bluuebunny/crossref_metadata_2025 huggingface dataset:
Experiments Related to the Performance of Gas Hydrate Kinetic Inhibitors
Authors: SVARTAAS T. M. , KELLAND M. A. , DYBVIK L.
Published: July 2010

Abstract: (1) The hydrate formation process and growth is described through three different stages: (a) an induction period (nucleation), (b) a slow growth period prior to (c) a final stage described by a catastrophic, fast growth rate. In this paper the effect of kinetic hydrate inhibitors (KI) is characterized by the total delay of the catastrophic growth process at given subcooling ratios at given pressures. (2) The effects of a 20,000 Mw PVCap on a structure I (sI) ethane hydrate and a sII synthetic natural gas (SNG) hydrate have been examined in sapphire cells. A baseline was first established for each of two hydrate forming systems to describe the respective induction periods, slow growth periods, and initial growth rates. Without inhibitor, at similar subcoolings, and at similar pressures a longer induction period and a slower growth rate were observed prior to the catastrophic stage for the sII hydrate system as compared to the sI hydrate system. By the addition of 5,000 ppm PVCap to the aqueous phase the total delay of the catastrophic growth stage increased by a factor 12 for the sII SNG‐hydrate system and by a factor 5 for the sI ethane‐hydrate system. (3) The effect of different kinetic hydrate inhibitors (KI) at various pressures ranging from about 65 bar and up to about 200 bar has been examined in high pressure sapphire cells using a sII hydrate forming condensate‐SNG‐synthetic sea water system (SSW, 3.6% salt). For all the experiments reported the degree of subcooling (ΔT) with respect to the hydrate equilibrium properties of the fluid system used was kept at a similar magnitude. This was done to examine KI effects at similar degrees of subcooling within the different pressure regions. The experiments at constant ΔT showed that the KI effect (i.e., total delay of the catastrophic growth stage) decreased with increasing pressure and that a dramatic decrease was observed for increasing pressures above 90 bar. The true driving force of a hydrate forming system is described through a chemical potential, Δμ, which is a function of pressure (i.e., fugacity) and absolute temperature (K). At a given ΔT the chemical potential is greater in the high‐pressure region than in the low‐pressure region.
Kinetics and Mechanisms of Gas Hydrate Formation and Dissociation with Inhibitors
Authors: MAKOGON Y. F. , MAKOGON T. Y. , HOLDITCH S. A.
Published: July 2010

Abstract: A common chemical used in petroleum industry for preventing hydrates is methanol. Other alcohols and glycols (thermodynamic inhibitors) can also be used to shift hydrate formation to lower temperatures and higher pressures. A new family of chemicals called kinetic inhibitors delays the formation of hydrates, but does not change the equilibrium formation conditions. We have constructed several new types of apparatus and present results on the kinetics of hydrate formation and dissociation in static and dynamic conditions with fresh water and different solutions of water, seawater, and with thermodynamic and kinetic inhibitors. We also present new morphological forms of hydrate crystal growth in different static and dynamic conditions.
A Model for Systems with Soluble Hydrate Formers
Authors: JAGER M. D. , DE DEUGD R. M. , PETERS C. J. , DE SWAAN ARONS J. , SLOAN E. D.
Published: July 2010

Abstract: The objective of this study was to measure and model hydrate phase equilibria in a system containing a water‐soluble hydrate former. The system investigated is methane + water + 1,4‐dioxane in the pressure range between 2 and 14 MPa. Experimental results show that the stability of hydrates is a strong function of 1,4‐dioxane concentration in the water phase. The hydrate phase equilibria data are modeled using the van der Waals and Platteeuw theory assuming that 1,4‐dioxane is a soluble sII former. Activity coefficients of the liquid phase can be calculated from water + 1,4‐dioxane vapor liquid equilibria. Under these assumptions, the predicted equilibrium pressures are within 5% of the experimental data up to a concentration of 20 mol% 1,4‐dioxane relative to water.
Natural Gas Storage Properties of Structure H Hydrate
Authors: KHOKHAR A. A. , SLOAN E. D. , GUDMUNDSSON J. S.
Published: July 2010

Abstract: Methane gas storage properties of structure H (sH) hydrate were investigated in a Jerguson rocking cell reactor. It was assumed that the methane gas will occupy five small cages (three 512 and two 435663) whereas the largest cage (one 51268) will be occupied by a large (e.g., neohexane) molecule in a unit structure. A theoretical gas storage comparison with this methodology of storing methane in small cages showed that one unit volume of sH hydrate will store 201 volumes of methane gas. Three types of experiments were conducted to measure the methane gas storage in sH hydrate. It was discovered that sH hydrate promotion occurs with 0.1 weight percent solutions of lecithin and polyvinylpyrrolidone (PVP). These promoters also showed hydrates stabilization as hydrates melted at higher temperature compared to pure water hydrate. The heats of dissociation (ΔHdiss) below 0°C were estimated using Clausius‐Clapeyron equation and the experimentally measured equilibrium data for three hydrate structures (sI, sII, sH). Comparison of the estimated and calorimeter measured values (ΔHdiss) showed good agreement.
Double Gas Hydrates at High Pressures: The Highest Decomposition Temperatures
Authors: LARIONOV E. G. , MANAKOV A. Yu. , DYADIN Yu. A. , ZHURKO F. V.
Published: July 2010

