Title: System-Level Analysis of Signal Transduction Networks by Quantitative Proteomics and Systems Biology
Dr. Masaaki Oyama, Assistant Professor, Medical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, Japan

The mass spectrometry-based analysis of small proteins expressed in human K562 cells provided the first direct evidence of translation of upstream ORFs in human full-length cDNAs. In his recent work, he established an integrated framework for analyzing tyrosine-phosphoproteome dynamics through temporal network perturbation, which enabled us to obtain a system-wide view of regulatory network clusters involved in signal transduction.

Title: Small is Beautiful: Protein Microarrays-an Array of Applications
Dr. Jutta Bachmann, Principal and Founder, Bachmann Consulting, Norway

Dr. Jutta Bachmann is principal and founder of Bachmann Consulting. She has been an advisor for microarray-related conferences and is the project manager of www.biochipnet.com as well as of an international portal on regenerative biology http://www.regenerationnet.com operated by BioRegio STERN Management GmbH, Germany.

Dr. Satoshi Nishizuka currently serves as Assistant Professor and Chief Principal Investigator in the Molecular Therapeutics Laboratory of the Department of Surgery at Iwate Medical University School of Medicine. He graduated from Iwate Medical University Graduate School of Medicine with M.D. (1994) and Ph.D. (1998) degrees. Originally trained as a surgical oncologist, he did postdoctoral research in the Department of Microbiology and Molecular Genetics at the University of California, Irvine. In 2001 he joined the Laboratory of Molecular Pharmacology at the U.S. National Cancer Institute (NCI) as a Research Fellow, where he developed a high-density "reverse-phase" protein lysate microarray (RPA) system using a NCI-60 cancer cell line panel in the context of drug sensitivity profiling at the protein level.

Title: Classification of Proteins into Structured and Unstructured Regions
Dr. Satoshi Fukuchi, Assistant Professor, Center for Information Biology and DNA Data Bank of Japan, National Institute of Genetics, Japan

It has long been known that eukaryotic proteins have complex domain structures, and recently revealed that considerable number of eukaryotic proteins have the so-called intrinsically disordered (ID) regions, which occasionally extend more than a few hundred residues. Those proteins with long ID regions have been known to play crucial roles in the important cell activity such as signal transduction, transcriptional regulation etc. The structural domains homologous to those registered in PDB can be identified with highly sensitive homology searches such as PSI-BLAST and HMM, while ID regions can be predicted because of their biased amino acid composition in the sequence. We have constructed a pipeline, DICHOT, to divide a protein molecule into structural domains and ID regions, which consists of the standard procedure of domain assignment, the ID-region prediction by the DISOPRED program, and a newly developed program (CLADIST) that discriminates domains from ID regions. The reliability was tested with human transcriptional factors, which are one of the typical proteins with long ID regions, showing a plausible result by referring some of the published domain-ID partitioning. All human proteins in the SwissProt database are loaded into the pipeline. The results indicate that 37% of total residues belong to ID regions, while 63% fall in structural domains including 10% of unknown structure. These predicted novel structural domains are good targets of structural genomics.

Title: Peptide Epitopes: Approach Fragment Based Drug Design from Plant Viruses
Dr. Virendra Gomase, Department of Bioinformatics, Padmashree Dr. D.Y. Patil University, India

The new paradigm in vaccine design is emerging, following essential discoveries in immunology and development of new MHC Class binding peptides. MHC molecules are cell surface glycoproteins, which take active part in host immune reactions. The involvement of MHC class in response to almost all antigens and the variable length of interacting peptides make the study of MHC Class molecules very interesting. MHC molecules have been well characterized in terms of their role in immune reactions. They bind to some of the peptide fragments generated after proteolytic cleavage of antigen. This binding acts like red flags for antigen specific and to generate immune response against the parent antigen. So a small fragment of antigen can induce immune response against whole antigen. This theme is implemented in designing subunit and synthetic peptide vaccines. Adducts of MHC and peptides complexes elicit the immune response for clearing various intracellular infections. Prediction methods based on the specificity of immunological assessment of functionally active subunit vaccines and will complement the wet lab experiments and speed up the knowledge discoveries on the basis of computational algorithms. These peptides can initiate antigen processing by generating larger fragments containing antigenic epitopes, the respective fragments are subsequently trimmed to their final size by exopeptidases.

