Principles of Systems Biology Scale Relativity for Multi

Indian J Physiol Pharmacol, Vol. 55, No. 5, Supplement – 2011 :

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Scale Relativity for Multi-Scale Integrationin Systems Biology

Charles Auffray

European Institute for Systems Biology &Medicine, Université Claude Bernard, Lyon,France

Systems approaches in biology are as oldas physiology founded by William Harvey inthe 17th century (Auffray and Noble Int. J.Mol. Sci. 2009, 10, 1658-1669). At a Nobelsymposium held in Stockholm in 2002, Ipresented two conjectures for systems biologyon stochasticity and biological space-time(Auffray et al. Phil. Trans. R. Soc. Lond. A2003, 361:1125-1139): “We conjecture thatbiological systems self-organize because theyoperate as a conjunction between therelatively variable part of a stable organizationand the relatively stable part of a chaoticnetwork of fluctuations, and in a space witha changing number of dimensions: biologicalspace-time.” I will argue that complementingthe four Cartesian precepts of objectivity,reductionism, causality and exhaustivity withthe four systemic precepts of contextualisation,relatedness, conditionality and pertinence isa necessary condition for systems approachesto biological systems to succeed. The nextquestion that arises in this context is the natureof the chaotic network of fluctuations in self-organizing systems. I will argue that the

International Symposium on Systems Biology in Physiology/Medicine

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Principles of Systems Biology

Denis Noble

University of Oxford, Oxford, United Kingdom

I define systems biology as a theory ofbiological relativity in which the first principleis that there is no privileged level of causality(Noble, 2008, 2012). This is necessarily truein systems with multiple levels of feedforward and feedback. Genes, and proteins,do nothing on their own. There are multipleforms of ‘downward’ causation that ‘play’ thegenome, with very different results indifferent cells, and in different circumstances.The te rm ‘gene ne twork’ i s thereforemisleading. So is the idea of a geneticprogram. The central dogma of biology hasbeen incorrectly interpreted (Noble, 2006;Shapiro, 2011). The full implications ofepigenetic mechanisms have yet to beappreciated. I will illustrate the systemsapproach using successful simulation of theheart and its application in the developmentof new therapeutic drugs.

Noble D (2006) The Music of Life. OUP, Oxford.

Noble D (2008) Genes and Causation. PhilosophicalTransactions of the Royal Society A 366, 3001-3015.

Noble D (2012) A Theory of Biological Relativity: noprivileged level of causation. Journal of the Royal SocietyInterface Focus 2, doi: 10.1098/rsfs.2011.0067.

Shapiro JA (2011) Evolution: a view from the 21st century.Pearson Education Inc, Upper Saddle River, NJ.

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chaotic network of fluctuations is an intrinsicand fundamental property in self-organizingsystems, and that it is not simply “noise”, butplays a key role in driving the behaviour ofbiological systems. Finally, I will discuss theextension of the principle of relativity toscales, as developed by Dr. Laurent Nottale,and how its associated mathematical tools canhelp formalizing biological space-time, helpmodeling and understanding biologicalsystems, and resolve theoretically andpractically the problem of integration acrossmultiple scales and levels of organisation inbiological systems, which is becoming afrontier challenge for the field (Auffray andNottale, Progr Biophys Mol Biol 2008, 97:79-114; Nottale and Auffray Progr Biophys MolBiol 2008, 97:115-157).

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Multi-Scale Structured Model forAnalyzing Disease States in MetabolicSyndrome

RS Pramod, KV Venkatesh*

Department of Chemical Engineering, IndianInstitute of Technology Bombay, Powai, Mumbai,India

Despite the progress in various disciplinesof Bio-medical research and availability ofhigh-throughput techniques, we still are faraway from the roots of various complexdiseases. This puts forth a greater challengeto bring about a paradigm shift from theconventional ways of approaching complexsystems. Systems biology is an emergingscience that strives to fil l this gap andsynchronizes both the approaches to addressthe issues in biological systems. It tries to

explore the inherent design principles of thebiological systems which nature hasengineered, and understand the mechanismof cause and effect. This approach has higherpotential in biomedical research to study thefunctioning of human body from cellular toorgan levels treating it as a whole operatingsystem.

Metabolic syndrome is among themost complex diseases with multiplecomplications associated with it such asinsulin resistance, central obesity, Type 2diabetes, hypercholesterolemia, hypertension,atherosclerosis and coronary artery disease.It has been found that these are system leveldiseases with defects at metabolic, signalingand genetic levels rather than defects inindividual biological entities. In metabolicsyndrome, insulin resistance is the key defectswhich affect various metabolic processes.Defects in insulin secretion, its activity, andits signaling generate insulin resistance.Insulin signaling pathway orchestrate withvarious other pathways coupled with feedbackmechanisms to generate the multiple desiredeffects. Moreover various other hormonesand inflammatory pathways are knownto modulate the insulin activity. Insulinresistance is the combinatorial effect of allthese factors.

The systems biological approach withmathematical modeling of the biologicalnetworks serves as an important way to assessthese diseases. We attempt to integrate themodels of meal simulation, whole bodymetabolism, insulin signaling pathway andinsulin secretion which scale from cellular toorgan levels. We resort to the kinetic modelingand analysis of the integrated network andanalyze the metabolic response with respect

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thereby fosters international collaboration inbuilding and updating comprehensive models.Eventually these models will become powerfulenough to provide and understanding ofmultigenic disorders.

Such models summarize and epitomizethe results of sometimes thousands ofexperiments, even though data sets arecommonly incomplete. The storage andretrieval of anatomic, physiological andpathological data and images is far morecomplicated than for genomic and proteomicdata, but now is the time to develop nationaland internationally supported databases tofacilitate building the models on the basis ofaccurate data. The combination of good dataand the evaluation of comprehensive, selfconsistent, quantitative models will putevidence-based medicine on a solid footing.

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Understanding Endometrial Receptivityfor Blastocyst Implantation using a SystemsBiology Approach

Jayasree Sengupta, Debabrata Ghosh*

Department of Physiology, All India Institute ofMedical Sciences, New Delhi, India

Time-synchronous development ofendometrium and embryo under adequatehormonal regulation is considered integral tothe process of blastocyst implantation in thehuman. Although several lines of evidencesubstantively corroborate the paradigm,several studies in past failed to align with it.It now appears that hypothesis-driven andcandidate-based deductive approach fails toexplain the complex control process of

to perturbation in various parameters of themodel. Parameter values and other constantsare collected from the literature and are alsoestimated through optimization and curvefitting for the model. The models are thensimulated for sensitivity and phase-planeanalysis to notice the key parameters that havemajor influence on the overall networkbehavior. Furthermore, perturbation analysisis performed to get the matrix of parametersfor healthy and disease phenotype. Such ananalysis helps in understanding the systemdynamics and help in answering various‘What-if’ kinds of questions that can aid inidentification of potential drug targets anddesign effective therapies.

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The Physiome Projects: Modeling towardHuman Health

James B. Bassingthwaighte

Department of Bioengineering, University ofWashington, Seattle, USA

As biological science deepens, integrativemodels of biological systems becomeof central importance in identifying andorganizing the current knowledge andaiding the planning of experimental studiesto make the next discoveries. The ease ofunderstanding models however diminishes asthe complexity increases, necessitating betterinterfaces and broader tutorials andoperational instructions. Modular constructionfavors identifiability of elements and theunderstanding of components. With newmethods one can automate the reconstructionof large models when components aremodified or new ones added. The modularity


endometrial receptivity toward blastocystimplantation. In the present study, we proposeto forward a systems biology approach toelucidate the control process underlying thephysiological basis of successful interfacingbetween embryo and endometrium towardsblastocyst implantation. Accordingly, asystems biology model of a hierarchicalarrangement of functional networks ofregulatory genomic expressional elements atseveral levels shall be put forward. Theexistence of functionally connected genes incontrolling the process of endometrialreceptivity to blastocyst implantation in themid-luteal phase endometrium with andwithout progesterone dominance, as well as,with and without viable embryo shall elaborateupon the polygenic nature of the process ofendometr ia l recept iv i ty and b las tocys timplantation. It is anticipated that a systemsbio logy approach , in one hand , sha l lprovide both te lescopic as wel l asmicroscopic pictures of the process and, onthe other hand, shall open up novel areasof basic, strategic and translational researchin the biology of embryo implantat ion.Supported by WHO-Rockefeller Foundationand DST.

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Pharmacogenomics of CardiovascularDrugs: Integration of Genomics,Transcriptomics and Biomarkers for aSystems Biology Approach

Gérard Siest

Génétique Cardiovasculaire, Nancy University,Faculté de Pharmacie, Nancy, France

Personalized medicine is based on a better

knowledge of biological variability betweenindividuals, considering the important part dueto genetics, without neglecting environmentalinfluences. Pharmacogenomics andpharmacoproteomics approaches of manycardiovascular drugs are very often essentiallylooking to the pharmacokinetic step with themain CYP involved in the oxidation of thedrugs and the ABC transporters. But themajority of these enzymes and systems aremembranous, localized in the endoplasmicreticulum and are rarely released into bloodor plasma. Fortunately, blood carries cellularand non-cellular components that could beuse.

WBC might be useful to follow through atranscriptomic approach the gene products ofmany drug metabolizing enzymes includingthe following CYP: 1A1, 1A2, 1B1, 2A6, 2B6,2C, 2D6, 2E1, 3A3, 4B1, 4F. Phase IIItransporters i.e. the ABC genes also expressedin lymphocytes could be surrogate markersfor testing individual responses tocardiovascular risks factors or tocardiovascular drugs such as statins orfibrates. We should not forget to looksimultaneously to the transcription factorspresent in WBC, particularly Ah receptor,other nuclear factors (RXR, CXR, PPAR)which are regulating the expression of drugmetabolizing enzymes.

We will attempt to review the situation ofall these enzymes and genes in prevision totheir use in pharmacogenomics and todescribe the biological variations of somemessenger RNAs. Drug metabolizing enzymesnot only can oxidize and hydrolyze drugs butalso participate in endobiotics naturalsubstrates metabolism. They act on endogenousarachidonic acid catalyzing its conversion into


epoxy-eicosatrienoic acids (EETs). Theepoxide ring of these EETs may be cleavedby the action of epoxide hydrolases to yieldthe corresponding vicinal diols.

Our study of the expression of CYP2C,8,9,18,19 and CYP 2J2 genes in vasculartissues demonstrated that they are differentlyexpressed in healthy and varicose veins.

In order to examine the potentialrelationship between the anti-inflammatoryproperties of EETs and the expression ofcytochromes P450, we studied the expressionof cyps in the Apo E-/- mouse model. Theseexperiments revealed a significant increase ofcyp 2j5, the mouse homologue of CYP 2J2,and cyp 2c in the arterial wall of this animalmodel and more after LPS treatment.

Next, we investigated the relation betweenCYP 2C19 polymorphisms in a sample ofvolunteers selected from the STANISLASCohort. The isoforms of these enzymesshowed differential activities which is due togenetic polymorphisms within CYP 2J2 andCYP 2C19 genes (deletions giving inactiveenzymes).

We genotyped 300 subjects from theSTANISLAS Cohort and in the non activeCYP 2C19 group the levels of TNFá, IL6 andCRP were increased, suggesting a possiblelink between the decreased CYP 2C19activity. It should then be possible to targetthese enzymes and epoxyde hydrolase formodulating inflammation related disorders.

In conclusion, integrating genetic data,transcriptomic and protein ones, is the strategyfor developing pharmacogenomics forpersonalizing the treatment and avoiding sideeffects and drugs interactions. This is typicallya systems biology approach.

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Synthesis of Systems Level GeneExpression and Genetic Analyses inEpilepsy

Abhay Sharma

Institute of Genomics and Integrative Biology,Council of Scientific and Industrial Research,Delhi, India

Not clearly understood in cellular andmolecular terms, epileptogenesis, i .e. ,development of epilepsy, is a networkproblem involving molecular, structural, andfunctional alterations in the brain. A systemslevel understanding of epileptogenesis isexpected to facilitate development of novelanti-epileptogenic, disease-modifying, andneuroprotective agents. Unbiased genome-wide expression analysis offers a promisingapproach to identify relevant pathwaysunderlying the pathopysiological mechanisms.The available expression data related tohuman epilepsy and animal models ofepileptogenesis differs with respect to theuse of brain regions, methods to triggerepileptogenesis, tissue sampling time-points,epilepsy phenotype assessment, animal speciesand strains etc. Results of these individualstudies do not compare well with each otherpossibly because of these differences.Considering that synthesis of the expressiondata may however stil l be possible, aconvergent analysis of genome levelexpression studies in epilepsy will bepresented. The genes and pathways identifiedthrough this convergent approach will befurther examined in view of the existinggenetic, chemogenomic, cellular and molecularevidence in epilepsy. The point will be made


that synthesis of diverse genome levelexpression analysis may potentially uncover themechanisms underlying complex brain disorders.