Abstract:CS‐II double clathrate hydrates of tetrahydrofuran, CHCl3, CCl4, SF6, and xenon as a “help gas” keep their structures in the pressure interval 1215,000 bar. Decomposition temperatures of these hydrates rise monotonically in the pressure interval under consideration. The decomposition temperature of the double clathrate hydrate of SF 6 and xenon reaches 129.48C at 14.8 kbar.
Neurochemical Effects of Environmental Chemicals: In Vitro and In Vivo Correlations on Second Messenger Pathwaysa
Authors: KODAVANTI PRASADA RAO S. , TILSON HUGH A.
Published: July 2010

Abstract: Polychlorinated biphenyls (PCBs) are persistent, bioaccumulative, toxic, and widely distributed environmental chemicals. There is now both epidemiological and experimental evidence that PCBs cause cognitive deficits; however, the underlying cellular or molecular mechanism(s) is not known. We have hypothesized that altered signal transduction/second messenger homeostasis by PCBs may be associated with these effects since second messengers in signal transduction pathways, such as calcium, inositol phosphates (IP), and protein kinase C (PKC), play key roles in neuronal development and their function. In vitro studies using cerebellar granule neurons and isolated organelle preparations indicate that ortho‐PCBs increase intracellular free Ca2+ levels by inhibiting microsomal and mitochondrial Ca2+ buffering and the Ca2+ extrusion process. Ortho‐PCBs also increase agonist‐stimulated IP accumulation and cause PKC translocation at low micromolar concentrations where no cytotoxicity is observed. On the other hand, non‐ortho‐PCBs are not effective in altering these events. Further SAR studies indicate that congeners with chlorine substitutions favoring non‐coplanarity are active in vitro, while congeners favoring coplanarity are relatively inactive. Subsequent in vivo studies have shown that repeated exposure to a PCB mixture, Aroclor 1254, increases PKC translocation and decreases Ca2+ buffering in the brain, similar to in vitro studies. These changes in vivo are associated with elevated levels of non‐coplanar ortho‐PCB congeners at levels equivalent to 40–50 μM in brain, the concentrations that significantly inhibited second messenger systems in neuronal cultures in vitro. Current research is focusing on PCB‐induced alterations in second messenger systems following developmental exposure.
Culture Models of Neurodegenerative Disease
Authors: FIGLEWICZ D. A. , DONG L. , MLODZIENSKI M. , TURCOTTE J. C.
Published: July 2010

Abstract: In order to investigate how mutant SOD1 protein or environmental exogenous stressors lead to the death of motor neurons, we have established several in vitro model systems. We describe some features of the various models in order to demonstrate the advantages and shortcomings of each system.
New Technologies to Prevent and Treat Contact Hypersensitivity Responses
Authors: TAKASHIMA AKIRA , MUMMERT MARK , KITAJIMA TOSHIYUKI , MATSUE HIROYUKI
Published: July 2010

Abstract: Allergic contact dermatitis is a common inflammatory skin disease caused by T cells that recognize environmental and industrial allergens (i.e., haptens). Langerhans' cells (LC), which are skin‐specific and “immature” members of the dendritic cell (DC) family of antigen‐presenting cells, play crucial roles in the induction of contact hypersensitivity (CH) responses. Upon exposure to haptens, LC migrate from the epidermis to draining lymph nodes, mature into T cell‐stimulatory DC, and activate hapten‐reactive T cells. Therefore, CH responses should be preventable at the sensitization phase by interfering with one of these changes that occur in LC. Our objective is to develop new technologies for the prevention and treatment of allergic contact dermatitis. In this article, we will introduce three technologies that we have recently developed. First, using a phage display strategy, we have identified a 12‐mer peptide (termed “peptide 1”) that binds and blocks the function of hyaluronan (HA), which is known to serve as an adhesive substrate for LC migration. Local injection of peptide 1 in mice before topical application of DNFB blocked almost completely the emigration of LC from the epidermis to the draining lymph node, where antigen presentation takes place. Peptide 1 represents a new strategy that is designed to inhibit the initial event of CH. Second, we have established an in vitro experimental system to study the terminal maturation of LC during antigen‐specific interaction with T cells. This experimental system, which employs a long‐term LC line and T cell clones, should provide a unique tool for the identification of new immunosuppressive agents that block LC terminal maturation selectively. Finally, under the hypothesis that LC, which are engineered to overexpress a death ligand, would deliver apoptotic signals instead of activation signals to T cells, we created a “killer” LC clone by introducing CD95L cDNA into our long‐term LC line XS106. In vivo administration of DNFB‐pulsed killer LC into mice, either before or after sensitization, resulted in marked suppression of CH responses to DNFB. The killer LC technology represents an entirely new immunosuppressive therapy that is designed to eliminate only the pathogenic T cells.
From Developmental Biology to Developmental Toxicology
Authors: BALLING RUDI , DE ANGELIS MARTIN HRABÉ
Published: July 2010

Abstract: Progress derived from the human genome project will have tremendous impact on toxicology. Questions concerning genetic susceptibility or resistance to toxic compound exposure and the dissection of the molecular mechanisms involved will be at the forefront of future toxicological research. In recent years, it was recognized that many of the molecular control mechanisms of embryogenesis have been conserved during evolution. The relevance of these observations for toxicology and the application of genetic approaches using mouse mutants as a tool for functional genome analysis are discussed.
Genetics of Parkinson's Disease
Authors: POLYMEROPOULOS MIHAEL H.
Published: July 2010

