bluuebunny/crossref_metadata_2025 huggingface dataset:
Signal Transduction Through Glyco(sphingo)lipids: Introduction and Recent Studies on Glyco(sphingo)lipid‐enriched Microdomainsa
Authors: HAKOMORI SEN‐ITIROH , YAMAMURA SOICHIRO , HANDA KAZUKO
Published: February 2006

ABSTRACT: The presence of microdomains enriched in clustered glycosphingolipids (GSLs) at the surface of plasma membranes and liposome membranes, and their functional role in signal transduction, have been suggested by a series of observations, as follows: (1) GSL clusters (patches) are observed by electron microscopy; (2) microvesicles enriched in GSLs and other sphingolipids can be isolated as detergent‐insoluble particles by sucrose density gradient ultracentrifugation; (3) such vesicles isolated from B16 melanoma cells contain >90% of cellular GM3, >90% of c‐Src and Ras, ∼50% of Rho, and ∼20% of Fak, despite the fact that this vesicle fraction contains only 0.5% of total cellular protein (this fraction is termed “detergent‐insoluble GSL‐enriched microdomain” (DIGEM)); (4) GM3 in DIGEM can be coimmunoprecipitated with c‐Src and Rho, indicating a close association of GM3 with these transducer molecules; (5) stimulation of GM3 in B16 melanoma cells by anti‐GM3 antibody or by Gg3 results in change of signal transduction. Thus, GSLs, together with various transducer molecules present at DIGEM, may directly induce signal transduction rather than modulate or modify signal transduction created through receptors of growth factors or hormones as previously observed.
Sphingosine‐1‐Phosphate in Cell Growth and Cell Deatha
Authors: SPIEGEL SARAH , CUVILLIER OLIVIER , EDSALL LISA C. , KOHAMA TAKAFUMI , MENZELEEV RAMIL , OLAH ZOLTAN , OLIVERA ANA , PIRIANOV GRISHA , THOMAS DIANNE M. , TU ZHENXING , VAN BROCKLYN JAMES R. , WANG FANG
Published: February 2006

ABSTRACT: Recent evidence suggests that branching pathways of sphingolipid metabolism may mediate either apoptotic or mitogenic responses depending on the cell type and the nature of the stimulus. While ceramide has been shown to be an important regulatory component of apoptosis induced by tumor necrosis factor alpha and Fas ligand, sphingosine‐1‐phosphate (SPP), a further metabolite of ceramide, has been implicated as a second messenger in cellular proliferation and survival induced by platelet‐derived growth factor, nerve growth factor, and serum. SPP protects cells from apoptosis resulting from elevations of ceramide. Inflammatory cytokines stimulate sphingomyelinase, but not ceramidase, leading to accumulation of ceramide, whereas growth signals also stimulate ceramidase and sphingosine kinase leading to increased SPP levels. We propose that the dynamic balance between levels of sphingolipid metabolites, ceramide, and SPP, and consequent regulation of different family members of mitogen‐activated protein kinases (JNK versus ERK), is an important factor that determines whether a cell survives or dies.
Coupling of the p75 Neurotrophin Receptor to Sphingolipid Signalinga
Authors: DOBROWSKY RICK T. , CARTER BRUCE D.
Published: February 2006

ABSTRACT:The neurotrophins are a family of growth factors involved in the survival and differentiation of specific populations of neurons and glial cells. Many of the trophic signals elicited by neurotrophins are initiated by the binding of these molecules to various Trk tyrosine kinase receptors. In contrast, recent data suggest that neurotrophin‐mediated death signals are generated through the interaction of nerve growth factor with the low‐affinity neurotrophin receptor, p75NTR. Neurotrophins may signal through p75NTRby stimulating sphingomyelin hydrolysis and generating ceramide in primary cultures of neurons and glial cells as well as in fibroblasts heterologously expressing p75NTR. The biochemical characteristics of p75NTR‐dependent ceramide generation are discussed relative to the role of ceramide in p75NTR‐dependent apoptosis and the activation of NF‐κB.
MyeliN‐associated Glycoprotein Binding to Gangliosides: Structural Specificity and Functional Implicationsa
Authors: SCHNAAR RONALD L. , COLLINS BRIAN E. , WRIGHT LATASHA P. , KISO MAKOTO , TROPAK MICHAEL B. , RODER JOHN C. , CROCKER PAUL R.
Published: February 2006

ABSTRACT: Myelin‐associated glycoprotein (MAG), which mediates certain myelin‐neuron cell‐cell interactions, is a lectin that binds to sialylated glycoconjugates. Gangliosides, the most abundant sialylated glycoconjugates in the brain, may be the functional neuronal ligands for MAG. Cells engineered to express MAG on their surface adhered specifically to gangliosides bearing an α2,3‐linked N‐acetylneuraminic acid on a terminal galactose, with the following relative potency: GQ1bα» GD1a, GT1b » GM3, GM4 (GM1, GD1b, GD3, and GQ1b did not support adhesion). MAG binding was abrogated by modification of the carboxylic acid, any hydroxyl, or the N‐acetyl group of the ganglioside's N‐acetylneuraminic acid moiety. Related immunoglobulin (Ig) superfamily members either failed to bind gangliosides (CD22) or bound with less stringent specificity (sialoadhesin), whereas a modified form of MAG (bearing three of its five extracellular Ig‐like domains) bound only GQ1bα. Enzymatic removal of sialic acids from the surface of intact nerve cells altered their functional interaction with myelin. These data are consistent with a role for gangliosides in MAG‐neuron interactions.
Sphingolipid Metabolism: Sphingoid Analogs, Sphingolipid Activator Proteins, and the Pathology of the Cella
Authors: SANDHOFF K. , KOLTER T. , VAN ECHTEN‐DECKERT G.
Published: February 2006