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Exploiting Host-Factor Dependencies: AnAlternate Approach to Drug TargetDiscovery

Kanury VS Rao

Immunology Group, International Centre forGenetic Engineering and Biotechnology, ArunaAsaf Ali Marg, New Delhi, India

The vast majority of pathogens of thehuman hosts have co-evolved along withthe host so as to be able to successfullyinfect the target cells, and survive in them.They are able to do so by adapting to theintracellular milieu through complex interplaywith host cell machinery. This host-pathogeninterplay manifests at every level of cellularregulatory machinery including signalingnetwork, metabolic network and transcriptionalregulatory network. Pathogen-derivedmolecules tend to co-opt these regulatorymodules and influence them in a manner thatfacilitates their survival within the host cell.This is especially true of Mycobacterriumtuberculosis (Mtb), which has evolvedelaborate strategies to survive within theendocytic vesicles of human macrophages.Subversion of the host cell by the microbehas been shown to be mediated throughinteractions with proteins secreted by theintracellular pathogen. Our thesis, therefore,is that an approach that can disrupt the keymolecular interactions that promote thisadaptation may provide an alternate strategyfor chemotherapy. To explore this, we have

adopted a two-phase strategy where the firstphase involves the generation of a complete‘parts list’ of the host cell regulatorymolecules that are either targeted or influencedby the pathogen. For this, we are currentlyperforming a genome-wide siRNA screen ofhuman macrophages infected with Mtb. Thisinformation obtained from this screen is alsobeing employed to identify the molecular axisthat is involved in regulating pathogensurvival. It is our hypothesis that thecomponents of such an axis will also serve asa list of candidate targets for the developmentof chemotherapeutic strategies aimed atdisabling the adaptive mechanisms of thepathogen. Thus our present approach seeksto extend systems biology, towards atranslation-oriented exercise that could perhapsbe termed as ‘systems pharmacology.’ Thetalk will focus on the progress made in theseexperiments, as well as elaborate on the novelconcepts emerging from this screeningexercise.

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In Search for the Regulatory Network ofAging

Jing-Dong Jackie Han

CAS-MPG Partner Institute for ComputationalBiology, Shanghai Institutes of BiologicalSciences, Chinese Academy of Sciences,Shanghai, China

Many fundamental questions on aging arestill unanswered or are under intense debate.These questions are frequently not addressableby examining a single gene or a singlepathway, but can best be addressed at thesystems level. Previously we have examined


the modular structure of the protein–proteininteraction (PPI) networks during fruitfly andhuman brain aging. We found that in bothnetworks, there are two modules associatedwith the cellular proliferation to differentiationtemporal switch that display opposite aging-related changes in expression. Recently, westarted to examine not only age-dependenttranscriptomic changes, but also geneexpression changes in the mouse liver underdifferent dietary conditions which resultin different life-spans and aging-relatedphenotypes in the liver. This allowed us toidentify genes and pathways that modulatethe aging process through dietary intervention.In addition to examining transcriptomicchanges, we also explored the epigeneticchanges during the aging process in C.elegans and Rhesus macaque using ChIP-seq, and identified key epigenetic eventsmodulating the aging process.

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Synthesis of Robust BiochemicalNetworks: An Algebraic Approach

Anirban Mukherjee

Department of Electrical Engineering, IndianInstitute of Technology – Kharagpur, WestBengal, India

The design methodology of a class ofsynthetic biochemical networks will bepresented in this paper. A set of sufficientconditions has been derived for analysing therobustness of nonlinear biochemical networkat its steady-state condition. These sufficientconditions are formulated as linear matrixinequalities (LMIs) in the framework ofcomputationally attractive convex optimization

problems. The synthetic system becomesrobust in terms of its sensitivity to bothintrinsic and extrinsic perturbations. An upperbound of this perturbation sensitivity has beenderived for the synthetic system. This upperbound has been minimized for enhancedrobustness to parameter perturbations. Aconstrained class of robust synthetic networkshas been designed preserving the structuraltopology of the biochemical networks.

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NeuroDNet: a Database for Constructingand Analyzing Neurodegenerative DiseaseNetworks

Suhas V Vasaikar, Aditya K Padhi, JamesGomes*

School of Biological Sciences, Indian Instituteof Technology - Delhi, New Delhi, India

Neurodegenerative disorders (NDDs) arecaused by aberration in the genetic circuitrythat controls the normal function in neuronalcells. The aberration may arise, for example,from a mutation of a gene leading to a lossof functional protein or a severe stresscondition resulting in an irreversible changein regulation. The large number of signalingmolecules, genes and proteins, and complexityof the network circuitry involved hasdiscouraged probing of molecular mechanismthat underlie neuronal deterioration. Thechallenge lies in the development of atheoretical framework that will enable theorganization of existing data, and permitthe interrogation and interpretation ofmechanisms causing disease. To address theseissues, we have created a database,NeuroDNet, that brings together under one


portal the information about the genes,proteins, signaling molecules and theirinteraction, associated with neurodegenerativediseases. It has a three-tier architecture -foundation, function and interface. Thefoundation table contains the human genomedata and the list of genes associated with theneurodegenerative diseases reported in clinicalstudies. Data for the other tiers were curatedfrom OMIM, NCBI, UniProt, GeneOntology,Cell Signalling, KEGG, BioCarta, Reactome,HPRD, BioGrid, MINT and DIP. These tiersare linked through functional features. Thecurrent version of the database integrates fiveneurodegenerative diseases. It contains 23857protein-coding genes and 380 risk alleles forneurodegenerative diseases. Using thefeatures offered by the NeuroDNet portal,interaction networks can be created andanalyzed with Boolean and differentialequation formalisms. The performance of theNeuroDNet for three case studies will bepresented. NeuroDNet is freely accessible athttp://bioschool.iitd.ac.in/NeuroDNet/.

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Systems Biology to Understand Host-Pathogen Interactions

Dhiraj Kumar

International Centre for Genetic Engineering andBiotechnology, Aruna Asaf Ali Marg, New Delhi,India

Discovery of antibiotics more than half acentury ago had raised the belief that era ofinfectious diseases could be well over. Severaldecades afterwards, infectious diseases are stilla cause of major health concern, rather in amore alarming state-what with evolution of

various multi- and extensively drug resistantstrains. Consequently, we are forced toreconsider the approaches that have beenadopted for targeting infectious diseases.Multi-target therapy however remains at thecore of novel strategies. Though not a newconcept as such, recent developments havepaved ways for identifying heterogeneoustargets for the multi-target therapy. In thiscontext, reliance of infectious agents on hostcellular factors have particularly come underextensive scrutiny, bearing on the fact thathost factors play a crucial role throughout theetiology of diseases. The identification of thesefactors could however be a difficult task giventhe complex nature of the host-pathogendynamics.

Recently utili ty of systems levelapproaches for addressing these and relatedconcerns have been highlighted throughstudies based on genome-wide screening,proteomic and transcriptomic analyses. Wewill discuss how combining these systemslevel approaches together could help usunderstand various infectious disease biologyand identifying novel approaches for theirmanagement.


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Physiology and Evolution

Denis Noble

University of Oxford, Oxford, United Kingdom

Gene-centric interpretations of evolution,and more particularly the selfish geneexpression of those interpretations, formbarriers to the integration of physiologicalscience with evolutionary theory (Noble,2011b). A gene-centred approach analyses therelationships between genotypes andphenotypes in terms of differences (changethe genotype and observe changes inphenotype). We now know that, mostfrequently, this does not correctly reveal therelationships because of extensive bufferingby robust networks of interactions. Bycontrast, understanding biological functionthrough physiological analysis requires anintegrative approach (Noble, 2011a) in whichthe activity of the proteins and RNAs formedfrom each DNA template is analysed innetworks of interactions (Kohl et al., 2010).These networks also include components thatare not specified by nuclear DNA. Inheritanceis not through DNA sequences alone (Gissis& Jablonka, 2011). The Modern Synthesistherefore needs to be extended or replaced(Pigliucci & Müller, 2010; Shapiro, 2011).

Gissis SB & Jablonka E, ed. (2011). Transformations ofLamarckism. From Subtle Fluids to Molecular Biology.MIT Press, Cambridge, Mass.

Kohl P, Crampin E, Quinn TA & Noble D. (2010). SystemsBiology: an approach. Clinical Pharmacology andTherapeutics 88, 25-33.

Noble D. (2011a). Differential and integral views of genetics

in computational systems biology. Journal of the RoyalSociety Interface Focus 1, 7-15.

Noble D. (2011b). Neo-Darwinism, the Modern Synthesis,and Selfish Genes: are they of use in physiology? Journalof Physiology 589, 1007-1015.

Pigliucci M & Müller GB, ed. (2010). Evolution - Theextended synthesis. MIT Press, Cambridge, Mass.

Shapiro JA. (2011). Evolution: a view from the 21st century.Pearson Education Inc, Upper Saddle River, NJ.

Symposium 1 (S1)

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Health Issues Relating to Glutamate Usein the Diet

John D Fernstrom

University of Pittsburgh School of Medicine,Pittsburgh, Philadelphia, USA

Claims of adverse effects of monosodiumglutamate (MSG) emerged in the 1960s.Themain claims were that MSG caused (a)Chinese Restaurant Syndrome (CRS),characterized as neck numbness, generalweakness and palpitation, and (b) a toxiceffect in brain, infants being most susceptible.Other claims have surfaced since. Muchresearch was subsequently conducted inanimals and humans, which led regulatorybodies to conclude that MSG is safe in thefood supply. Nonetheless, the question ofMSG safety occasionally resurfaces. Theissues are: (1) CRS, (2) neurotoxicity in brain,(3) obesity, and (4) hypertension. For CRS, acareful study of supposedly MSG-sensitivesubjects showed that no one gets consistent,reproducible reactions to MSG that qualify as

Plenary Lecture

1 0 I S S B Indian J Physiol Pharmacol, Vol. 55, No. 5, Supplement

CRS. For brain neurotoxicity, the keymechanism advanced was MSG penetrationfrom the gut into blood and then brain, whereit caused neuronal overexcitation and death,and brain dysfunction. Numerous studies haveshown that MSG ingestion does not pushglutamate into brain at any age. Hence,neurotoxicity does not occur when MSG isingested. Obesity has recently been claimedto be caused by MSG ingestion, based onepidemiologic findings. However, controlledstudies in animals do not find that dietaryMSG induces weight gain. Finally, a recentepidemiologic study reports a weak, positiveassociation between MSG intake and bloodpressure. However, studies in animals andhumans given MSG orally in large doses havenot found hypertensive effects. In sum, theextensive experimental literature in animalsand humans supports the conclusion that MSGis safe in the human diet.

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Multiple Receptor Systems for UmamiTaste Perception in Humans and Mice

Yuzo Ninomiya*, Ryusuke Yoshida, KeisukeSanematsu, Keiko Yasumatsu, NoriatsuShigemura

Section of Oral Neuroscience, Graduate Schoolof Dental Sciences, Kyushu University, Japan

Umami, first described by K. Ikeda abouta century ago, is the characteristic tastesensation elicited by the sodium salt of theamino acid glutamate (MSG) and 5’-ribonucleotides such as IMP (inositolmonophosphate) and GMP (guanidinemonophosphate). When added to many foods,these umami substances enhance their

palatability. Studies using a variety ofapproaches have indicated that the umamitaste is unique, that is distinct from the tastesof sweet, bitter, sour and salty, and play akey role in intake of amino acids. Recentmolecular biological studies have identifiedstrong candidates for umami receptors,including the heterodimer T1R1+T1R3, andtruncated type 1 and 4 metabotropic glutamatereceptors missing most of the N-terminalextracellular domain (taste-mGluR4 andtruncated-mGluR1) and brain-mGluR1 andbrain-mGluR4. The finding that humanT1R1+T1R3 heterologously expressed inhuman embryonic kidney cells preferentiallyresponds to glutamate, provides strongmolecular evidence for specific umamidetection in humans. Multiple lines ofevidence argue for the involvement ofT1R1+T1R3 in umami responses of bothhumans and mice. Although several studiesargue for the involvement of receptors otherthan T1R1+T1R3 in umami, the identity ofthose receptors remains unclear.

We have recently investigated potentialcontribution of these candidate receptors forumami taste responses in human genetic andmouse molecular and electrophysiologicalstudies. The results indicate that there is astrong association between recognitionthresholds for umami substances andgenetic variations in human TAS1R1,TAS1R3 and GRM1 (mGluR1). In mice, tastecells and nerve fibers that respond to umamicompounds are classified into multiple typesbased on their susceptibilities to specificinhibitors and antagonists for T1R1+T1R3 andmGluRs. These data provide further evidencefor the involvement of mGluRs in addition toT1R1+T1R3 in human umami perception andmouse umami taste responses.


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Brain-Taste-Gut Communication ofGlutamate Signaling during and afterMealing

Kunio Torii

Institute for Innovation, Ajinomoto Co Inc,Kawasaki, Japan

Gustatory and visceral stimulation of foodregulates digestion and absorbed nutrientutilization. Free glutamate (Glu) release fromfood induces the umami taste that increasesfood palatability. Dietary glutamate is the mainsource of energy for the intestinal mucosalabsorption and metabolism, thus, only a traceamount of Glu reaches the general circulationeven after the intake of dietary protein andGlu added in foods when umami tastesensation is not sufficient to be palatable. Inaddition to these roles, we demonstrated aunique gastric sensing system for Glu. Glu isthe only amino acid that activates rat gastricvagal afferents from the luminal side possiblyvia metabotropic Glu receptors on mucosalcells. Functional MRI (4.7T) analysis revealedthat luminal sensing with 1% Glu (mostpreferred concentration) in rat stomachactivates the medial preoptic area (bodytemperature control) and the dorsomedialhypothalamus (basic metabolic regulator),resulting in diet-induced thermogenesiswithout changes in food intake. Interestingly,rats fed a high fat and high sugar diet withfree access to 1% Glu and water showedthe strong preference for Glu solution, andsubsequently lower fat deposition, weightgain and blood leptin compared with thosewithout Glu. In addition, these brainfunctional changes were abolished in the case

of total vagotomized rats. Total and partialgastric and celiac branches vagotomy inducedsimilar results to each other, suggesting thatglutamate signaling should be yielded fromthe luminal side of the alimentary tract tocontribute to the maintenance of our healthydietary life.