Abstract: Several genetic factors have been recently recognized as related to the etiology of Parkinson's disease. Mutations in the genes coding for α‐synuclein and ubiquitin carboxy‐terminal hydrolase have been identified in families with autosomal dominant Parkinson's disease. Mutations in the Parkin gene are responsible for autosomal recessive parkinsonism. These first pieces of the molecular puzzle of Parkinson's disease offer novel insights into the pathophysiology of the illness.
Progress in Hereditary Tauopathies: A Mutation in the Tau Gene (G389R) Causes a Pick Disease‐like Syndrome
Authors: GHETTI BERNARDINO , MURRELL JILL R. , ZOLO PAOLO , SPILLANTINI MARIA GRAZIA , GOEDERT MICHEL
Published: July 2010

Abstract: We describe the clinical and pathologic phenotypes of the G389R mutation in exon 13 of the Tau gene. Progressive aphasia and memory disturbance are the initial signs and begin in the fourth or fifth decade of life, followed by apathy, indifference, hyperphagia, rigidity, pyramidal signs and dementia. Death occurs after two to five years. Magnetic resonance imaging and neuropathologic studies show frontal and temporal atrophy. Pick body‐like and axonal filamentous inclusions found in the neocortex and subcortical white matter, respectively, are tau immunoreactive. Immunoblot analysis of sarkosyl‐insoluble tau shows two major bands of 60 and 64 kDa that, upon dephosphorylation, resolve into four bands of three‐ and four‐repeat isoforms. Isolated tau filaments are often straight and occasionally twisted. Recombinant mutant tau protein shows a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. The present findings indicate that the G389R mutation in Tau can cause a dementia similar to that in Pick's disease.
Pathological Tau Phenotypes: The Weight of Mutations, Polymorphisms, and Differential Neuronal Vulnerabilities
Authors: MAILLIOT CHRISTEL , BUSSIÈRE THIERRY , HAMDANE MALIKA , SERGEANT NICOLAS , CAILLET MARIE‐LAURE , DELACOURTE ANDRÉ , BUÉE LUC
Published: July 2010

Abstract: In tauopathies, comparative biochemistry of tau aggregates shows that they differ in both phosphorylation and content of tau isoforms. Six tau isoforms are found in human brain that contain either three (3R) or four microtubule‐binding domains (4R). In Alzheimer's disease, all six of the tau isoforms are phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau55, 64, and 69). In corticobasal degeneration and progressive supranuclear palsy, only phosphorylated 4R‐tau isoforms aggregate and appear as a major tau doublet (tau64 and 69). In Pick's disease, only phosphorylated 3R‐tau isoforms aggregate into filaments and are characterized by another major tau doublet (tau55 and 64). Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in frontotemporal dementia with parkinsonism linked to chromosome 17. In the present study, the question of a relationship between tau isoforms and cell morphology is raised. To answer this question, stably transfected human neuroblastoma SY5Y cell lines with either 3R‐ or 4R‐tau isoforms are established. Cell morphology and tau phosphorylation were modified, suggesting that cells undergo profound changes in their metabolism and viability.
Modulation of Aβ Deposition in APP Transgenic Mice by an Apolipoprotein E Null Background
Authors: IRIZARRY M. C. , REBECK G. W. , CHEUNG B. , BALES K. , PAUL S. M , HOLZMAN D. , HYMAN B. T.
Published: July 2010

Abstract: Several lines of evidence implicate apolipoprotein E (apoE) and its receptor‐the low density lipoprotein receptor related protein (LRP)‐in Alzheimer's disease (AD) pathogenesis, including increased amyloid deposition in human AD brains of people containing the apoE ɛ4 allele, presence of apoE and LRP in amyloid plaques, and in vitro uptake of amyloid precursor protein (APP) and amyloid β protein (Aβ) by LRP. Studies of crosses of apoE knockout mice with APP transgenic mice support a complex interaction between apoE and Aβ deposition. In the Tg2576 mice expressing human APPK670N‐M671L, apoE determines the amount, morphology, vascular pattern, and neuropil response to Aβ deposits. In the PDAPP mice expressing human APPV717F, apoE also affects the anatomical localization of cerebral Aβ deposits. Thus, APP transgenic mice can serve as models to investigate genetic influences on the amount and timing of cerebral amyloidosis, the morphology of amyloid plaques, and the vulnerability of specific neuroanatomical regions to Aβ deposition.
Toward the Characterization and Identification of γ‐Secretases Using Transition‐state Analogue Inhibitors
Authors: MOORE CHAD L. , DIEHL THEKLA S. , SELKOE DENNIS J. , WOLFE MICHAEL S.
Published: July 2010

Abstract: The amyloid‐β protein (Aβ), strongly implicated in the etiology of Alzheimer's disease (AD), is formed from the amyloid‐β precursor protein (APP) through sequential proteolysis by β‐ and γ‐secretases. Cleavage by γ‐secretase takes place within the middle of the single transmembrane region of APP and results primarily in 40‐ and 42‐amino acid Aβ C‐terminal variants, Aβ40 and Aβ42. The latter form of Aβ is highly fibrillogenic, is invariably elevated in autosomal‐dominant forms of AD, and is the major Aβ component found presymptomatically in cerebral deposits. Thus, blocking production of Aβ in general and Aβ42 in particular is considered an important therapeutic goal. We have developed transition‐state analogue inhibitors of γ‐secretase as molecular probes for characterizing the active site of this enzyme, as pharmacological tools for understanding its role in biology, and as affinity labels toward its definitive identification. Specifically, we found that: (1) difluoro ketone and difluoro alcohol peptidomimetics are effective inhibitors of γ‐secretase activity in APP‐transfected cells, strongly suggesting an aspartyl protease mechanism; (2) γ‐secretases that form Aβ40 and Aβ42 are pharmacologically distinct but are nevertheless closely similar; (3) large hydrophobic P1 substituents increase the inhibitory potency of these peptidomimetics, suggesting a large complementary S1 pocket for γ‐secretases; (4) Aβ42 production is increased several fold over control by these γ‐secretase inhibitors after replacement with inhibitor‐free media; (5) a bromoacetamide derivative of one of these analogues continues to inhibit total Aβ and Aβ42 production hours after replacement with compound‐free media and should help identify the target(s) of these protease transition‐state mimics.
Imaging Tumors in Humans with Tc‐99m‐VIP
Authors: THAKUR M. L. , MARCUS C. S. , SAEED S. , PALLELA V. , MINAMI C. , DIGGLES L. , PHAM H. L. , AHDOOT R. , KALINOWSKI E. A. , MOODY T.
Published: July 2010

