bluuebunny/crossref_metadata_2025 huggingface dataset:
Cellular and Molecular Neuropathology of the Parahippocampal Region in Schizophrenia
Authors: ARNOLD STEVEN E.
Published: July 2010

Abstract: The entorhinal cortex, subiculum, and hippocampus have been regions of great interest in both clinical and neuropathological investigations of schizophrenia. Postmortem studies have identified numerous abnormalities, although many remain controversial or unconfirmed. Among the cellular and molecular neuropathological findings are (1) abnormal cytoarchitecture of the entorhinal cortex characterized by poorly formed layer II neuron clusters and laminar disorganization; (2) normal neuron density but smaller neuron size in the superficial lamina of the entorhinal cortex and subiculum; (3) abnormal expression of the microtubule‐associated protein MAP2 in the entorhinal cortex and subiculum; (4) aberrant glutamatergic and catecholaminergic innervation of the entorhinal cortex; (5) abnormal mRNA expression of various transcription factors, ion channels, and neurosecretory pathway‐related proteins in entorhinal stellate neurons; and (6) an absence of any neurodegeneration. Altogether, these findings suggest that aberrant neurodevelopmental processes play a key role in the pathobiology of schizophrenia and provide a neuroanatomic basis for understanding many of the clinical and neuropsychological abnormalities in the disorder.
Networks of the Hippocampal Memory System of the Rat: The Pivotal Role of the Subiculuma
Authors: NABER PIETERKE A. , WITTER MENNO P. , LOPES DA SILVA FERNANDO H.
Published: July 2010

Abstract: The hippocampal system, consisting of the hippocampus, subiculum, and adjacent parahippocampal region, is known to play an important role in learning and memory processes. It is also known that the originally proposed trisynaptic circuit is a simplified representation of the organization of this system. In this paper, we present evidence, both anatomically and electrophysiologically, for the existence of direct and indirect parallel pathways through the hippocampal memory system arising from the perirhinal and postrhinal cortex. These pathways form nested loops. The subiculum occupies a central position within these loops. In the subiculum, both “raw” and highly processed information will converge. Therefore, we propose that the subiculum occupies a pivotal position in the hippocampal memory system, both as recipient and comparator of signals and as a distributor of processed information.
The First Discovery of the Gas Hydrates in the Sediments of the Lake Baikal
Authors: KUZMIN M. I. , GELETIY V. F. , KALMYCHKOV G. , KUZNETSOV F. A. , LARIONOV E. G. , MANAKOV A. YU. , MIRONOV YU. I. , SMOLJAKOV B. S. , DYADIN YU. A. , DUCHKOV A. D. , BAZIN N. M. , MAHOV G. M.
Published: July 2010

Abstract: In 1997 an underwater borehole was drilled in the South part of Lake Baikal (water depth, 1,433 m; borehole depth, 225 m; the temperature at these depths is about 10°C). Samples of sediments containing methane hydrate were collected at depths 121 and 161 m below bottom. At present, this is the only example of the existence of gas hydrates in a fresh‐water basin under non‐permafrost conditions.
A Double Gas‐Hydrate Related Bottom Simulating Reflector at the Norwegian Continental Margin
Authors: ANDREASSEN KARIN , MIENERT JÜRGEN , BRYN PETTER , SINGH SATISH C.
Published: July 2010

Abstract: An unusual pattern of two bottom simulating reflections (BSRs) has been observed on seismic profiles from the continental margin offshore Western Norway. One of these reflections (BSR1) extends over large areas and has the characteristics of the classical BSR, that is a phase‐reversed reflection from the base of the gas‐hydrate stability zone. The second BSR (BSR0) occurs at approximately 70 ms two‐way travel time beneath BSR1 and is here called a double BSR. The distribution of BSR0 is more local than that of BSR1 and it does not show the phase‐reversal relative to the sea floor reflection that is characteristic for a BSR at the gas hydrate‐free gas boundary. Results from an industrial borehole, from full waveform inversion of multichannel seismic data, from high‐frequency ocean bottom hydrophones, and interpretation of seismic profiles, clearly indicate that BSR1 is reflected from the base of the methane hydrate equilibrium field. Results from full waveform inversion indicate that BSR0 corresponds to a 16–20 m zone where the velocity drops from about 1.8 km/s to a minimum of 1.4 km/s and then increases again. The low velocity of 1.4 km/s suggests the presence of free gas. The results support the hypothesis that BSR0 is a reflection from the base of gas hydrates containing hydrocarbons with a heavier molecular weight in addition to methane gas. Interference of reflections from the top and base of the low‐velocity zone associated with BSR0 explain why BSR0 is not phase‐reversed.
Resource Evaluation of Marine Gas Hydrate Deposits Using Seafloor Compliance Methods
Authors: WILLOUGHBY ELEANOR C. , LATYCHEV KONSTANTIN , EDWARDS R. NIGEL , MIHAJLOVIC GEORGE
Published: July 2010