ABSTRACT: Sphingolipid metabolism and function was investigated using sphingoid analogs, cells from human sphingolipidoses patients, and knockout animals. Treatment of primary cultured murine cerebellar cells with the structurally modified sphingosine base cis‐4‐methylsphingosine resulted in decreased sphingolipid biosynthesis accompanied by significant morphological changes. Plasma‐membrane‐derived glycosphingolipids (GSLs) destined for digestion are internalized through the endocytic pathway and delivered to lysosomes. There, GSLs are degraded by the action of exohydrolases, which are supported, in the case of GSLs with short oligosaccharide chains, by sphingolipid activator proteins (SAPs or saposins). The inherited deficiency of activators give rise to sphingolipid storage diseases. The analysis of cultured fibroblasts from corresponding patients suggests a new model for the topology of endocytosis and lysosomal digestion. Mice with disrupted genes for activator proteins and for GM2 degrading hexosaminidases turned out to be useful models for human diseases.
Use of BODIPY‐labeled Sphingolipids to Study Membrane Traffic along the Endocytic Pathwaya
Authors: PAGANO RICHARD E. , CHEN CHII‐SHIARNG
Published: February 2006

ABSTRACT: In this chapter we discuss the use of BODIPY‐labeled sphingolipids to study lipid transport along the endocytic pathway of cultured mammalian cells. The unique spectral properties of the BODIPY fluorophore allow the investigator to distinguish various populations of labeled endosomes and lysosomes within the living cell by fluorescence microscopy, and in conjunction with quantitative fluorescence microscopy, to estimate the concentration of these lipids in different intracellular compartments. This methodology is particularly useful for visualizing the accumulation of lipids in the lysosomes of storage disease fibroblasts and may provide a useful method for screening various agents that abrogate this accumulation.
The Role of GM1 and Other Gangliosides in Neuronal Differentiation Overview and New Findingsa
Authors: Ledeen Robert W. , Wu Gusheng , Lu Zi‐Hua , Kozireski‐Chuback Diane , Fang Yu
Published: February 2006

ABSTRACT:The pronounced increases in gangliosides belonging to the gangliotetraose family during the neurite outgrowth phase of neuronal differentiation have suggested a functional requirement for these substances related to process extension, arborization, and possibly synaptogenesis. Support for this hypothesis has come from a variety of experimental paradigms utilizing neuroblastoma cell lines, primary neuronal cultures, and observations on the developing nervous system. We have recently observed that differentiation of both primary neurons and neuroblastoma cells by Ca2+‐elevating stimulants is characterized by upregulation of GM1 in the nuclear membrane. Immunostaining revealed these Ca2+‐induced neurites to have axonal characteristics. Recent work has indicated that nuclear GM1 facilitates efflux of nuclear Ca2+, thereby contributing to the reduced level of nuclear Ca2+that characterizes the differentiated neuron. Thus, while GM1 is generally recognized as a pluripotent molecule with several modulatory roles in the plasma membrane of developing and mature neurons, regulation of Ca2+flux across the nuclear membrane is proposed as another critical function of this ganglioside in neuronal development, with special relevance to axonogenesis.
GM1 and the Aged Braina
Authors: HADJICONSTANTINOU MARIA , NEFF NORTON H.
Published: February 2006

ABSTRACT: Aging is associated with the loss of brain neurotransmitter function, which apparently is the substrate for an adverse constellation of age‐associated symptoms. In particular, cholinergic deficits have been associated with cognitive impairment in aging. Systemic administration of GM1 ganglioside, 30 mg/kg, ip, for 30 days, enhances the cholinergic neurochemical presynaptic markers, choline acetyltransferase, choline uptake, and acetylcholine, in the brain and spinal cord of aged 22–24‐month‐old Sprague‐Dawley rats. In addition to correcting cholinergic neurochemistry, it improves spatial learning and memory impairment, and restores the number and the size of the cholinergic neurons in the basal forebrain and striatum. The induced neuronal recovery by GM1 is long‐lasting.
Gangliosides and Neurotrophic Growth Factors in the Retina: Molecular Interactions and Applications as Neuroprotective Agentsa
Authors: DREYFUS HENRI , SAHEL JOSÉ , HEIDINGER VALÉRIE , MOHAND‐SAID SADDEK , GUÉROLD BERNARD , MEUILLET EMMANUELLE , FONTAINE VALÉRIE , HICKS DAVID
Published: February 2006