Abstract: Vasoactive intestinal peptide (VIP) was modified at the C terminus with a spacer and four amino acids to serve as a chelating moiety. The modified peptide, TP 3654, was labeled with Tc‐99m and evaluated in normal volunteers, as well as in patients with a history of cancer. Renal clearance (67%) was the primary route of excretion, with approximately 20% of the radioactivity clearing through the hepatobiliary system. No adverse reaction was noted in any of the subjects and all, except one small, of the known lesions as seen by CT, MRI, Tc‐99m‐MIBI, or mammography were correctly identified within a few minutes of an i.v. injection of approximately 10 mCi of Tc‐99m‐TP 3654 (specific activity 11.3 × 103 Ci/m mol). The scans were in concordance in nine patients. In the remaining two, one with a visible mass in the neck from high grade spindle cell sarcoma and the other with a palpable mass in a breast from ductal epithelial hyperplasia, were localized only with Tc‐99m‐TP 3654, but not with Tc‐99m‐MIBI. Both malignancies are known to express VIP receptors. The VIP analog promises to be a nontoxic and reliable agent for imaging cancers in humans that express VIP receptors.
Vasoactive Intestinal Peptide Mediation of Development and Functions of T Lymphocytes
Authors: DORSAM GLENN , VOICE JULIA , KONG YVONNE , GOETZL EDWARD J.
Published: July 2010

Abstract: The first phase in investigating neural regulation of immunity has delineated anatomical connections, shared mediators and receptors for mediators with distinctive effects, and the immune functional consequences of altering relevant neural activities. Vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase‐activating peptide (PACAP) are represented prominently in immune organs. They have potent novel effects on many aspects of immunity, are derived from and serve as autacoids in some sets of immune cells, and they participate in both physiological and pathological immune responses. The present phase of neuroimmune research has begun to elucidate the genetic determinants of expression and functions of neuromediators in immunity. Our evolving understanding of the novel mechanisms for adaptation and specificity in the VIP/PACAP neuroimmune network suggests the importance of immunoselective transcriptional control of expression of VIP/PACAP receptors in T cells, a dominant role for numerous cytokines, and the critical involvement of small subsets of VIP‐/PACAP‐responsive thymocytes and T cells.
PACAP Action in Nervous System Development, Regeneration, and Neuroblastoma Cell Proliferation
Authors: WASCHEK JAMES A. , DICICCO‐BLOOM EMANUEL M. , LELIEVRE VINCENT , ZHOU XINRONG , HU ZHONGTING
Published: July 2010

Abstract: Pituitary adenylate cyclase activating peptide (PACAP) may play a role in neurogenesis, nerve injury, and neural tumor growth. A PACAP ligand receptor system functionally coupled to cAMP production was found to be expressed in the embryonic mouse neural tube at the onset of neurogenesis. PACAP was found to inhibit DNA synthesis and antagonize sonic hedgehog signaling in cells isolated from the neural tube, suggesting that PACAP interacts with patterning factors to regulate neurogenesis and phenotypic specification in the developing CNS. PACAP and PACAP receptor (PAC1) mRNA levels were strongly increased and decreased, respectively, in motor neurons in adult rats after facial nerve axotomy, indicating that PACAP may also act in nerve regeneration. Experiments using a neuroblastoma tumor cell line model indicate that PACAP may execute growth‐related functions by activating MAP kinase in addition to cAMP‐dependent protein kinase A.
Molecular Characterization of the VIP Receptor Transcriptional Repressor Protein
Authors: PEI LIN
Published: July 2010

Abstract: The rat type 1 VIP receptor transcriptional repressor protein (VIPR‐RP) is a recently isolated novel transcription factor. In the study reported here, the functional domains of VIPR‐RP were characterized. To map the DNA binding domain, various regions of VIPR‐RP were either transcribed and translated in vitro or expressed in and purified from E. Coli as a glutathione S‐transferase (GST) fusion. The ability of the truncated proteins to bind to VIPR‐RP specific binding sequence was tested by gel mobility shift assays. The results indicated that the amino acid sequences between 367 and 475 play an essential role for VIPR‐RP DNA binding. To determine the amino acid sequences required for transcriptional repression, fusion proteins containing the GAL4 DNA binding domain and various parts of VIPR‐RP were constructed, and their ability to repress transcription of the reporter gene containing GAL4 DNA binding sequences were tested in transiently transfected COS7 cells. The results showed that VIPR‐RP contains two separate transcriptional repression domains located between amino acids 50 to 101 and 470 to 527.
Essential Structural Motif in the C‐Terminus of the PACAP Type I Receptor for Signal Transduction and Internalization
Authors: PISEGNA JOSEPH R. , LYU RONG‐MING , GERMANO PATRIZIA M.
Published: July 2010