Abstract: We introduce the theory and practice of the compliance method: a new tool for assessing offshore methane hydrate deposits. Compliance is defined as the transfer function between the vertical displacement of the seafloor and the corresponding pressure expressed as a function of frequency. It is sensitive to the elastic parameters of the underlying sediments, particularly the shear modulus. We have measured normalized compliance from 0.001 to 0.049 Hz, using ocean surface gravity waves as a source, at sites in Cascadia near the Ocean Drilling Program (ODP) hole 889B. A differential pressure gauge, datalogger, and self‐leveling gravimeter were lowered to the seafloor, and each site was occupied for eight hours. The compliance estimates are reproducible and are consistent with other available data and simple models of sediment physical properties. Shear strength is increased from a normal profile in the uppermost few hundred meters, possibly an effect of grain cementation within a known hydrate layer. The magnitude of the increase may be associated with the total mass of hydrate present irrespective of the details of its distribution.
Electromagnetic Modeling and In Situ Measurement of Gas Hydrate in Natural Marine Environments
Authors: BOISSONNAS RÉMI , GOLDBERG DAVE , SAITO SANEATSU
Published: July 2010

Abstract: During Ocean Drilling Program Leg 170, electromagnetic logs were acquired at three sites on the Costa Rica continental margin. Gas hydrate was observed in sediment cores from nearby holes. These data provide the first opportunity to study and quantify hydrate concentration using logging‐while‐drilling, a technique used to record logs before in situ conditions change significantly. We develop a mixture model that allows for separation of the sediment, pore fluid, and hydrate volume fractions from dielectric permittivity and conductivity measurements. However, the relatively low frequency (2 MHz) of these measurements and the high formation conductivity in this setting do not allow for quantitative estimates of hydrate concentration using the dielectric effect. Pseudoporosity logs can nevertheless be derived from the mixture model and compare well with core measurements. We recommend that future in situ electromagnetic measurements be made at frequencies greater than about 20 MHz in order to increase the influence of the dielectric permittivity on such measurements.
Microscopic Character of Marine Sediment Containing Disseminated Gas Hydrate: Examples from the Blake Ridge and the Middle America Trench
Authors: LORENSON THOMAS D.
Published: July 2010

Abstract: The presence of disseminated gas hydrate was inferred based on pore fluid geochemistry and downhole logging data, but was rarely observed at Ocean Drilling Program (ODP) Leg 164 (Blake Ridge), and Leg 170 (Middle America Trench, offshore from Costa Rica) drilling sites. Gas hydrate nucleation is likely to occur first in larger voids rather than in constricted pore space, where capillary forces depress the temperature‐pressure stability field for gas hydrate formation. Traditional macroscopic descriptions of sediment fail to detect the microscopic character of primary and secondary porosity in sediment hosting disseminated gas hydrate. Light transmission and scanning electron microscopy of sediments within and below the depth of gas hydrate occurrences reveal at least four general types of primary and secondary porosity: (1) microfossils (diatoms, foraminifera, and spicules) void of infilling sediment, but commonly containing small masses of pyrite framboids; (2) infauna burrows filled with unconsolidated sand and or microfossil debris; (3) irregularly shaped pods of nonconsolidated framboidial pyrite; and (4) nonlithified volcanic ash.
MRI Measurement of Hydrate Growth and an Application to Advanced CO2 Sequestration Technology
Authors: HIRAI SHUICHIRO , TABE YUTAKA , KUWANO KUNIHIRO , OGAWA KUNIYASU , OKAZAKI KEN
Published: July 2010

Abstract: MRI measurements of hydrate thickness growth have been measured and this phenomenon applied to advanced CO2 ocean dissolution technology. CO2 droplets dissolve during the process of sinking from their release point into deep ocean, by forming fine hydrate particles inside CO2 droplets before the droplets are released from a towed pipe on a moving ship. This results in a sufficiently long sequestration period from the atmosphere and further reduces biological impact. The increasing rate of hydrate film thickness in forming hydrate particles was measured by an ultrahigh‐pressure magnetic resonance imaging (MRI) technique.
Dynamics of Reformation and Replacement of CO2 and CH4 Gas Hydrates
Authors: KOMAI TAKESHI , YAMAMOTO YOSHITAKA , OHGA KOTARO
Published: July 2010

Abstract: The dynamics of reformation and replacement of gas hydrates were studied under nonequilibrium conditions. It was found that the reformation of gas hydrates is largely affected by the state of the gas‐water system and the restarting temperature. This suggests that the effects are caused by changes in the structure of the aqueous solution at a molecular level. Pure samples of CH4 gas hydrate were synthesized from ice crystals and the dissociated solution using the reformation method. Replacement of CO2 gas hydrate is achieved within a short duration in the solid‐phase sample of CH4 gas hydrate, if the pressure and temperature is precisely controlled in a pressure vessel.
A New Class of Kinetic Hydrate Inhibitor
Authors: KELLAND MALCOLM A. , SVARTAAS THOR M. , ØVSTHUS JORUNN , NAMBA TAKASHI
Published: July 2010

Abstract: Low dosage hydrate inhibitors (LDHI) offer a recently developed hydrate control technology that can be more cost‐effective than traditional practices, such as the use of thermodynamic inhibitors (e.g., methanol and glycols). One class of LDHI, called kinetic inhibitors, is already being successfully used in the field. This paper describes efforts to develop a new class of kinetic inhibitor that shows various improvements over existing commercial technology. The polymer chemistry of the inhibitors and experiments carried out in high pressure cells and wheel/loops is described.
Hydrate Dissociation in Pipelines by Two‐Sided Depressurization: Experiment and Model
Authors: PETERS DAVID , SELIM M. SAMI , SLOAN E. DENDY
Published: July 2010