ABSTRACT: Polypeptide growth factors and gangliosides can both be considered as trophic agents involved in almost all stages of neural cell development, differentiation, survival, and pathology. In most cases their physiological roles are still not clear due to the considerable complexity in their regulation. Several growth factors [e.g., basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF)] and one species of ganglioside (GM1) have been shown to exert interactions with each other and also to exhibit neuroprotective effects against retinal ischemia in vivo and cerebral excitotoxicity in vitro. Different experimental models are used to investigate their relevance to ischemic and excitotoxic conditions in the retina, and it is shown that (1) both bFGF and EGF show very effective neuroprotection for rat retinal neurones exposed to toxic levels of glutamate or its nonphysiological agonist kainate in vitro; (2) GM1 (10−5 M) used under the same conditions does not afford protection; (3) retinal glial cells also suffer morphological perturbations following glutamate or kainate treatment, but this effect is dependent on neuron‐glial interactions, indicating the existence of intermediate neuron‐derived messenger molecules; (4) these glial changes can be corrected by posttreatment with either bFGF or EGF in vitro; (5) using an in vivo animal model involving anterior chamber pressure‐induced ischemia in adult rats, it is shown that either pretreatment by intraperitoneal injection of GM1, or posttreatment by intraocular injection of the same ganglioside, reduces significantly histological damage to inner nuclear regions; and (6) in cultured retinal Müller glial cells the existence of molecular and metabolic interactions between both types of trophic factors is demonstrated. Hence both these groups of trophic molecules show interesting features for retinal ischemic treatment.
Effects of GM1 Ganglioside Treatment on Dopamine Innervation of the Striatum of MPTP‐treated Mice
Authors: ROTHBLATA DAVID S. , SCHNEIDER J.S.
Published: February 2006

ABSTRACT: GM1 ganglioside has been shown to stimulate repair of the nigrostriatal dopamine system after injury. This has been particularly evident in the mouse MPTP model of Parkinsonism. Systemic administration of GM1 has been shown to increase striatal dopamine levels and lead to increased density of substantia nigra pars compacta neurons after MPTP administration versus mice treated with MPTP and saline. The purpose of the present study was to assess regional changes in dopaminergic innervation of the striatum of mice treated with MPTP then GM1. Studies consisted of [3H] mazindol binding of dopamine uptake sites, postmortem striatal tissue dopamine levels, and peak dopamine release in response to KCl stimulation measured in vivo. Results showed that measures of dopamine innervation were significantly increased in most striatal areas in MPTP+GM1‐treated mice compared to MPTP+saline‐treated controls. The results indicate that GM1 treatment increases measures of dopaminergic innervation after an MPTP lesion, possibly through sprouting of new terminals or increased dopamine production and release from remaining terminals.
Exogenous Gangliosides: How Do They Cross the Blood‐Brain Barrier and How Do They Inhibit Cell Proliferation?a
Authors: SCHENGRUND CARA‐LYNNE , MUMMERT CHRISTINE M.
Published: February 2006

ABSTRACT: Gangliosides have been used to treat specific central nervous system lesions and to inhibit proliferation of neuroblastoma cells in vitro. However, the mechanisms by which they (1) cross the blood‐brain barrier and (2) inhibit cell proliferation have not been clearly defined. Evidence is presented in support of the hypotheses that (1) serum albumin functions in the transport of gangliosides across the blood‐brain barrier, and (2) when gangliosides inhibit cell proliferation, they do so by inhibiting the activity of DNA polymerases α and β.
The Role of Antiglycolipid Antibodies in Neurological Disordersa
Authors: FREDMAN PAM
Published: February 2006

ABSTRACT: Glycolipids have been shown to be antigens for circulating antibodies in autoimmune processes affecting the nervous system like neuropathy associated with IgM paraproteinemia, Guillain Barré syndrome (GBS), multifocal neuropathy, and variants thereof. The antibody titers, the Ig‐classes, and the antibody specificity vary between studies and disease groups. The immunogens are in general unknown. However, GBS is often associated with an infection with Campylobacter jejuni, which expresses a lipopolysaccharide structure similar to the carbohydrate epitopes in sialic acid containing glycolipids and gangliosides and thus a potential primary antigen for antiganglioside antibodies. The antiglycolipid specificity will most likely reflect the primary antigen carbohydrate epitopes, which also determine the target cell or tissue structure and the pathology. These factors might add to the inconsistent results obtained and that have led to the question: Are antiglycolipid antibodies of any clinical significance?
Antiglycosphingolipid Immune Responses in Neurology: The Vienna Experience with Isotypes, Subclasses, and Diseasea
Authors: GATTERBAUER B. , NEISSER A. , BERNHEIMER H. , SCHWERER B.
Published: February 2006

ABSTRACT: IgM, IgG, IgA, and IgG subclass anti‐GM1, anti‐GQ1b, and anti‐asialo‐GM1 (anti‐GA1) antibodies, respectively, were investigated by ELISA in serum from neurological and other patients. Increased anti‐GM1 occurred mostly in ∼35–15% of the cases without statistical differences; high percentages were found in Guillain‐Barré syndrome (GBS) preceded by gastrointestinal infection and multifocal motor neuropathy. Roughly, IgM anti‐GM1 was most frequent; however, distinct IgG and IgA reactions were found i.a. in GBS. A particular IgM anti‐mono‐ and disialoganglioside pattern occurred in a patient with sensorimotor neuropathy and paraproteinemia. Anti‐GQ1b was elevated in all Miller‐Fisher patients, with some prevalence of IgG2 among IgG subclasses. Cross‐reactivity of anti‐GQ1b was demonstrated with Campylobacter jejuni lipopolysaccharides. Increased anti‐GM1 and/or anti‐GA1 was more frequent in systemic lupus erythematosus with central nervous system involvement than without. Incidence of anti‐GM1 and anti‐GA1 in X‐adrenoleukodystrophy was relatively high.