Title: Revealing Targets of the Low Abundance Proteome; The Essence of Biomarker Discovery
Dr. Dian Er Chen, Principal Investigator, Proteomics R&D, Sigma-Aldrich, Inc., USA

Dr. Chen has significant multidisciplinary scientific research and management expertise gained through a career largely spent at Sigma-Aldrich Corporation. Dr. Chen's research experience is extremely broad, encompassing a range of disciplines including Organic Chemistry, Protein Chemistry, and Immunology-as well as other Life Sciences areas.

Title: Optimisation and Standardisation of Sample Preparation with the Bead-beating Technology in Proteomics Research
Ms. Elina Machefer, Asia Area Manager, Bertin Technologies, Hong Kong

In the context of sample preparation and cell lysis, Bertin Technologies (France) has developed a technology dedicated to the homogenization and grinding of soft to hard materials. The goal is to improve the first critical step in any molecular biology process and follow the latest requirements of analysis equipments which have radically improved in terms of throughput, reproducibility, detection limits and linearity.Following specific mechanical engineering studies of bead beating technology, a high speed figure-8 multidirectional motion gives shaking energy to the beads that grind/homogenize samples in sealed tubes. This patented solution Precellys24 plays a large part in the analyse chain of rapid method to extract and detect or quantify DNA, RNA or proteins. Thanks to Cryolys option, temperature inside Precellys24 tubes is maintained at an optimal level during homogenization. Cryolys technology permits temperature-sensitive molecules to keep their native state for any analysis.

Title: Analytical Methods for Studying Physical and Chemical Instabilities of Lenograstim
Dr. Jasmina Tonic-Ribarska, MSci. Pharm. Assistant, Center of Drug Quality Control, Faculty of Pharmacy, University “Ss Cyril and Methodius”, Macedonia

The stability of protein - based pharmaceuticals is significant in terms of their pharmaceutical quality and biological activity. A right choice of suitable analytical methods is needed in order to detect the early formation of degradation products or modified forms. Aggregation and oxidation are the dominant physical and chemical pathways that degrade protein molecules, leading to the inactivity of protein pharmaceuticals. Therefore, t he analytical methods for the assessment of the formation of aggregates in glycosylated form of recombinant human granulocyte colony – stimulating factor ( rHuG-CSF), lenograstim under physiological conditions and the investigation of the effect of hydrogen peroxide on oxidation of methionine residues in lenograstim will be discussed.

Title: Modern Optical Analytical Devices for the Express Peptide and Protein Discovering at the Diagnostics and Environmental Monitoring
Dr. Nickolaj F. Starodub, Professor of National University of Life and Environmental Sciences of Ukraine, Kiev, Ukraine

N. Starodub and his colleagues have developed a number optical biosensors, in particular, based on the nano structured porous silicon, fiber optics, surface plasmon resonance and total internal reflection for the determination of specific antigens and antibodies as well as some mycotoxins and bacteria at the diagnostics of number of diseases (autoimmune status of diabetics, retroviral infections, influence, birds flu, heart failure and others) and monitoring of environmental objects. The last is connected with the revealing of nonylethoxylates and such mycotoxins as: T2, aflatoxins, patulin, searelenone and others. Among the developed biosensors there are principal new ones based on photoluminescence and light induced photoconductivity. To replace non stable biological materials at the formation of selective structures of biosensors and to express remove above enumerated toxic substances, in particular, from water resources it was proposed number of substances as calyx[4]arenas for the practical application. It is discovered a principal new way to modelling selective binding sites in the analytical devices and at the express decontamination of environmental objects, especially, water sources.

Title: Advances in Biomarker Verification / Validation Strategies Using QTRAP? LC/MS/MS System Technology
Mr. Byunghee Shin, Mass Spectrometry System Division, Part of Life Technologies, Applied Biosystems, South Korea

As the study of protein biomarkers increases in importance, technical limitations to the detection of low abundance proteins and to high-throughput, high precision quantitation remain to be overcome. Targeted quantitation by multiple reaction monitoring (MRM) on triple quadrupole based MS systems is being used increasingly for quantitative monitoring of peptides/proteins in complex biological samples. Strategies for overcoming the key challenges (need for rapid assay development, need for higher multiplexing and need for assay robustness) are becoming critical. Solving these problems will require a combination of robust instrumentation, intelligent acquisition and processing software, and appropriate use of internal standard strategies. In this talk, we will discuss the new trends in targeted quantitative proteomics and the key tools available for performing high quality biomarker verification assays.

