, on the contrary, if one asks the question of what was in the past, we find ourselves staring directly back at a putative Beginning after all.
Did God Create Our Universe?
Authors: RUSSELL ROBERT JOHN
Published: July 2010

Abstract: The sciences and the humanities, including theology, form an epistemic hierarchy that ensures both constraint and irreducibility. At the same time, theological methodology is analogous to scientific methodology, though with several important differences. This model of interaction between science and theology can be seen illustrated in a consideration of the relation between contemporary cosmology (Big Bang cosmology, cosmic inflation, and quantum cosmology) and Christian systematic and natural theology. In light of developments in cosmology, the question of origins has become theologically less interesting than that of the cosmic evolution of a contingent universe.
A Universe with No Designer
Authors: WEINBERG STEVEN
Published: July 2010

Abstract: Does the universe shows signs of having been designed by a deity like those of traditional monotheistic religions? Physics is in a better position than religion to give a partly satisfying explanation of the world. Recent developments in cosmology help explain why the measured values of the cosmological constant and other physical constants are favorable for the appearance of intelligent life. The presence of evil and misery disturbs those who believe in a benevolent and omnipotent God. It is not necessary to argue that evil in the world proves that the universe is not designed, but only that there are no signs of benevolence that might have shown the hand of a designer.
Is the Universe Designed? Yes and No
Authors: GRIFFIN DAVID RAY
Published: July 2010

Abstract: Addressing the title's question from the perspective of Whitehead's process theology, fourteen basic notions of which are explained, I argue that the universe is not designed in six common senses of that notion: It was not created out of nothing, all at once, through punctuated creationism, from a blueprint, solely for humans, or even with humans specifically in mind. But it is designed in two looser senses of the term: It reflects a divine aim at richness of experience, and it involved a divine establishment of this cosmic epoch's fundamental contingent principles—an idea that is consistent with process theism's view of divine power as purely persuasive.
The Outlook for Cosmic Company
Authors: SHOSTAK SETH
Published: July 2010

Abstract: The last 100 million years or so has seen a continued increase in encephalization for several terrestrial species. Intelligence has survival value. Developments in astrobiology suggest that what was once considered enormously improbable, namely life, is now suspected of being ubiquitous. It may be that the evolution of intelligence is unlikely, but in a finite, breathtakingly large universe (1022 stars) small probability likely does not matter. Even if nature is indifferent to producing intelligence, SETI might still succeed. Biological intelligence may be rare, but it has the potential for creating engineered synthetic intelligence, capable of rapid and directed self‐evolution. The galaxy could be rife with such long‐lived, communicating devices, even if intelligent protoplasm is both rare and fleeting. SETI is looking for narrow‐band, microwave signals that are not produced naturally. Ultimately, SETI is more exploration than experimentation.
Prospects for Development of a Vaccine against the West Nile Virus
Authors: MONATH THOMAS P.
Published: July 2010

Abstract: Vaccination provides the ultimate measure for personal protection against West Nile disease. The development of a West Nile vaccine for humans is justified by the uncertainty surrounding the size and frequency of future epidemics. At least two companies (Acambis Inc. and Baxter/Immuno) have initiated research and development on human vaccines. West Nile encephalitis has also emerged as a significant problem for the equine industry. One major veterinary vaccine manufacturer (Ft. Dodge) is developing formalin‐inactivated and naked DNA vaccines. The advantages and disadvantages of formalin‐inactivated whole virion vaccines, Japanese encephalitis vaccine for cross‐protection, naked DNA, and live attenuated vaccines are described. A novel technology platform for live, attenuated recombinant vaccines (ChimeriVax™) represents a promising approach for rapid development of a West Nile vaccine. This technology uses yellow fever 17D as a live vector for envelope genes of the West Nile virus. Infectious clone technology is used to replace the genes encoding the prM and E structural proteins of yellow fever 17D vaccine virus with the corresponding genes of West Nile virus. The resulting virion has the protein coat of West Nile, containing all antigenic determinants for neutralization and one or more epitopes for cytotoxic T lymphocytes. The genes encoding the nucleocapsid protein, nonstructural proteins, and untranslated terminal regions responsible for replication remain those of the original yellow fever 17D virus. The chimeric virus replicates in the host like yellow fever 17D but immunizes specifically against West Nile virus.