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Flavor Perception, Imprinting, and InfantGrowth

Gary K Beauchamp

Monell Chemical Senses Center, Philadelphia,USA

Many of the most common human healthproblems are related to the amounts andkinds of food eaten. Since the flavor senses,mainly taste and smell, play a central role indetermining food choice, an understanding ofthe factors that determine human flavorpreferences is critical if we are to developstrategies to diagnose, treat and ultimatelyprevent these nutritionally related diseases.Some taste preferences and aversions areinnately organized although early experiencescan modify their expression. Both beforeand after birth humans are exposed to abewildering variety of flavors that caninfluence subsequent liking and choice. Wehave been studying as a model system flavorlearning in infants that are fed formulascontaining hydrolyzed casein as their aminoacid source. To adults these formulas areextremely unpalatable but very young infantsaccept them readily. We have discovered asensitive period when exposure to theseflavors renders them highly palatable –possibly for the rest of their l ives.


Interestingly, these formulas are very high infree glutamate and in this regard resemblehuman milk. In very recent studies, we foundthat infants fed these casein hydrolyzedformulas grow at a rate that resembles theoptimal rate for the breast fed infant whereasinfants fed regular cow milk formulas growfaster and, according to some studies, aremore prone to later obesity. We are currentlyentertaining the hypothesis that thehydrolyzed protein formulas are moresatiating than unhydrolyzed cow milk formulaand that the agent(s) mediating this satiationeffect may be free amino acids, perhapsincluding glutamate.

Symposium 2 (S2)

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Sertoli-Germ Cell Interactions in Initiationof Spermatogenesis

SS Majumdar*, I Bhattacharya, M Gautam, SBasu, BS Pradhan

National Institute of Immunology, New Delhi

Testicular Sertoli cells (Sc) have a crucialrole in the initiation and maintenance ofspermatogenesis. Although circulating levelsof LH, FSH and testosterone (T) in infantmonkeys (< 4 months-old) and boys (< 6months old) are similar to that found duringpuberty, Sc fails to support spermatogenesisduring infancy. Xenografting studies haveshown that infant germ cells are quite capableof undergoing differentiation when graftedin conducive environment, suggestingthat functions of infant Sc are suboptimalor defective during infancy. Lack ofspermatogenesis in the phase of high

hormones during infancy is a situation similarto that found in certain categories of maleinfertil i ty. To investigate this intriguingsituation, Sc were isolated and cultured fromvarious age groups of monkeys. Androgenreceptor (AR) and FSH receptor (FSHR)signaling in Sertoli cells (Sc) isolated fromtestes of infant monkeys were compared withthose in Sc from spermatogenically activetestes of pubertal monkeys. Although AR andFSHR mRNA expressions were comparableat these two stages of development, androgenbinding ability of AR and FSH mediated cAMPproduction by Sc were extremely low duringinfancy. Testosterone (T) and FSH failed toaugment the expression of T responsive gene,claudin11, and FSH responsive genes, inhibin-B, stem cell factor (SCF) and Glial cell linederived neurotrophic factor (GDNF) by infantSc. However, intracellular stimulation of FSHRby cholera toxin (CT) augmented cAMPproduction in infant Sc. Similarly in rats,infancy is associated with sufficient circulatinghormones but lack of spermatogenesis. RatSc studies suggested that AR activity is limitedin neonatal life but improves with Sc maturityafter 12-days of age whereas, responsivenessof Sc towards FSH changes in between 9 to12-days of age due to improved binding ofFSH to FSH-R. From these observations, webelieve that compromised AR and FSHRmediated signaling in infant Sc might beresponsib le for the azoospermia in theinfan t i le tes tes in sp i te of adequatehormonal milieu, a situation similar to thatin cer ta in forms of id iopa th ic maleinfertility. With the help of available tools,age specific genes expressed by the Sc frominfant and puber ta l monkey and ra t Scare a l so be ing examined to f ind the i rcorrelation with the status of germ celldevelopment in the testis.


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Modulation of Gonadal Developmentthrough Circadian Oscillations

Chandra Mohini Chaturvedi

Department of Zoology, Banaras HinduUniversity, Varanasi, India

Reproductive cycle generally seems to besynchronized with external and internalfactors such as photoperiod, availability offood, favorable conditions, neural inputs,hormonal balance etc. Neural, endocrine,biochemical and behavioral rhythms providethe basis for temporal organization ofreproductive functions which also involvetemporal synchronization of reproductiveevents within the population as well asbetween the individual and the externalenvironment. Effects of all the external and/or internal factors regulating reproduction arefunneled through hypothalamo-hypophyseal-gonadal axis. A large number of studiesfrom our laboratory have reported that thecircadian phase relation of serotonergic anddopaminergic oscillations may regulateseasonality such as reproduction (HPG axis),fattening, hormonal changes in seasonallybreeding birds and mammals. Moreover, apossible role of circadian organization has alsobeen observed in the puberty attainment ofan avian (Japanese quail) and a mammalian(mice) model. In a specific protocol serotonergicand dopaminergic precursor drugs 5-hydroxytryptophan (5-HTP) and 3, 4-dihydroxy-L-phenylalanine (L-DOPA) wereinjected intra-peritoneally (5mg/100gm bodyweight) at specific time interval (0, 4, 8, 12,16 or 20 hr) over a period of 11-13 days.This set of treatment induced long term effect

on the reproductive performance of thespecies tested so far. In general 8-hr relationsuppresses and 12-hr relation of these drugsstimulates gonadal growth, development andfertil i ty in seasonally breeding species.These findings indicate the importance oftemporal synergism of neural oscillations inthe reproductive regulation (both pubertyattainment and fertility/ sterility) of differentspecies through neuroendocrine axis andsuggest the role of circadian organization inbody physiology.

Abs.S2.3

Sperm DNA Damage and TransgenerationalChanges in Genomic Instability

Satish Kumar Adiga

Clinical Embryology Service & Research,Kasturba Medical College, Manipal University,Manipal, India

Male factor infertility remains a significantproblem contributing approximately 40% ofcases attending infertility clinics. In manyinfertile men, the standard laboratory analysisof the semen reveals no detectableabnormality and therefore, the couple isdiagnosed with unexplained or idiopathicinfertility. Sperm DNA integrity is necessaryfor accurate transmission of geneticinformation to the offspring. There is nowclinical evidence to show that damage tohuman sperm DNA may adversely affectreproductive outcomes and that spermatozoaof infertile men possess substantially moreDNA damage than do spermatozoa of fertilemen. The germ-line instability caused byvarious environmental agents and occupationalfactors is able to persist in populations for


several generations and this instability wouldlead to a significant increase in mutation load.Using mouse model we reported a hierarchyin damage response in preimplantationembryo derived from the DNA damagedsperm. In addition, the implantation potentialof the embryos derived from the DNA damagedsperm was reduced and the feto-placental ratiowas altered in relation to the extent of spermDNA damage. The genetic instability is equallyelevated in the germ line and somatic tissuesof first generation (F1) offspring suggeststhat implantation and post implantationdevelopmental competence of the embryosand the genomic instability are compromisedin relation to sperm DNA damage load.

Abs.S2.4

Chromium and Vanadium InducedTesticular Toxicity

AK Chandra

Department of Physiology, University of Calcutta,University College of Science & Technology,Kolkata, India

Gonadal disruption under the influence ofenvironmental pollutants is of current interestin reproduction. The objective of the studywas to evaluate the physiology of testiculardisruption under exposure of chromium andvanadium respectively in an animal model,to study its mode of action and possibleprevention. The study was conducted in adultSprague Dawley rats after exposure ofchromium and vanadium respectively at sub-lethal doses with different concentrations fordifferent durations. The parameters studiedwere morphology and histology of testis,accessory organs, sperm count followed by

assay of the activities of steroidogenicenzymes viz. Δ5-3β HSD and 17β HSD, assayof hormonal profiles viz. FSH, LH andtestosterone for the evaluation of testiculardegeneration. Possible mode of actioninvestigated through generation of oxidativestress by LPO, SOD and Catalase in testis.Subsequently, prevention was assayed aftersupplementing Vitamin C, E, zinc-chelator andcurcumin including testosterone therapy. Theresults revealed that the morphology, histologyand even the epididymal sperm count weresignificantly altered after exposure to theseheavy metals depending on dose and duration.Biochemical observations showed markedalteration in the activities of steroidogenicenzyme and alteration of hormonal profiledeveloping a hypogonadal state. DecreasedSOD and Catalase activities followed byenhanced LPO were noted in the treatedanimals compared to control while testicularmorphological, histological and histometricparameters, testicular stress enzymes statusremained almost unaltered in treated animalswhich were simultaneously supplemented withantioxidants. Sublethal doses of these heavymetals results in testicular disruption dependingon the dose and the duration of their exposurethat generated oxidative stress. However,simultaneous antioxidant supplementationmay prevent the disruption.

Abs.S2.5

Cellular and Molecular Regulation ofBlastocyst Hatching

Polani B Seshagiri

Department of Molecular Reproduction,Development and Genetics, Indian Institute ofScience, Bangalore, India


In mammals, including humans, blastocysthatching and implantation failures lead toearly embryonic loss and infertility. Prior toimplantation, the blastocyst must hatch outof the acellular glycoprotein coat i.e. zonepellucid (ZP) of the preimplantation embryo.The phenomenon of blastocyst hatching isbelieved to be regulated by a variety ofmolecules such as growth factors, cytokinesand proteases. Moreover, dynamic cellularcomponents such as trophectodermalprojections (TEPs) appear to be involved inhatching (Seshagiri et al., 2002; Sireesha etal., 2008). We have been keenly investigationthe spatio-temporal regulation of zonalysisduring the peri-hatching development byblastocyst derived-cellular and molecularfactors. Our functional studies show thatblastocyst hatching, in the golden hamster, isaccelerated by growth factors i.e., heparinbinding epidermal growth factor or leukemiainhibitory factor. Using a range of proteaseinhibitors of the three classes of cysteineproteases, we show that embryo-derived,cysteine protease(s) i .e. , cathepsisns arepotentially responsible for zonalysis duringblastocyst hatching. Moreover, inhibition ofthe inducible enzyme cyclooxygenase (COX-2) and the estrogen receptor (ER)-á in culturedembryos result in impaired hatching. Wealso show that during the peri-hatchingdevelopment, blastocysts exhibit extensiveactin-based TEPs, which are intimatelyinvolved with lysing ZP. Interestingly, TEPsenrich and harbor a few of the abovedescribed key hatching-enabling factors viz.,cathepsins (-L and -P) and their potentialregulators: COX-2, ER-á and NFkB. Takentogether, we show that blastocyst-derivedcathepsins and TEPs and the associated

signaling biomolecules are functionallyinvolved in hatching. These observationsprovide new insights into our understandingof the phenomenon of mammalian blastocysthatching (Support: DST, New Delhi).

Abs.S2.6

Maternal Fetal Interaction in the ABOBlood Group System: A Study on FetalWastage in a Bengalee Population

AR Bandyopadhyay, M Chatterjee*

Department of Anthropology, University ofCalcutta, Kolkata, India

The selective effects on genotypes couldbe perceived by its manifestation in prezygotic and post zygotic stages which maybe extendable to neonatal and post natalperiods. Selective elimination of genotypescould generally be understood by the studyof reproductive performance of the couple onthe basis of mating types. Actual studies onproducts of conception of these couplesessential for understanding the process ofselective elimination of the alleles. Selectionadjudicated by relative fitness of the genotypesdetermines their incidence in the nextgeneration. The present study comprised of992 abortive parents, 124 spontaneousaborted foeti and 1000 newborns along withtheir 1814 parents. The result of the presentstudy indicated significantly (p<0.05) higherfrequency of ABO incompatibility among thecouple having spontaneous abortions incomparison with the couple combination ofthe parents of the newborns. Furthermore,significant heterogeneity has been found inthe distributions of ABO blood group alleles


between the couple having spontaneousabortions compare to the couple of thenewborns. However, significantly (P<0.05)higher A alleles revealed among the fetuscompare to the newborns. Therefore thepresent study vindicated ABO incompatibilitybetween the couples is likely to be a riskfactor for early spontaneous abortions and alsothe heterozygote selection of ABO bloodgroup genotypes.

