bluuebunny/crossref_metadata_2025 huggingface dataset:
Transgenic Mice Expressing Human β‐APP751, But Not Mice Expressing β‐APP695, Display Early Alzheimer's Disease‐like Histopathologya
Authors: HIGGINS L. S. , CATALANO R. , QUON D. , CORDELL B.
Published: December 2006

Mice transgenic for the 751 amino acid isoform of the human β‐amyloid precursor protein (β‐APP) driven by the rat neuron specific enolase (NSE) promoter (NSE:β‐APP751) show features of early Alzheimer's disease (AD) pathology. These features, which were evident in multiple pedigrees, include: 1) preamyloid deposits which stain with antibodies that are specific for the β‐amyloid peptide and stain AD amyloid deposits and plaques, and 2) neuronal soma and processes which stain with an antibody (Alz50) that detects abnormal isoforms of tau which are characteristic of AD. The quality and distribution of both types of immunoreactivity revealed in the NSE:β‐APP751 mouse brains most closely resemble those seen in brains of young adults with Down's syndrome. Both structures are rarely, if ever, observed in brains from mice transgenic for the 695 amino acid isoform of β‐APP (NSE:β‐APP695) or in wild type mice.
Cholinergic and Non‐cholinergic Synaptic Mechanisms in the Aged Rat Hippocampusa
Authors: POTIER B. , LAMOUR Y. , DUTAR P.
Published: December 2006

We compared age‐related alterations in the electrophysiological and pharmacological properties of CA1 hippocampal pyramidal neurons in three strains of rats (Sprague‐Dawley, Fisher 344 and Wistar) at 3–4 and 25–32 months of age, using the in vitro slice preparation. The most consistent age‐related alterations were: a decrease in membrane excitability, a decrease in the amplitude and duration of inhibitory postsynaptic potentials and a decreased sensitivity to the effect of the cholinergic agonist carbachol. In contrast, no consistent alterations in calcium‐dependent events were observed in these strains of rats. The age‐related changes in the duration of the after‐hyperpolarization (AHP) were different (and even opposite) depending on the strain studied. Our results show that age‐related changes observed in a given strain are not necessarily present in all strains of the same species.
Age‐related Cognitive Deficits in Rats Are Associated with a Combined Loss of Cholinergic and Serotonergic Functionsa
Authors: RICHTER GAL , SEGAL MENAHEM
Published: December 2006

The cholinergic hypothesis of senile dementia proposes that an age‐dependent reduction of central cholinergic functions accounts for the severe cognitive deficits seen in aged rats. A careful examination of the experimental evidence cited in support of this hypothesis reveals that it cannot account for some behavioral observations. We have modified this hypothesis and wish to propose that serotonin and acetylcholine interact to allow normal cognitive functions in the brain. Thus, a partial reduction in both cholinergic and serotonergic functions will cause severe memory impairment in young as well as in aged rats. We found that restoration of the serotonergic innervation in the hippocampus of serotonin depleted rats, using tissue transplants, can restore impaired behavior. We have localized a memory‐related interaction between serotonin and acetylcholine in the hippocampus and are in the process of identifying a physiological function which may underly this interaction.
Local Compactness of Hyperspacesa
Authors: BURDICK BRUCE S.
Published: December 2006

ABSTRACT. Those uniform spaces whose uniform hyperspaces are locally compact are characterized. Some properties of the set of points of local compactness of a uniform hyperspace are investigated.
The Topological‐Algebraic System(βN, +, ˙)a
Authors: HINDMAN NEIL
Published: December 2006

ABSTRACT. The interaction of the left continuous extensions of ordinary addition and multiplication to the Stone‐Čech compactification of N is studied.
Primes in Preordered Sets: A Question of Henriksen and Kopperman
Authors: JOHNSON D. , KIST J.
Published: December 2006

ABSTRACT. Let X be a family of nonempty proper subsets of the set R; for a |Ge R, let Xa={I |Ge X: a ∉I), and denote the collection (Xa: a |Ge R} byXR.

Henriksen and Kopperman have shown that if XR is closed under finite intersection, then R can be given the structure of a commutative semigroup so that each element of X becomes a prime semigroup ideal; they then ask if the same conclusion can be drawn if the family XR is merely a base for a topology on X. In this paper, certain notions from the theory of preordered sets are used to produce a large family of examples that respond negatively to the Henriksen‐Kopperman question.
Green's Equivalences and Related Concepts for Semigroups of Continuous Selfmaps
Authors: MAGILL K. D.
Published: December 2006

ABSTRACT. Green's equivalences are characterized for regular elements of general transformation semigroups and the largest proper left ideal, the largest proper right ideal, and the largest proper two‐sided ideal are all explicitly described when the semigroup has a right identity, a left identity, and a two‐sided identity, respectively. It is shown that the largest proper left ideal and the largest proper right ideal (if they exist) of any semigroup are prime and that the largest proper ideal may, or may not be prime. These results have applications to such semigroups as the semigroup of all endomorphisms of a vector space as well the semigroup, S(X), of all continuous selfmaps of a topological space X. However, the semigroup S(X) is our primary focus here. For example, it is shown that if X is any local dendrite with finite branch number that is not an arc, then Mon(S(X)), the semigroup of monomorphisms from S(X) into S(X), is isomorphic to the dual of the complement of the largest proper right ideal of S(X). Furthermore, the complement of the largest proper left ideal of S(X) is a homomorphic image of Mon (S(X)). Some results are then discussed concerning Green's equivalences for polynomial functions (many of which are irregular) in the semigroup of all continuous selfmaps of the space of real numbers. Finally, the partially ordered families L (S(X)) and.R (S(X)) are discussed where L (S(X)) consists of the equivalence classes of S(X) induced by Green's.L‐equivalence and. R(S(X)) consists of the equivalence classes of S(X) induced by Green's R‐equivalence. For example, if X and Y are any two compact 0‐dimensional spaces, then the following four statements are equivalent: (1) L (S(X)) and L (S(Y)) are order isomorphic, (2) R (S(X)) and. R(S(Y)) are order isomorphic, (3) the semigroups S(X) and S(Y) are isomorphic, (4) the topological spaces X and Y are homeomorphic.
Infinitesimal R‐Trees Associated with Lifts of Quadratic Differentials without Connections in the Unit Disk
Authors: SLUTSKIN LEV
Published: December 2006