Title: Human Serum Glycome for Disease Biomarker Discovery
Dr. Hyun Joo An, Associate Specialist, Clinical Glycomics Mass Spectrometry Facility, University of California, USA

She and colleagues have established a company, Glycometrix Inc., to develop the patented technology in July 2004. She is a director, Technology development. She is currently working on the application of F ourier transform mass spectrometry in bio-analysis. Her specific research interests include oligosaccharide analysis (glycomics), biomarker discovery for infectious diseases and cancer and glycoprotein analysis (glycoproteomics) to determine the site specific glycosylation.

Title: Biochemical Markers of Bilirubin-Induced Neurotoxicity in Newborns; Tau and S100B Proteins
Dr. Nurullah Okumus, Specialist of Neonatology, Division of Neonatology, Dr. Sami Ulus Children's Hospital, Ankara, Turkey

Dr. Ching-Hwa Kiang, Professor, Department of Physics & Astronomy, Rice University, USA

Title: AFM Studies of the Resistance to Unfolding of Titin and Von Willebrand Factor (VWF)
Dr. Ching-Hwa Kiang, Professor, Department of Physics & Astronomy, Rice University, USA

Kiang's current research focuses on single-molecule manipulation. Kiang used single-molecule manipulation technique to stretch a protein and follow the trajectory to understand the folding pathways (Harris et al. 2007). Because protein misfolding may result in malfunction of biological processes and even disease, understanding how proteins fold into their correct shape may help us to develop strategies for treating diseases resulted from protein misfolding, such as Alzheimer's, Parkinson's, and mad cow diseases. The technique can also be applied to any proteins as well as RNA and DNA. Kiang won the 2007 Best of Small Tech Researcher of the Year award for this research accomplishment.

Title: Unraveling Amyloidogenic Behaviour from Computational Analyses
Dr. Flavio Seno, Professor, Department of Physics, University of Padua, Italy

Upon completation of his Ph.D. on Critical Phenomena at the University of Padua, he joined in 1991 the Theoretical Physics Group in Oxford working on the magnetic properties of rare earth by using spin models with competing interactions. Afterwards he got a position as Researcher (1994) and as Professor (2001) at the University of Padua working first on equilibrium and non equilibrium statistical mechanics. The main results have been obtained in the topics of phase transitions and critical phenomena, of the renormalization group, of spin systems, of surface critical phenomena, of conformational properties of polymers and random surfaces. In the last years most of his research has been devoted to the application of tools of statistical mechanics to understand biologically inspired problems. Important results have been obtained in the modelling of single molecule experiments, particularly in understanding the unzipping and the overstretching conformational transitions. Other important results have been obtained on the inverse protein folding problem, in the analysis of topological models to mimic the folding problem and in developing an unifying framework to explain the reduced menu of protein folds. More recently he develops an algorithm “Pasta” (Prediction of Amyloid Structure Aggregation) which portions of a given protein or peptide sequence forming amyloid fibrils are stabilizing the specific inter-molecular pattern of hydrogen bondend amino-acids. The results of the whole research are contained in about 80 publications.

We have been focused on the mechanism of amyloid fibril formation in relation with structural and physicochemical properties of folded proteins including -lactoglobulin whose involvements in diseases are unclear. Results from these studies provided a significant insight into the role of dynamical properties of protein structures in the formation of amyloid fibrils and a fundamental concept for the negative design principle that is included in the folded protein to protect them against aggregation. We will also discuss the effect of protein aggregates on the structure of lipid membrane as to provide an insight into the mechanism of cytotoxic properties of protein aggregates.

Title: The Role of Phosphorylation Motifs in Dissecting MAP Kinase Signaling
Dr. Richard R. Vaillancourt, Associate Professor of Pharmacology & Toxicology, Department of Pharmacology & Toxicology, University of Arizona College of Pharmacy, USA

Dr. Vaillancourt received his B.A. at St. Anselm College in Manchester , N.H. and Ph.D. from the University of Wisconsin-Madison. For his doctoral work, he did radiosynthetic chemistry and developed photoaffinity probes of NAD + to study the structure of the retinal G protein, transducin. As a post-doctoral fellow at the National Jewish Medical & Research Center in Denver , Colorado , he studied specific phosphorylation sites on the platelet-derived growth factor receptor tyrosine kinase and their regulation of the ERK MAP kinase pathway. At the University of Arizona , Dr. Vaillancourt has been studying the MAP3K family of serine/ threonine kinases. Specifically, his research group has identified phosphorylation sites on MEKK3 that are critical for activity. Serine 526 has been identified as an autophosphorylation site that is required for MEKK3 catalytic activity. In addition, serine 166 has been identified as a Pim kinase phosphorylation site, thus linking Pim kinase activity with MEKK3. On going studies are aimed at defining the role of phosphoserine 166 in MEKK3 activity.