Abs.S2.7

Role of Gene-Environment Interaction inAdverse Reproductive Outcomes

BD Banerjee

Environmental Biochemistry & Molecular BiologyLaboratory, Department of Biochemistry,University College of Medical Sciences & GTBHospital, University of Delhi, Delhi, India

Many human disorders result from acomplex interaction between an individual’sgenetic make-up and environmental stressorsHumans are exposed to numerous xenobioticsconstantly and unavoidably such as pesticides,metals, PCBs etc. Endocrine disruption,genetic predisposition, altered immunesurveillance, inflammation and subsequentoxidative stress may antedate adversereproductive outcomes and contribute to itspathogenesis. Although environmental factorsare important, genetics clearly plays a role inadverse reproductive outcomes. Identificationof genetic susceptibility variants will lead tobetter understanding of the role of variablefactors in adverse reproductive outcomes. Ithas been observed that a lot of women withgenetic polymorphism do experience normaldelivery while some do not. It can be

hypothesized that genetic polymorphismrequires the presence of certain environmentalstimuli to have consequences of clinicalsignificance. The recent abundance ofepidemiologic research examining associationsbetween polymorphic genes that codefor enzymes involved in xenobioticbiotransformation and disease has on occasiongenerated interesting findings. Recent studiesfrom our laboratory clearly showed theimportance to assess the role of variations inthe human genome (polymorphisms) inmodifying the effect of exposures toxenobiotics to define “Gene–EnvironmentInteraction”, which render some individualsor groups in the population more or lesslikely to develop adverse health effect.Current and future efforts to identify newpolymorphisms in genes involved inenvironmental response with larger samplesize will broaden the scope of potentialgenetic effect modifiers. Currently, ourlaboratory is involved in studying the role of“Gene-Environment Interaction” withreference to xenobiotic metabolism andoxidative stress related genes in variousdiseases such as cancer, neurodegenerativediseases, chronic kidney disease, hypospadiasand we have reported the association oforganochlorine pesticides (OCPs) with manyof adverse reproductive outcomes such aspreterm birth, intrauterine growth retardation,recurrent miscarriage. Our effort in this areamay also lead to the development of possiblebiomarker(s) to screen individuals, exposedto pesticides and preventive measures for safereproductive outcomes. Determining the effectof these polymorphisms along with OCPsburden will be of paramount importance inan early diagnostic strategy and preventivemeasures for adverse reproductive outcomes


with reference to environmental toxins.

Abs.S2.8

Antimicrobial Peptides and EarlyPlacentation

J Sengupta*, D Ghosh

Department of Physiology, All India Institute ofMedical Sciences, New Delhi, India

Antimicrobial peptides are fast emergingas alternative to conventional antibiotics towhich various bacterial strains are increasinglyshowing resistance. Antimicrobial peptidesknown as host defense peptides form anevolutionarily conserved component of innateimmune response. In this category the geneencoded cationic antimicrobial peptidespreferentially interact with negatively chargedlipids, which are major components ofbacterial cell membranes resulting inmembrane perturbations such as poreformation, alterations of the curvature strainand induction of lipid-peptide domainformation resulting in membrane dysfunction.In mammalian cell membranes, negativelycharged moiety such as phosphatidylserine(PS) line inner cell membranes with theexception that in the placenta the PS flip andits externalization involves syncytialization.Placental growth in the first trimester isexponential and is derived from the progenitorpopulation of cytotrophoblast cells.Cytotrophoblast cells differentiate intointermediate type or transitional type ofcytotrophoblasts that undergo fusion toform the multinucleated outer layer ofsyncytiotrophoblast. Therefore we undertooka study to examine the potential toxicity ifany of first trimester placental cytotrophoblast

cells to an in vitro exposure to a syntheticAMP, Ala8,13,18-magainin II amide (AMA).Administration of AMA resulted in attenuationof differentiation, enhancement in apoptosisand loss of viability in early placental villitrophoblast cells in primary culture. It appearsthat administration of alpha-helical AMP mayadversely affect the process of placentationand pregnancy outcome.

Abs. S2.9

Trophoblast and Fusion

B Huppertz

Institute of Cell Biology, Histology andEmbryology, Medical University of Graz, Graz,Austria

In the human placenta, the chorionic villiare covered by a two-layered epithelial layer,the villous trophoblast. Mononucleated stemcells resting on the basement membrane, thevillous cytotrophoblast, proliferate, leave thecell cycle and start to differentiate. Their finaldifferentiation step is syncytial fusion withthe second layer, the multinucleatedsyncytiotrophoblast. Villous cytotrophoblastdifferentiation and fusion with the overlyingsyncytiotrophoblast is regulated by factorssuch as growth factors, cytokines,transcription factors, structural membraneproteins and proteases. Differentiation andsubsequent fusion of villous cytotrophoblastwith the overlying syncytiotrophoblast is anessential process for growth and maintenanceof the villous trophoblast layer in the humanplacenta. The understanding of intrinsicmechanisms behind this process is in itsinfancy, while the list of suggested factors,involved in intercellular fusion of villous


trophoblast, rapidly increased in the recentpast and promises progress on this issue. Theearly stages of the apoptosis cascade, inparticular caspase 8, was suggested to triggerdifferentiation of the cytotrophoblast, primingthem for upcoming fusion. This may soundparadoxical, especially for those who stillassociate caspase activity with apoptosis only.During the last decade we have shownevidence that activity of apoptosis relatedmechanisms is a prerequisite for the processof syncytial fusion. Especially, caspase 8, anaspartate-specific cysteine protease, alsoknown as one of the initiator caspases duringapoptosis, has been shown to be crucial forvillous trophoblast differentiation. It ishypothesized that caspase 8 is activated invillous cytotrophoblast just prior to fusion ofthese cells and escorts the nuclei from themononucleated to the syncytial state. Here,data on caspase 8 in the villous trophoblastlayer will be summarized, with a specificfocus on localization of pro and active forms,the sites of its activation and deactivation,and its role and regulation during fusion.

Symposium 3 (S3)

Abs.S3.1

Role of Adenosine in the Regulation ofSleep during Hypobaric Hypoxia

Ray K, Kumar S, U Panjwani*

Neurophysiology Division, Defence Institute ofPhysiology and Allied Sciences, Timarpur, Delhi,India

Objective : Sleep disturbance in hypobarichypoxia and role of brain monoamines is

being investigated by this laboratory. Thepresent study aimed to investigate the role ofanother neurotransmitter adenosine and itsreceptor subtype in sleep in continuoushypobaric hypoxia.

Method : Rats were exposed to simulatedaltitude ~ 7620 m( 282mm Hg, partial pressureof O2 59 mmHg) for 7 and 14 dayscontinuously in an animal decompressionchamber. During the period of hypoxiaexposure, adenosine A1 receptor agonist andantagonist were injected intraperitoneally andsleep was recorded after 7 and 14 days ofexposure. Rats were sacrificed and brainadenosine levels were estimated by HPLC.

Results : After administration of adenosineA1 agonist, quiet awake stage wassignificantly decreased (P<0.05) and quietsleep, deep sleep and REM sleep stages andtotal sleep time significantly increased(P<0.05). After administration of A1antagonist quiet awake increased (P<0.01),while deep sleep and total sleep timedecreased (P<0.01),with no significant changein REM sleep and quiet sleep stages. Brainadenosine level significantly increased after7 (P<0.05) and 14 days (P<0.01) of hypoxicexposure.

Conclusion : Changes in total sleep time anddifferent sleep stages by adenosine A1receptor agonist and antagonist point to amodulatory role of adenosine in hypobarichypoxia.

Abs.S3.2

High Altitude Physiology: Neural Basis ofHypobaric Hypoxia Induced CognitiveDeficits


BS Shankaranarayana Rao*, ADJ Titus, TRRaju

Department of Neurophysiology, NationalInstitute of Mental Health and Neuro Sciences(NIMHANS), Bangalore, India

Hypobaric hypoxia (HBH) encountered athigh altitude is known to have deleteriouseffects on cognitive functions. Individualsexposed to HBH commonly confronted withproblems such as acute mountain sickness,high altitude pulmonary and cerebral edema.Simulated hypobaric hypoxia (HBH),resembling high altitude hypoxia severelyaffects the CNS and results in severalphysiological changes. The hippocampus isclosely associated with learning and memoryand an insult to this region affects cognition.Previous studies suggest that rapid orprolonged exposure to HBH is associated withpsychomotor and cognitive impairments. Thedefense personnel, mountain climbers andrescue teams are exposed to such harshenvironment and thus it demands a systematicstudy emphasizing the subtle effects of suchextreme environments on cognitive function.To suggest a solution to this problem itis necessary to understand in detail themechanisms of underlying cognitive deficitsat HBH. We have demonstrated that the short-term hypobaric hypoxic exposure results inhippocampal dendritic atrophy and isassociated with learning and memoryimpairment in adult rats. Further, chronicexposure to HBH severely impaired thelearning and memory in radial arm maze taskand this was associated with decreasedhippocampal long-term potentiation (LTP) andreduction in the levels of biogenic aminesand acetycholinesterase activity in thehippocampus. Our study suggests that

hippocampal dendritic atrophy, reduced LTP,decreased cholinergic and aminergicneurotransmission on exposure to HBH couldbe the basis for the cognitive deficits.Understanding the neural basis of deleteriouseffects of HBH can lead to the developmentof therapeutic strategies in the treatment ofhigh altitude associated disorders includingcognitive decline.

Abs.S3.3

Differential Regulation of AutonomicResponses in Acclimatized Lowlanders onProlonged Stay at High Altitude

Sunil K Hota1*, Priyanka Dhar1, Vijay KSharma1, Kalpana B Hota1, Ravi B Srivastava1,Shashi B Singh2

1Defence Institute of High Altitude Research,Defence Research & Development Organisation,Leh-Ladakh, India.2Defence Institute of Physiology and AlliedSciences, Defence Research & DevelopmentOrganisation, Timarpur, Delhi, India

Global hypoxia at high altitude is reportedto cause sympathetic dominance that maycontribute to the pathogenesis of high altitudeillnesses. Although, there is evidence thatexposure to high altitude leads to severalpathophysiological alterations including highaltitude pulmonary edema (HAPE) or highaltitude cerebral edema (HACE), the effect ofprolonged stay at high altitude on autonomicfunctions, however, remains to be explored.Thus, the present study aimed at investigatingthe duration dependent effect of high altitudeon autonomic neural control of cardiovascularresponses. A total of 229 subjects, 55 of thetrans-Himalayan native population (4500 m),


58 of acclimatized low landers (ALL) stayingat an altitude for < 6 months (4500-5000 m)and 60 of ALL staying for >18 months (4500-5000 m) were studied and compared with 56of the sea level low landers (720 m). ECGrecordings were measured and heart ratevariability (HRV) parameters were calculatedto determine the sympatho-vagal responses.The physiological indices viz. blood pressure,pulse rate, SpO2 and BMI were alsoinvestigated. Blood urea nitrogen, creatinine,serum lipids, alanine aminotransferase,aspartate aminotransferase, homocysteine,folate, Vitamin B12, Angiotensin II andangiotensin converting enzyme activity werealso estimated from serum samples. Wedemonstrate here for the first t ime thatprolonged stay at extreme altitudes >4500 mabove sea level resulted in a persistentsympathetic dominance (P<0.01) whencompared to sea level populations. Theincreased LF/HF ratio on 6 months stay(P<0.01) at high altitude was regulated byelevated Angiotensin II (P<0.01) whilesubsequent blunting of the vagal response on18 months stay (P<0.05) could be attributedto increased homocysteine levels that wereindependent of folate concentration. Hence,our findings provide new insights to thesympathetic dominance at high altitude whichis differentially regulated by angiotensin IIand homocysteine depending on the durationof stay.

Abs.S3.4

Dyspnea at High Altitude

K Ravi

Department of Physiology, V.P. Chest Institute,University of Delhi, Delhi, India

Dyspnea is often defined as an abnormallyuncomfortable awareness of breathing.Various terminologies such as, air does notgo all the way down, tightness or tiredness inthe chest, choking sensation, breathlessness,an urge to breathe etc., are often used bypatients to describe dyspnea. Young subjects(soldiers) who are exposed to high altitudewith established high altitude pulmonaryedema (HAPE) complain of dry cough,breathlessness, and chest pain. Since HAPEis an end-stage where there is alveolarinfiltration, it is likely that such symptomsare initiated much earlier when there ispulmonary congestion. Thus, there is thepossibility that starting from the initial stageand proceeding to the later stage, thepulmonary sensory receptor afferent systemmay show a progressive stimulation.

This possibility was examined recently inrabbits. Adult rabbits (Group II, n=6) wereexposed to an altitude of 15,000 feet for 12hours in a high altitude simulation chamber.They were subsequently anesthetized andvagal afferent activity originating from airwayrapidly adapting receptors (RARs) wasrecorded. Another group of rabbits (Group I,n=6) exposed to room air served as controls.Lung histology was performed in both thegroups. It was observed that with this altitude,for this duration, when there was onlypulmonary congestion, there was a significantincrease in the basal activity of RARs in GroupII compared to the basal RAR activity inGroup I. When the duration of high altitudeexposure was extended to 36 hours in anothergroup of rabbits (Group III), there was alveolaredema. Again, there was an increase inthe basal activity of RARs, which wassignificantly higher than those in Groups Iand II. The results indicate that the RARs may


be an afferent mechanism for the respiratorysymptoms reported by subjects who ascendto high altitudes with or without radiologicalevidence of alveolar infiltration.

Pulmonary hypertension is anotherprominent symptom of high altitude exposure.Even though hypoxia per se could raise thepulmonary artery pressure, it could also bedue to increased production of vasoconstrictorneuropeptides such as substance P (SP).Evidence was obtained in Groups II and IIIthat with the respective exposures, there wasan increase in lung SP concentration.Additionally, in these two groups, even sub-threshold doses of SP stimulated the RARssignificantly. The results indicate that at highaltitude, endogenous SP may accentuate therespiratory symptoms through the stimulationof RARs.

