bluuebunny/crossref_metadata_2025 huggingface dataset:
Involvement of Non‐Neuronal Cells in Entorhinal‐Hippocampal Reorganization Following Lesions
Authors: BECHMANN INGO , NITSCH ROBERT
Published: July 2010

Abstract: Entorhinal lesion leads to anterograde degeneration of perforant path fibers in their main hippocampal termination zones. Subsequently, remaining fibers sprout and form new synapses on the denervated dendrites. This degeneration and reorganization is accompanied by sequential changes in glial morphology and function. Within a few hours following the lesion, amoeboid microglia migrate into the zone of denervation. Some hours later, signs of activation can be seen on astrocytes in the zone of denervation, where both cell types proliferate and remain in an activated state for more than two weeks. These activated glial cells might be involved in lesion‐induced plasticity in at least two ways: (1) by releasing cytokines and growth factors which regulate layer‐specific sprouting and (2) by phagocytosis of axonal debris, because myelin sheaths act as obstacles for sprouting fibers in the central nervous system. Whereas direct evidence for the former is still missing, the latter was investigated using phagocytosis‐dependent labeling techniques. Both microglial cells and astrocytes incorporate axonal debris. Phagocytosing microglial cells develop the immune phenotype of antigen‐presenting cells, whereas astrocytes strongly express FasL (CD95L), which induces apoptosis of activated lymphocytes. Thus, the interaction of glial cells with immune cells might be another, previously underestimated, aspect of reorganization following entorhinal lesion.
Hydrate Research‐From Correlations to a Knowledge‐based Discipline: The Importance of Structure
Authors: RIPMEESTER JOHN A.
Published: July 2010

Abstract: This contribution gives a short historical perspective on the development of fundamental knowledge about gas hydrates, and how such fundamental knowledge is important for a variety of problems related to hydrate prevention (pipelines), hydrate formation (CO2 sequestration), or hydrate decomposition (permafrost or marine natural gas hydrates). It is shown that early correlations derived from measurements on hydrates, many of which were made as early as the 1800s, could not be understood properly until around 1950 when X‐ray diffraction measurements gave a structural understanding of the materials we now know as clathrates, or host‐guest materials. In turn, this led to a statistical mechanical description and a thermodynamic model that has considerable predictive power. Recently, it has become apparent that there is considerable complexity and subtlety in the relationship between structure and the size of the hydrate formers once more than a single species is present. This emphasizes the need to obtain structural information together with thermodynamic measurements, especially in multicomponent systems. Such developments have encouraged the adoption of additional structural techniques such as NMR and vibrational spectroscopy. Current interest in hydrate formation and decomposition requires the adaptation and development of new approaches that allow the acquisition of time‐resolved structural information. Furthermore, an understanding of the morphology of hydrate crystals and how to modify this morphology, as well as understanding of interfacial properties, are all key to learning how to control hydrates. Although a great deal of progress has been made, much remains to be learned.
An Empirical Model of γ‐Secretase Activity
Authors: MURPHY M. P. , WANG R. , FRASER P. E. , FAUQ A. , GOLDE T. E.
Published: July 2010

Abstract: γ‐Secretase catalyzes the cleavage at the carboxyl terminus of Aβ to release it from the APP. While γ‐secretase is a major therapeutic drug target for the treatment of Alzheimer's disease (AD), it appears to be an unusual proteolytic activity, and, to date, no protease responsible for this activity has been identified. Based on studies of APP transmembrane domain (TMD) mutants, it is apparent that there are multiple pharmacologically distinct γ‐secretase activities that are spatially restricted and that presenilins (PS) regulate cleavage by γ‐secretases in a protease independent fashion. Based on these studies, we propose a multiprotease model for γ‐secretase activity and predict that the γ‐secretases are likely to be closely related proteases.
PACAP Peptides Modulate Guinea Pig Cardiac Neuron Membrane Excitability and Neuropeptide Expression
Authors: PARSONS RODNEY L. , ROSSIGNOL TODD M. , CALUPCA MICHELLE A. , HARDWICK JEAN C. , BRAAS KAREN M.
Published: July 2010

Abstract: Morphological studies identified PACAP‐immunoreactive nerve fibers in dense pericellular arrangements around virtually every cholinergic parasympathetic neuron of guinea pig cardiac ganglia; all postganglionic cardiac neurons expressed membrane‐associated PAC1 receptor protein. Characterization of the alternative splice variants established predominant expression of the PAC1 (very short) receptor transcript containing neither HIP nor HOP exons. PACAP depolarized cardiac neurons and increased membrane excitability; the excitability resulted from neither altered action potential properties nor inhibition of IM. Treatment of cardiac ganglia explants with PACAP significantly reduced the numbers of cholinergic neurons coexpressing somatostatin immunoreactivity, which did not appear to be correlated with prosomatostatin mRNA expression. The PACAP‐mediated decrease in somatostatin immunoreactive neurons required calcium influx through L‐type calcium channels and activation of adenylyl cyclase, whereas activation of phospholipase C or protein kinase A was not required. These observations indicate that PACAP through the PAC1 receptors elicits complex actions on guinea pig parasympathetic cardiac ganglia neurons, including modulation of membrane ion conductances and modulation of neuropeptide expression.
Role of PACAP1 Receptor in Regulation of ECL Cells and Gastric Acid Secretion by Pituitary Adenylate Cyclase Activating Peptide
Authors: PISEGNA JOSEPH R. , OHNING GORDON V. , ATHMANN CHRISTOPHE , ZENG NINGXIN , WALSH JOHN H. , SACHS GEORGE
Published: July 2010