It is shown that each pair of transverse measured foliations without connections between singularities on a compact surface contains within it a geometric structure that becomes an R‐tree on the universal covering space. It is proved that the trees can be parameterized by sequences of positive numbers that reflect both their topological and geometric structures.
Dugundji Spaces in the Coset Space G/H
Authors: HERNÁNDEZ SALVADOR , SANCHIS MANUEL
Published: December 2006

ABSTRACT: In this paper we consider a closed subgroup, H, of a topological group, G, satisfying that for each open neighborhood, U, of the identity element of the group there exists another open neighborhood of the identity, V, such that HV⊆UH. We prove that any compact Gδ‐set of the coset space G/H is a Dugundji space.
THE GALACTIC CENTER
Authors: Genzel R. , Eckart A. , Krabbe A.
Published: December 2006

The Galactic center is a superb laboratory of modern astrophysics where astronomers can study at unprecedented spatial resolution and across the entire electromagnetic spectrum physical processes that may also happen at the cores of other galaxies. Following a brief review of the phenomena observed in the central few hundred parsecs, we discuss two main issues in more detail. The source(s) of luminosity in the central parsec and the nature of the compact radio source SgrA*, the most likely candidate for a massive central black hole.
Evaporation of Companions in VLMXBs and Binary Millisecond Pulsarsa
Authors: SHAHAM JACOB
Published: December 2006

Abstract. Irradiation‐induced companion winds and a new model for the evaporation of the companion of the millisecond pulsar B1957+20 are discussed. The model may account for all companionless millisecond pulsars observerd today.
Production of Corticotropin‐releasing Hormone‐deficient Mice by Targeted Mutation in Embryonic Stem Cells
Authors: MUGLIA LOUIS , JACOBSON LAUREN , MAJZOUB JOSEPH A.
Published: December 2006

The generation of transgenic mice by introduction of intact or altered genes into the pronuclei of fertilized oocytes has proven a powerful tool in elucidating the consequences of ectopic or tissue‐appropriate overproduction of a given gene product; in defining DNA elements responsible for gene‐specific patterns of temporal, spatial, and regulated transcription; and in targeted oncogenesis for the development of cell culture lines for detailed in vitro study. This technology, however, has had limited success in addressing the role and essential function of specific peptides in the intact organism, except in the circumstance in which dominant negative alleles, capable of abrogating function of the normal allele, are available.1,2 With the establishment of embryonic stem (ES) cell culture systems amenable to in vitro manipulation for introduction of mutated genes, methods for selection of relatively rare homologous recombination events, and most importantly, the sustained capacity of these ES cells to contribute to the germline of chimeric mice, a method of addressing the consequences of loss of gene function has emerged.3,5 Targeted gene inactivation in ES cells with subsequent generation of deficient mice yields inheritable, complete loss of function at all stages of development and in all tissues. This is an advantage when assessing ontogenic importance, ability of interacting systems to compensate for loss of function, and the effects of chronic deficiency. These factors can also impair whole‐organism analysis of function, inasmuch as chronic deficiency may allow up‐regulation of compensatory systems, masking the in vivo function of the mutation, and global deficiency may make characterization at a specific site of synthesis difficult to determine. Most severely, loss of expression at all stages of development may lead to organism inviability.
Functional Changes in Neuronal Systems Induced by Phencyclidine Administrationa
Authors: NABESHIMA TOSHITAKA , KITAICHI KIYOYUKI , NODA YUKIHIRO
Published: December 2006

To analyze the mechanisms of PCP abuse, we investigated the changes in PCP‐induced motivational properties and neuronal functions in animals. First, we determined that PCP‐induced withdrawal syndrome may, in part, be produced by 5‐HTergic neuronal systems. Second, using rats treated with subacute PCP, we established that subacute PCP may produce behavioral changes (stereotyped behaviors and hyperlocomotion), mediated by both dopaminergic, 5‐HTergic neuronal, and NO systems. Third, using the place conditioning paradigm, we confirmed that (1) both dopamine‐D1 and 5‐HT2A receptors, but not sigma receptors, may be involved in PCP‐induced place aversion, and (2) subacute PCP produces place preference. Finally, we demonstrated that subacute PCP may produce neurochemical changes (the number of 5‐HT2A receptors, dopamine turnover, NO synthesis, and immediate early gene expression).