Supported by a research grant from DIPAS, Delhi

Symposium 4 (S4)

Abs.S4.1

A Role for mGluR5 in the Pathogenesis ofFragile X

Gul Delen

Department of Psychiatry & Behavioral Sciences,Larry I. Lokey Stem cell Research Building(SIMI), Stanford, California. USA

Fragile X (FX) is the leading inheritedcause of mental retardation and an identifiedcause of autism. The metabotropic glutamatereceptor (mGluR) theory of fragile X positsthat FMRP and Gp1 mGluRs normallywork in functional opposition, and that in the

absence of FMRP, unchecked mGluR-dependent protein synthesis leads to thepathogenesis of FX. The goal of these studieswas to test the mGluR theory. By reducingmGluR5 gene dosage by 50%, we were ableto bring 7 of 8 fragile X phenotypessignificantly closer to normal. Although theprecise molecular basis of the interactionremains to be determined, the data showunambiguously that mGluR5 and FMRP actas an opponent pair in several functionalcontexts, and support the theory that manyCNS symptoms in fragile X are accounted forby unbalanced activation of Gp1 mGluRs.These findings have major therapeuticimplications for fragile X syndrome andautism.

Abs.S4.2

Calcium Channels and G Protein CoupledReceptors – a Lipid Connection

Tora Mitra Ganguly

National Brain Research Centre, Manesar,Haryana

Nociceptive stimulation from the peripheryand visceral organs causes dorsal root ganglianeurons to release substance P (SP) ontothe soma and dendrites of dorsal horn(DH) neurons. These DH neurons expresstachykinin receptors (NK-1R) and N-typecalcium channels (N-channels). SP, theprincipal neuropeptide mediating pain, bindsto NK-1R. Pharmacological blockers of N-channels are used as analgesics thusimplicating N-channels in pain perception.Yet the complete mechanism by which SPmodulates N-channel activity is unknown. Gq-coupled M1 muscarinic receptors enhance and


inhibit native N-type calcium current (N-current) at negative and positive potentialsrespectively; arachidonic acid (AA) mimicsthis modulation. Blocking cytoplasmicphospholipase A2 (cPLA2) minimizes thismodulation. Here, by monitoring recombinantchannel (Cav2.2, α2δ and β3) activity inHEK-293 cells using whole-cell patch clamptechniques, we show that N-current inhibitionby 250 nM SP involves NK-1R activation ofextracellular receptor kinases (ERK1/2), PLA2and downstream release of fatty acids,possibly AA. In separate studies, ERK1/2activation has been reported downstream ofGq-coupled NK-1R activation and upstreamof cPLA2 activation. Here we show thatactivation of NK-1R, ERK1/2 and PLA2 occurin a linear pathway leading to N-currentmodulation. We also show that SP inhibits orenhances N-current depending on the type ofβ subunit co-expressed with N-channels. Whileβ3-containing channels exhibit inhibition,β2a-containing channels exhibit enhancement.Among the different β subunits, β2a isuniquely palmitoylated on its two amino-(N-)terminal cysteine residues. We previouslyhypothesized that the palmitoyl groups on β2ablock N-current inhibition to reveal latentenhancement. Using HEK cells expressingNK-1R, Cav2.2, β3, α2δ and eGFP, we foundthat pre-incubation of cells with free palmiticacid (10 µM) eliminates SP-mediatedinhibition of N-current that normally occurswith β3 expression. In contrast, directapplication of palmitic acid has no effect ofits own on N-channel activity. These findingssupport our model that palmitoylation isnecessary and sufficient to block inhibitionof N-current. This novel role of palmitoylationprovides a possibility of plasticity at amolecular level in the pain pathway

Abs.S4.3

Disruption of Calcium Signaling inNeurons in Cerebral Ischemia : Role ofAMPA Receptors

Sudha Mishra*, Lakshmi C

Department of Biophysics, National Institute ofMental Health and Neurosciences (NIMHANS),Bangalore

The pathogenesis of cerebral ischemiainvolves massive ATP depletion leading toloss of ion homeostasis in neurons. Ampleevidence shows that intracellular calcium([Ca2+]i) overload as a consequence ofcerebral ischemia is a major contributingfactor towards acute and delayed neuronalinjury. Multitudes of mechanisms have beensuggested to elevate neuronal cytosolic calcium.Amongst these the [Ca2+]i rise mediated byelevated extracellular glutamate is proposedto be a key regulator of neuronal injury. BothNMDA and AMPA subtype of glutamatereceptors have been implicated in mediationof glutamate induced [Ca2+]i rise. NMDAmediated [Ca2+]i increase and subsequentneuronal injury has been extensively studied.Some of the recent studies indicate a morecentral role for AMPARs as their antagonistsare potentially more effective in neuroprotectionthat NMDA antagonists in rat models ofcerebral ischemia. AMPARs undergo constitutiveand synaptic activity dependent translocationfrom intracellular pools to membrane surface.Activity of AMPA receptor-channels, whichare heterotetramers of GluR1-4 subunits,depends on its subunit composition. Thefunctional AMPARs which are assembledfrom GluR1, 3, 4 subunits are permeable tocalcium whereas GluR2 containing AMPARsare impermeable to divalent cations. Fewrecent reports have suggested that following


ischemia GluR2 subunit surface expression isreduced and GluR2 lacking AMPARs aredirected to synaptic sites resulting in delayedneuronal injury.

Based on this evidence we investigatedthe involvement of AMPARs in mediatingacute and delayed Ca2+ rise and resultanttoxicity in rat hippocampal neuronal culturesusing oxygen glucose deprivation as anin vitro model for ischemia. Quantitativemeasurements by fluorescence imagingsuggest equal contribution of both AMPA andNMDA receptors in inducing [Ca2+]i riseduring the acute phase of ischemia.Interestingly, contrary to earlier reports ourstudy shows no enhancement in AMPAinduced [Ca2+]i rise in post ischemichippocampal neurons. This suggests thatelectrophysiologically measured increase inGluR2 lacking AMPAR current is nottranslated into significant AMPA receptormediated cytosolic elevation in calcium.

Abs.S4.4

HIV-1 and Drugs of Abuse – It Takes Twoto Tango

Pankaj Seth*, Shaily Malik

NeuroAIDS Laboratory, Molecular and CellularNeuroscience, National Brain Research Centre,Manesar, India

Central nervous system (CNS) infectionby HIV-1 cause glial cell mediated irreversibledamage to the neurons leading to progressivemotor and cognitive dysfunctions and otherdementia like symptoms, collectively calledHIV-associated neurocognitive disorders(HAND). Our findings suggest HIV-1transactivating protein, Tat affects proliferationand differentiation ability of human neural

stem cells. An enhanced damage to brainfunctions has been reported in HIV/AIDSpatients that are drug abusers. Severalexperimental studies in primates and humanpostmortem studies have revealed that damageto dendritic spines, synaptic functions,neurons and glial cells is far greater thanin cases not exposed to drugs of abuse.However, the molecular mechanismsunderlying opioid mediated enhancement ofHIV neuropathogenesis are still unknown andwarrant extensive explorations. We attemptedto fill this gap by a step wise approach usinga well characterized human neuronal cellculture system. We studied neuronal damageby looking into alterations in mitochondrialfunctions and cell signaling mechanisms ofneurons exposed to the double insult of HIV-1 Tat and Morphine. Significant alterations inmitochondrial membrane homeostasis wereobserved following co-exposure of neuronalcells to HIV Tat and morphine. Extensivestudies into MAPK signaling pathwaysrevealed involvement of JNK and ERK1/2pathways in enhanced toxicity of Tat andmorphine. Our findings provide insights intocellular and molecular basis for the enhanceddamaged seen in neuronal cells due to co-morbidity of HIV-1 viral proteins and morphine.These findings correlate well with clinicalobservation of enhanced cognitive and motordeficits in drug abusing HIV/AIDS patients.

Abs.S4.5

Plasticity of Inhibition in the BasolateralAmygdala

Jai S. Pollepalli

Stanford University School of Medicine,California, USA


The lateral amygdala (LA) plays a keyrole in emotional learning and is the mainsite for sensory input into the amygdala.Within the LA, pyramidal neurons comprisethe major cell population with plasticity ofinputs to these neurons thought to underliefear learning. Pyramidal neuron activity istightly controlled by local interneurons, andGABAergic modulation strongly influencesamygdala-dependent learning. Synaptic inputsto some interneurons in the LA can alsoundergo synaptic plasticity, but the identityof these cells and the mechanisms that underliethis plasticity are not known. We showthat long-term potentiation (LTP) in LAinterneurons is restricted to a specific type ofinterneuron that is defined by the lack ofexpression of synaptic NR2B subunits. Wefind that LTP is only present at cortical inputsto these cells and is initiated by calcium influxvia calcium-permeable AMPA receptors. LTPis maintained by trafficking of GluR2-lackingAMPA receptors that require an interactionwith SAP97 and the actin cytoskeleton.Our results define a novel population ofinterneurons in the LA that control principalneuron excitability by feed-forward inhibitionof cortical origin. This selective enhancedinhibition may contribute to reducing theactivity of principal neurons engaged duringextinction of conditioned fear.

Symposium 5 (S5)

Abs.S5.1

Introduction to Biologics

Nusrat Shafiq

Department of Pharmacology, PGIMER,Chandigarh, India

Biologics include a wide range of productssuch as vaccines, blood and bloodcomponents, allergenics, somatic cells, genetherapy, tissues, and recombinant therapeuticproteins. Biologics can be composed ofsugars, proteins, or nucleic acids or complexcombinations of these substances, or may beliving entities such as cells and tissues.Biologics are isolated from a variety of naturalsources - human, animal, or microorganism -and may be produced by biotechnologymethods and other cutting-edge technologies.In contrast to most drugs that are chemicallysynthesized and their structure is known,most biologics are complex mixtures that arenot easily identified or characterized. Betterunderstanding of pathogenic processes,particularly the immune system, topped withadvances in medicinal chemistry has led tothe evolution of biologics as therapeuticagents. In the previous decade severalbiologics were approved for human useto address the unmet medical needs ofconditions such as cancer, rheumatoidarthritis, psoriasis, ulcerative colitis, etc.

The bench to bedside process of biologicsdevelopment albeit similar to the drugdevelopment process has certain peculiarities.These may include identification ofappropriate animal species for toxicity testing,dosage conversions, development of analyticalmethods and a possibility of life threateningunpredictable adverse effects (TGN 1412).Cost of biologics (running into lakhs ofrupees), resurgence of latent tuberculosis arethe other issues pertinent to developingcountries like ours. Unlike the genericsavailable for off-patent drugs, the processesand regulatory issues for biosimilars need tobe streamlined. To top it the real efficacy ofmany of these agents is only in a small subset


of population. These and other emerging factsare important for health care policy makersparticularly in resource limited settings likeours.

Considering the fact that biologics arecurrently nearly 30 billion dollar marketand the fact that drug pipeline is constantlydiminishing, pharmaceutical companies areincreasingly shifting their focus to biologics.However, since most of the lead research thatleads to the development of biologics, takesplace in academic institutes, these figures maybe disproportionately inflated for the interestof innovator companies. Pharmaceuticalcompanies and regulatory agencies are gearingup to tap this market. For the interest of healthsciences, academic research institutes shouldtake the lead in pioneering research to unmetmedical needs and partner with governmentand pharmaceutical companies to developcost-effective biologics for greater commongood.

Abs.S5.2

Special Aspects of Conducting ClinicalTrials with Biologics

Samir Malhotra

Department of Pharmacology, PGIMER,Chandigarh, India

Broadly, biologics include proteins,antibodies, peptides, and some vaccines. Mostof the times their route of administration isparenteral as they are poorly absorbed orally.

Clinical trials are needed for new drugsincluding biologics to demonstrate that theproduct is safe and effective. These trials areplanned and conducted by the sponsor, which

is usually a biotech company in case ofbiologics.

These trials need to be conducted as perGCP, international and national regulatoryguidances as well as ethical principles. Mostof the aspects of conducting these trialsremain similar in case of drugs and biologicsalthough there a few differences.

The fundamental issues related to clinicaltrials remain unchanged, i.e. a controlled trial,control can be concurrent (placebo, activedrug) or historical; randomization, ifapplicable; blinding, if possible; and so on. Itis the responsibility of the Investigators tochoose the most appropriate design that willhelp them answer the scientific question posedby the trial. The other elements like inclusion/exclusion criteria, methods of measurement,adherence, etc are all broadly similar.

Early exploratory trials with biologics dopresent some challenges distinct from thoseseen with “typical” drugs. For instance, about25% of patients with inflammatory boweldisease that participated in the early clinicaltrials of the biologic agent infliximabdeveloped severe delayed hypersensitivityreactions due to development of anti-infliximab antibodies after they were re-exposed to inflixamab after its marketing,preventing them from using that drug eventhough they had responded well in the trials.

Also, in phase 1 trials, the risk benefitassessment with biologics is different ascompared to drugs and in many of the phase1 trials, patients are recruited instead ofhealthy volunteers. Moreover, the instead ofthe concept of maximum tolerated dose wemay use “less is more”. The FDA guidanceon safe starting dose for biologics should be


seen when planning phase 1 trials. It may bepreferable to estimate the starting dose usingthe Minimal Anticipated Biological EffectLevel (MABEL) in addition to NOAEL.Staggered enrolment is preferred so that thereis sufficient time between two dose levels.The methods of evaluation of safety of thenew agent are also different as biologicspresent greater challenges – keep in mindparticularly the Tegenero experience. Doseescalation schemes may involve lesserincrements as compared to drugs andBayesian methods are useful.

Adaptive designs may be preferable inphase 2/3 trials with biologics to maintain agreater degree of flexibility in the trial designso that incoming information is taken intoconsideration while proceeding further. Safetyconsiderations are of prime importancebecause the biologic agents have the potentialto lead to derangement in multiple cascadingpathways in the organism. Manufacturingissues also assume greater importance becauseimpurities can severely jeopardize the safetyof the compound. Risk of infections may begreater with biologics and longer follow-upperiods may be needed to detect some adverseeffects because of their nature.