Abstract: We previously reported that PAC1 is expressed on ECL cells resulting in stimulation of [Ca2+]i, histamine and acid secretion. The study reported here characterized the signaling by PAC1m on ECL cells; determined the effects of PACAP on the gastric acid secretion in vivo, and determined the effects of chronic administration of PACAP‐27 on ECL cell proliferation. PACAP‐27 dose dependently stimulated ECL cell Ca2+ and AC with detectable stimulation at 1 nM and maximal stimulation at 100 nM (six‐fold). In rats PACAP‐27 administration (10 pmol/kg/h) increased the rate of gastric acid secretion when an antisomatostatin antibody was co‐administered. Chronic administration of PACAP (10 pmol/h for seven days) via osmotic pump resulted in a more than twofold increase in BrdU incorporation into ECL cells. PACAP acting at the PAC1 results in dual signaling responses to both [Ca2+]i. AC in ECL cells stimulates gastric acid secretion via the actions of histamine acting at the parietal cell and in whole animals leads to proliferation of ECL cells when administered chronically.
DX‐8951f: Summary of Phase I Clinical Trials
Authors: DE JAGER R. , CHEVERTON P. , TAMANOI K. , COYLE J. , DUCHARME M. , SAKAMOTO N. , SATOMI M. , SUZUKI M. ,   THE DX‐8951F INVESTIGATORS
Published: July 2010

Abstract: Exatecan mesylate (DX‐8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT‐11, including watersolubility, greater potency against topoisomerase I, lack of esterase‐dependent activation, broad antitumor activity, and low cross‐resistance against MDR‐1 overexpressing tumors. In preclinical studies, the compound demonstrated a favorable toxicology profile with hematologic dose‐limiting toxicity and moderate gastrointestinal toxicity, linear pharmacokinetics, P450 hepatic metabolism (CYP3A4 and CYP1A2), and predominately fecal excretion. The results of six U.S. and European phase I clinical trials as well as two Japanese studies are presented including total DX‐8951 and lactone DX‐8951 pharmacokinetics. The toxicity profile was similar for all schedules of administration. Hematologic toxicity was dose‐dependent and reversible. Neutropenia was dose‐limiting in minimally pretreated patients, whereas neutropenia and thrombocytopenia were dose‐limiting in heavily pretreated patients. Non‐hematologic toxicity included moderate gastrointestinal toxicity (nausea, vomiting>diarrhea), transient elevation of hepatic transaminases, asthenia, and alopecia. Two cases of acute pancreatitis not predicted by preclinical toxicology were also observed. Antineoplastic activity was detected in several solid tumor types: non‐small cell lung cancer, extrapulmonary small cell cancer, colorectal cancer, hepatocellular cancer, and sarcoma. Antitumor activity was seen in CPT‐11 and topotecan‐resistant tumors. Pharmacokinetics were linear within the dose range tested. A pharmacokinetic/pharmacodynamic model predictive of DX‐8951f‐induced neutropenia in individual patients was developed. The daily ×5, every 3‐week schedule with the drug administered as a 30‐minute intravenous infusion was selected for future phase II clinical trials based on its superior antitumor activity.
The Argument from Design
Authors: CASE‐WINTERS ANNA
Published: July 2010

Abstract: This article offers a brief overview of the argument for God's existence grounded in the evidence of design. It pays particular attention to the way the argument has evolved over time and in relation to changing scientific perspectives. The argument from design has in fact been formulated and reformulated in response to the discoveries and challenges it has encountered from the field of science. The conclusion of the article explores the theological importance of this argument with respect to its extent and its limits
Nature, Nurture, and the Disunity of Knowledge
Authors: Meaney Michael J.
Published: July 2010

Abstract: The Human Genome Project and the tools of modern molecular biology bring enormous promise for the understanding of human biology. Juxtaposed, however, is a conceptual stagnation reflected in the continued nature/nurture debate. More sophisticated models reflecting the inevitable interdependence of gene and environment are essential if we are to realize the potential offered by today's technological advances.
Regulation of Hemangioblast Development
Authors: LACAUD GEORGES , ROBERTSON SCOTT , PALIS JAMES , KENNEDY MARION , KELLER GORDON
Published: July 2010

Abstract: The in vitro differentiation of embryonic stem (ES) cells provides a powerful approach for studying the earliest events involved in the commitment of the hematopoietic and endothelial lineages. Using this model system, we have identified a precursor with the potential to generate both primitive and definitive hematopoietic cells as well as cells with endothelial characteristics. The developmental potential of this precursor suggests that it represents the in vitro equivalent of the hemangioblast, a common stem cell for both lineages. ES cells deficient for the transcription factor scl/tal‐1 are unable to generate hemangioblasts, while those deficient for Runx1 generate reduced numbers of these precursors. These findings indicate that both genes play pivotal roles at the earliest stages of hematopoietic and endothelial development. In addition, they highlight the strength of this model system in studying the function of genes in embryonic development.
Antiapoptotic Properties of Rasagiline, N‐Propargylamine‐1(R)‐aminoindan, and Its Optical (S)‐Isomer, TV1022
Authors: MARUYAMA WAKAKO , YOUDIM MOUSSA B.H. , NAOI MAKOTO
Published: July 2010