Abstract: Experimental data were obtained on the dissociation of short methane hydrate plugs in a simulated pipeline. The hydrate plugs were dissociated by the method of two‐sided depressurization. Results indicated that plug dissociation occurred radially and not axially. This results in extreme safety concerns, listed herein. When the system was depressurized to atmospheric pressure, ice was formed from the dissociating hydrate plug, which aided in the dissociation process. A model describing hydrate dissociation assumes that heat is conducted radially into the plug from the surroundings. The model is in quantitative agreement with the data using no fitted parameters. A rapid pressure reduction to atmospheric pressure on both ends of the hydrate plug leads to the optimal dissociation rate.
Hydrate Technology for Capturing Stranded Gas
Authors: GUDMUNDSSON J. S. , ANDERSSON V. , LEVIK O. I. , MORK M.
Published: July 2010

Abstract: The use of natural gas hydrate (NGH) technology in stranded gas applications is presented in terms of a process description and a capital cost estimate. The cost estimated is based on a NGH hydrate slurry process developed in a joint industry project at Norwegian University of Science and Technology (NTNU). The slurry process is suitable for offshore production of oil and gas; for example, on a floating production storage and offloading (FPSO) unit.
Methane Hydrate Fuel Storage for All‐Electric Ships: An Opportunity for Technological Innovation
Authors: MAX M. D. , JOHN V. T. , PELLENBARG R. E.
Published: July 2010

Abstract: New industrial processes for forming methane hydrate, combined with the knowledge that small changes in gas hydrate‐forming mixtures can greatly expand the pressure‐temperature field of hydrate stability, suggest that virtually solid gas hydrates can be formed and stored in fuel tanks of any shape at near sea level ambient conditions. Development of this technology may allow a gas hydrate fuel transport medium to be devised and applied. Reduction‐to‐practice of this special fuel storage medium could have a significant impact upon the design and engineering of future Navy vessels and concurrently upon the future of naval operations.
Eutectic Freeze Crystallization Using CO2 Clathrates
Authors: VAESSEN R.J. C. , van der HAM F. , WITKAMP G. J.
Published: July 2010

Abstract: Highly soluble salts can be separated from aqueous solutions by eutectic freeze crystallization (EFC). This technique delivers significant energy savings in comparison with evaporative crystallization. The eutectic temperature can be raised by crystallizing CO2 clathrates instead of normal ice. Application of this process is especially efficient for salt solutions with eutectic points at low temperatures, such as CaCl2 (−55°C). In this work the shift of the eutectic point is predicted by use of a model for NaCl and CaCl2 solutions. Experiments are executed under eutectic conditions, with these substances proving the feasibility of the eutectic clathrate freezing process. Energy calculations show that by using eutectic clathrate crystallization instead of regular EFC the electric energy consumption can be reduced by 32%.
A Remote Station to Monitor Gas Hydrate Outcrops in the Gulf of Mexico
Authors: McGEE THOMAS M. , WOOLSEY J. ROBERT
Published: July 2010

Abstract: Outcrops of gas hydrates will be monitored via a remote station installed on the continental slope of the Northern Gulf of Mexico. The project, driven by the need to initiate collection of a data base for assessing stability of the sea floor, will also address other factors associated with the formation and dissociation of gas hydrates. A group of experts has been organized to supervise the assembly and operation of the station, which will monitor physical and chemical parameters of sea water and sea floor sediments on a more or less continuous basis.
Methane Hydrate Dissociation Rates at 0.1 MPa and Temperatures above 272 K
Authors: CIRCONE SUSAN , STERN LAURA A. , KIRBY STEPHEN H. , PINKSTON JOHN C. , DURHAM WILLIAM B.
Published: July 2010

Abstract: We performed rapid depressurization experiments on methane hydrate under isothermal conditions above 272 K to determine the amount and rate of methane evolution. Sample temperatures rapidly drop below 273 K and stabilize near 272.5 K during dissociation. This thermal anomaly and the persistence of methane hydrate are consistent with the reported recovery of partially dissociated methane hydrate from ocean drilling cores.
Determination of the Intrinsic Rate of Gas Hydrate Decomposition Using Particle Size Analysis
Authors: CLARKE MATTHEW , BISHNOI P. R.
Published: July 2010

Abstract: An experimental technique to determine the intrinsic kinetics of gas hydrate decomposition is presented and a new mathematical model is developed. The experimental technique uses an on‐line particle size analyzer. The new mathematical model accounts for the distribution of particle sizes in the hydrate phase when determining the intrinsic rate constant of decomposition. Results from an experiment for the decomposition of ethane gas hydrates are presented.
In Situ Observations of Methane Hydrate Formation Mechanisms by Raman Spectroscopy
Authors: UCHIDA T. , OKABE R. , MAE S. , EBINUMA T. , NARITA H.
Published: July 2010

Abstract: We compared time‐resolved Raman spectroscopic measurements of CH4‐saturated aqueous solution with CH4 hydrate crystal formed from the same solution. At 287.1 K and 6.6 MPa the C‐H stretching mode for CH4 molecules in the solution (νsol= 2911.7 cm−1) was intermediate between that in the large cage (νL= 2905.1 cm−1) and that in the small cage (νS= 2914.1 cm−1), thus indicating an intermediate molecular environment. Comparison of these results with previous work on the CO2‐H2O system indicated that water molecules in the type‐I small‐cage‐like structure surrounded CH4 molecules in the solution. Furthermore, the free energy barrier for CH4 hydrate nucleation is likely to be formation of the large cage structure, which is probably larger than that for CO2 hydrate formation.
A Molecular Dynamics Study of the Mechanism of Kinetic Inhibition
Authors: STORR MARK T. , RODGER P. MARK
Published: July 2010