Abs.S5.3

Development of Biosimilars : Challengesand Opportunities

Rajan Mittal

Clinical Pharmacology, Dr. Reddy’s LaboratoriesLtd, Hyderabad, India

Biosimilars are products similar in quality,safety and efficacy to the originator’s licensedbiological products. Due to high cost of

therapy, biological products have remainedout of reach of majority of the people indeveloping countries. Thus a huge need existsfor biosimilars in countries like India. As perthe market research, biological products withglobal sales of over $60billion will lose patentprotection over the next 5 years. IndianPharmaceutical industry, having alreadydeveloped and launched biosimilars, is poisedto play a major role in the global biosimilars’market.

The pharmaceutical industry has evolvedfrom developing non-specific natural productsto developing highly specific chemical drugsand biological drugs. Developing genericversions for chemical drugs is relatively easydue to precise chemical processes involvedand the small size of the molecules. However,complexities of structure and massive size ofthe protein molecules, and the complexmanufacturing and production processesmakes development of biological productswhich are absolutely identical difficult. As themanufacturing process for a biosimilar isdifferent from that of the innovator’s product,some differences in the final product areexpected. However, even minor changes inmanufacturing process can affect the threedimensional structure of the protein, thepost-translational modifications such asglycosylation profile and the impurity profileof the product. These subtle differences canalter the quality, efficacy and safety of theproduct, including immunogenicity. Thus theCMC, non-clinical and clinical studies ofbiosimilar products need to be more extensivethan the pharmaceutical and bioequivalencestudies for generics of chemical drugs.

Guidance documents regarding data to begenerated for licensing of biosimilar drugs are


available from the EMEA, WHO and variousregulatory agencies including Korea andMalaysia. All guidance documents stresson exhaustive comparative studies of thebiosimilar product with the referencebiological product, including physicochemicaland in-vitro biological similarity, comparativenon-clinical pharmacodynamics and toxicology,and therapeutic equivalence. In addition,extensive immunogenicity studies need to beconducted in human subjects as the animalstudies are usually not predictive of theimmunogenicity in humans. Further, theimmune reaction to impurities can render thedeveloped product non-similar to thereference product. Due to complexitiesinvolved, a case-to-case approach is thusneeded for the development of biosimilarproducts.

In addition to complexities involved in thedevelopment of biosimilars, examples ofsuccessful and unsuccessful attempts atdeveloping biosimilars will also be discussedduring the talk.

Conclusion: Development of biosimilarsis complex and challenging. Companies thatare able to overcome these hurdles will likelyplay a major role in the pharma sector in thefuture.

Symposium 6 (S6)

Abs.S6.1

Diabetic Cardiomyopathy : Insights intoPathogenesis and Therapeutic Approaches

Sanjay K Banerjee

Division of Pharmacology, Indian Institute ofChemical Technology, Hyderabad, India

Cardiovascular disease is responsible for80% of deaths among diabetic patients muchof which has been attributed to coronaryartery disease. There is an increasingrecognition that diabetic patients suffer froman additional cardiac insult termed “Diabeticcardiomyopathy”. Experimental as well asclinical studies suggest that extensivemetabolic and molecular changes may underlieboth functional and structural alterations ofthe diabetic myocardium.

Translational studies are, however, limitedand only partly explain why diabetic patientsare at increased risk of cardiomyopathy andheart failure. The most important mechanismsof diabetic cardiomyopathy are metabolicdisturbances (alteration of glucose transporters,increased free fatty acids, carnitine deficiency,changes in calcium homeostasis), myocardialfibrosis, cardiac autonomic neuropathy(denervation and alterations in myocardialcatecholamine levels), epigenetic changes andinsulin resistance. Treatment paradigms arevery much limited to interpretation and needmore attention. There is an urgent need toconduct pathogenetic, diagnostic andtherapeutic studies specifically in diabeticpatients with cardiomyopathy to betterunderstand the molecular mechanisms whichinitiate and progress diabetic cardiomyopathyand to formulate more effective andappropriate treatments.

Abs.S6.2

The Space Odyssey of Heart :Pharmacological Protection for the Heartin Space

Pradeep T, Santosh B, Suvro Chatterjee*


Vascular Biology Lab, Anna University – K.B.Chandrasekhar Research Centre, MIT Campus,Chrompet, Chennai, India

During spaceflight, astronauts experiencemicrogravity which has profound effects onthe circulatory system. Though the heart andthe vascular system is adapted to work againstgravity, a new environment such as microgravitymakes adaptation difficult since the heart nolonger has to work hard, partly because thereis less fluid to pump through and so it shrinks.Nitric Oxide (NO), a vasodilator and signalingmolecule, is an important determinant ofbasal cardiac functions. Alteration of NOmetabolism is primarily responsible for theassociated cardiovascular deconditioning. Ourprevious work showed that microgravityinduces NO production in endothelium andpromotes angiogenesis. Based on thoseobservations, we hypothesize that alteredgravity disturbs NO homeostasis in the heartas well to bring about cardiac malfunctions.

To study cardiac functions in-vivo underaltered gravity, we subjected zebrafish andchick embryos to alerted gravity by employingthe in-house fabricated clinostat, whichsimulates microgravity. The heart rate ofzebrafish and chick was calculated fromvideos records of heart movements after twohours of treatment with gravity or microgravityin the presence and absence of NO. Weobserved that microgravity increases the heartrate in zebrafish. Simultaneously we alsomonitored NO production in the heart undermicrogravity treatments. The heart rate of thechick and zebrafish embryos came back tonormal when they were treated with specificNO scavengers. Further, we studied themechanis t ic aspec ts of microgravi typerturbations in cardiac functions in relation

to NO. The results of the study indicate thatmicrogravity promoted NO modulates actinpolymerization of cardiomyocytes to enhancethe heart beat under altered gravity conditions.

We conclude that NO recovers alteredgravity effects on cardiovascular system inchick and zebrafish respectively.

This work was supported by a grant fromIndian Space Research Organization (ISRO)(Microgravity: Anna-Univ:11) to SC.

Abs.S6.3

Regeneration of Infarcted Myocardiumwith Resveratrol-modified Cardiac StemCells: Role of Micro-RNA

Nikolai Gorbunov1, Goran Petrovsky2,Narasimman Gurusamy3, Diptarka Ray2,Do Han Kim2, Dipak K Das3

1Cardiovascular Research Center, University ofConnecticut Schol of Medicine, Farmington, CT,USA. 2Walter Reed Army institute, Bethesda, MD,USA. 3Harvard Uiversity Medical Center, Boston,MA, USA

The major problem in stem cell therapyincludes viability and engraftment efficacy ofthe stem cell after transplant. Indeed, the vastmajority of host-transfused cells do not survivebeyond 24 to 72 hours. In order to increasesurvival and engraftment of implanted cardiacstem cells in host we developed a techniqueof treatment of the cells with resveratrol, andtested this technique in rat model of LAD(the left anterior descending) occlusion. Withthis goal the multipotent clonogenic cardiacstem cells (the cardiac stem cells) isolated fromrat heart were stably transfected with EGFPfor purpose of tracking in tissue and were


pre-treated with 2.5 µM resveratrol for 60minutes. Rats were anesthetized, hearts openedand the LAD was occluded to induce heartattack. The animals were divided into twogroups each of them was subjected totransplant with either resveratrol-treated orresveratrol-non-treated cardiac stem cells. Oneweek after the LAD occlusion, the cardiacreduced environment was confirmed inresveratrol treated rat hearts by the enhancedexpression of nuclear factor-E2-related factor-2 (Nrf2) and redox effector factor-1 (Ref-1).M-mode echocardiography was performed todetermine cardiac function up to four monthsafter the stem cell therapy. Initially after 7days, both groups revealed improvement incardiac function, but only resveratrol-modifiedstem cell group revealed improvement incardiac function (left ventricular ejectionfraction, fractional shortening and cardiacoutput) at the end of one month, two monthsand four months period. The improvement ofcardiac function was accompanied by theenhanced stem cell survival and proliferationas evidenced by the expression of cellproliferation marker Ki67 and differentiationof stem cells towards the regeneration of themyocardium as evidenced by the expressionof EGFP up to four months after LADocclusion in the resveratrol treated stem cellgroup of hearts. Some of the results weresubstantiated with the results of microRNAs.Our results demonstrate that resveratrolmaintained a reduced tissue environmentby over-expressing Nrf2 and Ref-1 in ratheart up to four months resulting in anenhancement of the regeneration of the adultcardiac stem cells as evidenced by increasedcell survival and differentiation leading toimproved cardiac function. Expression of SDFand myosin conclusively demonstrated homing

of stem cells in the infracted myocardium, itsregeneration leading to improvement ofcardiac function. Role of microRNAs will alsobe discussed.

Abs.S6.4

Molecular Mechanisms in EndothelialRegulation of Cardiac Function

CC Kartha

Rajiv Gandhi Center for Biotechnology,Trivandrum, India

Endothelium is now recognized as amassive, regionally specific, multifunctionalorgan. Given its strategic anatomic locationbetween the circulating blood components andthe vascular smooth muscle or the cardiacmuscle, it is a biologically significant interfacewhose dysfunction can be a critical factor invarious pathological conditions. Two types ofendothelial cells are recognized in the heart,the endocardial endothelial (EE) cells andthe microvascular endothelial cells (MVE).Both produce common autacoids and sharesimilar roles in signal transduction inducedby neurotransmitters, hormones or mechanicalstimuli. They are however two distinct cellpopulations with dissimilar embryologicalorigin, cytoskeletal organization, receptormediated functions and electrophysiologicalproperties. Both the MVE and EE aremodulators of cardiac performance. Myocardialcontraction may be modulated by cardioactiveagents such as nitric oxide, prostanoids,endothelin, natriuretic peptides, angiotensinII, kinins, reactive oxygen species and adenylpurines released from the cardiac endothelium.Two mechanisms have been proposed for thesignal transduction from EE to the underlying


myocytes: stimulus-secretion-contractioncoupling and blood-heart barrier. Nitric oxide,bradykinin and myofilament desensitizingagent are probably important in short-termregulation of myocardial functions. Endothelinand Angiotensin II are probably involved inlong-term regulation. Besides its sensoryfunction and paracrine modulation ofmyocardial performance, EE as a blood-heartbarrier could be of significance for the ionichomeostasis of the cardiac interstitium. Incardiac diseases, the damage to EE or MVEleading to failure of the endothelial cells toperform its regulatory and modulatorfunctions may have serious consequences. Theinfluence of EECs on cardiac fibroblasts is ofconsiderable interest because cardiacfibroblasts, as the principal cellular constituentof the interstitium, play an important role inmaintaining the structural and functionalintegrity of the myocardium. Specifically, theeffects of paracrine factors, such as ET-1 andTGF-â derived from EECs, on cardiacfibroblast proliferation and collagen synthesisare of interest. Our studies have demonstratedthe influence of endocardial endotheliumon cardiac interstitium that could contributeto the development of myocardial fibrosisand ventricular remodeling. A betterunderstanding of the endothelial signalingpathways in cardiac physiology andpathophysiology may lead to the developmentof novel strategies for therapy in cardiacfailure.

Abs.S6.5

Functional Variants of the PhysiologicalAnti-hypertensive Peptide Catestatin in anIndian Population

Nitish R Mahapatra

Cardiovascular Genetics Lab, Department ofBiotechnology, IIT Madras, Chennai, India

Catestatin, an endogenous cationic andamphiphilic peptide, is a novel regulator ofblood pressure and cardiac functions. It isgenerated by proteolytic cleavage of theprohormone chromogranin A, a major proteinco-stored and co-released with catecholaminesfrom the storage vesicles in adrenal chromaffincells and adrenergic neurons. Catestatinpotently inhibits catecholamine release byacting on the neuronal nicotinic acetylcholinereceptor (nAChR) as a non-competitiveantagonist. Recently, we have sequenced thecatestatin region in an Indian population(~500 hypertensives and ~500 normotensives)and discovered two variants of this peptide:Gly364Ser and Gly367Val. As many as ~15%of our population harbors these variants.Interestingly, while the 364Ser variant is about3-times more frequent in our study populationas compared to a European population,367Val variant is a novel one in our Indianpopulation. Subjects with 364Gly/Sergenotype display lower systolic bloodpressure than those with 364Gly/Gly genotype.This is consistent with the significantly lowerlevels of plasma catecholamines in subjectshaving the 364Gly/Ser genotype. Functionalanalyses in chromaffin cells using syntheticpeptides show that both these catestatinvariants are significantly less potent than thewild-type peptide. Structural analysis revealsthat the differential potencies of the catestatinvariants arise due to alteration in thesecondary structure of the peptide leading toaltered interaction with the nAChR (viz.binding affinity with the receptor as well asthe extent of blockade of the receptor pore).These findings provide new insights into themechanism of blood pressure regulation.