Title: To Bind - or not to Bind: Differential Presentation of a Self-peptide by HLA-B27 Subtypes
Dr. Andreas Ziegler, Full Professor and Founding Director, Institute for Immune Genetics, Charite University Medicine Berlin, Germany

Andreas Ziegler studied genetics and biochemistry at the universities of Darmstadt and Heidelberg ( Germany ). He was trained at the Max Planck Institute for Medical Research in Heidelberg (diploma), the Basel Institute for Immunology (PhD dissertation, Basel, Switzerland), and the MRC Laboratory of Molecular Biology (post-doctoral research, Cambridge, UK). Following work at the universities of Tübingen and Marburg ( Germany ), he became full professor and founding director of the Institut für Immungenetik ( Charité-Universit?tsmedizin Berlin , Freie Universit?t Berlin ). He is interested in the biology of gene complexes, structure–function relationships of MHC molecules and selection processes that take place within the human immune and reproductive systems. Andreas Ziegler is the author of more than 200 peer-reviewed publications.

Title: Structure- function of the Calcium Release Channel by Cryo-electron Microscopy
Dr. Montserrat Samsó, Assistant Professor, Anesthesia, Pain and Perioperative Medicine, Harvard Medical School, USA

Dr. Samsó received her PhD degree in Biochemistry and Molecular Biology from the Autonomous University of Barcelona in 1993 and did her postdoctoral training at the New York State Department of Health ( Albany, NY ). Her research centered in the structure-function analysis of macromolecular complexes using single-particle electron microscopy with contributions such as the first structural determination of the molecular motor dynein (Samso and Koonce, 2004; Samso et al., 1998), the 3D mapping of physiological modulators of the calcium channel RyR1 (Samso et al., 1999; Samso and Wagenknecht, 2002), and the development of a novel classification method for electron microscope images (Samso et al., 2002). Dr. Samsó joined the Anesthesia Department at Harvard Medical School in 2004 where she is an Assistant Professor. Her current studies center on the structural study of membrane proteins using cryo-electron microscopy in conditions as close as possible to their native state in order to understand their function. For the calcium channel RyR1 she is elucidating the structure of its gating unit and the basis of its long-range alosterism. She has provided the first description of its ion pathway (Samso et al., 2005) and its detailed interactions with its associated subunit, the FKBP12 protein (Samso et al., 2006).

Title: X-ray Crystallographic Evidence for a Triple Conformation of An HLA-B*2705 -bound Self-peptide
Dr. Barbara Uchanska-Ziegler, Group Leader and Head of Structural Biology, Institute of Immunogenetics, Charité-University Medicine Berlin, Freie University of Berlin, Germany

Barbara Uchanska-Ziegler studied animal breeding and genetics at the Agricultural University of Warsaw ( Poland ). She was trained at the Nuclear Research Center in Warsaw and later at the Medizinische Klinik in Tübingen ( Germany ). She obtained her PhD degree in microbiology from the Biological Faculty of the university in Tübingen. She then worked as a post-doc at the Medizinische Klinik in Tübingen. Following work at the University of Marburg ( Germany ), she became group leader and head of structural biology at the Institut für Immungenetik (Charité- Universit?tsmedizin Berlin , Freie Universit?t Berlin ). She is interested in structure–function relationships of MHC molecules, using X-ray crystallography and spectroscopic techniques, and in producing and characterizing monoclonal and recombinant antibodies with T cell receptor-like specificity. Barbara Uchanska-Ziegler is the author of more than 80 peer-reviewed publications.