Abstract: Rasagiline and structurally related propargylamines protected dopaminergic SH‐SY5Y cells from apoptosis induced by 6‐OHDA and peroxynitrite‐generating SIN‐1. It was suggested that the intracellular mechanism of the neuroprotection is related to the stabilization of mitochondrial membrane potential, as indicated by use of a fluorescent indicator, JC‐1. The opening of the permeability transition pore (PTP) was prevented by rasagiline, even in isolated mitochondria. The activation of apoptotic cascade by the oxidative stress and neurotoxins, such as activation of caspase 3 and DNA fragmentation, was also inhibited by pretreatment with rasagiline. These propargylamines may prevent or rescue declining neurons induced by mitochondrial apoptotic cascade and may be applicable as “neuroprotective agents” in aging and age‐related neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases.
ENaC Subunits Are Molecular Components of the Arterial Baroreceptor Complex
Authors: DRUMMOND HEATHER A. , WELSH MICHAEL J. , ABBOUD FRANÇOIS M.
Published: July 2010

Abstract: Mechanosensation is essential to the perception of our environment. It is required for hearing, touch, balance, proprioception, and blood pressure homeostasis. Yet little is known about the identity of ion‐channel complexes that transduce mechanical stimuli into neuronal responses. Genetic studies in Caenorhabditis elegans suggest that members of the DEG/ENaC family may be mechanosensors. Therefore we tested the hypothesis that mammalian epithelial Na+‐channel (ENaC) subunits contribute to the mechanosensor in baroreceptor neurons. The data presented here show that ENaC transcripts and proteins are expressed in mechanosensory neurons and at the putative sites of mechanotransduction in baroreceptor sensory‐nerve terminals. Additionally, known ENaC inhibitors, amiloride and benzamil, disrupt mechanotransduction in arterial baroreceptor neurons. These data are consistent with the hypothesis that DEG/ENaC proteins are components of mechanosensitive ion‐channel complexes.
Cardiorespiratory Interactions in Neural Circulatory Control in Humans
Authors: SHAMSUZZAMAN ABU S. M. , SOMERS VIREND K.
Published: July 2010

Abstract: The reflex mechanisms and interactions described in this overview provide some explanation for the range of neural circulatory responses evident during changes in breathing. The effects described represent the integrated responses to activation of several reflex mechanisms, including peripheral and central chemoreflexes, arterial baroreflexes, pulmonary stretch receptors, and ventricular mechanoreceptors. These interactions occur on a dynamic basis and the transfer characteristics of any single interaction are, in all likelihood, also highly dynamic. Nevertheless, it is only by attempting to understand individual reflexes and their modulating influences that a more thorough understanding of the responses to complex phenomena such as hyperventilation, apnea, and obstructive sleep apnea can be better understood.
Analysis of Clonality in Cutaneous T Cell Lymphoma and Associated Diseases
Authors: WOODY GARY S.
Published: July 2010

Abstract: The T cell receptor (TCR) is the antigen‐specific receptor for T cells. During its differentiation, each T cell undergoes rearrangement of its TCR genes. This results in novel nucleotide sequences that constitute a unique signature or fingerprint for each T cell and all its clonal progeny. Analysis of TCR gene rearrangements in cutaneous T cell lymphoma (CTCL) has lead to several findings concerning CTCL tumor biology. First, like most other lymphomas, CTCL is a monoclonal lymphoproliferative disorder. Second, rather than being truly a cutaneous lymphoma, CTCL is actually a lymphoma of the skin‐associated lymphoid tissue (SALT). Even when disease appears confined to the skin clinically, there can be low‐level trafficking of tumor cells through the peripheral lymph nodes via the lymphatics and blood vessels. Furthermore, CTCL is a mature SALT lymphoma capable of trafficking to sites of cutaneous inflammation analogous to normal SALT T cells. Third, the earliest manifestation of CTCL may be “clonal dermatitis.” This is a form of chronic dermatitis that harbors a dominant T cell clone but lacks histologic features diagnostic for CTCL. About 25% of clonal dermatitis cases progress to overt CTCL within five years. Fourth, other lymphoproliferative disorders that are associated with CTCL share the same TCR gene rearrangements and therefore arise as subclones of the original tumor. These include lymphomatoid papulosis, large‐cell lymphoma, and Hodgkin's disease.
Human Experience with Canalith Repositioning Maneuvers
Authors: EPLEY JOHN M.
Published: July 2010

Abstract: Three distinct pathological conditions, related to different means by which dense intralabyrinthine particles interfere with the function of a semicircular canal and cause nystagmus and vertigo, are amenable to treatment with repositioning maneuvers. Known as benign paroxysmal positional vertigo and variants, these conditions are better designated collectively by the term “vestibular lithiasis.” Each form requires a different treatment strategy of head maneuvers and application of other modalities to restore normal semicircular function and thereby eliminate the positional nystagmus and vertigo. Real‐time observation of the nystagmus induced by the particles during the maneuvers can greatly facilitate the repositioning process.
Endocrine and Paracrine Regulation of Endometrial Angiogenesis
Authors: TAYLOR ROBERT N. , LEBOVIC DAN I. , HORNUNG DANIELA , MUELLER MICHAEL D.
Published: July 2010