Although anti‐GSL antibodies seem to have limited diagnostic value, studies of isotypes, subclass patterns, and cross‐reactivities may lead to further insight into the origin of (auto)immune responses and their immunepathogenetic role in disease.
GM1 Ganglioside in the Treatment of Parkinson's Diseasea
Authors: SCHNEIDER J. S.
Published: February 2006

ABSTRACT: Since the early 1980s, numerous studies have been reported by laboratories around the world documenting the beneficial effects of GM1 ganglioside treatment on the damaged dopamine system in various animal and in vitro models. Based on the strength of these data, the first clinical studies designed to assess the efficacy and safety of chronic GM1 use in the treatment of Parkinson's disease were performed. In a double‐blind placebo‐controlled study, significant improvements in GM1‐treated patients were demonstrated in clinical motor ratings, timed tests of motor function, activities of daily living, and some aspects of neuropsychological functioning. Patients who have elected to continue using GM1 in an open extension trial have either continued to improve over time or have shown initial functional improvements and their disease has remained stable (i.e., no symptom progression) after two years. These results suggest that long‐term use of GM1 is safe and may work to partially reverse the degenerative process in established Parkinson's disease patients.
Clinical Trials of Pharmacotherapy for Spinal Cord Injury
Authors: GEISLER FRED H.
Published: February 2006

ABSTRACT:Spinal cord injury remains with limited natural recovery and only a few general ineffective treatment options. Recent publications have reported enhanced neurologic recovery with the use of methylprednisolone and GM‐1 ganglioside. The results of the Maryland GM‐1 Ganglioside Study reported a significant drug effect with respect to the fraction of patients that had a change of two or more Frankel grades from entrance into the study to 1‐year follow‐up. This study formed the basis for the currently ongoing larger placebo‐controlled multicentered study using Sygen® GM‐1 following acute spinal cord injury. This study has entered 797 patients and is expected to present results in early 1998.
Effects of Prenatal Cocaine on Hearing, Vision, Growth, and Behaviora
Authors: CHURCH MICHAEL W. , CROSSLAND WILLIAM J. , HOLMES PAMELA A. , OVERBECK GEORGE W. , TILAK JACQUELINE P.
Published: February 2006

ABSTRACT: The illicit use of cocaine has increased dramatically over the last 10–12 years. There has been a corresponding increase in cocaine abuse among obstetric patients and in the number of “cocaine babies.” According to some estimates, these children make up more than half of the drug‐associated births. This problem is therefore a major public health concern. Consequently, our laboratory investigated the effects of prenatal cocaine exposure on hearing, vision, growth, and exploratory/stress behavior. This chapter summarizes the literature on animals and humans on these topics and presents new observations from our laboratory. In terms of maternal toxicity, prenatal cocaine exposure causes hypertension, placental abruption, spontaneous abortion, poor pregnancy weight gain, and undernutrition secondary to appetite suppression. Some offspring effects include in utero growth retardation, cephalic hemorrhage, fetal edema, altered body composition, congenital malformations, and even pre‐ and postnatal death. The offspring can also exhibit a variety of behavioral, visual, hearing, and language disorders. Differential effects of animal strain and late gestational cocaine exposure are discussed. Comparisons are made between prenatal cocaine, the fetal alcohol syndrome, and the effects of prenatal undernutrition. Recommendations for clinical assessment and intervention are made.
Prenatal Cocaine Exposure: Long‐Term Deficits in Learning and Motor Performancea
Authors: ROMANO ANTHONY G. , HARVEY JOHN A.
Published: February 2006

ABSTRACT: We have developed a rabbit model of in utero exposure to intravenous injections of cocaine given twice daily to dams from gestational days 8–29. At the doses employed (4 mg/kg, injected twice daily), no differences were found in the body weight gain of dams, time to delivery, litter size, and body weight or other physical characteristics of the offspring. However, cocaine‐exposed pups displayed an abnormal structural and neurochemical development of the anterior cingulate cortex which persisted into adulthood. In agreement with the known functions of the anterior cingulate cortex, we found that adult, sexually mature rabbits, exposed to cocaine prenatally, demonstrate impairments in motor function, alterations in associative learning and severe impairments in discrimination learning. Moreover, the alterations in discrimination learning were interpreted to be due to deficits in attentional processes. Specifically, cocaine progeny preferentially attend to more salient stimuli even when these are not relevant to the task. Consequently they have difficulty in attending to less salient but relevant stimuli when more salient but irrelevant stimuli occur in the same context. We concluded that the learning deficits are a reflection of the morphologic and neurochemical abnormalities of the anterior cingulate cortex. Alterations in dopamine function of the caudate nucleus may also contribute to the deficits in motor performance.
State Control in the Substance‐Exposed: Fetus I. The Fetal Neurobehavioral Profile: An Assessment of Fetal State, Arousal, and Regulation Competency
Authors: GINGRAS JEANNINE L. , O'DONNELL KAREN J.
Published: February 2006

ABSTRACT: Behavioral states are stable structures of behaviors that become more definable and coordinated with increasing age. With ultrasound we can see the fetus move, breathe, and react to changes in its environment. Ultrasound used in conjunction with Doppler fetal heart rate recording provides behavioral and neurophysiologic data useful in state determination. The Fetal neurobehavioral Profile (FNP) was developed by our group as an assessment of fetal behaviors reflecting CNS integrity in the drug‐exposed fetus. The FNP was designed to parallel methods of examining the newborn infant, especially in state‐related behaviors. The FNP measures: fetal responsiveness and arousal after environmental perturbation with vibroacoustic stimulation (VAS);habituation to VAS; state recovery; and self‐regulation post‐VAS. From the behavioral and physiologic recordings, the constructs of state differentiation, organization, and regulation as well as fetal arousal and regulation competency can be measured.