Title: The EGFR-trypsin-PAR-2 Pathway in Cell Growth and the α4β1 Integrin/VCAM-1 Interactions in Pre-B Cell Repopulation Were Controlled by Fucosyltransferase
Dr. Akihiro Kondo, Professor, Graduate School of Medicine, Osaka University, Japan

From 2002 to present, he was a Professor at Osaka University Graduate School of Medicine, Osaka , Japan . His works have been specialized in carbohydrate chemistry and analytical chemistry. Major works include ‘Oligosaccharide Analysis by Fluorescence Labeling' and ‘Development of the Test Method for Detection of Endocrine Disrupting Activity Using DNA Microarrays' in ‘Toxicogenomics'.

Title: Coarse-grained Molecular Dynamics Simulation of Membrane Proteins
Dr. Ken Takahashi, Assistant Professor, Graduate School of Medicine, Nagoya University, Japan

Molecular dynamics simulation is a powerful tool to analyze functions of proteins. While conventional all-atom simulation requires massive computational cost, recently-developed coarse-grained simulation can analyze the dynamics of biological molecules up to microsecond order with less expensive cost. We report recent development of this state of the art technique by introducing a bacterial mechanosensitive ion channel MscL as an example.

Title: Bacterial F0F1-aTPase Association with Secondary Transport Systems and Membrane Ensymes under Fermentation
Dr. Armen Trchounian, Professor, Department of Biophysics, Yerevan State University, Armenia

The experimental results, hypotheses and models allow to offer a novel look at the bacterial F0F1-ATPase associated with K+ transport system and/or enzymes of anaerobic oxidation-reduction (formate hydrogen lyase) under fermentation. Some evidence of cysteine-residue in F0 b subunit that can be involved in this association is also obtained. Regulatory pathways of such associations by one of the trk genes, by the Arc-system for control of synthesis of enzymes in aerobic (respiratory) metabolism as well as by environmental factors (pH, ionic content, osmolarity, temperature, redox potential etc) are being investigated.

Steven Bodovitz, PhD, is a Principal at BioPerspectives, a renowned research and strategy consultancy in San Francisco, California. He is an expert at analyzing markets and developing strategies for the biotechnology industry. He has worked with a range of companies, from start-ups to Fortune 500. He has published a guide on business plan writing for the biotechnology industry, and he has written more than 20 business plans for biotechnology companies encompassing diagnostics, therapeutics and tools. He has written 16 comprehensive market analysis reports on topics ranging from immunoassays to microarrays to proteomics to RNAi therapeutics. He has published articles in Trends in Biotechnology, Drug Discovery Today and Drug Discovery World . He has presented his market analyses at biotechnology conferences in the US, Europe, and Japan, and he has been quoted in Science, Nature Biotechnology and The Economist . In addition to BioPerspectives, Dr. Bodovitz also served as Interim CEO of AminoArrays, an early-stage company with a patented method for array-based amino acid analysis. Dr. Bodovitz took over a company without ongoing product development and without a sound financial position and engineered an international collaboration between the leading low-density microarray platform company and the world's leading expert in the biochemistry underlying the core technology. Prior to becoming a biotechnology analyst and strategist, Dr. Bodovitz received his PhD in neuroscience from Northwestern University, where he studied the molecular mechanisms of Alzheimer's disease.

Title: High-throughput Screening of Antibody-Mimic Peptide by Using Protein Microarray Chip
Dr. Soo-Ik Chang, Professor, Department of Biochemistry, Chungbuk National University, South Korea

By using ProLinkerTM as a new chemical surface technology, ProteoChipTM has been developed as a novel protein microarray chip. We investigated the application of ProteoChipTM in screening of antibody-mimic peptides which inhibits the antibody/antigen interaction. Anti-antigen antibody microarray immobilized on the ProteoChipTM was employed to screening novel peptides against antigen from multiple hexapeptide sublibraries of a positional scanning synthetic peptide combinatorial library (PS-SPCL). The anti-antigen antibody/antigen interaction was successfully demonstrated on the anti-antigen antibody microarray in a dose-dependent manner. Novel peptides which inhibit the interaction between anti-antigen antibody and antigen were identified from the peptide libraries with this chip-based screening system by a competitive inhibition assay in a simultaneously and high-throughput fashion. These results suggest that the ProteoChipTM is a promising tool for high-throughput screening of antibody-mimic peptides in new therapeutic antibody development.