The human endometrium is a complex tissue comprised of different cell types, including epithelial, stromal, inflammatory, perivascular, and blood vessel cells. The hormonal receptivity and distribution of these cell populations change during the menstrual cycle. Cyclical endometrial growth is dependent on its ability to regenerate a vascular capillary network, which grows in parallel with the proliferation and differentiation of the endometrial lining. Natural hormonal effects on the endometrium and endocrine manipulation of this tissue, in response to the use of exogenous steroid therapies, can affect endometrial capillary proliferation and function, leading to clinical abnormalities of uterine bleeding. We propose that the regulation of endometrial angiogenesis is mediated indirectly via complex interactions among cell types. Our laboratory has focused on a prototypical member of the angiogenic proteins, vascular endothelial growth factor (VEGF)‐A. In this paper we present data demonstrating that VEGF‐A expression in normal endometrial epithelial and stromal cells and in Ishikawa adenocarcinoma cells is increased by an ovarian steroid, estradiol. Infiltrating immune cells, particularly polymorphonuclear granulocytes, also are sources of VEGF‐A. In inflammatory conditions involving the endometrium (e.g., endometriosis), a proinflammatory cytokine, IL‐1β, can mediate neoangiogenesis by inducing VEGF‐A gene transcription. Thus, endometrial vascularization is effected by both endocrine and paracrine pathways.
Cell Biology of Vascular Endothelial Cells
Authors: NISHIKAWA SHIN‐ICHI , HIRASHIMA MASANORI , NISHIKAWA SATOMI , OGAWA MINETARO
Published: July 2010

Abstract: The number of molecules identified as being involved in the development of the vascular system has been increasing recently. Among those are secretory molecules and their receptors that collaborate in concert to regulate the process. Of note, however, is that we know little about the response of normal endothelial cells to different stimuli. In this study, we established a method of producing a normal endothelial population from embryonic stem cells. This new culture system was used to analyze the behavior of endothelial cells to various angiogenic stimuli. Our study demonstrated clearly that this culture system is extremely useful in revealing the behavior of developing endothelial cells. Implications derived from our observations are discussed.
Role of Chemokine SDF‐1/PBSF and Its Receptor CXCR4 in Blood Vessel Development
Authors: NAGASAWA TAKASHI
Published: July 2010

Abstract: Chemokines are a family of small, structurally related molecules that regulate cell trafficking. We isolated a chemokine, stromal cell‐derived factor/pre‐B cell growth‐stimulating factor (SDF‐1/PBSF), as a molecule that stimulates the growth of B lymphocyte precursors and then found its multiple physiological functions in development. SDF‐1/PBSF is essential for embryonic viability, B lymphopoiesis, bone marrow myelopoiesis, and cardiogenesis. Moreover, a primary physiologic receptor for SDF‐1/PBSF is a seven‐transmembrane G‐protein‐coupled receptor, CXCR4, that also functions as a coreceptor for strains of HIV‐1. In recent years, we have shown that SDF‐1/PBSF and CXCR4 chemokine ligand receptor system is required for vascularization of the gastrointestinal tract by analyzing mice deficient in these molecules, thus defining a new signaling system for organ vascularization during embryogenesis.
Annexin II
Authors: BROWNSTEIN CARRIE , FALCONE DOMENICK J. , JACOVINA ANDREW , HAJJAR KATHERINE A.
Published: July 2010

Abstract: It has become increasingly evident that the generation of cell surface proteases including plasmin is fundamental to a wide variety of in vivo biological processes. Cell surface receptors allow for specific controlled proteolysis, provide protection from inhibitors, and enhance catalytic efficiency. Here we describe one such receptor, annexin II, which serves as a coreceptor for tissue plasminogen activator and plasminogen and is found on a wide variety of cell types including endothelial cells, some tumor cells, monocytes and macrophages, and neuronal cells. Evidence indicates that annexin II may be crucial to the efficient generation of cell surface plasmin, endothelial cell formation of new blood vessels, and maintenance of vascular patency. Additionally, it has been shown that annexin II expression in acute promyelocytic leukemia contributes to the bleeding diathesis seen in this disease and that inhibition of annexin II may be an important mechanism in the formation of atherosclerotic plaque. Furthermore, emerging evidence reveals the importance of annexin II on the surface of monocytes and macrophages, where it may contribute to the cells' ability to degrade extracellular matrix proteins and migrate to sites of injury or inflammation.
Role of Oxidized LDL in Atherosclerosis
Authors: KITA TORU , KUME NORIAKI , MINAMI MANABU , HAYASHIDA KAZUTAKA , MURAYAMA TOSHINORI , SANO HIDETO , MORIWAKI HIDEAKI , KATAOKA HIROSHI , NISHI EIICHIRO , HORIUCHI HISANORI , ARAI HIDENORI , YOKODE MASAYUKI
Published: July 2010

Abstract: A critical event in the early stages of atherosclerosis is the focal accumulation of lipid‐laden foam cells derived from macrophages. In various cholesterol‐fed animal models of atherosclerosis, localized attachment of circulating monocytes to arterial endothelial cells appeared to precede the formation of foam cells. It is suggested that monocyte recruitment into early lesions depends on the endothelial adhesiveness for monocytes and lymphocytes. In vivo and in vitro experiments have identified molecules, such as ICAM‐1, VCAM‐1, and P‐selectin, that can support the adhesion of monocytes and lymphocytes. Moreover, oxidized LDL, lysophosphatidyl‐choline, and oxidized fatty acids induce the expression not only of these adhesion molecules but also of scavenger receptors, such as CD‐36, SR‐A, and LOX‐1. Recently, we isolated and characterized the novel receptors for oxidized LDL, namely, LOX‐1 and SR‐PSOX. Expression of LOX‐1 is found on endothelial cells, smooth muscle cells, and macrophages, whereas SR‐PSOX is expressed on macrophages. In this paper the significance of oxidized LDL and its receptors, LOX‐1 and SR‐PSOX, in terms of atherogenesis is discussed.
Ligation of CD40 on Vascular Smooth Muscle Cells Mediates Loss of Interstitial Collagen via Matrix Metalloproteinase Activity
Authors: HORTON DANIEL B. , LIBBY PETER , SCHÖNBECK UWE
Published: July 2010