These results suggested that several neuronal changes may be related to behavioral changes induced by subacute PCP. Furthermore, it is hypothesized that the alternations of several neuronal systems may establish PCP abuse via the changes of the immediate early gene expression and NO activity induced by subacute PCP treatment. Further studies using receptor selective ligands and sensitive probes that could associate with the pharmacological actions of PCP may elucidate the mechanisms of PCP abuse.
Characterization of Single‐Stranded cAMP Response Element Binding Protein (ssCRE‐BP) from Mouse Cerebellum
Authors: OSUGI TAKESHI , DING YUN , MIKI NAOMASA
Published: December 2006

It has been speculated that opiate tolerance and dependence may occur at the level of gene expression. Our previous studies have shown that the binding activity of a nuclear factor (ssCRE‐BP) to single‐stranded CRE of somatostatin gene is altered by long‐term treatment with morphine in the mouse cerebellum. ssCREBP was purified from the mouse cerebellum by a combination of chromatography on DNA affinity agarose and Mono Q HR. The native protein exhibited a molecular size of 110–150 kDa by gel filtration, and two polypeptides of about 35–40 kDa were observed on SDS‐PAGE. The cloning and sequencing of a cDNA encoding ssCRE‐BP showed that the protein possesses a glycine‐rich domain and a glutamine‐rich domain in the amino terminus and the carboxyl terminus, respectively. To investigate the function of ssCRE‐BP in the brain, recombinant glutathione‐S‐transferase (GST) fusion proteins containing ssCRE‐BP were expressed in bacterial systems. Rabbit anti‐ssCRE‐BP antibodies were raised against a GST‐ssCRE‐BP fusion protein. Using the antibodies in western blot analysis, a polypeptide of ∼66 kDa was detected in the brain. These findings indicate that ssCRE‐BP is involved in opiate tolerance and dependence.
Alteration of G Protein Subclass mRNAs in Methamphetamine–Induced Behavioral Sensitization
Authors: IWASA HIROTO , KIKUCHI SHUICHI , HASEGAWA SHUJI , SUZUKI KAORI , SATO TOSHIO
Published: December 2006

Guanine nucleotide‐binding regulatory proteins (G proteins) play an obligatory role in the transmembrane signaling system and are concerned with the neurochemical basis of several psychiatric disorders. We examined the alteration in the mRNA levels of G protein subclasses (Gil α, Gi2 α and Go α) in behavioral sensitized rats using subchronic treatment with methamphetamine (MAP). Adult male Sprague‐Dawley rats received intraperitoneal injections of MAP (4 mg/kg) or saline (control) once daily for 14 days. A remarkable increase in the levels of Gi2 α mRNA was observed in both sides of striatum at 48 hours after the last injection of MAP. The changes in the Gi2 α mRNA levels were not significant at two weeks after the last injection of MAP. The levels of Go α and Gil α mRNA were not changed at 48 hours and at two weeks after the last injection of MAP. These results suggest that the changes in the Gi2 mRNA level might be responsible for the reinforcement of the generation of stereotyped abnormal behavior by repeated administration of MAP rather than the persistence of the reverse tolerance phenomenon.
Acute and Chronic Administration of Ibogaine to the Rat Results in Astrogliosis That Is Not Confined to the Cerebellar Vermisae
Authors: O'CALLAGHAN JAMES P. , ROGERS TINA S. , RODMAN LARRY E. , PAGE JOHN G.
Published: December 2006

Acute administration of high doses of ibogaine (IBG) to the male rat results in degeneration of Purkinje cells and reactive gliosis in the cerebellar vermis.1,2
One‐Way Cross‐Sensitization and Cross‐Tolerance to Seizure Activity from Cocaine to Lidocainea
Authors: SHIMOSATO KAZUAKI , WATANABE SATORU , MARLEY RODNEY J. , SAITO TAIICHI
Published: December 2006

The present study examined the effects of daily treatment with a subconvulsant dose (50 mg/kg) of cocaine or lidocaine on susceptibility to seizures induced by dose cross‐injections of the same dose of the other local anesthetic, and to seizures induced by pentylenetetrazol (PTZ) or N‐methyl‐dl‐aspartate (NMDLA) in ddY mice. Repeated administration of 50 mg/kg cocaine caused the development of sensitization to cocaine‐induced seizures during an initial 3 or 4 days, followed by the development of tolerance on days 4–6. The same dose of lidocaine, however, or no seizure activity following repeated administration. In contrast, produced little when injected 24 hr after 2–4 days of cocaine treatment, 50 mg/kg lidocaine produced severe seizures. Interestingly, this cross‐sensitization from cocaine to lidocaine diminished upon further cocaine treatment. In contrast, treatment with lidocaine for 2–6 days had no effect on subsequent changes in seizure susceptibility following repeated cocaine injections. Neither treatment with cocaine nor lidocaine for 2 or 5 days influenced susceptibility to seizures induced by a challenge injection of PTZ (50 mg/kg, i.p.) or NMDLA (300 mg/kg, i.p.) 24 hr after treatment. HPLC analyses revealed that the cocaine treatment paradigm used in these studies in‐ creased the levels of the polyamines, putrescine and spermidine, in mouse brain, while lidocaine treatment had no effect on cerebral polyamine levels. These results suggest that there are differences in the neural mechanisms underlying the convulsant properties of cocaine and lidocaine in ddY mice.
Apolipoprotein E. Structure, Function, and Possible Roles in Alzheimer's Diseasea
Authors: MAHLEY R. W. , NATHAN B. P. , PITAS R. E.
Published: December 2006