Title: The Application of Microarrays in High-throughput Enzyme Profiling
Dr. Mahesh Uttamchandani, Defence Medical and Environmental, Research Institute (DMERI) , DSO National Laboratories, Singapore

It has been estimated that 18-29% of eukaryotic genomes encode enzymes. However only a limited proportion of enzymes have thus far been characterized and little is understood about the physiological roles, substrate specificity and downstream targets of the vast majority of these important proteins. A key step towards the biological characterization of enzymes, as well as their adoption as drug targets, is the development of global solutions that bridge the gap in understanding these proteins and their interactions. I will herein present advances in catalomics that facilitate the study of enzymes and their properties in a high-throughput manner using microarrays. We have over the years introduced and developed a variety of such enabling platforms for many classes of enzymes including kinases, phosphatases and proteases. For each of these different types of enzymes, specific design considerations are required to develop the appropriate chemical tools to characterize each enzyme class. These tools include activity-based probes and chemical compound libraries, which are rapidly assembled using efficient combinatorial synthesis or “ click chemistry ” strategies. The resulting molecular assortments may then be screened against the target enzymes in high-throughput using peptide/small molecule microarrays, offering a powerful means to study, profile and also discover potent small molecules with which to modulate enzyme activity.

Despite the fact that many genomes have been decoded, proteome chips composed of individually purified proteins have been reported only in the budding yeast, mainly because of the complexity and difficulty in high-throughput protein purification. To facilitate proteomics studies in prokaryotes, we developed a new high-throughput protein purification protocol that allows us to purify 4,256 proteins, encoded by Escherichia coli K12 strain, as HisX6 fusions within ten hours. The purified proteins were then spotted on glass slides to form the first E. coli proteome chips. To demonstrate its application in basic research, we established assays to identify proteins involved in the recognition of potential base damages in DNA using a group of DNA probes each containing a mismatched base pair or an abasic site. We found a handful of proteins that were able to recognize each type of probe with a high affinity and specificity. Two positive proteins, YbaZ and YbcN, were further evaluated with biochemical analysis. The assembly of libraries containing DNA probes with specific modifications and the availability of E. coli proteome chips hold promise to rapidly reveal important protein–nucleic acid interactions that are difficult to obtain with other techniques.

Title: Highly Enhanced Fluorescence Detection of Biomolecular Microarrays Using Large-area Metal Pattern
Dr. Hee-Tae Jung, Associate Professor, Department of Chemical & Biomolecular Engineering, Korea Advanced Institute of Science & Technology, South Korea

Here, we significantly increase the sensitivity of MEF for biological molecule detection by using a combination of a large-area metal nanopattern and layer-by-layer assembly of polyelectrolyte (PET) films, in a development of a DNA microarray. To implement our strategy, w e used capillary force lithography (CFL) to fabricate nanopatterns with various feature sizes on large patterned area. F lexibility of generating various pattern sizes from a single prepattern makes this approach very attractive, and it has significant advantage of low cost and high-efficiency. The feature dimension variations of the resultant patterns are also obtained from the masters with many different dot sizes, periods and height.

Title: A Protein Chip Approach to Unraveling Networks and Pathways
Dr. Heng Zhu, Assistant Professor, Department of Pharmacology & Molecular Sciences, The High-throughput Biology Center, Viral Oncology Center, The Johns Hopkins University School of Medicine, USA

The protein chip technology is emerging as a versatile tool in the field of proteomics. It provides an unbiased, high-throughput, and comprehensive platform to investigate various aspects of protein properties; the results from which greatly facilitate construction of networks and pathways on a global scale. Our group has established new assays and applied them to globally investigate protein posttranslational modifications, with focus on lysine residues. We have also built new protein chip platform to decode the DNA-protein interactome in humans. In this presentation, exciting new discoveries will be shared with the audience.

Here he will discuss a major bovine milk protein -lactoglobulin ( -LG), containing primarily a calyx for vitamin D3 binding. Whether there are two binding sites in each -LG molecule has been a subject of controversy. Using X-ray crystallography and fluorescence spectral analyses, Dr. Chen and his collaborative group has identified the second vitamin D3 binding site that is near the surface at the C-terminus with a remarkable feature that it combines an amphipathic -helix providing non-polar residues and a -strand providing a non-polar and a buried polar residue and linked by a hydrophobic loop. This finding provides a new insight into the interaction between vitamin D3 and -LG, in which the exosite may provide another route for the transport of vitamin D3 in vitamin D3 fortified dairy products (Yang et al., 2008, 2009).
Dr. Chen received his Ph.D. in Crystallography from the University of Pittsburgh in 1999 and extended his scientific training as a postdoctoral research fellow at the Department of Biochemistry and Molecular Biology at the University of Georgia in U.S.A. Since 2001, Dr. Chen has been the faculty in National Synchrotron Radiation Research Center and the joint professor with National Tsing-Hua University and National Cheng-Kung University in Taiwan. His major research interest is the study, by synchrotron protein crystallography, of the structure and functional relations of biological macromolecules.