Abstract: Over the past 10 years interest in the use of kinetic inhibitors for preventing gas hydrate blockages has gained momentum. This interest stemmed from the discovery of a protein in the fish Winter Flounder that depressed the freezing point of water as well as retarding the rate of ice nucleation and growth, so allowing the fish to survive in Arctic conditions. In this paper we present results of a series of molecular dynamics simulations aimed at investigating the action of a family of sulfonate compounds whose structures are related to a group of known quaternary amine kinetic inhibitors.
Application and Extension of Aasberg‐Petersen Model for Prediction of Gas Hydrate Formation Conditions in Mixtures of Aqueous Electrolyte Solutions and Alcohol
Authors: JAVANMARDI JAFAR , MOSHFEGHIAN MAHMOOD , MADDOX ROBERT N.
Published: July 2010

Abstract: A new thermodynamic model for calculating the hydrate formation temperature of different hydrate formers in aqueous solutions of both electrolytes and alcohols is described. This method uses a generalization of the Aasberg‐Petersen model for water activity. To calculate the activity of water in the presence of electrolytes, the effect of alcohols was taken into account without using any new fitting parameters. The results are in good agreement with published experimental data. Calculated values of the hydrate forming temperature in the presence of alcohols and electrolytes are compared with values calculated by using other models.
Measurements and Predictions of Hydrate Equilibrium Conditions
Authors: GJERTSEN LARS HENRIK , FADNES FINN HALLSTEIN
Published: July 2010

Abstract: The main objective of this study was to demonstrate the importance of reliable hydrate equilibrium data for thorough mitigation and remediation of hydrate problems. Hydrate prevention strategies generally rely on extensive use of different hydrate simulators that, in turn, are based on experimental data. Erroneous hydrate predictions may severely jeopardize the established hydrate strategy and can have severe economic implications. In this study the hydrate equilibrium conditions for eight different hydrocarbon systems were investigated by experimental measurements and by hydrate simulator predictions. The results clearly verify the importance of having due control over the experimental parameters, especially the heating gradient. The error in the determination of the hydrate equilibrium temperature seems to increase with the complexity of the system; for example, when inhibitors are added to the aqueous phase.
Calculation of Gas Hydrate Equilibrium in Presence of Aqueous Salt Solutions Using a New Predictive Activity Model
Authors: JØSSANG ASLE , STANGE ELLEN
Published: July 2010

Abstract: The objective of this work is to develop a general and predictive hydrate model for hydrates in equilibrium with brines. The model developed only needs the ionic radius, the charge on the ions, and the concentration of each salt to predict the inhibition effect of the salts in the brines. The model has proven to be consistent with experimental data.
A Novel Approach for Oil and Gas Separation by Using Gas Hydrate Technology
Authors: ØSTERGAARD K. K. , TOHIDI B. , DANESH A. , BURGASS R. W. , TODD A. C. , BAXTER T.
Published: July 2010

Abstract: It is known that gas hydrates remove the light ends from reservoir fluids. Therefore, controlled hydrate formation in reservoir fluids could be an attractive option for separating oil and gas; that is, to replace conventional production facilities. In this communication we present the results of an integrated experimental and modelling study on the feasibility of the process, and the impact of the various parameters on the rate of hydrate formation. The study investigated the impact of parameters, such as mixing, water history, temperature, pressure, volume of reactor, heat removal requirements, and the quality of separated liquid. The work identified the major parameters and some of the technological requirements. Based on the experimental data, a simplified mass transfer model was constructed to simulate the kinetics of the separation process and to calculate the reactor volume and heat requirements at a specified degree of conversion. The results showed that it is possible to remove most of the lights from the liquid hydrocarbon phase by hydrate formation. The resulting liquid phase could be suitable for pipeline export or tanker loading after some treatment. Associated gas could be recovered locally from the hydrate phase. Alternatively, in cases where there is no infrastructure for transporting this gas, it might be exported as a hydrate slurry, as proposed by Gudmundsson and coworkers.
Laboratory for Continuous Production of Natural Gas Hydrates
Authors: GUDMUNDSSON JON STEINAR , PARLAKTUNA MAHMUT , LEVIK ODD IVAR , ANDERSSON VIBEKE
Published: July 2010

Abstract: Natural gas hydrate technology is an attractive alternative for storing and transporting natural gas. A high‐pressure laboratory has been built to provide experimental data for use in the design and development of hydrate‐based processes for the oil and gas industry. In the laboratory, hydrate is produced from liquid water‐and water‐in‐oil emulsions‐and injected natural gas mixtures. The hydrate reactor and circulation loop can operate at pressures up to 120 bar and constant temperatures in the range 0–20°C. The hydrate slurry produced can be circulated at up to 100 liter/minute through 4‐m long pipes equipped with differential pressure transducers and flow meters to determine their rheological characteristics under laminar and turbulent flow conditions. The laboratory can also be used for various flow assurance studies.
Structural Transition Studies in Methane + Ethane Hydrates Using Raman and NMR
Authors: SUBRAMANIAN S. , KINI R. A. , DEC S. F. , SLOAN E. D.
Published: July 2010