Previous work using the FNP showed that those fetuses with abnormal or suspect fetal state regulation demonstrated impaired performance on the NBAS (Am. J. Obstet. Gynecol. 161: 685,1989). To expand these observations, three populations are currently being studied: prenatal nicotine‐exposed, prenatal cocaine‐exposed, and controls. Data are from 97 women/fetus dyads and a total of 236 FNP at ages 28–30 weeks gestational age, 31–34 weeks gestational age, and > 36 weeks gestational age. Although there are no group differences in the ability to achieve state by 36 weeks, interesting trends emerge: fetuses prenatally cocaine‐exposed spend less time in 1F, more time in 4F, and have fewer transitions. At FNP1, fewer cocaine‐exposed fetuses had an initial reaction to VAS, whereas fewer nicotine‐exposed fetuses habituated. Although the ability to habituate to VAS did not discriminate the cocaine group from the control or nicotine groups, the number of stimuli required for habituation differed between groups: 7 for the cocaine‐exposed, 3 for the nicotine, and 5 for the control groups. Thus latency, a measure of arousal, differs among these groups Preliminary data also susggest a correlation of prenatal data with postnatal outcome.
Long‐Term Neurodevelopmental Risks in Children Exposedin Uteroto Cocaine: The Toronto Adoption Studya
Authors: KOREN GIDEON , NULMAN IRENA , ROVET JOANNE , GREENBAUM RACHEL , LOEBSTEIN MICHAL , EINARSON TOM
Published: February 2006

ABSTRACT:Children exposedin uteroto cocaine are at risk for long‐term neurobehavioral damage not just because of the drug itself, but also because of clustering of other health determinants, including low socioeconomic status, low maternal education, and maternal addiction, to mention a few. One methodologic approach to separate the direct neurotoxic effects of cocaine from these synergistic insults is to follow up a cohort of children exposedin uteroto cocaine and given up for adoption to middle‐upper class families.

The Toronto Adoption Study, supported by Health Canada, has proven the direct neurotoxic effects of cocaine on IQ and language. These effects are mild to moderate as compared to those measured in children exposedin uteroto cocaine and reared by their natural mothers.
Prenatal Exposure to Cocaine and Other Drugs: Outcome at Four to Six Yearsa
Authors: CHASNOFF IRA J. , ANSON AMY , HATCHER ROGER , STENSON HERB , IAUKEA KAI , RANDOLPH LINDA A.
Published: February 2006

ABSTRACT: In a longitudinal, prospective study, 95 children born to mothers who used cocaine and other drugs during pregnancy and 75 matched, nonexposed children born to mothers who had no evidence of alcohol or illicit substance use during pregnancy were evaluated for cognitive and behavioral outcome at 6 years of age. Prenatal exposure to cocaine and other drugs had no direct effect on the child's cognitive outcome (measured as IQ), but it had an indirect effect as mediated through the home environment. However, prenatal exposure to cocaine and other drugs did have a direct effect on the child's behavioral characteristics at 4–6 years of age, with the home environment having little impact. This study helps us to understand the fragile interaction of biological and environmental factors affecting the cognitive and behavioral development of children prenatally exposed to cocaine and other drugs.
Policies towards Pregnancy and Addiction: Sticks without Carrots
Authors: CHAVKIN WENDY , WISE PAUL H. , ELMAN DEBORAH
Published: February 2006

ABSTRACT: Throughout this century in the United States, tension has existed between those who believe drug abuse is best combatted through the criminal justice system and those who emphasize a medical/public health model of prevention and treatment. In the last decade this debate has centered around the person of the pregnant addict. The former have construed her addiction as willful harm to the fetus punishable on criminal and child abuse grounds. The latter have countered that pregnancy is a moment of increased motivation for treatment and focused on expansion and improvement of treatment options. Both managed care and welfare reform have exacerbated conditions between these opposing policy approaches. The addicted woman is increasingly caught between policies that punish her drug use without options for overcoming addiction.
Molecular Wires: Charge Transport, Mechanisms, and Control
Authors: RATNER MARK A. , DAVIS BILL , KEMP MATHIEU , MUJICA VLADIMIRO , ROITBERG ADRIAN , YALIRAKI SOPHIA
Published: February 2006

ABSTRACT:By molecular wires, one generally means molecular structures that transmit a signal between two termini. We discuss some theoretical models and analysis for electronically conductive molecular wires in which a single molecule conducts charge between two electrodes. This situation resembles both intramolecular non‐adiabatic electron transfer, in which electronic tunneling between donor and acceptor is seen, and mesoscopic quantum transport.