Abs.S6.6

Differential Adrenergic Signaling in Heart :When and How It Goes Wrong

Shyamal K Goswami

School of Life Sciences, Jawaharlal NehruUniversity, New Delhi, India

Depending on the dose, norepineprine(NE) can induce hypertrophy or apoptosis incardiac myocytes. Reactive oxygen species(ROS) play a key role in mediating bothresponses, but the mechanisms are notunderstood as yet. Nonetheless, the twopathways are marked by the differentialinduction of fosB and fra-1, two genesencoding closely related members of the AP-1 family of transcription factors. AlthoughNE induces both the genes via reactiveoxygen species (ROS), the two pathways aremechanistically different and depend upon thecellular context. Molecular analysis suggeststhat multiple cis-elements in the genepromoters mediate the redox responsewherein transcription factor SP-1 is a directsensor of cellular redox state. To furtherdelineate the biochemical basis of suchdifferential redox signaling; we observed thatH9c2 cardiac myoblasts upon treatment with2 ìM NE (hypertrophic dose) generateROS only till 2 hours, while those treated with100 ìM NE (apoptotic dose) sustains it till 48hour, till the onset of apoptosis. Noticeably,although the levels of ROS were comparableunder both the treatments, it was differentiallyquenched by various ROS quenchers, suggestingthe existence of NE dose specific assortmentof ROS. NE treatment (2 and 100 ìM)also caused sustained generation of HPFsensitive highly reactive species peroxynitrite.

However, oxidative DNA damage, asmeasured by the increase in 8-OHdG content;and induction of GRP78, a hallmark of ERstress/unfolded protein response; was seenonly in cells treated with the 100 ìM dose ofNE. This study thus infers that hypertrophicand apoptotic doses of NE generate distinctRO/NS profile leading to discrete downstreameffects.

Abs.S6.7

Novel Pharmacological Strategies forCardiac Hypertrophy

Subir K Maulik1*, Rajesh Enjamoori1, Amit KDinda2, Sandeep Seth3

1Departments of Pharmacology, 2Pathology,3Cardiology, All India Institute of MedicalSciences, New Delhi, India

Soy intake has been associated with lowprevalence of chronic diseases, like cancerand cardiovascular diseases. This has beenespecially observed in Asian population wheresoy is widely consumed as soy milk, soy flour,isolated soy protein and soy concentrates. Soyis rich in isoflavone content especially,genistein which possesses phytoestrogenic andantioxidant properties. Experimental studieshave shown that genistein prevents rightventricular hypertrophy and vascularremodeling. However, no information isavailable on its effect on left ventricularhypertrophy, an important risk factor for heartfailure and sudden cardiac death. Therefore,we have evaluated its preventive potentialin isoproterenol-induced left ventricularhypertrophy in rats. The study was approvedby the Institute Animal Ethics Committee incompliance with the NIH guidelines.


Laboratory bred male Wistar rats (150-200gm, 10-12 weeks old) were randomly assignedto different experimental groups. Isoproterenol(5 mg/kg, body weight) was injectedsubcutaneously once daily for 14 days toinduce cardiac hypertrophy. Two doses ofgenistein (Sigma, India; 0.1 and 0.5 mg/kg,s.c. once daily), were administered along withisoproterenol. In separate groups, L-NAME(2 mg/kg; non-selective NOS inhibitor) andaminoguanidine (100 mg/kg; selective iNOSinhibitor) were administered either alone oralong with isoproterenol and/or genistein. Ratswere subjected to two dimensional M-modeechocardiography for the estimation of LVmass and % fractional shortening (% FS).Heart samples were analyzed for TBARS,GSH, SOD and catalase levels. Formalin storedhearts were used for histopathology, myocytesize and picro sirius red stain for fibrosis.Isoproterenol treatment caused significantincrease in heart weight to body weight ratio(P<0.001). Genistein (0.1 and 0.2 mg/kg)significantly prevented these effects (P<0.001).However, L-NAME prevented this salutaryeffect of genistein, while aminoguanidine didnot. Similarly L-NAME only prevented thesalutary effects of genistein on isoproterenol-induced increase in IVS thickness (P<0.001),posterior wall thickness (P<0.05) andmyocardial collagen content (P<0.001).Genistein prevented isoproterenol-inducedincrease in myocardial oxidative stressas manifested by increase in TBARS,accompanied with decreased levels of SOD,catalase and GSH. While L-NAME preventedthis beneficial effect of genistein,aminoguanidine did not have any modulatoryeffects. Genistein significantly preventedisoproterenol-induced increase in myocytesize (P<0.001). Only L-NAME, but not

aminoguanidine prevented this effect.Similarly L-NAME prevented the salutaryeffect of genistein on isoproterenol-inducedincrease in fibrosis (P<0.001).

NO plays an important role in cardiachypertrophy and remodeling. Transient andlow release of NO by eNOS has been shownto be beneficial, while high and sustainedrelease by iNOS may be detrimental. In ourstudy, the beneficial effects of genistein onisoproterenol-induced cardiac hypertrophywas blocked by a non-selective iNOS inhibitorand not by a selective iNOS inhibitor.Interestingly, the selective iNOS inhibitor perse prevented isoproterenol-induced cardiachypertrophy. This highlights that genistein actsthrough inhibiting iNOS and increasing eNOSactivity, the latter effect when blocked by L-NAME caused a loss of the beneficial effectof genistein.

Symposium 7 (S7)

Abs.S7.1

Psycho-Physiology of Meditation

JPN Mishra*, PS Shekhawat, YS Khangarot

Department of Science of Living, PrekshaMeditation and Yoga, Jain Vishva BharatiUniversity, Ladnun, Rajasthan

Meditation is not an irrational emotionalor religious experiences but a deliberatemental operation of psychoanalysis. It is aform of psychotherapy for destroying therepressing and repressed forces which haveproduced and would continue to produceinhuman tendencies and irrational behavior ifnot destroyed. Eradication of these forces


would enable us to develop our true humannature and justify our claim of being thehighest product of the cosmic process. Asecondary benefit of meditation is generallyknown as ‘relaxation’, which accurseincidentally from its practice. Relaxation isthe result of triggering of an innate protectivemechanism, which counteracts the dangerouseffects of environmental and emotionalstresses. Physiological functions could becontrolled through various meditationaltechniques. Regular practice of meditationcould reduce the blood-pressure, heart-rateand metabolism. Modern scientific investigationshave confirmed that (i) meditation produceschange in the bioelectrical activity in thenervous system; (ii) omission of more Alphabrain waves representing the state of calmness;and (iii) mechanism of the autonomous nervoussystem can be activated through the controlof certain voluntary mental actions. Scientificinvestigations have also provided evidencethat meditation can influence the control orcommand mechanisms which are ultimatelyresponsible for the homeostasis in the body.In addition to that meditation is also anapparatus for regulating and controlling one’sbestial instincts of anger, aggression, cruelty,vindictiveness and fear; i t is a tool forawakening and developing one’s consciousreason and thereby modifying one’s thoughts,actions and behaviour to be truly worthy of ahuman being; it is a process of remedyinginner incompleteness and reducing innerdiscord. It may be proactive to acquire notonly psychical goodness but also to acquirepsychical goodness too by eradicating all evilfrom one’s thoughts, speech and action. Anobjector may at this point raise a doubt thatanger, fear, aggression, etc., are naturalcomponents of human nature which cannot

possibly be changed. To this, a reassuringanswer comes from modern psychology andendocrinology. Mental states, emotions andbehavioural pattern of an individual areprofoundly influenced by the synthesizationof hormones secreted and distributed by theductless glands. In fact all passions, emotionsand impulses are the expressions of theendocrine system. And so, when we talk ofhuman nature, we really mean its expressionand this can most definitely and thoroughlybe changed by controlled mental practices.Since mental tendencies and human behaviorare almost completely governed by theintegration of neuro-endocrine products,transmutation of the latter must produce thedesired development of the integratedpersonality of man. Removal of allpsychological distortions-hate, fear, cruelty,etc. through transmutation of chemicalmessengers will immensely strengthen theendocrine secretions are modified andcontrolled by conscious reason, the repressedand repressive forces building up thepsychological explosive will be defused andlose its power to overwhelm and distort therational judgment. This can be achievedthrough meditation only. The pathway ofmechanism explaining the stepwise details ofthe operations will be discussed.

Abs.S7.2

Yoga as an Intervention for Mental Health

Sat Bir Singh Khalsa

Department of Medicine, Harvard Medical School,Boston, MA, USA

The pace and demands of modern societyare subjecting many individuals to the burden


of continuing and often chronic stress at bothwork and home. Unmanaged stress is nowbelieved to be one of the most consistentpredictive factors contributing to thedevelopment of mental health and behaviouralproblems in both adolescents and adults.Statistics suggest that the majority ofadolescents and adults will experience amental health disorder in their l ifetime.Although personal resources such asmastery and self-regulation skills are knownto be consistently associated with enhancedresilience to the onset of mental healthdisorder episodes, our society has noestablished training or education programsin our schools or workplaces for stressmanagement. Yoga is a comprehensive andholistic set of mind-body practices includingphysical exercises and postures, breathingtechniques, relaxation strategies, meditation/mindfulness practices and applied psychology/philosophy. Research studies have shown thatyoga is highly effective in the managementof acute and chronic stress both psychologicallyand physiologically. Furthermore, a growingbody of clinical research trials has indicatedthat a variety of mental health conditions canbe effectively managed with therapeuticapplication of yoga practices. This presentationwill overview the evidence for the preventiveand therapeutic application of yoga for mentalhealth and the potential underlying mechanismsof its action.

Abs.S7.3

Effect of Yoga and Lifestyle Interventionson Risk Factors of Metabolic Syndrome

Sunita Tiwari

Department of Physiology, CSM MedicalUniversity, Lucknow, India

Excess of body fat is associated withsevere risk factors and may develop MetabolicSyndrome X (MS) which is characterized bycentral obesity, hypertension, impairedglucose tolerance, low HDL Cholesterol levels,and/or hypertriglyceridemia. Abdominal obesityis associated with an excess accumulation ofvisceral fat which is an important correlate ofthe insulin dyslipedemic syndrome.Role ofyogic exercise in preventing the progressionof metabolic syndrome has been recognized.Lifestyle interventions have clearly shown thata well-designed exercise programme producesseveral beneficial effects in well-motivatedobese subjects. Effect of a yoga practice for12 weeks on lipid profiles of 56 obesesubjects (32 females and 24 males) age rangedfrom 20 to 45 yrs were evaluated. Resultsrevealed a significant (P<0.01) decreasein anthropometric variables (weight, bodymass index, waist circumference and hipcircumference). Further, total cholesterol,triglyceride, very low density lipoprotein, lowdensity lipoprotein and fasting plasma glucosedecreased significantly (P<0.01) while highdensity lipoprotein increased significantlywhen compare to the basal variables beforeintervention given (P<0.01). A significant andpositive correlation was evident amongpretreatment anthropometric variables(P<0.01) while most of the lipid profilesparameters also showed a significant (P<0.05or P<0.01) positive or negative correlationwith each other. The pretreatment weight(r=0.49; P<0.01), waist circumference (r=0.39;P<0.01) and hip circumference (r=0.26;P<0.05) showed significant and positivecorrelation with pretreatment triglyceride. Thechange (improvement) in weight and TG weresignificantly (r=0.49, P<0.01) associated witheach other. Thus, yoga may be an adjuvant


therapy for the management of risk factorsfor metabolic syndrome.

Abs.S7.4

Importance of Yoga and Naturopathybased Healthy Life Style and Diet Practices

BT Chidananda Murthy

Central Council for Research in Yoga &Naturopathy, Government of India, New Delhi

The prevalence of chronic diseases suchas Hypertension, Diabetes Mellitus, CoronaryArtery Disease, Back Pain, Asthma, Arthritisetc are rapidly increasing in developingcountries. Epidemiological studies in Indiahave revealed that the prevalence of thesechronic diseases are increasing with the time.If current trends continue they anticipate thatnumber to essentially double. This increase,most marked in the urban population, is likelyto be related to changing life-styles and stress.The increased economy has brought us allthe comforts has led to reduced physicalactivity and recourse to wrong way of habitsand dietary patterns such as consuming excesstea, coffee, developing a habit of smoking,drinking alcohol, consuming high spicy andprocessed foods etc have led to the occurrenceof these life style chronic disorders. Studieshave clearly shown that all these chronicconditions are related to each other, presenceof one condition predisposes to occurrenceof other condition. Promising in this regard isappropriate healthy living habits such asphysical activity, regulated dietary habits,proper relaxation, good sleep and stress freelife. Studies have clearly shown to reducebody weight, BP, glucose level andcholesterol. Yoga & Naturopathy as a way of

life forms a healthy life style system consistingof various postures (Asana), breathing(Pranayama), Relaxation techniques andmeditation techniques and ancient healthypractices such as massage, fasting,hydrotherapy etc have been shown to havetherapeutic benefits for individuals with a widerange of health conditions, includinghypertension, diabetes, asthma, arthritis, backpain etc. Yoga also is effective in reducingstress and improving exercise tolerance as itis related to cardiovascular response.

Symposium 9 (S9)

Abs.S9.1

Patho-physiology of Oxidative Stress inObstructive Sleep Apnea

Deepak Shrivastava

School of Medicine, University of CaliforniaDavis, Davis, California, USA. Sleep Laboratory,San Josquin General Sleep Center Stockton,University of California, California, USA

Obstructive sleep apnea (OSA) ischaracterized by repetitive cycles of hypoxiaand reoxygenation that promotes theformation of reactive oxygen species (ROS)and nitrogen species (RNS). Reactive oxygenand nitrogen species are molecules withunpaired electron(s) in their outer orbit. Theseelectrons render them highly prone tochemical reactions. ROS such as superoxideanion (O2–), hydroxyl radical (OH–) andperoxynitrite (ONOO–) are injurious to cellsthrough a process called lipid peroxidation,which damages cell membranes and generatesmore ROS and RNS in a chain reaction.