Abstract: Methane and ethane are each known to form structure I (sI) hydrates. However, Raman and NMR measurements made on hydrates formed from gas mixtures of methane (CH4) and ethane (C2H6) indicate that structure II (sII) forms in this system for certain gas compositions. Raman band frequencies for ethane obtained from different CH4+ C2H6 hydrates at 274.2 K indicate a change in hydrate structure from sI to sII between 72.2 and 75 mole% of CH4 in the vapor. A significant increase in the amount of methane incorporated into the hydrate is observed with change in hydrate structure from sI to sII. Solid‐state 13C CPMAS NMR measurements at 253 K confirm that CH4+ C2H6 gas mixtures can form sII hydrates at certain feed compositions.
Equilibrium Conditions of Methane and Ethane Hydrates in Aqueous Electrolyte Solutions
Authors: MAEKAWA TATSUO , IMAI NOBORU
Published: July 2010

Abstract: In this work, we determined the equilibrium conditions for gas hydrates of methane and ethane in aqueous solutions containing various electrolytes, such as NaCl, NaBr, NaI, and Na2SO4. We have developed experimental apparatus in which a light beam through solutions was used to detect the formation and dissociation of gas hydrate. To model the experimental data of this work, a statistical thermodynamic model based on the classical adsorption model proposed by van der Waals and Platteeuw 1 is used. The water activity of the aqueous solutions containing electrolytes, which affects the gas hydrate stability, was evaluated by the model of Englezos and Bishnoi.2
In Situ Observation of CO2 Hydrate by X‐ray Diffraction
Authors: TAKEYA SATOSHI , HONDOH TAKEO , UCHIDA TSUTOMU
Published: July 2010

Abstract: In situ observations of CO2 hydrate growth using high‐energy X‐rays were done at high‐pressures and the growth rates of CO2 hydrate from ice particles were measured. Assuming a model of diffusion through CO2 hydrate layers, interdiffusion coefficients of CO2 and H2O molecules were calculated between 233 K and 272.5 K. The diffusion coefficient at 263 K was 7.4 × 10−16 m2/s, and the activation energy of diffusion was 0.40 eV.
Occurrences of Natural Gas Hydrates beneath the Permafrost Zone in Mackenzie Delta: Visual and X‐ray CT Imagery
Authors: UCHIDA TAKASHI , DALLIMORE SCOTT , MIKAMI JUN
Published: July 2010

Abstract: The JAPEX/JNOC/GSC Mallik 2L‐38 research well was drilled to a depth of 1,150 m beneath the permafrost zone in the Mackenzie Delta, N.W.T., Canada, early in 1998. A large amount of natural gas hydrates were successfully retrieved from a variety of sandy and gravel sediments. Over 110 m of gas hydrate‐bearing sediments were found to be distributed between 897 m and 1,100 m deep. Approximately 37 meters of core were recovered in this interval with most of the recovered gas hydrates being less than 2 mm in size occurring mainly in intergranular porosity of silty to clean massive sand and conglomerate (granule to pebble). Typically, hydrate‐bearing strata were between 10 cm and more than one meter thick with an estimated porosity of 25 to 35%. The largest form of hydrate was about 2 cm in diameter, occurring as clasts and intergranular porosity within granular sands. Occurrences of natural gas hydrate have been observed visually at the drill site and in core samples preserved in pressurized storage vessels utilizing an X‐ray CT scanner technique. Quantitative assessments of gas hydrate concentrations in core samples have been made based on pressure response of dissociation vessels and direct volumetric measurements. Six types of gas hydrate have been recognized: (1) pore‐space hydrate, (2) platy hydrate, (3) layered/massive hydrate, (4) disseminated hydrate, (5) nodule hydrate, and (6) vein/dyke hydrate. The X‐ray CT images proved useful for characterizing macroscopic forms of gas hydrate. Finer grained occurrences were more difficult to study, however the distribution of gas hydrates and granular grains can be recognized. The occurrences of natural gas hydrates in the Mallik well are compared to the previous natural gas hydrate core samples obtained from ODP/DSDP programs and other field studies.
“Gene‐Swap Knock‐in” Cassette in Mice to Study Allelic Differences in Human Genes
Authors: NEBERT DANIEL W. , DALTON TIMOTHY P. , STUART GARY W. , CARVAN MICHAEL J.
Published: July 2010

Abstract:Genetic differences in environmental toxicity and cancer susceptibility among individuals in a human population often reflect polymorphisms in the genes encoding drug‐metabolizing enzymes (DMEs), drug transporters, and receptors that control DME levels. This field of study is called “ecogenetics”, and a subset of this field‐concerning genetic variability in response to drugs‐is termed “pharmacogenetics”. Although human‐mouse differences might be 3‐ to perhaps 10‐fold, human interindividual differences can be as great as 20‐fold or more than 40‐fold. It would be helpful, therefore, to study toxicokinetics/pharmacokinetics of particular environmental agents and drugs in mice containing these “high‐” and “low‐extreme” human alleles. We hope to use transgenic “knock‐in” technology in order to insert human alleles in place of the orthologous mouse gene. However, the knock‐in of each gene has normally been a separate event requiring the following: (a) construction of the targeting vector, (b) transfection into embryonic stem (ES) cells, (c) generation of a targeted mouse having germline transmission of the construct, and (d) back‐cross breeding of the knock‐in mouse (at least 6–8 times) to produce a suitable genetically homogeneous background (i.e., to decrease “experimental noise”). These experiments require 1½ to 2 years to complete, making this very powerful technology inefficient for routine applications. If, on the other hand, the initial knock‐in targeting vector might include sequences that would allow the knocked‐in gene to be exchanged (quickly and repeatedly) for one new allele after another, then testing distinctly different human polymorphic alleles in transgenic mice could be accomplished in a few months instead of several years. This “gene‐swapping” technique will soon be done by zygotic injection of a “human allele cassette” into the sperm or fertilized ovum of the parental knock‐in mouse inbred strain or by the cloning of whole mice from cumulus ovaricus cells or tail‐snip fibroblasts containing the nucleus wherein each new human allele has already been “swapped.” In mouse cells in culture using heterotypic lox sites, we and others have already succeeded in gene swapping, by exchanging one gene, including its regulatory regions, with a second gene (including its regulatory regions). It is anticipated that mouse lines carrying numerous human alleles will become commonplace early in the next millennium.
In Vitroand Human Testing Strategies for Skin Irritation
Authors: ROBINSON MICHAEL K. , OSBORNE ROSEMARIE , PERKINS MARY A.
Published: July 2010