We discuss formal methods for predicting conductance in molecular wire circuits. The critical component that differs from the usual conductivity is the interface between electrode continuum and the discrete levels of the molecule. This can be described in several ways. We present an analysis based on the Bardeen tunneling formula. Specific problems (electron polarization, disorder, nuclear scattering, charge distribution) are discussed. Finally, the differing mechanisms expected for the conductance, ranging from ballistic tunneling to gated transfer, are outlined.
Ab initio Methods for the Study of Molecular Systems for Nanometer Technology: Toward the First‐Principles Design of Molecular Computers
Authors: SEMINARIO JORGE M. , TOUR JAMES M.
Published: February 2006

ABSTRACT: A top‐priority objective in the area of nanoelectronics is the design of logical circuits using single molecules so that the feature size of present computers can be dramatically reduced by several orders of magnitude, thus allowing an enormous increase in speed and leading us toward the design of a molecular CPU. Achieving this goal clearly requires a good understanding of the factors that determine single interactions between unitary molecules, as well as the means to predict these interactions for proposed target molecules prior to undertaking what are often lengthy and costly synthetic efforts. The use of ab initio techniques will help us to learn how structural, electronic and external factors influence the communication between molecules, and to develop computational approaches that will allow us to quantitatively predict the characteristics of molecular scale electronics device architectures.
Transport in (10,10) Carbon Nanotubes with Defects
Authors: ANANTRAM M. P. , HAN JIE , GOVINDAN T. R.
Published: February 2006

ABSTRACT: In this paper, we numerically calculate the conductance characteristics of a uniform (10,10) carbon nanotube in the presence of an applied bias. It is shown that for long tubes, the conduction mechanism involves only the four nondegenerate sub‐bands when the applied bias drops slowly across the tube. The focus of our work is to calculate the transmission coefficient and low bias conductance of carbon nanotubes with defects. Our calculations show that (1) a weak uniform disorder in the tube does not cause a significant change in the zero bias conductance and (2) substitutional defects which are strong scatterers, can cause a gap in the transmission coefficient versus energy at the middle of the band resulting in a significant change in the low bias conductance
Carbon Nanotubes: Molecular Electronic Components
Authors: SRIVASTAVA DEEPAK , SAINI SUBHASH , MENON MADHU
Published: February 2006

ABSTRACT: The carbon nanotube junctions have recently emerged as excellent candidates for use as the building blocks in the formation of nanoscale molecular electronic networks. While the simple joint of two dissimilar tubes can be generated by the introduction of a pair of heptagon‐pentagon defects in an otherwise perfect hexagonal graphene sheet, more complex joints require other mechanisms. In this work we explore structural characteristics of complex 3‐g38 point junctions of carbon nanotubes using a generalized tight‐binding molecular‐dynamics scheme. The study of pi‐electron local densities of states (LDOS) of these junctions reveal many interesting features, most prominent among them being the defect‐induced states in the gap.
A Self‐Assembled Single‐Electron Tunneling Device
Authors: PERSSON S.H. M. , OLOFSSON L. , HEDBERG L. , SUTHERLAND D. , OLSSON E.
Published: February 2006

ABSTRACT: Single‐electron tunneling devices were made by self‐assembly of colloidal ligand‐stabilized gold clusters in the small gap between two gold electrodes, which were covered with a self‐assembled monolayer of 1,8‐octanedithiol. With this method we control the size of the active part of the device which is smaller than the traditional lithographic resolution, with chemical methods and use self‐positioning of the particle by weak forces between the substrate and the particle. The current voltage characteristic of the devices exhibit a Coulomb staircase and gate effect at 4.2 K, and a prominent Coulomb blockade at room temperature.
Recent Advances in Molecular Scale Electronics
Authors: TOUR JAMES M. , REINERTH WILLIAM A. , JONES LEROY , BURGIN TIMOTHY P. , ZHOU CHONG‐WU , MULLER C. J. , DESHPANDE M. R. , REED MARK A.
Published: February 2006

ABSTRACT: This paper describes four significant breakthroughs in the syntheses and testing of molecular scale electronic devices. The 16‐mer of oligo(2‐dodecylphenylene ethynylene) was prepared on Merrifield's resin using the iterative divergent/convergent approach which significantly streamlines the preparation of this molecular scale wire. The formation of self‐assembled monolayers (SAMs) and multilayers on gold surfaces of rigid rod conjugated oligomers that have thiol, α,ω‐dithiol, thioacetyl, or α,ω‐dithioacetyl end groups have been studied. The direct observation of charge transport through molecules of benzene‐1,4‐dithiol, which have been self‐assembled onto two facing gold electrodes, has been achieved. Finally, we are reporting initial studies into what effect varying the molecular alligator clip has on the molecular scale wire's conductivity.
Macromolecular and Supramolecular Architectures for Molecular Electronics
Authors: MÜLLEN K. , RABE J. P.
Published: February 2006

ABSTRACT: The benzene ring is introduced as a modular building block into carbon‐rich 1D‐, 2D‐ and 3D‐polymers. Remarkable synthetic products are functionalized poly(para‐phenyleneethynylene)s as rigid rods, giant polycyclic aromatic hydrocarbons as molecular models for graphite and polyphenylene dendrimers as shape‐persistent nanoparticles. Supramolecular ordering of these unprecedented molecular structures is a key prerequisite when elucidating their role as media for charge carrier transport in molecular electronics. Current‐potential curves recorded for single disc‐type molecules and the drastic increase of charge mobility as a result of supramolecular order in π‐stacked columnar arrays are outstanding physical results.
Self‐Assembly, Manipulation, and Discrimination of DNA Molecules by Scanning Tunneling Microscope (STM) on Solid Surfaces
Authors: KAWAI TOMOJI
Published: February 2006