Apolipoprotein (apo) E is associated with the two characteristic neuropathologic lesions of Alzheimer's disease–extracellular neuritic plaques representing deposits of amyloid beta (Aβ) peptide and intracellular neurofibrillary tangles representing filaments of a microtubule‐associated protein called tau. Incubation of the apoE4 isoform with the Aβ peptide in vitro results in the formation of a dense, stable network of very long monofibrils, while incubation of apoE3 with the Aβ peptide results in the formation of a less dense, less stable network. The more complex nature of the plaques formed with the Aβ peptide in the presence of apoE4 in vivo may impair the normal clearance process and enhance plaque formation. Alternatively or additionally, apoE may alter the cytoskeletal structure and function and, under certain conditions, may promote the formation of the neurofibrillary tangles. Our studies have demonstrated that apoE3 and apoE4 exert differential effects on neuronal growth (i.e., neurite extension and branching) in vitro. When combined with a source of lipid, apoE3 stimulated neurite extension in peripheral nervous system neurons (dorsal root ganglia), whereas apoE4 inhibited it. Similar results were obtained with central nervous system neurons (murine neuroblastoma Neuro‐2a cells). Addition of free apoE3 or apoE4 without β‐VLDL had no effect on neurite outgrowth. There was also differential accumulation of apoE3 and apoE4 by the neuroblastoma cells: apoE3 accumulated within cell bodies and neurites to a greater extent than apoE4. Thus, apoE3 may facilitate cytoskeletal activity, whereas apoE4 may inhibit it, which would be detrimental during synaptic remodeling.
Anti‐Inflammatory Drugs in the Fight against Alzheimer's Diseasea
Authors: McGEER P. L. , McGEER E. G.
Published: December 2006

Lesions in Alzheimer disease are characterized by the assembly of a variety of cells and proteins associated with the immune system. Activated microglia express high levels of MHC glycoproteins and receptors for complement. Small numbers of T‐lymphocytes infiltrate tissue. Proteins of the classical complement pathway are closely connected with β‐amyloid deposits. Several materials associated with senile plaques, including β‐amyloid protein itself, bind C1q in vitro and activate the pathway. The membrane attack complex of complement, as well as proteins which defend against that complex, colocalize with dystrophic neurites. These data imply that an autodestructive process is occurring in Alzheimer's disease, and that anti‐inflammatory drugs might be an effective form of therapy. Some epidemiological evidence and results of a pilot clinical trial support this hypothesis.
APP Gene Family Alternative Splicing Generates Functionally Related Isoformsa
Authors: SANDBRINK R. , MASTERS C. L. , BEYREUTHER K.
Published: December 2006

The Alzheimer's βA4‐amyloid protein precursor (APP) and the APP‐like proteins (APLPs) are transmembrane glycoproteins with a similar modular domain structure. APP exists in 8 isoforms generated by alternative splicing of exons 7, 8, and 15, of which the L‐APP mRNAs lacking exon 15 are ubiquitously expressed in rat tissues but not in neurons. Rat APLP2, the nearest relative of APP, is similarly expressed in 4 different isoforms due to alternative splicing of inserts encoding a Kunitz protease inhibitor domain (KPI, homologous to exon 7 of APP) and a divergent region of 12 amino acids on the NH2‐terminal side of the transmembrane domain (12 aa exon). KPI‐APLP2 transcripts are highly expressed in neurons, in contrast to KPI‐APPs, while L‐APLP2 mRNA isoforms lacking the 12 aa exon are predominantly expressed in non‐neuronal rat tissues, similar to L‐APPs. Further examination of the divergent domains in APP and APLP2 harboring the similarly alternatively spliced APP exon 15 and the 12 aa exon of APLP2 revealed some structural similarities of the amino acid sequences and the predicted secondary structures. In both L‐APLP2 and L‐APP, a putative xylosyl‐transferase recognition site for chondroitin sulfate glycosaminoglycan attachment is present that is interrupted in APP and APLP2 isoforms expressing APP exon 15 or the 12 aa exon of APLP2. Thus, a related function of the divergent domains and the corresponding alternatively spliced APP and APLP2 isoforms in regulation of the binding properties of the ectodomain is suggested. Additionally, β‐secretase cleavage of APP might be sterically hindered selectively in proteoglycan L‐APP but not in APP lacking the proteoglycan attachment site. Neurons which have a uniquely low portion of L‐APP and high content of APP might therefore be especially susceptible to βA4‐protein liberation. This could explain the selective vulnerability of neurons that is observed in Alzheimer's disease.
A Metric Approach to Control Flow Semantics
Authors: DE BAKKER J.W. , DE VINK E.P.
Published: December 2006

The authors' monograph “Control Flow Semantics” (MIT Press 1996) gives an extensive exposition of comparative programming language semantics using techniques from metric topology. In the book Banach's fixed‐point theorem for complete metric spaces plays a prominent role in the construction and comparison of semantical models. Here we present the basic idea of exploiting Banach's theorem. The approach is illustrated with the definition of an operational and a denotational model for an abstract programming language with parallelism.