The imbalance between oxidant producingsystems and antioxidant defense systemreduces the bioavailability of nitrous oxide.This contributes to oxidative/nitrosativestress in the vasculature that affectsendothelial function, vascular inflammationand atherosclerosis. In health, homeostasis isprovided by the redox balance system. Oxidativestress activates redox-sensitive transcriptionfactors which regulate inflammatory cytokines,chemokines and adhesion molecules.

Intermittent hypoxia results in activationof pro-inflammatory transcription factors suchas nuclear factor kappa B (NF-kB) andactivator protein (AP)-1. These promoteactivation of various inflammatory cells,particularly lymphocytes and monocytes withthe resultant expression of pro-inflammatorymediators that may lead to endothelialdysfunction. TNF-alpha and IL-6 in particularcould play a major role.

Two major mechanisms have beenproposed to explain the morbid consequencesof OSA, namely increased generation andpropagation of reactive oxygen species andinitiation and amplification of inflammatoryprocesses. OAS exerts an enhanced intravascularoxidative stress reaction. Oxidative stress islinked to CVD with increased adhesion toendothelial cells.

Abs. S9.2

Sleep Deprivation : Are the EffectsDifferent in a Developing Brain ?

Rama Maganti

Department of Neurology, Barrows NeurologicalInstitute, Pheonix, Arizona, USA

Study Objectives : To examine the effects ofacute and chronic sleep deprivation (SD) on

spatial learning, reference memory andhippocampal longterm potentiation (LTP) inpubertal mice.

Design and Measurements : Pubertal C57/Bl6strain of mice, were subjected to acute SDfor 72 hrs or chronic SD for 2 weeks startingat P24. Chronic group were further subdividedinto chronic sleep restriction (chronic-SD) orchronic sleep fragmentation (SF). Spatiallearning and memory was examined usingMorris water maze studies, and LTP wasexamined after stimulation of schaffercollaterals in CA-1 region of hippocampus inall groups at the end of SD protocol. Animalactigraphy was used during the period of SDto monitor rest-activity patterns.

Results : A significant impairment of spatiallearning and reference memory as well as LTPinduction and maintenance in pubertal miceis seen with 72 hrs of acute-SD, but not withchronic sleep restriction or fragmentation.Actigraphy showed no “shifts” in thecircadian rest-activity patterns during theperiod of SD in any of the groups comparedto controls while activity counts are higherduring periods of SD. Stress was not a factorin the SD methodology used.

Conclusions : During development acute SDis associated with impaired learning andmemory as well as synaptic plasticity. Similarimpairment was not seen with chronic sleeprestriction or fragmentation in pubertal miceperhaps due to adaptation or compensationby allosteric or homeostatic responses. Furtherstudies are needed to understand themolecular mechanisms of differences seenwith acute and chronic sleep loss.

Abs. S9.3

REM – Sleep Disorders

Karuna Datta


Department of Physiology, Army Medical College,New Delhi

REM sleep is characterised by atonia ofvoluntary muscles except extraocular muscles,elevated autonomic activity and dreaming.REM related parasomnias might involve eitherthe incoordination of these processes or theinappropriate admixture of REM sleep andwakefulness.

REM Behaviour Disorders (RBD), sleepparalysis and nightmare disorders are REMsleep related sleep disorders. RBD arecharacteristically acute/chronic forms whereacute form is associated with drugs or evenwithdrawal of alcohol. Chronic form can beidiopathic or secondary to neurological diseaseseg. Parkinson’s disease. Polysomnography(PSG) is necessary for confirming thediagnosis. The sleep study shows that amountand cycling of sleep stages from NREM toREM is normal. Elevated muscle tone orincreased phasic muscle activity in submentalor anterior tibialis EMG during REM sleep isseen. Sometimes gross/subtle body movementsmay be recorded. PSG may be helpful inexcluding other causes of sleep problemsleading to RBD like Sleep disorderedbreathing.

Sleep paralysis refers to a conscious stateat the onset or offset of sleep associated withparalysis of voluntary musculature,probablydue to inappropriate REM intrusion intowakefulness or the failure to mantain sleepduring REM persists. Typically occur in firsttwo hours of sleep or at the time of finalawakening.

Nightmares occur in the latter third of thenight when REM proportion is increasing.Nightmares are not associated with overtmotor dream enactment but are characterisedby recurrent dreams followed by awakening

with often detailed recall of the dream andfear is the most predominant emotion recalled.

REM sleep disorders should bedistinguished from other forms of parasomniasand also from other sleep disorders which mayaggravate or coexist with these disordersshould also be ruled out.

Abs.S9.4

EEG Dynamics after Acute and ChronicSleep Loss

Kamalesh K Gulia

Comprehensive Centre for Sleep Disorders,Biomedical Technology Wing, Sree ChitraTirunal Institute for Medical Sciences &Technology, Thiruvananthapuram, Kerala, India

Examination of the global features of EEGis traditionally practiced to derive theunderlying neurophysiological connotationsduring different vigilant states. The EEGsignals are generated regionally in neuronalpopulations of various cortical modules andtheir emergent interactions contribute to globalpatterns in the EEG. It is interesting to monitorthe micro-features of EEG at the level of singleneuron in individual cortical units and atthe subcortical levels. The rest-activity in formof sleep-wakefulness is a dynamic EEGconstruct of underlying neural networksoperating at various levels. Sleep deprivationor restriction of different magnitude isbecoming an integral component of our dailylife in the current civilization some of whichare also reflected in our cognitive functioningincluding lapses in attention, anxiety, memoryimpairment etc. The assessment of brainactivity through high resolution EEG systemis commonly employed for stochasticevaluation of the EEG dynamics to decipherfunctional properties of the neural networks


during reduced sleep. Though, a globalincrease in the delta power after acute sleepdeprivation is considered a gold standard fordetecting the homeostatic drive, the spectralanalysis of EEG time series and spatialproperties of the EEG spectrum appearpromising in deciphering the neural networkproperties after acute or chronic sleep loss.The local and global features of the crucialneural networks after the acute and chronicsleep loss are highlighted to make anunderstanding of the role of EEG dynamicsin sleep homeostasis.

Symposium 10 (S10)Abs.S10.1

A Look at Interactions between Emotionand Attention using ERPs

Narayanan Srinivasan

Centre of Behavioural and Cognitive Sciences,University of Allahabad, Allahabad, India

Recent studies investigating therelationship between emotion and attentionhave shown reciprocal relationships betweenthem. Broad scope of attention is linked tohappy expressions and narrow scope ofattention is linked to sad expressions. Giventhese links between emotion and attention,we performed two studies using emotionalstimuli investigating shifts in attention andexecutive control. We also exploredhemispherical asymmetries. Shifts of attentionwere studied using the phenomenon ofinhibition of return (IOR) using a exogenouscue paradigm with schematic happy and sademotional target faces. Reaction times andERPs were measured. Results revealedreduced IOR for left compared to right visualfield with sad faces but no such asymmetryfor happy faces. Cued N1 amplitudes weresuppressed for happy targets but not for sad

targets presented to the left visual field.Nd amplitudes were enhanced for right-hemispheric sad faces especially with object-based IOR. The results indicate right-hemispheric advantage in the capture ofattention by negative emotion especially withobject-based selection.

Executive control was studied using aflanker task with happy and threatening faces.Results showed hemispheric asymmetries inthe flanker interference effect with largerflanker effect in the right hemisphere forthreatening faces and in the left hemispherefor happy faces. Happy faces were processedfaster compared to threatening faces asindicated by increased N100 amplitudes andfaster RTs. In addition, error related negativitymagnitudes were dependent on the emotionalcontent. These studies show changes in ERPsindicating differences in attentional processesas a function of emotional content.

Abs.S10.2

Brain Basis of the Capacity Limits ofInformation Processing

Shobini L Rao*, Anusha S, George A, GirijaS, Bennett N, Ullal D

Department of Clinical Psychology, NationalInstitute of Mental Health and Neurosciences,Bangalore, India

Background : The human brain has immensecapacity for parallel processing of information.The possibility for simultaneous processingof large amounts of information is constrainedby capacity limitations of attention/workingmemory. This capacity which was earlier setat 7 bits of information is now found to be 4bits of information. The brain basis of thecapacity limitation needs to be ascertained.Further the process of chunking may increasethe capacity limit.


Aim : The present study aimed to answerwhether the brain basis of this capacity limitcould be located to the networks of attention/working memory/perception.

Method : Three studies were conducted tostudy the capacity limitation with visualdisplays of words, digits and figures. Eachtype of stimulus was displayed under twoconditions. The chunked condition had stimuliwhich favored chunking through arrangementof the stimuli. In the non chunked conditionthe stimuli were arranged randomly and hencedid not favor chunking.

Sample : In each of the three studies 20normal healthy right handed college educatedvolunteers of both participated after givinginformed consent.

EEG Recording : Surface EEG was recordedfrom 28 channels with horizontal and verticaleye movements being recorded from fourchannels. The stimulus appeared for 200 msfollowed by a probe after 500 ms. The probeeither matched or did not match the stimulus.The subject pressed a button to indicatewhether the probe matched the stimulus ornot.

Results : The accuracy was high across the 3tasks. P300 component appeared after thestimulus. In some of the tasks a prolongedpositivity appeared. The distribution of theP3 differed across the 3 tasks. The effects ofchunking and of matched probe would bediscussed in the presentation.

Abs.S10.3

Biomarkers for Neurodegenerat iveDisorders using State-of-the-Art Multi-Modal Imaging Modalities : Detection

and Mapping of Anti-oxidant Marker‘Glutathione’

Pravat K Mandal1,2*, Manjari Tripathi3,Sreedevi Sugunan1

1Neurospectroscopy and Neuroimaging Laboratory,National Brain Research Center, Gurgaon, India.2Department of Radiology, Johns HopkinsMedicine, Baltimore, Maryland, USA.3Department of Neurology, All India Institute ofMedical Sciences, New Delhi, India

Glutathione (GSH) serves as an importantanti-oxidant in the brain by scavengingharmful reactive oxygen species that aregenerated during different molecularprocesses. The GSH level in the brainprovides indirect information on oxidativestress of the brain. We report in vivo detectionof GSH non-invasively from various brainregions (frontal cortex, parietal cortex,hippocampus and cerebellum) in bilateralhemispheres of healthy male and femalesubjects and patients with mild cognitiveimpairment (MCI) and Alzheimer’s disease(AD) patients. All AD patients whoparticipated in this study were on medicationwith cholinesterase inhibitors. Healthy youngmale (age 26.4±3.0) and healthy young female(age 23.6±2.1) subjects have higher amountof GSH in the parietal cortical region and aspecific GSH distribution pattern (parietalcortex> frontal cortex >hippocampus~cerebellum) was found. Overall mean GSHcontent is higher in healthy young femalecompared to healthy young male subjects andGSH is distributed differently in twohemispheres among male and female subjects.Both young female and male subjects,statistically significant (P=0.02 for youngfemale and P=0.001 for young male)difference in mean GSH content is found whencompared between left frontal cortex (LFC)


and right frontal cortex (RFC). In healthyyoung female subjects, we report statisticallysignificant correlation (positive) of GSHcontent between RFC and LFC (r=0.641,P=0.004) as well as right parietal cortex (RPC)and left parietal cortex (LPC) (r=0.797,P=0.000) regions. In healthy young malesubjects, statistically significant correlation(positive) of GSH content was observedbetween LFC and LPC (r=0.481, P=0.032)regions. The difference in mean of GSHcontent between healthy control young femaleand female patients in RFC region (P=0.003)and difference in mean of GSH content incontrol healthy young male and male patients(P=0.05) in LFC region is found to bestatistically significant.

Abs.S10.4

Realization of Delayed Intention : AnElectrophysiological Approach

Azizuddin Khan

Psychophysiology Lab, Department of Humanitiesand Social Sciences, Indian Institute of TechnologyBombay, Powai, Mumbai, India

Prospective memory (PM) involvesforming an intention and then realizing it atsome appropriate time or in response to someexternal cue in the future (Harris, 1984). Inthis talk, I will discuss the processesunderlying the encoding and performance offuture intentions and planned actions in thecontext of event-related brain potentials(ERPs) to explore the neural activityassociated with the formation and realizationof an intention. ERPs have been used toexamine the temporal dynamics of the neuralprocesses underlying prospective memory.Modulations of the ERPs elicited duringprospective memory have been associated with

the detection of prospective cues and theretrieval of intentions from memory.

Greater negativity over the frontal-polarregion was associated with intention formationtrials in which the intention was later realized.On PM cue trials, N300 was associated withthe detection of a cue. A late positive complexwas observed that might have reflected theretrieval of an intention from memory, and afrontal slow wave was observed that mighthave reflected the activity of a neural systemthat supported disengagement from theongoing activity when the cue was detected.The N300 is greater in amplitude forprospective hits (i.e., prospective cues thatelicit a prospective response) than prospectivemisses (i.e., prospective cues that fail toelicit a prospective response) or ongoingactivity trials, leading to the suggestionthat this modulation of the ERPs is associatedwith the detection of prospective memorycues.

The prospective positivity reflects asustained positivity over the parietal regionbetween 500 and 1000 ms after stimulus onset(West et al., 2001). There is evidence that theP3b component contributes to the prospectivepositivity. The later portion of the prospectivepositivity (between 600 and 800 ms) is alsogreater in amplitude when there are multiplecue-intention associations relative to whenthere is a single cue-intention association(West et al., 2003b), leading to the proposalthat the prospective positivity is associatedwith the activity of a neural mechanism thatsupports the retrieval of an intention frommemory (West & Ross-Munroe, 2002).Overall , the talk will delineate progresstowards understanding realization of delayedintention by using of electrophysiologicalmethod.

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