Abstract:Prior to the manufacture, transport, and marketing of chemicals or products, it is critical to assess their potential for skin toxicity (corrosion or irritation), thereby protecting the worker and consumer from adverse skin effects due to intended or accidental skin exposure. Traditionally, animal testing procedures have provided the data needed to assess the more severe forms of skin toxicity, and current regulations may require animal test data before permission can be obtained to manufacture, transport, or market chemicals or the products that contain them. In recent years, the use of animals to assess skin safety has been opposed by some as inhumane and unnecessary. The conflicting needs of the industrial toxicologist to (1) protect human safety, (2) comply with regulations, and (3) reduce animal testing have led to major efforts to develop alternative, yet predictive, test methods. A variety ofin vitroskin corrosion test methods have been developed and several have successfully passed initial international validation. These have included skin or epidermal equivalent assays that have been shown to distinguish corrosive from noncorrosive chemicals. These skin/epidermal equivalent assays have also been modified and used to assess skin irritation potential relative to existing human exposure test data. The data show a good correlation betweenin vitroassay data and different types of human skin irritation data for both chemicals and consumer products. The effort to eliminate animal tests has also led to the development of a novel human patch test for assessment of acute skin irritation potential. A case study shows the benefits ofin vitroand human skin irritation tests compared to the animal tests they seek to replace, and strategies now exist to adequately assess human skin irritation potential without the need to rely on animal test methods.
The Role of Tumor Necrosis Factor α in Chemical‐Induced Hepatotoxicity
Authors: LUSTER MICHAEL I. , SIMEONOVA PETIA P. , GALLUCCI RANDLE M. , BRUCCOLERI ALEX , BLAZKA MARK E. , YUCESOY BERRAN , MATHESON JOANNA M.
Published: July 2010

Abstract: Only recently have toxicologists come to understand the role of inflammation, and TNFα specifically, in classical toxicological processes. This relationship appears fairly complex, as inflammation and proliferation may well be only one facet of a time‐ and dose‐dependent continuum of toxicological and repair processes. Not surprisingly, considerable efforts are being undertaken using our newly found understanding of molecular control to develop specific and safe chemical, biological, and molecular regulators of TNFα for potential therapeutic use. Their effectiveness in controlling environmental or occupational diseases has yet to be established.
Transient Modulation of Gene Expression in the Neurulation Staged Mouse Embryo
Authors: HUNTER E. SIDNEY , HARTIG PHILLIP
Published: July 2010

Abstract: Transient modulation of gene expression in the embryo during early organogenesis will allow studies to be conducted that determine tissue‐ and stage‐specific function(s) of genes. To achieve this goal, viral vectors and antisense oligodeoxynucleotides have been used to produce gain‐of‐function and loss‐of‐function models. Adenoviral transduction of whole embryos, embryonic heart and vasculature, and primary neural crest cell culture has been reported. The morphological consequences of overexpression or decreasing expression of selected genes have been evaluated using these tools. Gene‐teratogen interaction studies have also been performed. The viral vectors appear to be important tools for modulating gene expression and hold great promise for future research.
Clinical and Neuropathological Correlates of Dementia with Lewy Bodies
Authors: GÓMEZ‐TORTOSA E. , IRIZARRY M. C. , GÓMEZ‐ISLA T. , HYMAN B. T.
Published: July 2010

Abstract: Dementia with Lewy bodies (DLB) is characterized pathologically by widespread Lewy body (LB) neuronal inclusions in the brain, but the contribution of LBs to the clinical syndrome of dementia and parkinsonism is unclear. In a clinical‐pathological study of 25 cases with DLB, we examined the regional neuroanatomical distribution of Lewy‐related pathology using α‐synuclein immunostaining to evaluate the relationship between LBs, neuronal loss, Alzheimer‐type changes, and the clinical phenotype. Compared to traditional ubiquitin immunostaining, α‐synuclein immunohistochemistry was more specific and slightly more sensitive, staining about 5% more intracytoplasmic structures. There was a consistent pattern of vulnerability to LB formation across subcortical, paralimbic, limbic, and neocortical structures, which was independent of concomitant Alzheimer‐type changes. There were no significant differences in regional LB densities among patients with or without cognitive fluctuations, visual hallucinations, delusions, recurrent falls or parkinsonism. Duration of disease correlated weakly with LB density. There was no neuronal loss in superior temporal sulcus or entorhinal cortex in pure DLB cases compared to nondemented controls. Thus, DLB is characterized by a specific neuroanatomical vulnerability to LB pathology, distinct from AD pathology, with a complicated relationship to clinical symptoms.
Physiology and Pathophysiology of α‐Synuclein: Cell Culture and Transgenic Animal Models Based on a Parkinson's Disease‐associated Protein
Authors: KAHLE PHILIPP J. , NEUMANN MANUELA , OZMEN LAURENCE , HAASS CHRISTIAN
Published: July 2010