Note: The work reported here is not novel, but intended to provide an introduction of the metric approach to programming language semantics for a nonspecialist audience.
IP* Sets in Product Spaces
Authors: BERGELSON VITALY , HINDMAN NEIL
Published: December 2006

An IP* set in a semigroup (S,·) is a set which meets every set of the form FP(〈xn〉∞n=1) = {∏nεFxn: F is a finite nonempty subset of ℕ}, where the products are taken in increasing order of indices. We show here, using the Stone‐Cech compactification of the product space S1×S2×…×Sℓ, that if each Si is commutative, then whenever C is an IP* set in S1×S2×…×Sℓ, and for each iε {1, 2, …, ℓ}, 〈xi,n〉∞n=1 is a sequence in Si, C contains Cartesian products of arbitrarily large finite substructures of FP(〈x1,nℓn=1〉) ×FP(〈x2,nℓn=1〉) ×…×FP(〈xℓ,nℓn=1〉). (The notion of “substructure” is made precise in Definition 2.4.) We show further that C need not contain any product of infinite substructures and that the commutativity hypothesis may not be omitted. Similar results apply to arbitrary finite products of semigroups. By way of contrast, we show in Theorem 2.3 that a much stronger conclusion holds for some cell of any finite partition of S1×S2×…×Sℓ, without even any commutativity assumptions.
Bi‐neighborhood Posets
Authors: PROKOP FRANK P.
Published: December 2006

Bi‐neighborhood (bi‐nbhd) lattices are a generaliization of bitopological spaces which use a natural duality that associates nbhd filters with dual nbhd ideals to view a lattice as a “top down” structure, in which points are unnecessary and which uses ideals to determine dual nbhds. This leads to a definition of dual continuous functions between dual neighborhood lattices. The link between dual nbhd continuity and topological (top) continuity is established by proving that if f: X → Y is a one‐to‐one and onto function between top spaces X and Y, then f is top continuous if and only if the direct image function is a dual nbhd continuous function mapping P(X), the power set of X, onto P(Y). In addition, bi‐nbhd lattices are used to generate examples of Urysohn collections and quasiproximities.
Metrizability of Asymmetric Spaces
Authors: SHORE S.D. , ROMAGUERA SALVADOR
Published: December 2006

Recent research has spawned an evolving application of non‐Hausdorff topologies [22] generated bynonsymmetricdistance functions to areas within mathematics (e.g., posets and continuous lattices [6]) as well as to allied areas that might seem remote (e.g., computer science ([24],[4],[16]) and biology [25]).

The study of nonsymmetric distance can be traced to the 1910 thesis of T.H. Hildebrandt [11], written at the University of Chicago under the direction of E.H. Moore. In a spirit parallelling that of Hildebrandt's, this paper undertakes a study of nonsymmetric distance for which an equivalent symmetric distance can be constructed. This illuminates situations in which an associatedmetricexists.

Of particular interest in our study are distances that are either locally symmetric or locally satisfy the triangle inequality. We recall Niemytzki's classical result [19] that a topological space is metrizable if, and only if, there is a semimetric for the space thatlocallysatisfies the triangle inequality. We investigate two forms in which a nonsymmetric distance might locally satisfy the triangle inequality. In either case, we show that such spaces are metrizable, when the distance islocallysymmetric. Although many of our results are known, the approach is particularly straightforward in providing an explicit construction of a distance with the desired properties.
Lines as Topological Graphsa
Authors: SMYTH M.B.
Published: December 2006

We present a unified theory of digital and continuous lines, arcs, etc., in terms of a (relatively) new notion of topological graph.
Characterization of the Club Forcing
Authors: ZAPLETAL JINDRICH
Published: December 2006

We provide an external characterization of the algebra RO(R), where R is Baumgartner's poset for adding a club with finite conditions. As a corollary, we show that many complete subalgebras of RO(R) must be isomorphic to either ℂR1 or RO(R).
IYOBA, THE QUEEN MOTHER OF BENIN
Authors: KAPLAN FLORA EDOUWAYE S.
Published: December 2006

Today, the 38th Oba of Benin, Omo N'Oba N'Edo Uku Akpolokpolo, is the traditional ruler of some 2 million Edo‐speaking peoples whose homelands are in southwestern Nigeria. A tropical forest kingdom, in medieval times it expanded to dominate other ethnic groups to the east beyond the Niger River, and to the west beyond Lagos. In 1897 a British military expedition ended five hundred years of indigenous and independent rule. Benin City, the Palace, and the Oba (restored to the throne in 1914) continued to be the focal points of the culture throughout the colonial period that lasted until 1960. As part of the Western Region, and later as capital of post colonial Midwest State, Benin City and the surrounding territory encompassed a number of ethnic groups. Within the boundaries of modern Edo State, Benin City is home to many Igbos, Yorubas, Etsakos, Itsekiris, Hausas, Europeans, and others. This pluralistic population in Benin City and elsewhere accommodates each other more easily than they did in the last century; friction nowadays is most often the outcome of new groups moving onto lands held by local villagers.

The Oba's Palace in the heart of Benin City, capital of Edo State, Federal Republic of Nigeria, occupies a site dated to the 13th century, and possibly dates to the 11th century (Connah 1975). Benin expanded in the early 16th century with the aid of Portuguese mercenaries and foreign guns. To the north and elsewhere over the centuries the Benin's warred with their neighbors and exacted tribute. Like their conquests, their fortunes ebbed and rose under different kings (obas) who ruled up to the end of the 19th century. The 1950s census reported Benin City's population at about 50,000. The 1990s national census reported a pluralistic population of some 200,000 people, showing the city's growth and continued diversity.
Analysis of Satellite Observations of Large Meteoroid Impacts
Authors: NEMTCHINOV I. V. , JACOBS C. , TAGLIAFERRI E.
Published: December 2006