Abstract: The objectives of the study reported here were to identify amino acid residues of the C‐terminus that are critical for intracellular signaling. A total of nine amino acid substitution and truncation mutants were constructed by PCR and confirmed by sequencing. Mutant and wildtype receptors were stably transfected into NIH/3T3 fibroblasts and studied for their ability to bind PACAP‐27 and activate phospholipase C (PLC) and adenylyl cyclase (AC). Receptor affinity of 125I‐PACAP‐27 for the wildtype and mutants were similar (Kd= 0.6–1.5 NM). However, truncation of the entire 63 amino acids of the hPAC1 resulted in no signaling to either AC or IP. Addition of the proximal 10 amino acids of the C‐Terminus failed to restore AC or IP signaling, whereas addition of the proximal 27 amino acids of the C‐terminus resulted in reconstitution of complete AC and IP responses, identical to the WT. Point mutations within this 17 amino acid region identified specific amino acids involved in PAC1 signaling. These results indicate that a structural motif within the proximal region of the carboxyl terminus is critical for G protein coupling.
New Developments in the Biology of the Glucagon‐Like Peptides GLP‐1 and GLP‐2
Authors: DRUCKER DANIEL J. , LOVSHIN JULIE , BAGGIO LAURIE , NIAN MIN , ADATIA FEISAL , BOUSHEY ROBIN P. , LIU YUANFANG , SALEH JUMANA , YUSTA BERNARDO , SCROCCHI LOUISE
Published: July 2010

Abstract: Glucagon‐like peptides 1 and 2 (GLP‐1 and GLP‐2) are coencoded within a single mammalian proglucagon precursor, and are liberated in the intestine and brain. GLP‐1 exerts well known actions on islet hormone secretion, gastric emptying, and food intake. Recent studies suggest GLP‐1 plays a central role in the development and organization of islet cells. GLP‐1 receptor signaling appears essential for β cell signal transduction as exemplified by studies of GLP‐1R−/− mice. GLP‐2 promotes energy assimilation via trophic effects on the intestinal mucosa of the small and large bowel epithelium via a recently cloned GLP‐2 receptor. The actions of GLP‐2 are preserved in the setting of small and large bowel injury and inflammation. The biological actions of the glucagon‐like peptides suggest they may have therapeutic efficacy in diabetes (GLP‐1) or intestinal disorders (GLP‐2).
Analysis of VIP and CGRP Plasma Levels After Radiotherapy for Treatment of Metastasis from Prostatic Carcinoma
Authors: FORSGREN S. , LANDSTRÖM F. , KJÖRELL U. , HENRIKSSON R. , FRANZÉN L.
Published: July 2010

Abstract: It has previously been shown that radiotherapy leads to an increased level of neuropeptides in various organs. In the study we report here, we examined whether the plasma levels of two neuropeptides, vasoactive intestinal peptide (VIP) and calcitonin gene‐related peptide (CGRP), are influenced by radiotherapy. Blood was collected at four time intervals after radiotherapy; 1–12 days after treatment for skeletal metastasis from prostatic carcinoma. The VIP‐ and CGRP‐plasma levels, as analyzed by radioimmunoassay, were not statistically different between the different time points analyzed.
Dual Contacts between Peptide Agonist Ligands and the Secretin Receptor Directly Established by Photoaffinity Labeling
Authors: DONG MAOQING , WANG YAN , MILLER LAURENCE J.
Published: July 2010

Abstract: Structural analysis of secretin in solution has demonstrated extended helical domains within both amino‐ and carboxyl‐terminal halves, with a possible turn in between. However, the conformation of this peptide as it resides in its binding site within the receptor has not been established. In the work reported here, we performed affinity labeling of the secretin receptor with radioiodinated secretin analogues having photolabile benzoyl‐phenylalanine residues positioned in each half of the peptide. The probes had sites of covalent attachment in positions 6 and 22, and have been recently synthesized and characterized to represent high affinity agonist ligands. Both covalently labeled the secretin receptor in a saturable, specific, and efficient manner. After purification of the labeled receptor, we used a series of chemical and enzymatic cleavage techniques to define the domain of labeling. We complemented this by receptor mutagenesis, followed by additional cleavage and Edman degradation sequencing to refine our insights into the labeled residues. This has allowed us to demonstrate that sites of attachment were both within the extracellular amino‐terminal domain of the receptor. Of particular interest, both probes labeled residues within the amino‐terminal thirty residues at the distal end of the receptor. It will be particularly interesting to use these molecular approximations to model the binding domain of this important receptor.
The Cascade Radical Annulation Approach to New Analogues of Camptothecins: Combinatorial Synthesis of Silatecans and Homosilatecans
Authors: CURRAN DENNIS P. , JOSIEN HUBERT , BOM DAVID , GABARDA ANA E. , DU WU
Published: July 2010

Abstract: An overview of the cascade radical annulation approach to the camptothecin family of antitumor drugs is presented. This combinatorial synthetic approach involves two key steps: (1) N‐propargylation of a lactone/pyridone D/E ring fragment and (2) cascade radical annulation of an A‐ring isonitrile to form rings B and C. The synthesis is probably the most flexible and general route to the camptothecin class of molecules. The parallel synthesis of several libraries of silatecan and homosilatecan libraries is summarized. One of the first‐generation silatecans, DB‐67, is emerging as a serious candidate for cancer chemotherapy.
Modified Lactone/Carboxylate Salt Equilibria in Vivo by Liposomal Delivery of 9‐Nitro‐Camptothecin
Authors: CHOW DIANA S‐L. , GONG LING , WOLFE MICHAEL D. , GIOVANELLA BEPPINO C.
Published: July 2010