Abstract: The 15–20 kDa synuclein (SYN) phosphoproteins are abundantly expressed in nervous tissue. Members of the family include α‐ and β‐SYN, and the more distantly related γ‐SYN and synoretin. SYN genes have been identified in Torpedo, canary, and several mammalian species, indicating an evolutionary conserved role. Expression of α‐SYN was found to be modulated in situations of neuronal remodeling, namely, songbird learning and after target ablation of dopaminergic striatonigral neurons in the rat. The presynaptic localization of α‐SYN is further supportive of a direct physiological role in neuronal plasticity. The extensive synaptic co‐localization of α‐ and β‐SYN might indicate functional redundancy of these highly homologous synucleins. However, α‐SYN was the only family member identified in Lewy bodies and cytoplasmic inclusions characteristic for multiple system atrophy. Moreover, α‐SYN was genetically linked to familial Parkinson's disease. The two Parkinson's disease‐associated mutations accelerated the intrinsic aggregation property of α‐SYN in vitro. Post‐translational modifications, such as phosphorylation and proteolysis, and/or interaction with other proteins, might regulate α‐SYN fibril formation in vivo. Cytoskeletal elements and signal transduction intermediates have been recently identified as binding partners for α‐SYN. Preliminary data available from transgenic mice suggest that (over)expressed human α‐SYN proteins are less efficiently cleared from the neuronal cytosol. Thus, Parkinson's disease‐associated mutations might perturb axonal transport, leading to somal accumulation of α‐SYN and eventually Lewy body formation.
Amyloidogenesis in Familial British Dementia Is Associated with a Genetic Defect on Chromosome 13
Authors: GHISO J. , VIDAL R. , ROSTAGNO A. , MIRAVALLE L. , HOLTON J. L. , MEAD S. , RÉVÉSZ T. , PLANT G. , FRANGIONE B.
Published: July 2010

Abstract: Familial British dementia (FBD) is a disorder characterized by the presence of amyloid deposits in cerebral blood vessels and brain parenchyma coexisting with neurofibrillary tangles in limbic areas. The amyloid subunit (ABri) is a 4 kDa fragment of a 266 amino acid type II single‐spanning transmembrane precursor protein encoded by the BRI gene located on chromosome 13. In FBD patients, a single base substitution at the stop codon of this gene generates a larger 277‐residue precursor (ABriPP‐277). Proteolytic processing by a furin‐like enzyme at the C‐terminus of the elongated precursor generates the 34 amino acid ABri that undergoes rapid aggregation and fibrillization. ABri is structually unrelated to all known amyloids including Aβ, the main component of the amyloid lesions in Alzheimer's disease (AD), indicating that cerebral deposition of amyloid molecules other than Aβ can trigger similar neuropathological changes leading to neuronal loss and dementia. These data support the concept that amyloid deposition in the vascular wall and brain parenchyma is of primary importance in the initiation of neurogeneration.
Familial British Dementia: Expression and Metabolism of BRI
Authors: KIM SEONG‐HUN , WANG RONG , GORDON DAVID J. , BASS JOSEPH , STEINER DONALD F. , THINAKARAN GOPAL , LYNN DAVID G. , MEREDITH STEPHEN C. , SISODIA SANGRAM S.
Published: July 2010

Abstract: Vidal et al. (1999. Nature 399: 776–778) discovered that the underlying genetic lesion in familial British dementia (FBD) is a T‐A transversion at the termination codon of a membrane protein, termed BRI. The mutation creates an arginine codon; translational read‐through generates a novel protein, termed BRI‐L, that is extended by 11 amino acids at the carboxyl‐terminus. BRI‐L is the precursor of the ABri peptide, a component of amyloid deposits in FBD brain. We demonstrate that both BRI and its mutant counterpart are constitutively processed by furin, resulting in the secretion of carboxyl‐terminal peptide derivatives that correspond to all, or part of, ABri. Notably, elevated levels of peptides are generated from the mutant BRI precursor, suggesting that subtle conformational alterations at the carboxyl‐terminus may influence furin‐mediated processing. We have examined BRI/BRI‐L processing by other members of the prohormone convertase (PC) family (PACE4, LPC, PC 5/6) and found that these enzymes also process BRI, albeit inefficiently. Moreover, BRI‐L processing by the other PC members is severely compromised. Finally, our electron microscopic studies reveal that synthetic ABri peptides assemble into insoluble b‐pleated fibrils. Collectively, our results support the view that enhanced furin‐mediated processing of mutant BRI generates amyloidogenic peptides that initiate the pathogenesis of FBD.
Pathogenic Mechanisms of Alzheimer's Disease Analyzed in the APP23 Transgenic Mouse Model
Authors: STURCHLER‐PIERRAT CHRISTINE , STAUFENBIEL MATTHIAS
Published: July 2010