ABSTRACT: Observations from high altitude (> 20,000 km) space‐based infrared and optical sensors which have detected over 200 bright flashes in the atmosphere since 1972 are interpreted in terms of geographical distribution, lightcurves, aerodynamic interaction of the fragments, and heat transfer and luminosity coefficients. The luminosity efficiency for meteorite explosive disintegration is estimated to be about 2 to 3 times smaller than for energetically equivalent nuclear explosions. Explanations for this difference are offered.
Space Debris Issue at the United Nationsa
Authors: LÁLA PETR
Published: December 2006

ABSTRACT: The space debris issue has been discussed by the United Nations Committee on the Peaceful Uses of Outer Space (COPUOS) for many years. In recognition of its importance, at the 1994 session of the Scientific and Technical Subcommittee of COPUOS, it became a separate agenda item. The Committee agreed that international cooperation is needed to evolve appropriate and affordable strategies to minimize the potential impact of space debris on future space missions. This paper summarizes discussions held during the last two sessions of the Subcommittee, including inter alia space debris measurement techniques, mathematical modelling of the debris environment, characterizing the space debris environment, and spacecraft design measures to protect against space debris. The focus of the 1995 session was on the subject of acquisition and understanding of data on the characteristics of the space debris environment, which is closely related to the observations of NEO.
Can Deposition of Amyloid Be Prevented in Alzheimer's Disease?a
Authors: KISILEVSKY ROBERT
Published: December 2006

ABSTRACT: Amyloid is a generic term referring to extracellular fibrillar protein deposits defined by their unique tinctorial, ultrastructural, and protein conformational properties. At least 17 different forms have been identified. In each form the deposit consists of a disease‐specific (or pathologic process–specific) protein and a set of common components. The disease‐specific protein serves as the basis for the classification of the amyloids. In inflammation‐associated (AA) amyloid it can be demonstrated that interactive processes between serum amyloid A (SAA), the AA precursor, and the common components, are likely responsible for AA amyloid deposition. Understanding the details of these interactions provide targets for therapeutic interference that are successful in vivo. Analogous interactions take place between the common components and the β‐protein and β‐protein precursor responsible for the congophilic angiopathy and neuritic plaque amyloid in Alzheimer's disease. Interference with β‐protein/common component interaction in vitro both prevents and reverses β‐protein fibril assembly, indicating that successful delivery of effective agents across the blood–brain barrier should prevent and possibly reverse amyloid deposition in Alzheimer's disease.
Coronary Artery Disease, Hypertension, ApoE, and Cholesterol: A Link to Alzheimer's Disease?
Authors: SPARKS D. LARRY
Published: December 2006

ABSTRACT: The premature presence of senile plaques (SP) in coronary artery disease (CAD), and neurofibrillary tangles (NFT) as well as SP in hypertension (HyperT), suggest a neuropathologic link between CAD, HyperT, and AD. Previous MI, CAD and HyperT often occur in and may increase the risk of AD. Expression of Apo‐E4 likely increases risk of CAD by elevating blood cholesterol and the risk of AD via proposed interactions with β‐amyloid and/or free radicals (FRs). Any Apo‐E4 effect is vague, but FRs probably mediate vascular damage in HyperT. Increasing FR content in the blood is related to increasing CAD severity, while the severity of elevated FR level correlates with how deep into a blood vessel there is activation of the FR scavenger enzyme, superoxide dismutase (SOD). The ApoE genotype and SP/NFT areal densities were determined in a large population of non‐demented CAD, HyperT and non‐heart disease (non‐HD) control subjects, and compared to findings in a similar number of AD patients. ApoE immunoreactivity was determined in many individuals. Cholesterol content in cortex was determined by HPLC in a small, loosely age‐matched group of Apo‐E4 genotype‐matched AD, CAD and non‐HD subjects. SOD immunoreactivity was also assessed in a number of subjects. The Apo‐E4 genotype frequency was increased in CAD, HyperT and AD compared to non‐HD controls. Dose of Apo‐E4 correlated with SP densities, but not NFT, and only in the non‐demented groups. Essentially all SP in CAD, HyperT and non‐HD subjects were ApoE‐immunoreactive. Cortical cholesterol was increased in CAD and AD compared to controls. SOD immunoreactivity was similar in HyperT and AD; SP were immunodecorated in both. AD, CAD and HyperT may be linked, while CAD and HyperT subjects may die of heart disease before showing cognitive change.
Combined Tacrine and Estrogen Replacement Therapy in Patients with Alzheimer's Diseasea,b
Authors: SCHNEIDER LON S. , FARLOW MARTIN
Published: December 2006

ABSTRACT: In light of evidence that estrogen replacement might affect cholinergic function, we examined possible effects of estrogen replacement therapy (ERT) on clinical response to the cholinesterase inhibitor tacrine in women with Alzheimer's disease (AD). In a previously reported 30‐week, randomized, double‐blind, placebo‐controlled, multicenter clinical trial, 14.5% of 318 women with evaluable data had been receiving ERT before randomization. They were randomly assigned to receive placebo or tacrine. Women receiving ERT who were randomized to tacrine improved more than women not receiving ERT who were randomized either to tacrine or to placebo as assessed by cognitive (p < 0.01) and clinical global (p= 0.02) tests. These results provide evidence that prior and continuing ERT may enhance response to tacrine in women with AD. Furthermore, among women on ERT receiving tacrine, there tended to be greater improvement relative to placebo among those without an APOE‐ɛ4 allele. Randomized trials are needed.
“Amyloid Is Not a Tombstone”— A Summation
Authors: REGELSON WILLIAM , HARKINS S. W.
Published: December 2006