Abstract: The lactone stability of camptothecins is critical for their anticancer activity. A stable liposomal 9‐nitro‐camptothecin formulation was developed to circumvent the drawbacks of low aqueous solubility and lactone instability and to provide sustained release of the agent in blood circulation. The potential merits of the formulation were demonstrated by its profoundly improved lactone stability in vivo, favorable pharmacokinetic and biodistribution characteristics in rats, and enhanced preclinical efficacy in tumor‐bearing athymic mice.
Alternative Administration of Camptothecin Analogues
Authors: VERSCHRAEGEN C. F. , JAECKLE K. , GIOVANELLA B. , KNIGHT V. , GILBERT B. E.
Published: July 2010

Abstract: The binding of camptothecin (CPT) to the DNA‐topoisomerase complex is reversible, but it needs to be maintained for maximal inhibitory activity. It is also dependent on the chemical structure of CPT. The lactone form is thought to be necessary for the activity. In human serum, the equilibrium between lactone and carboxylate is in favor of the latter. For these reasons, alternative administration of CPT analogues is being evaluated. The ideal compound would remain in lactone form and would expose the host for long periods of time to its effects. Oral administration of irinotecan (CPT‐11) and topotecan (TPT) is discussed by other investigators. We studied oral rubitecan and reported a low lactone to total drug area under the plasma concentration time curve (AUCP) ratio (14.7%), with low plasma concentration over time despite repeated administrations and the presence of an enterohepatic cycle. Aerosolization of a liposomal formulation of rubitecan is currently under study. Six patients have been treated once a day for 5 days every 3 weeks. The dose was 6.7 μg/kg/day. Plasma levels are dose for dose higher than those after oral administration, but the ratio of lactone versus total drug is low. No toxicity was observed. The study will continue with increasing doses and lengths of administration. Intrathecal administration of topotecan has been studied in a phase I trial in children. Doses of 0.4 mg are tolerated without toxicity, and clinical responses have been seen in patients with refractory meningial carcinomatosis. Phase II studies are planned. Intraperitoneal (ip) administration of topotecan has been studied in a phase I trial as a 24‐hour infusion in 5% dextrose at pH 3.5 every 21 days. Dose‐limiting toxicity is 4 mg/m2. Toxic effects are neutropenia, anemia, emesis, fever, and pain. Five of 10 patients with ascites had symptomatic relief. Pharmacokinetic analysis demonstrates a second‐order kinetics with elimination half‐lives of 0.49 and 2.7 hours. The peritoneal to plasma AUC ratio was 31.2. Intramuscular, transdermal, and subcutaneous administrations have been extensively studied in the mouse.
Scientific Cosmology Meets Western Theology
Authors: GINGERICH OWEN
Published: July 2010

Abstract: Traditional sacred geography of Christendom met a challenge not so much from Copernicus' heliocentrism per se as from the greatly explanded vision of the cosmos that it ushered in. The twentieth‐century view of the vastness of both space and time has brought revolutionary conceptual changes to the sacred landscape. From a theistic perspective, God is not simply the source of the Big Bang, but the Creator in the larger sense of designer and intender of the universe.
The Idea of a “Beginningless” World‐Process
Authors: BALSLEV ANINDITA N.
Published: July 2010

Abstract: This paper, while seeking to expose some of the basic ideas of Hindu cosmology, focuses on the philosophical and soteriological dimensions of the notions of “beginning” and “beginningless” in the discourses associated with dominant world‐religions. It is hoped that a deeper grasp of these issues in a multi‐religious context will help to bridge the distance between diverse traditions of thinking as well as facilitate the science‐religion dialogue.
The Meaning of “Design”
Authors: LESLIE JOHN
Published: July 2010

Abstract: Our universe obeys elegant laws that permit living beings to evolve. This can suggest divine design. So can fine tuning of physical and cosmological parameters in ways that seem essential to life. Understanding the idea of design is, however, difficult for many reasons. For instance, could a designer be said to “fine tune” through choosing all‐dictating laws very carefully? Again, would taking advantage of early quantum indeterminacies be a case of design, or would it be design‐destroying interference? Can we speak of “design” if God is not a mind but an abstract Platonic principle? And what if, as Spinoza believed, the structure of our universe is just the structure of divine thinking? If such thinking extended to other universes which were lifeless, could those “exhibit design” simply through being orderly?
Cosmology, Life, and the Anthropic Principle
Authors: BARROW JOHN D.
Published: July 2010

Abstract: We discuss some ways in which the age, size, and structure of the Universe, together with the values of its defining constants, satisfy the necessary conditions for life. The implications for teleology and the existence of other universes are also discussed.
Understanding the Universe
Authors: POLKINGHORNE JOHN
Published: July 2010

Abstract: Physics constrains metaphysics but does not determine it. The central metaphysical question is that of scope; a true theory of everything must take personal experience as seriously as the impersonal. Science raises questions of intelligibility and anthropic fine‐tuning that go beyond its own self‐limited power to answer. Theism provides a coherent response, as well as furnishing a foundation for the human encounter with value. Evolutionary insight affords some insight in relation to problems of physical evil, but eventual cosmic futility can only find an answer in the faithfulness of a Creator whose purposes are not frustrated by death.
What Did the Mystic Say to the Hot Dog Vendor?
Authors: KUSHNER LAWRENCE
Published: July 2010