ABSTRACT: DNA base molecules form novel low‐dimensional superstructures on Cu(111) surfaces through hydrogen bonding among molecules and through their epitaxial growth on the surface. The chemical inertness of the Cu(111) substrate allows the molecules to diffuse over the surface to self‐assemble spontaneously into their own unique structures. Molecular orbital calculations explain the mechanism of the observed self‐assemblies induced by base‐base hydrogen bonding. High‐resolution molecular imaging and manipulation of DNA base molecules and DNA oligomers have also been successfully carried out on SrTiO3(100) and Cu(111) surfaces under ultra‐high vacuum conditions by STM.
Is There A Minimum Size and a Maximum Speed for a Nanoscale Amplifier?
Authors: JOACHIM C. , BERGAUD C. , PINNA H. , TANG H. , GIMZEWSKI J. K.
Published: February 2006

ABSTRACT: The C60 electromechanical amplifier is a working 3‐terminal device based on the modulation of the tunnel‐transport regime through a C60 molecule by a reversible deformation of its cage. We present the advantages of the planarization of this triode such as a surface extension lower than 0.05μm2 on the wafer and a large gain (Gd > 40). High‐speed operation (bandwidth greater than 1 GHz) and low energy dissipation in the attojoules range are discussed together with the technological difficulties to fabricate such a planar molecular triode.
Atom Electronics: A Proposal of Atom/Molecule Switching Devices
Authors: WADA YASUO
Published: February 2006

ABSTRACT:This paper proposes very fast (more than Tera (1012) Hz) and very small (less than a few nm) devices, atom relay transistors (ART), supra molecular atom relay transistors (SMART), and molecular single electron switching transistors (MOSES), which would supersede the MOSFET (metal‐oxide‐semiconductor field effect transistor) for future information processing. Their performances are evaluated on the basis of the characteristics necessary for integrated circuit devices and they are found to be the most promising candidates among the nanoscale devices including quantum devices and superconductor devices. Atom/molecule manipulation technology using the scanning tunneling microscope (STM) would be the key factor in achieving these devices. The basic technology developments toward the realization of ART, SMART, and MOSES are reported, including the beam‐assisted scanning tunneling microscope (BASTM) for insulator observation, needle formation, and tip imaging (NFTI) for atom‐scale evaluation of the STM tip apex, micromachine STM (μ‐STM) for single molecule manipulation and the atom wire fabrication technology development on a silicon (100) hydrogen terminated surface.
Molecular Photodiodes with Langmuir‐Blodgett Films Driven by Scanning Probe Microscopy
Authors: FUJIHIRA MASAMICHI
Published: February 2006

ABSTRACT: Molecular photodiodes were fabricated with Langmuir‐Blodgett (LB) films containing A‐S‐D triads for charge separation and H antenna molecules. Here, A, S, and D stand for electron acceptor, sensitizer, and electron donor moieties of the triad, and H for light harvesting moiety of the antenna, respectively. These functional amphiphiles mainly consisting of hydrocarbon (HC) can be phase‐separated from fluorocarbon (FC) amphiphiles in mixed monolayers of HC and FC to form small domains. The phase‐separated structure of the HC‐FC mixed monolayers was studied with various scanning probe microscopes (SPM). SPM can be also used to detect the photo‐induced charge separation in the molecular photodiodes.
Aging: Phenomena and Theories
Authors: HARMAN DENHAM
Published: February 2006

ABSTRACT: Aging is the accumulation of diverse adverse changes that increase the risk of death. These changes can be attributed to development, genetic defects, the environment, disease, and the inborn aging process. The chance of death at a given age serves as a measure of the number of accumulated aging changes, that is, of physiologic age, and the rate of change of this measure, as the rate of aging. As living conditions in a population approach optimum, the curve of the logarithm of the chance of death versus age shifts towards a limit determined by the sum of (1) the irreducible contributions to the chance of death by aging changes that can be prevented to varying degrees, and (2) those due to the intrinsic aging process. In the developed countries living conditions are now near optimum, and the ALE‐Bs are about 6‐9 years less than the potential maximum of around 85 years. The inborn aging process is now the major risk factor for disease and death after about age 28. By age 28 only 1 to 2% of a cohort is dead, the remaining 98 to 99% die at an exponentially increasing rate determined by the aging process. This process ensures that few reach 100 years and none exceed about 122 years. Many theories have been advanced to account for the aging process. No single theory is generally accepted. Theories that can contribute to the important practical goal of increasing the healthy, useful span of humans will endure.
Somatic Mutation and Aging
Authors: MORLEY ALEC
Published: February 2006

ABSTRACT: A key prediction of the somatic mutation theory of aging is that there is an invariant relationship between life span and the number of random mutations. A number of studies at a number of gene loci have shown that somatic mutations of a variety of types accumulate with age. Dietary restriction, which prolongs life span, results in slowed accumulation of HPRT mutants in mice. Conversely, senescence‐accelerated mice, which have been bred to have a shortened life span, show accelerated accumulation of somatic mutations.
The Nature of Gerontogenes and Vitagenes: Antiaging Effects of Repeated Heat Shock on Human Fibroblasts
Authors: RATTAN SURESH I. S.
Published: February 2006