Abstract: Interstitial collagen constitutes the predominant structural component of the fibrous cap of atherosclerotic plaque. The balance between synthesis and degradation of this extracellular matrix protein probably determines plaque stability and hence the tendency for plaque rupture. The CD40/CD40L signaling dyad has been implicated as an important regulatory pathway of collagen‐degrading activity in atherosclerosis via the induction of matrix metalloproteinases (MMPs). However, the role of CD40 signaling in the synthesis of interstitial collagen and thus in the overall rate of collagen turnover has remained unknown. We demonstrate here that CD40 ligation on cultured human vascular smooth muscle cells (SMCs) diminishes the detectable content of de novo synthesized interstitial procollagens. Notably, the loss of collagen is not accompanied by a reduction in collagen transcript expression but can be prevented by MMP inhibition. These data demonstrate that CD40 signaling in human vascular SMC shifts interstitial collagen turnover towards the loss of this extracellular matrix protein by accelerating its degradation without concomitantly diminishing its synthesis. Thus, CD40/CD40L interactions might play a key role in rendering atheromatous lesions prone to rupture.
CD36, a Member of Class B Scavenger Receptor Family, Is a Receptor for Advanced Glycation End Products
Authors: OHGAMI NOBUTAKA , NAGAI RYOJI , IKEMOTO MAMORU , ARAI HIROYUKI , KUNIYASU AKIHIKO , HORIUCHI SEIKOH , NAKAYAMAA HITOSHI
Published: July 2010

Abstract: Interaction of advanced glycation end products (AGE) with AGE‐receptors induces several cellular phenomena relating potentially to diabetic complications. Five AGE‐receptors identified so far are RAGE (receptor for AGE), 80 K‐H, OST‐48, galectin‐3, and SR‐A (macrophage scavenger receptor type I and II). Since SR‐A belongs to the class A scavenger receptor family and the scavenger receptor collectively represents a family of multiligand lipoprotein receptors, it is possible that CD36 belonging to the class B scavenger receptor family (SR‐B) can recognize AGE‐proteins as a ligand. This was tested in the present study at the cellular level using CHO (Chinese hamster ovary) cells overexpressing human CD36 (CHO‐CD36 cells). 125I‐AGE‐BSA (bovine serum albumin) was endocytosed in a dose‐dependent fashion and underwent lysosomal degradation by CHO‐CD36 but not wild‐type CHO cells. Endocytic uptake of 125I‐AGE‐BSA by these cells was inhibited 50% by oxidized LDL (Ox‐LDL) and 60% by FA6‐152, an anti‐CD36 antibody inhibiting cellular binding of Ox‐LDL. Our results indicate that CD36 expressed by these cells mediates endocytic uptake and subsequent intracellular degradation of AGE‐proteins. Because CD36 is one of the major Ox‐LDL receptors and is upregulated in macrophage‐ and smooth muscle cell‐derived foam cells in human atherosclerotic lesions, the present results suggest that, like Ox‐LDL, AGE‐proteins generated in situ are recognized by CD36, which might contribute to the pathogenesis of diabetic macrovascular complications.
Differential Signaling for MCP‐1‐Dependent Integrin Activation and Chemotaxis
Authors: ASHIDA NOBORU , ARAI HIDENORI , YAMASAKI MASAHIDE , KITA TORU
Published: July 2010

Abstract: Transmigration of monocytes to the subendothelial space is the initial step in atherosclerotic plaque formation and inflammation. Integrin activation and chemotaxis are two important functions in monocyte transmigration. To delineate the signaling cascades leading to integrin activation and chemotaxis by monocyte chemoattractant protein‐1 (MCP‐1), we investigated the roles of MAPK in THP‐1 cells, a monocytic cell line. MCP‐1 stimulated β1 integrin‐dependent, but not β2 integrin‐dependent cell adhesion in a time‐dependent manner. MCP‐1‐mediated cell adhesion was inhibited by a MEK inhibitor, but not by a p38‐MAPK inhibitor. By contrast, MCP‐1‐mediated chemotaxis was inhibited by the p38‐MAPK inhibitor, but not by the MEK inhibitor. These data indicate that ERK is responsible for integrin activation and that p38‐MAPK is responsible for chemotaxis mediated by MCP‐1. This study demonstrates that two distinct MAPKs regulate two dependent signaling cascades, leading to integrin activation and chemotaxis induced by MCP‐1 in THP‐1 cells.
Molecular Mechanisms of Morning Onset of Myocardial Infarction
Authors: MAEMURA KOJI , LAYNE MATTHEW D. , WATANABE MASAFUMI , PERRELL MARK A. , NAGAI RYOZO , LEE MU‐EN
Published: July 2010