Abstract: APP23 transgenic mice overexpress human APP with the Swedish double mutation. The mice start to develop amyloid plaque pathology at about six months of age, followed somewhat later by vascular amyloid deposits. Plaques are mostly of the compact type and increase exponentially during aging. Female mice show a slightly more rapid Ab plaque deposition than do male animals. Associated with the amyloid are inflammatory reactions, neuritic and synaptic degeneration as well as tau hyperphosphorylation. Older mice have a reduced cholinergic fiber length and a reduced neuron number in the hippocampal CA1 region. Crossbreeding with transgenic mice expressing human presenilin 1 carrying Alzheimer's disease‐linked mutations lead to an enhancement of the pathology. The APP23 line is a suitable model to analyze the contribution of APP, Ab, and amyloid to the pathogenesis of Alzheimer's disease.
Prions: Pathogenesis and Reverse Genetics
Authors: AGUZZI ADRIANO , KLEIN MICHAEL A. , MONTRASIO FABIO , PEKARIK VLADIMIR , BRANDNER SEBASTIAN , FURUKAWA HISAKO , KÄSER PASCAL , RÖCKL CHRISTIANE , GLATZEL MARKUS
Published: July 2010

Abstract: Spongiform encephalopathies are a group of infectious neurodegenerative diseases. The infectious agent that causes transmissible spongiform encephalopathies was termed prion by Stanley Prusiner. The prion hypothesis states that the partially protease‐resistant and detergent‐insoluble prion protein (PrPsc) is identical with the infectious agent, and lacks any detectable nucleic acids. Since the latter discovery, transgenic mice have contributed many important insights into the field of prion biology. The prion protein (PrPc) is encoded by the Prnp gene, and disruption of Prnp leads to resistance to infection by prions. Introduction of mutant PrPc genes into PrPc‐deficient mice was used to investigate structure‐activity relationships of the PrPc gene with regard to scrapie susceptibility. Ectopic expression of PrPc in PrPc knockout mice proved a useful tool for the identification of host cells competent for prion replication. Finally, the availability of PrPc knockout and transgenic mice overexpressing PrPc allowed selective reconstitution experiments aimed at expressing PrPc in neurografts or in specific populations of hemato‐ and lymphopoietic cells. The latter studies helped in elucidating some of the mechanisms of prion spread and disease pathogenesis.
α1‐Antichymotrypsin Inhibits Aβ Degradation in Vitro and in Vivo
Authors: ABRAHAM CARMELA R. , McGRAW WALKER T. , SLOT FRANCHOT , YAMIN RINA
Published: July 2010

Abstract: The neuropathology of Alzheimer's disease (AD) is characterized by extensive deposition of the toxic amyloid β peptide (Aβ) in selected regions of the brain and brain vasculature (Selkoe, 1999). Thus, lowering the levels of Aβ may be beneficial for AD patients. Aβ is a proteolytic fragment derived from the amyloid precursor protein (APP). The mechanisms of Aβ formation from its precursor have been studied extensively; however, considerably less effort has been invested into studying Aβ clearance. We find that the degradation of Aβ in our system is dependent upon the presence of a metallopeptidase E.C.3.4.24.15 (MP24.15) (Yamin et al., 1999). We have previously purified MP24.15 to homogeneity from AD brain and identified it as an APP‐processing protease in vitro (Papastoitsis, 1994). To confirm its role in cell culture, we transfected SKNMC neuroblastoma cells with sense and antisense cDNAs of MP24.15 and with a mock construct. Compared to mock conditioned media (CM), CM of MP24.15‐overexpressing cells had very high Aβ‐degrading activity. Conversely, CM of antisense‐expressing cells lacked Aβ‐degrading activity. These results suggested that MP24.15 is involved in Aβ degradation. Characterization of the proteolytic activity directly responsible for Aβ degradation using a spectrum of protease inhibitors revealed that only serine protease inhibitors completely blocked Aβ degradation. Therefore, MP24.15 appears to activate a serine protease, which then cleaves Aβ. Interestingly, α1‐antichymotrypsin (ACT) which we discovered to be highly elevated in AD brain (Abraham, et al., 1988) also inhibited Aβ degradation. To our delight, ACT proved to be an inhibitor of Aβ degradation in vivo as well. When we crossed transgenic mice expressing human ACT with plaque‐producing mice expressing human APP, the doubly transgenic mice had twice as many plaques at 20 months of age as the APP mice (Mucke et al., 2000). Successful completion of this study could lead to the design of reagents that would reduce the amyloid load in AD patients.
Activated Mitogenic Signaling Induces a Process of Dedifferentiation in Alzheimer's Disease That Eventually Results in Cell Death
Authors: ARENDT THOMAS , HOLZER MAX , STÖBE ANDREA , GÄRTNER ULRICH , LÜTH HANS‐JOACHIM , BRÜCKNER MARTINA K. , UEBERHAM UWE
Published: July 2010

Abstract: Neurodegeneration in Alzheimer's disease (AD) is associated with the appearance of dystrophic neuronal growth profiles that most likely reflect an impairment of neuronal reorganization. This process of morphodysregulation, which eventually goes awry and becomes a disease itself, might be triggered either by a variety of life events that place an additional burden on the plastic capability of the brain or by genetic pertubations that shift the threshold for decompensation. This paper summarizes recent evidence that impairment of the p21ras intracellular signal transduction, which is is mediated by a hierarchy of phosphorylation signals and eventually results in loss of differentiation control and an attempt of neurons to re‐enter the cell‐cycle, is critically involved in this process. Neurodegeneration might thus be viewed as an alternative effector pathway of those events that in the dividing cell would lead to cellular transformation. This hypothesis might be of heuristic value for the development of a therapeutic strategy.