ABSTRACT: Our survival and the physical quality of life depends upon an efficient functioning of various maintenance and repair processes. This complex network of the so‐called longevity assurance processes is composed of several genes, termed vitagenes. The homeodynamic property of living systems is a function of such a vitagene network. Because aging is characterized by the failure of homeodynamics, a decreased efficiency and accuracy of the vitagene network can transmutate it into a gerontogene network. It is not clear how various components of the vitagene network operate and influence each other in a concordant or a discordant manner. Experimental strategies through which this transmutation of vitagenes into virtual gerontogenes may be elucidated include induction of molecular damage, antisense intervention, and genetic screening for varied efficiencies of the members of the vitagene family. A reversal of this approach by maintaining or recovering the activity of vitagenes will lead to a delay of aging, a decreased occurrence of age‐related diseases, and a prolongation of a healthy life span.
Causes of Aging
Authors: HOLLIDAY ROBIN
Published: February 2006

ABSTRACT: A broad biological approach makes it possible to understand why aging exists and also why different mammalian species have very different maximum longevities. The adult organism is maintained in a functional state by at least ten major mechanisms, which together constitute a substantial proportion of all biological processes. These maintenance mechanisms eventually fail, because the evolved physiological and anatomical design of higher animals is incompatible with continual survival. The life span of each mammalian species depends on the efficiency of maintenance of their cells, tissues, and organs, and there is much evidence that such maintenance is more effective in long‐lived species, such as humans, than in short‐lived small mammals. It is also evident that there is an inverse relationship between reproductive potential and longevity, which would be expected if available metabolic resources are shared between investment in reproduction and investment in the preservation of the adult body. It is proposed that the eventual failure of maintenance leads to the pathological changes seen in age‐associated disease. Although we now have a biological understanding of the aging process, much future research will be needed to uncover the cellular and molecular changes that give rise to age‐associated diseases. The major aim of such research is to devise procedures to delay or prevent the onset of these diseases.
Age‐associated Changes in the Innervation of Muscle Fibers and Changes in the Mechanical Properties of Motor Units
Authors: LUFF ANTHONY R.
Published: February 2006

ABSTRACT: In both humans and animals there is a progressive loss of muscle strength with age. Tests of handgrip and knee extension in men show that some decline in strength is evident by the age of 55 years and is pronounced by the age of 65, compared with the 25‐ to 35‐year period when strength is at a maximum. A comparable age‐related decline in peak force development has also been shown in hindlimb muscles of aged rats. Motoneurons and consequently motor units are lost with age, and this is apparent in man after the age of 60. Again, a comparable decline has been demonstrated in the motoneuron population of hindlimb muscles of rats aged 20‐24 months. Loss of motoneurons in young adults (through either injury or disease) results in the remaining intact motoneurons sprouting to innervate the denervated fibers. This capacity for sprouting has been shown to be seriously impaired in the hindlimb muscles of aged rats. Furthermore, the well‐established relationship between motor unit size and fatigability (smaller units tend to be more fatigue resistant) also tends to break down, with large units just as likely to be fatigable as fatigue resistant. The normally large, fatigable motor units also appear to be reduced in size in the aged muscles. The age‐related loss of motoneurons and associated loss of muscle fibers accounts in part for the reduced functional capacity of muscle with age. The reason for the impairment of the aged motoneuron remains to be investigated, but it may relate to the integrity of the oxidative metabolic pathways within the cell, given that mitochondrial respiratory chain function is known to be reduced with age.
Oxidative Damage and Mutation to Mitochondrial DNA and Age‐dependent Decline of Mitochondrial Respiratory Functiona
Authors: WEI YAU‐HUEI , LU CHING‐YOU , LEE HSIN‐CHEN , PANG CHENG‐YOONG , MA YI‐SHING
Published: February 2006

ABSTRACT: Mitochondrial respiration and oxidative phosphorylation are gradually uncoupled, and the activities of the respiratory enzymes are concomitantly decreased in various human tissues upon aging. An immediate consequence of such gradual impairment of the respiratory function is the increase in the production of the reactive oxygen species (ROS) and free radicals in the mitochondria through the increased electron leak of the electron transport chain. Moreover, the intracellular levels of antioxidants and free radical scavenging enzymes are gradually altered. These two compounding factors lead to an age‐dependent increase in the fraction of the ROS and free radical that may escape the defense mechanism and cause oxidative damage to various biomolecules in tissue cells. A growing body of evidence has established that the levels of ROS and oxidative damage to lipids, proteins, and nucleic acids are significantly increased with age in animal and human tissues. The mitochondrial DNA (mtDNA), although not protected by histones or DNA‐binding proteins, is susceptible to oxidative damage by the ever‐increasing levels of ROS and free radicals in the mitochondrial matrix. In the past few years, oxidative modification (formation of 8‐hydroxy‐2′‐deoxyguanosine) and large‐scale deletion and point mutation of mtDNA have been found to increase exponentially with age in various human tissues. The respiratory enzymes containing the mutant mtDNA‐encoded defective protein subunits inevitably exhibit impaired respiratory function and thereby increase electron leak and ROS production, which in turn elevates the oxidative stress and oxidative damage of the mitochondria. This vicious cycle operates in different tissue cells at different rates and thereby leads to the differential accumulation of mutation and oxidative damage to mtDNA in human aging. This may also play some role in the pathogenesis of degenerative diseases and the age‐dependent progression of the clinical course of mitochondrial diseases.