Abstract: The universe is not designed by a deity outside, beyond, and other than the universe. The design of the universe is experienced in its unity, dynamic interdependency, and interconnectedness. The designer is to be found in the experience of such design, not beyond it. Within Judaism, the Kabbalah is one expression of this religious vision of the universe.
Searching for Life in the Universe
Authors: NEALSON KENNETH H.
Published: July 2010

Abstract: Space programs will soon allow us to search for life in situ on Mars and to return samples for analysis. A major focal point is to search for evidence of present or past life in these samples, evidence that, if found, would have far‐reaching consequences for both science and religion. A search strategy will consider the entire gamut of life on our own planet, using that information to frame a search that would recognize life even if it were fundamentally different from that we know on Earth. We discuss here how the lessons learned from the study of life on Earth can be used to allow us to develop a general strategy for the search for life in the Universe.
Theology after Contact
Authors: HAUGHT JOHN F.
Published: July 2010

Abstract: The prospect of encountering extraterrestrial intelligent life raises important questions for religion and theology. Even if an actual encounter with extraterrestrials never actually takes place, or proves impractical, terrestrial religious thought already has resources that can render intelligible and allow us theologically to appreciate such an eventuality.
West Nile Virus: Uganda, 1937, to New York City, 1999
Authors: HAYES CURTIS G.
Published: July 2010

Abstract: West Nile virus, first isolated in 1937, is among the earliest arthropod‐borne viruses discovered by humans. Its broad geographical distribution, not uncommon infection of humans, transmission by mosquitoes, and association with wild birds as enzootic hosts were well documented by the mid‐1960s. However, West Nile virus was not considered to be a significant human pathogen because most infections appeared to result in asymptomatic or only mild febrile disease. Several epidemics had been documented prior to 1996, some involving hundreds to thousands of cases in mostly rural populations, but only a few cases of severe neurological disease had been reported. The occurrence between 1996 and 1999 of three major epidemics, in southern Romania, the Volga delta in southern Russia, and the northeastern United States, involving hundreds of cases of severe neurological disease and fatal infections was totally unexpected. These were the first epidemics reported in large urban populations. A significant factor that appeared in common to all three outbreaks was the apparent involvement of the common house mosquito, Culex pipiens, as a vector. This species had not previously been implicated as important in the transmission of West Nile virus. In addition the epidemic in the northeastern United States was unusual in the association of West Nile virus infection with fatal disease of birds, suggesting a change in the virulence of the virus toward this host. Understanding the risk factors that contributed to these three urban epidemics is important for minimizing the potential for future occurrences. This review will attempt to compare observations on the biology of West Nile virus made over about 60 years prior to the recent epidemics to observations made in association with these urban epidemics.
West Nile Virus Transmission and Ecology in Birds
Authors: McLEAN ROBERT G. , UBICO SONYA R. , DOCHERTY DOUGLAS E. , HANSEN WALLACE R. , SILEO LOUIS , McNAMARA TRACEY S.
Published: July 2010

Abstract: The ecology of the strain of West Nile virus (WNV) introduced into the United States in 1999 has similarities to the native flavivirus, St. Louis encephalitis (SLE) virus, but has unique features not observed with SLE virus or with WNV in the old world. The primary route of transmission for most of the arboviruses in North America is by mosquito, and infected native birds usually do not suffer morbidity or mortality. An exception to this pattern is eastern equine encephalitis virus, which has an alternate direct route of transmission among nonnative birds, and some mortality of native bird species occurs. The strain of WNV circulating in the northeastern United States is unique in that it causes significant mortality in exotic and native bird species, especially in the American crow (Corvus brachyrhynchos). Because of the lack of information on the susceptibility and pathogenesis of WNV for this species, experimental studies were conducted at the USGS National Wildlife Health Center. In two separate studies, crows were inoculated with a 1999 New York strain of WNV, and all experimentally infected crows died. In one of the studies, control crows in regular contact with experimentally inoculated crows in the same room but not inoculated with WNV succumbed to infection. The direct transmission between crows was most likely by the oral route. Inoculated crows were viremic before death, and high titers of virus were isolated from a variety of tissues. The significance of the experimental direct transmission among captive crows is unknown.
West Nile Virus Infection in Birds and Mammals
Authors: KRAMER LAURA D. , BERNARD KRISTEN A.
Published: July 2010

Abstract: West Nile virus (WNV) was found throughout New York State in year 2000. The epicenter was located in New York City with a high level of activity in the immediately surrounding counties, including Rockland, Westchester, Nassau, and Suffolk. During 2000, WNV testing was performed by the Wadsworth Center on 3,687 dead birds, representing 153 species, 46 families, and 18 orders. There were 1,203 WNV‐positive birds, representing 63 species, 30 families and 14 orders. The percentage of WNV‐positive birds was 33% for all birds tested throughout the state, with no significant difference in infection rates in migratory versus resident birds, although significantly more resident birds were submitted for testing. The highest apparent mortality for the entire season was observed in American crows in Staten Island, a location that also showed the highest minimal infection rate in Culex pipiens complex mosquitoes. Studies examining tissue tropism of WNV in corvids and noncorvids from the epicenter and from remote locations indicated that the kidney was the most consistently infected tissue in birds, regardless of level of infection. The brain was the next most consistently positive tissue. The differences in infection among the tissues were most apparent when low levels of virus were present. Experimental mouse inoculation demonstrated a classical flavivirus infection pattern.
Hormonal Prevention of Hereditary Breast Cancer
Authors: NAROD STEVEN A.
Published: July 2010