ABSTRACT: This paper represents our summary interpretation of this symposium and provides our own suggestions as to cause and therapeutic approaches that could modulate the cerebrovascular and CSF dynamics that might reverse the pathology of Alzheimer's dementia.
Cancer Genetics in the New Era of Molecular Biology
Authors: LYNCH HENRY T. , FUSARO RAMON M. , LYNCH JANE F.
Published: December 2006

ABSTRACT: The role of primary genetic factors in the etiology of cancer has become of intense interest to the research and clinical community. This interest has been heightened by recent discoveries that germ‐line mutations such as BRCA1 and BRCA2 in hereditary breast cancer are responsible for an increasing percentage of common solid tumors. A potpourri of proto‐oncogenes and tumor‐suppressor genes has been identified in hereditary as well as certain common sporadic and rare cancer types, and new cancer genes will likely be discovered every month to account for the 5 to 10% of the cases of cancer that can be attributed to primary genetic factors.

Molecular mechanisms in the pathogenesis of hereditary cancer can result in more‐targeted cancer‐control measures. At least four mutator genes (MHS2, MLH1, PMS1 and PMS2) appear to account for 70–80% of hereditary nonpolypoid colorectal cancer (HNPCC). When one of these germ‐line mutations is present in an HNPCC family, the physician is then able to determine the patient's lifetime cancer destiny with an accuracy of about 90% (limited only by the penetrance of the gene). This will enable highly targeted surveillance to be initiated early, such as colonoscopy beginning at ages 20 to 25 or prophylactic subtotal colectomy. Also, in multiple endocrine neoplasia syndromes (MEN 2A and 2B), the identification of the culprit RET proto‐oncogene now enables a secure diagnosis and permits testing of children who might benefit from prophylactic total thyroidectomy.

Central to translation of these momentous molecular genetic discoveries into patient care is the necessity of determining who requires DNA testing. The cancer family history is the linchpin in making this decision.
Alterations in G1/S Cell‐Cycle Control Contributing to Carcinogenesis
Authors: KAELIN WILLIAM G.
Published: December 2006

ABSTRACT: Mutations involving the retinoblastoma tumor‐suppressor gene (RB‐1) have been described in a variety of human neoplasms. In addition, many tumors that retain a wild‐type RB‐1 allele harbor mutations that indirectly impair the function of the RB‐1 gene product (pRB). pRB is a nuclear protein that regulates cell‐cycle progression and, in at least certain tissues, differentiation. The former has been linked to its ability to form complexes with members of the E2F transcription factor family. E2F DNA‐binding sites have been identified in the regulatory regions of a number of genes involved in cell‐cycle progression. pRB‐E2F complexes actively repress transcription when bound to these sites. All tumor‐derived pRB mutants have lost the ability to bind to E2F. Conversely, activation of E2F‐responsive genes is sufficient to overcome a pRB‐induced cell‐cycle block and, in certain cell types, can lead to transformation. Thus, E2F appears to be a physiologically relevant target of pRB action, and deregulation of E2F‐responsive genes is a common, and possibly universal, step in human carcinogenesis.
The Ethic of Genetic Counseling and the Ethos of Managed Care
Authors: PARENS ERIK
Published: December 2006

ABSTRACT: This essay explores how the values at the heart of the ethic of genetic counseling are and are not congenial with the institutional habits of managed care. As integrated delivery systems with the resources to look at the big picture of the patient's health, managed care organizations (MCOs) can be very good at helping patients to look at the genetic parts of that picture. Genetic counseling aimed at truly informed consent is a crucial feature of looking at the genetic part of the picture. As such, there is a fundamental respect in which the ethic of genetic counseling and the ethos of managed care are congenial. But nondirective genetic counseling, which aims at truly informed consent, takes time and thus costs money. It will be tempting for some MCOs to balk at reimbursing the time‐ and skill‐intensive counseling called for by the ethic of genetic counseling. More generally, MCOs are committed to aggregating risks and benefits for populations. But genetic counselors are concerned solely with the needs and decisions of individuals. And whereas one of the main missions of MCOs is disease prevention, it is not for genetic counselors. Moreover, whereas MCOs derive much of their efficacy from sharing information among the parts of the organization, genetic counselors are committed to ensuring clients that their genetic information will remain private unless written consent is given. In principle it is possible that MCOs will provide genetic counseling much like that called for by professional genetic counselors. But to do so, MCOs will have to recognize and directly address the tensions between the ethos of managed care and the ethic of genetic counseling.
Neuropathology of Suicide
Authors: BACHUS SUSAN E. , HYDE THOMAS M. , AKIL MAYADA , WEICKERT CYNTHIA SHANNON , VAWTER MARQUIS P. , KLEINMAN JOEL E.
Published: December 2006

ABSTRACT: Neuropathology is one approach to the effort to elucidate the pathophysiology of suicide. Initial neurochemical studies focusing on the roles of serotonin (5‐HT) and noradrenaline (NE) abnormalities in brains of suicide victims have been somewhat inconsistent. More recently developed methodologies, including quantitative receptor autoradiography, immunoblotting, immunohistochemistry, cell morphometry, in situ hybridization, Northern analysis, solution hybridization/RNase protection assay, reverse transcriptase polymerase chain reaction, and genotyping, which have already been applied successfully in studies of other disorders of brain structure or function, are now increasingly being adopted for postmortem studies of suicide. These new strategies are adding convergent evidence for brain 5‐HT and NE dysfunction in the etiology of suicide susceptibility, refining the neuroanatomical localization of this dysfunction, and in addition, implicating heretofore unsuspected candidate neurotransmitter systems in the neuropathological substrates of suicide susceptibility. It is argued here that the confluence of the availability of suitable postmortem samples and this augmentation of our armamentarium of techniques promises the attainment of important new insights into the biological underpinings of suicide from postmortem research. It is to be hoped that this new knowledge might inspire novel inspire novel pharmacotherapeutic strategies for the prevention of suicide.
Neurobiology of Serotonin in Depression and Suicidea
Authors: STOCKMEIER CRAIG A.
Published: December 2006