Abstract: We recently isolated a novel bHLH/PAS protein, CLIF (cycle like factor), by yeast two‐hybrid screening of human umbilical endothelial cell cDNA library. CLIF is preferentially expressed in endothelial and neuronal cells. Because CLIF is expressed in vascular endothelial cells and forms a heterodimer with CLOCK, the key transcription factor controlling the circadian rhythm, we hypothesized that CLIF regulates the circadian oscillation of PAI‐1 gene expression in endothelial cells. Northern blot analysis of mouse organs showed circadian oscillations of PAI‐1 mRNA levels. In addition, the clock‐related genes also showed circadian oscillation in peripheral tissues. In endothelial cells, the heterodimer of CLIF and CLOCK upregulated the PAI‐1 gene expression through E‐box sites. Furthermore, Period and Cryptochrome, which are negative regulators in the feedback loop of the biological clock, inhibited PAI‐1 promoter activation by the CLOCK:CLIF heterodimer. These results suggest that the peripheral tissues have their own biological clock and CLIF regulates the circadian oscillation of PAI‐1 gene expression in endothelial cells. This study suggests a novel molecular mechanism of the morning onset of myocardial infarction. Here we review our recent work and literature.
Catalytic Oligonucleotides Targeting EGR‐1 As Potential Inhibitors of In‐Stent Restenosis
Authors: KHACHIGIAN LEVON M.
Published: July 2010

Abstract: This brief review discusses recent strategies targeting the zinc finger transcription factor and immediate‐early gene product Egr‐1 with catalytic DNA in efforts to inhibit postangioplasty restenosis.
An in vivo/in vitro Model to Assess Endocrine Disrupting Activity of Xenoestrogens in Uterine Leiomyoma
Authors: HODGES LESLIE C. , HUNTER DEBORAH S. , BERGERSON JILL S. , FUCHS‐YOUNG ROBIN , WALKER CHERYL L.
Published: July 2010

Abstract: Xenoestrogens with endocrine disrupting activity have been associated with the dysregulation of reproductive function and promotion of malignancies in experimental animals and human populations. The high incidence of uterine leiomyomas, a benign estrogen‐responsive neoplasm of the uterine myometrium, calls into question the potential influence of xenoestrogens in the pathogenesis of these tumors. An in vivo/in vitro animal model, the Eker rat, that can be used to assess the estrogen‐like agonist activity of potential endocrine disruptors in the uterine myometrium is discussed. Using this model, several in vitro assays are developed that demonstrate that compounds from three major classes of xenoestrogens can mimic the effect of estrogen on leiomyoma cells and act as estrogen receptor (ER) agonists: phytoestrogens, organochlorine pesticides and pharmacologic agents. These compounds can stimulate transcription via the ER and upregulate the expression of an estrogen‐responsive gene in uterine leiomyoma cells. The use of these in vitro assays has also advanced our ability to predict the agonist activity of potential therapeutic agents in the uterine myometrium. Selective estrogen receptor modulators (SERMs), while able to act as agonists in some tissues such as the bone and uterine endometrium, act as antagonists in vivo in the uterine myometrium and in our in vitro assays. This antagonist activity in the uterine myometrium suggests that SERMs may be useful in the treatment of uterine leiomyoma.
Effects of Estrogen and Selective Estrogen Receptor Modulators on Hemostasis and Inflammation
Authors: CUSHMAN MARY
Published: July 2010

Abstract: Postmenopausal hormone replacement therapy (HRT), tamoxifen, and raloxifene all share an increase of about three‐fold in the risk of venous thromboembolism (VTE). Currently, it is thought that HRT transiently increases the risk of myocardial infarction (MI), followed by subsequent reduction in risk, at least among women with established coronary heart disease. Raloxifene and tamoxifen are not known to share this apparent clinical effect. Study of hemostasis and inflammation factors, as surrogate end points, can be useful to form hypotheses concerning the pathophysiology related to clinical effects of these agents. Data presented here suggest differences among these agents that might relate to differences in clinical outcomes. From the vascular perspective, future studies need to focus on interactions of treatment with these biochemical parameters and their genetic correlates in order to define low‐ or high‐risk subgroups for intervention with these therapies.
Benefit/Risk Assessment of SERM Therapy
Authors: COSTANTINO JOSEPH P.
Published: July 2010

Abstract: Benefit/risk assessment (B/rA) can be used in a variety of circumstances encompassing clinical practice and research settings. Subsequent to the reporting of the results from the Breast Cancer Prevention Trial (BCPT), methodology was developed to perform B/rA for the use of the selected estrogen receptor modulator (SERM), tamoxifen. Although the methodology was specifically developed and applied to the use of tamoxifen, it is a generalized procedure that can be readily modified and applied to other forms of therapy including other SERMs. Recently, the methodology has been incorporated into the Study of Tamoxifen and Raloxifene (STAR) trial, a randomized clinical trial designed to compare the chemopreventive effects of two SERMs—tamoxifen and raloxifene. The B/rA of SERMs is complex because SERMs are known to exhibit properties that can reduce or increase the incidence of several health outcomes. This paper summarizes the uses of B/rA in the clinical practice and clinical trial settings and describes the constraints of the methodology as it is being applied to the assessment of therapy with SERMs.
Defining Benefits and Risks for SERMs in Clinical Trials and Clinical Practice
Authors: JOHNSON SUSAN R. , DUNN BARBARA K. , ANTHONY MARIETTA
Published: July 2010