Women who carry a mutation in the BRCA1 or BRCA2 genes face a lifetime risk of developing breast cancer that approaches 80%. Among women with predisposing BRCA mutations, the risk of breast cancer is influenced by environmental factors and by modifying genes. Through the study of cohorts of female BRCA1 and BRCA2 carriers, several modifying factors have been identified. The risk of breast cancer is increased by early parity and is decreased by breast feeding, by oophorectomy, and by cigarette smoking. Many of the stragegies for breast cancer prevention involve estrogen deprivation and it is important to consider the acute and long‐term effects of induced menopause in young women at high risk for breast cancer. There are no data so far on whether hormonal replacement therapy is hazardous in carriers of BRCA mutations.
Early Lung Cancer Action Project
Authors: HENSCHKE CLAUDIA I. , YANKELEVITZ DAVID F. , LIBBY DANIEL M. , McCAULEY DOROTHY , PASMANTIER MARK , ALTORKI NASSER K. , SMITH JAMES P. , MIETTINEN OLLI S.
Published: July 2010

The advent of helical CT imaging held promise for the early diagnosis, and thereby, for enhanced curability of lung cancer—a highly fatal disease. In 1993, the Early Lung Cancer Action Project (ELCAP) was initiated and experimentally screened a cohort of 1,000 high‐risk persons. Here we summarize the results of the baseline and annual repeat CT screening of these 1,000 subjects. CT‐based screening (compared to traditional radiology) was clearly shown to enhance the detection of lung cancer at earlier and more curable stages. A discussion follows of the meaning of the results and possible future screening protocols.
The Future of Prostate Cancer Prevention
Authors: BRAWLEY OTIS W. , BARNES SHAKIA , PARNES HOWARD
Published: July 2010

The dramatic international variation in prostate cancer mortality rates suggest an environmental influence. This combined with a building understanding of the genetic mechanisms of carcinogenesis encourages a search for ways to prevent it. Androgenic stimulation over a period of time has been suggested a cause of prostate cancer. The corollary to this hypothesis is that lowering androgenic stimulation over time will prevent prostate cancer. Decreasing androgenic stimulation of the prostate with 5‐α‐reductase inhibitors such as finasteride has been shown to decrease prostate size and may prevent prostate cancer. A large, long‐term clinical trial is underway using finasteride to determine if it can prevent prostate cancer. Results are expected in 2004. Epidemiologic and laboratory studies also suggest that high selenium and vitamin E intake lowers risk of prostate cancer. Recent serendipitous findings of two randomized clinical trials support the hypothesis that selenium and vitamin administration will decrease prostate cancer risk. A study to assess these compounds is beginning. Other promising, but less developed, interventions in chemoprevention of prostate cancer include vitamin D supplementation and diet modification. All will need to be rigorously evaluated before they can be advocated for prostate cancer prevention.
Cancer Preventive Effect of Morinda citrifolia (Noni)
Authors: WANG M. Y. , SU C.
Published: July 2010

Morinda citrifolia (Noni) has been extensively used in folk medicine by Polynesians for over 2,000 years. It has been reported to have broad therapeutic effects, including anticancer activity, in both clinical practice and laboratory animal models. The mechanism for these effects remains unknown. The hypothesis that Morinda citrifolia possesses a cancer preventive effect at the initiation stage of carcinogenesis was studied. Our preliminary data indicated that 10% Tahitian Noni® Liquid Dietary Supplement or Tahitian Noni® Juice (TNJ), made from Morinda citrifolia fruit by Morinda Inc, in drinking water for one week was able to prevent DMBA‐DNA adduct formation. The levels of DMBA‐DNA adducts were reduced by 30% in the heart, 41% in the lung, 42% in the liver, and 80% in the kidney of female SD rats. Even more dramatic results were obtained in male C57 BL‐6 mice: 10% TNJ was able to reduce DMBA‐DNA adduct formation by 60% in the heart, 50% in the lung, 70% in the liver, and 90% in the kidney. In order to explore the mechanism of this preventive effect, the antioxidant activity of TNJ was examined in vitro by lipid hydroperoxide (LPO) and tetrazolium nitroblue (TNB) assays. In the LPO assay, LPO oxidizes leucomethylene blue to methylene blue in the presence of hemoglobin. The resultant blue color was quantified at 660 nm spectrophotometrically. In the TNB assay, superoxide anion radicals (SAR) reduce TNB into formazan blue that was also measured by absorption at 602 nm. TNJ showed a dose‐dependent inhibition of both LPO and SAR in our system. The antioxidant activity of TNJ was compared to the effects of vitamin C, grape seed powder (GSP), and pycnogenol (PYC) at the daily dose per serving level recommended by U.S.RDAs or manufacturers. The results suggest that prevention of carcinogen‐DNA adduct formation and the antioxidant activity of TNJ may contribute to the cancer preventive effect of Morinda citrifolia.
Evaluation of Cancer‐Preventive Agents and Strategies
Authors: VAINIO HARRI , BIANCHINI FRANCA
Published: July 2010

About five years ago, the International Agency for Research on Cancer (IARC) initiated a new program, IARC Handbooks of Cancer Prevention, aimed at evaluating the evidence base for the cancer‐preventive activity of various agents and strategies. To date (2001) 5 volumes have been published—1. Non‐steroidal Anti‐inflammatory Drugs, 2. Carotenoids, 3. Vitamin A, 4. Retinoids, and 5. Sunscreens—and volume 6 (Weight Control and Physical Activity) is in press. Future volumes will include evaluations of breast cancer screening (vol. 7) and fruits and vegetables (vol. 8).