ABSTRACT: Alternations in serotonin neurotransmission have been implicated in the pathophysiology of major depression and suicide. However, a clear picture of serotonergic abnormalities has not emerged from postmortem studies of depression and suicide. In suicide victims with major depression and psychiatrically normal control subjects, we have examined various indices of serotonergic neuro transmission in axonal projection areas such as prefrontal cortex and hippocampus, and cell bodies of origin within the dorsal raphe nucleus (DR).Although there were no significant differences between suicide victims with major depression and psychiatrically normal control subjects in serotonin‐1A or serotonin‐2A receptors in the right prefrontal cortex (area 10) or the hippocampus, there were region‐specific alternations in suicide victims with major depression in G‐proteininduced activation of the phosphoinsitide signal transduction system and in the levels of G‐protein alpha subunits involved in cyclic AMP synthesis. A pilot study examining the ventrolateral subnucleus of the DR (DRvl) reveals that serotonin‐1A receptors are increased in suicide victims with major depression as compared to normal control subjects. Altered signal transduction in cerebral cortex and altered regulation of serotonin neurons in the DR may be important in the pathophysiology of major depression and suicide.
Therapeutic Expression of an Anti-Death Receptor 5 Single-Chain Fixed-Variable Region Prevents Tumor Growth in Mice
Authors: Shi Juan , Liu Yanxin , Zheng Yong , Guo Yabin , Zhang Jinchun , Cheung Pik-to , Xu Ruian , Zheng Dexian
Published: December 2006

The clinical use of the single-chain fixed-variable (scFv) fragments of recombinant monoclonal antibodies as credible alternatives for classic therapeutic antibodies has two limitations: rapid blood clearance and inefficient local expression of functional molecules. In attempt to address these issues, we have developed a novel gene therapy protocol in which the anti-death receptor 5 (DR5) scFv fragments were either in vitro expressed in several tumor cell lines, or in vivo expressed in mice, using recombinant adeno-associated virus (rAAV)–mediated gene transfer. Viral transduction using the rAAV-S3C construct, which encodes a scFv molecule (S3C scFv) specific to DR5, led to stable expression in tumor cell lines and showed apoptosis-inducing activity in vitro, which could be inhibited by recombinant DR5 but not by DR4. A single i.m. injection of rAAV-S3C virus in nude mice resulted in stable expression of DR5-binding S3C scFv proteins in mouse sera for at least 240 days. Moreover, the expression of S3C scFv was associated with significant suppression of tumor growth and the increase of tumor cell apoptosis in previously established s.c. human lung LTEP-sml and liver Hep3B tumor xenografts. (Cancer Res 2006; 66(24): 11946-53)
Activation of DNA Methyltransferase 1 by EBV LMP1 Involves c-Jun NH2-Terminal Kinase Signaling
Authors: Tsai Chia-Lung , Li Hsin-Pai , Lu Yen-Jung , Hsueh Chuen , Liang Ying , Chen Chi-Long , Tsao Sai Wah , Tse Ka-Po , Yu Jau-Song , Chang Yu-Sun
Published: December 2006

EBV latent membrane protein 1 (LMP1) activates cellular DNA methyltransferases, resulting in hypermethylation and silencing of E-cadherin. However, the underlying mechanism remains to be elucidated. In this study, we show that LMP1 directly induces the dnmt1 promoter activity through its COOH-terminal activation region-2 YYD domain. Using (i) LMP1 mutants, (ii) dominant negative mutants c-jun NH2-terminal kinase (JNK)-DN, p38-DN, and constitutive active mutant IκB, as well as (iii) dsRNAs targeting c-Jun, JNK, and tumor necrosis factor receptor–associated death domain protein, and (iv) signal transduction inhibitors, we show that LMP1-mediated DNA methyltransferase-1 (DNMT1) activation involves JNK but not nuclear factor κB and p38/mitogen-activated protein kinase signaling. In addition, LMP1 is unable to activate dnmt1-P1 promoter with activator protein-1 (AP-1) site mutation. Chromatin immunoprecipitation assay results also confirm that LMP1 activates P1 promoter via the JNK-AP-1 pathway. Furthermore, chromatin immunoprecipitation assay data in LMP1-inducible cells disclose that LMP1 induces formation of a transcriptional repression complex, composed of DNMT1 and histone deacetylase, which locates on E-cadherin gene promoter. Treatment with JNK inhibitor, SP600125, prevents the formation of this repression complex. Statistical analyses of the immunohistochemical staining of 32 nasopharyngeal carcinoma (NPC) biopsies show LMP1 expression (18 of 32, 56.25%), DNMT1 expression (31 of 32, 97%), and phospho-c-Jun (27 of 32, 84.38%), suggesting that overexpression of these proteins is observed in NPC tumor. Overall, these results support a mechanistic link between JNK-AP-1 signaling and DNA methylation induced by the EBV oncogene product LMP1. (Cancer Res 2006; 66(24): 11668-76)