Abstract: Differences between clinical trials and clinical practice with respect to defining benefits and benefit/risk ratios for SERMs are discussed. These differences stem from the perception that there is discordance between the statistical significance and the “clinical meaningfulness” of research data in the minds of the practitioner and patient. One way that we can obtain data that are more clinically meaningful is to solicit input in the planning stages of clinical trials from practicing community clinicians and their patients. However, there are drawbacks to community input, such as potentially unrealistic expectations. A further issue is the need to characterize clinically meaningful drug benefits and acceptable benefit/risk ratios for a drug. Individual patients have differences regarding their views of optimal benefits and acceptable risks, so a method or tool for determining what is clinically meaningful would be helpful in presenting comprehensive information to the patient. To present useful information to clinicians, head‐to‐head comparisons of a new drug with a standard agent should be undertaken. NIH's support in this area of comparator trials is critical to their implementation. Estrogen has been considered the standard for comparison of agents for conditions associated with menopause in clinical trials. Estrogen has been the “gold standard” in clinical practice as well. In fact, challenging the position of estrogen, even where scientifically supported, has proven to be an uphill battle. In the practice setting, we elaborate the challenges of keeping up with the scientific literature and of then communicating this information in a fashion that is relevant to the individual patient.
The Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute
Authors: ANSHER SHERRY S. , SCHARF RAMI
Published: July 2010

Abstract: The mission of the Cancer Therapy Evaluation Program (CTEP), a clinical research program of the National Cancer Institute (NCI), is to reduce the burden of cancer. CTEP plans, reviews, and coordinates clinical trials for investigational anticancer agents, from the inception of protocols through the preparation and submission of Investigational New Drug Applications (INDs) to the Food and Drug Administration (FDA). CTEP also serves as a liaison to the FDA for the extramural clinical research community and industry collaborators. Other CTEP functions include managing, tracking, and reviewing clinical protocols as well as monitoring, planning, and maintaining regulatory compliance of the clinical trials. In addition, CTEP coordinates the distribution of the investigational agents from industry collaborators for use in all NCI‐sponsored clinical trials. The advantages of collaborating with CTEP are described as well as details about the contractual framework, either a Clinical Trials Agreement (CTA) or a Cooperative Research and Development Agreement (CRADA), for such a collaboration. Many of the concerns raised by industry collaborators with respect to intellectual property, data access, and publications are also addressed.
Nonlinear Gravitational Growth Inside and Outside the Standard Cosmology
Authors: Gaztañaga E. , Lobo J. A.
Published: July 2010

Abstract: We reconsider the problem of nonlinear structure formation inside and outside General Relativity (GR), both in the weakly and strongly nonlinear regime. We show how these regimes can be explored observationally through clustering of high‐order cumulants and through the epoch of formation, abundance and clustering of collapse structures, using Press and Schechter (1974, Astrophys. J. 187: 425‐438) formalism and its extensions.
Emergence of Anomalous Distributions in Disordered Systems
Authors: Muttalib K. A. , Wölfle P.
Published: July 2010

Abstract: The present day non‐gaussian distribution of mass density of the universe evolved from an initial gaussian distribution in the presence of nonlinear interactions. We discuss an analog in disordered condensed matter system where increasing the disorder changes the distribution of conductances from a gaussian at weak disorder to a log‐normal at strong disorder. The highly asymmetric “one‐sided” log‐normal distribution in the intermediate crossover regime can be understood as a simple hybrid of these two limiting distributions.
Protein Oxidation in Aging and Age‐Related Diseases
Authors: Stadtman Earl R.
Published: July 2010

Abstract: Although different theories have been proposed to explain the aging process, it is generally agreed that there is a correlation between aging and the accumulation of oxidatively damaged proteins, lipids, and nucleic acids. Oxidatively modified proteins have been shown to increase as a function of age. Studies reveal an age‐related increase in the level of protein carbonyl content, oxidized methionine, protein hydrophobicity, and cross‐linked and glycated proteins as well as the accumulation of less active enzymes that are more susceptible to heat inactivation and proteolytic degredation. Factors that decelerate protein oxidation also increase the life span of animals and vice versa. Furthermore, a number of age‐related diseases have been shown to be associated with elevated levels of oxidatively modified proteins. The chemistry of reactive oxygen species‐mediated protein modification will be discussed. The accumulation of oxidatively modified proteins may reflect deficiencies in one or more parameters of a complex function that maintains a delicate balance between the presence of a multiplicity of prooxidants, antioxidants, and repair, replacement, or elimination of biologically damaged proteins.
Caloric Restriction in Primates and Relevance to Humans
Authors: Roth George S. , Ingram Donald K. , Lane Mark A.
Published: July 2010

Abstract: Dietary caloric restriction (CR) is the only intervention conclusively and reproducibly shown to slow aging and maintain health and vitality in mammals. Although this paradigm has been known for over 60 years, its precise biological mechanisms and applicability to humans remain unknown. We began addressing the latter question in 1987 with the first controlled study of CR in primates (rhesus and squirrel monkeys, which are evolutionarily much closer to humans than the rodents most frequently employed in CR studies). To date, our results strongly suggest that the same beneficial “antiaging” and/or “antidisease” effects observed in CR rodents also occur in primates. These include lower plasma insulin levels and greater sensitivity; lower body temperatures; reduced cholesterol, triglycerides, blood pressure, and arterial stiffness; elevated HDL; and slower age‐related decline in circulating levels of DHEAS. Collectively, these biomarkers suggest that CR primates will be less likely to incur diabetes, cardiovascular problems, and other age‐related diseases and may in fact be aging more slowly than fully fed counterparts.

Despite these very encouraging results, it is unlikely that most humans would be willing to maintain a 30% reduced diet for the bulk of their adult life span, even if it meant more healthy years. For this reason, we have begun to explore CR mimetics, agents that might elicit the same beneficial effects as CR, without the necessity of dieting. Our initial studies have focused on 2‐deoxyglucose (2DG), a sugar analogue with a limited metabolism that actually reduces glucose/energy flux without decreasing food intake in rats. In a six‐month pilot study, 2DG lowered plasma insulin and body temperature in a manner analagous to that of CR. Thus, metabolic effects that mediate the CR mechanism can be attained pharmacologically. Doses were titrated to eliminate toxicity; a long‐term longevity study is now under way. In addition, data from other laboratories suggest that at least some of the same physiological/metabolic end points that are associated with the beneficial effects of underfeeding may be obtained from other potential CR mimetic agents, some naturally occurring in food products. Much work remains to be done, but taken together, our successful results with CR in primates and 2DG administration to rats suggest that it may indeed be possible to obtain the health‐ and longevity‐promoting effects of the former intervention without actually decreasing food intake.
Consciousness and the Brain
Authors: LLINÁS RODOLFO , RIBARY URS
Published: July 2010

Abstract: The goal of this paper is to explore the basic assumption that large‐scale, temporal coincidence of specific and nonspecific thalamic activity generates the functional states that characterize human cognition.
The Quest for Universals in Temporal Processing in Music
Authors: DRAKE CAROLYN , BERTRAND DAISY
Published: July 2010

Abstract: Music perception and performance rely heavily on temporal processing: for instance, each event must be situated in time in relation to surrounding events, and events must be grouped together in order to overcome memory constraints. The temporal structure of music varies considerably from one culture to another, and so it has often been supposed that the specific implementation of perceptual and cognitive temporal processes will differ as a function of an individual's cultural exposure and experience. In this paper we examine the alternative position that some temporal processes may be universal, in the sense that they function in a similar manner irrespective of an individual's cultural exposure and experience. We first review rhythm perception and production studies carried out with adult musicians, adult nonmusicians, children, and infants in order to identify temporal processes that appear to function in a similar fashion irrespective of age, acculturation, and musical training. This review leads to the identification of five temporal processes that we submit as candidates for the status of “temporal universals.” For each process, we select the simplest and most representative experimental paradigm that has been used to date. This leads to a research proposal for future intercultural studies that could test the universal nature of these processes.
Music and the Neurologist
Authors: BRUST JOHN C. M.
Published: July 2010

Abstract: Neurological disorders affecting musical function can produce either positive or negative symptoms. Positive phenomena include musicogenic epilepsy (seizures triggered by music), musical partial seizures (hallucinated music as the expression of the seizure), musical release hallucinations (nonepileptic musical hallucinations, usually associated with impaired hearing), and synesthesia (hallucinated colors triggered by musical tones). Negative phenomena comprise the amusias, which can be receptive, expressive, or both, and can selectively involve particular components of musical processing, including pitch, interval, contour, rhythm, meter, timbre, and emotional response. Amusia is often accompanied by aphasia, but each can occur in the absence of the other. Neurological disorders provide evidence that musical processing is multimodal and widely distributed in both cerebral hemispheres.
How Many Music Centers Are in the Brain?
Authors: ALTENMÜLLER ECKART O.
Published: July 2010

Abstract: When reviewing the literature on brain substrates of music processing, a puzzling variety of findings can be stated. The traditional view of a left‐right dichotomy of brain organization—assuming that in contrast to language, music is primarily processed in the right hemisphere—was challenged 20 years ago, when the influence of music education on brain lateralization was demonstrated. Modern concepts emphasize the modular organization of music cognition. According to this viewpoint, different aspects of music are processed in different, although partly overlapping neuronal networks of both hemispheres. However, even when isolating a single “module,” such as, for example, the perception of contours, the interindividual variance of brain substrates is enormous. To clarify the factors contributing to this variability, we conducted a longitudinal experiment comparing the effects of procedural versus explicit music teaching on brain networks. We demonstrated that cortical activation during music processing reflects the auditory “learning biography,” the personal experiences accumulated over time. Listening to music, learning to play an instrument, formal instruction, and professional training result in multiple, in many instances multisensory, representations of music, which seem to be partly interchangeable and rapidly adaptive. In summary, as soon as we consider “real music” apart from laboratory experiments, we have to expect individually formed and quickly adaptive brain substrates, including widely distributed neuronal networks in both hemispheres.
Cortical Plasticity and Music
Authors: RAUSCHECKER JOSEF P.
Published: July 2010

Abstract: Auditory experience changes the make‐up of areas in the cerebral cortex that are involved in the processing of complex sounds, including music. Evidence for this comes from various lines of research. Early blindness results in an expansion of auditory‐responsive areas in the parietal cortex and a refinement in the selectivity of neurons in the auditory cortex. Occipital areas normally used only for vision are activated by auditory stimuli in the early blind. This lends credibility to the claim that blind individuals have greater musical abilities. The cross‐modal changes in auditory cortical representations are based on activity‐dependent modifications of synaptic circuitry. Imagery and anticipation of music also lead to activation of the auditory (and frontal) cortex. It is conceivable, therefore, that even with mental practice alone we can sharpen our musical representations in the cerebral cortex.