Title: Identification of Putative Peptide Ligands and Receptors Involved in Control of Cell-separation Processes in Plants
Dr. Reidunn Birgitta Aalen, Professer, Department of Molecular Biosciences, University of Oslo, Norway

Upon completion of her doctorate in bacterial genetics at the University of Oslo in 1985 she switched to plant science. She worked as a Research scientist at Laboratory for Plant Molecular Biology, Agricultural University of Norway, focusing on the identification of tissue-specific transcripts expressed in barley grains. In 1989-99 Aalen had a research stay at the at Max-Planck-Institut für Züchtungs-forschung, Cologne, Germany, where she learnt plant transformation. She was appointed Associate Professor at the Department of Biology, Division of General Genetics, University of Oslo in 1991, and established Arabidopsis as a model organism at the Department. Aalen is since 1998 Professor, now at Department of Molecular Biosciences, University of Oslo. During the latest years she has pursued two lines of research. One is related to epigenetics where her lab has contributed to the identification of Arabidopsis counterparts of Methyl-CpG-Binding Domain proteins and histone methyltransferases (SET-domain Proteins). The other field is the elucidation of floral organ abscission and other cell separation events in plants, again using Arabidopsis as a model organism. Aalen 's lab identified the gene INFLORESCENCE DEFICIENT IN ABSCISSION ( IDA ) that is absolutely required for abscission to take place in Arabidopsis. Recently her lab provided genetic evidence suggesting that IDA is a small peptide ligand interacting with the Receptor-like kinases HEASA and HEASA-LIKE2.

Coffee Break

Title: Pre-infectional Secretomics – Apoplastic Interaction of Rice and M. grisea Secretomes
Dr. Nam-Soo Jwa, Associate Professor, Department of Molecular Biology, College of BioScience, Sejong University, South Korea

Recently, Nam-Soo started to work on pre-infectional interactions of host-pathogen in the apoplastic region before fungal penetration into host cytoplasm. This work is focused on secretome analysis from two different organisms including host and fungal pathogen. He has applied LC-MS/MS based proteomic analysis for secretome identification for pre-infectional interactions and Yeast-Two Hybrid screening for MAPK cascade networking analysis for understanding of cytoplasmic networking. This work will be expected to lead broad understanding of host-fungal pathogen interactions and plant protections through pre-infection as well as cytoplasmic interactions during disease development.

Coffee Break

Title: Extracellular HSC70 as a Novel Mediator of Myocardial Inflammatory Response to Ischemia and Reperfusion
Dr. Xianzhong Meng, Professor, Director of Cardiothoracic Inflammation Research, Department of Surgery, University of Colorado Denver, USA

Title: Heme Oxygenase-1: A Novel Therapeutic Target against Oxidative Tissue Injuries in Acute Inflammation
Dr. Toru Takahashi, Senior Assistant Professor, Department of Anesthesiology and Resuscitology, Okayama University Medical School, Japan  

Title: Discovery of Chemokines Mediating Fibrotic Complications in Renal Diseases in Humans
Dr. Frederick Wai Keung TAM, Imperial College Kidney and Transplant Institute, Renal Section, Imperial College London, United Kingdom

Fibrosis is a major cause of morbidity and mortality in patients suffering from chronic kidney diseases. Encapsulating peritoneal sclerosis (EPS) is a rare but live threatening complication in patients receiving long term treatment with peritoneal dialysis. We studied the cytokines in the spent dialysate from patients receiving long term peritoneal dialysis. Using specific ELISA, we detected increased concentrations of monocyte chemoattractant protein-1 (CCL2) in the spent dialysate. The amount of dialysate CCL2 correlated with the severity of peritoneal membrane dysfunction. In order to examine the cytokine network involved in this clinical complication, we used an antibody array to examine 120 cytokines simultaneously. We discovered very high concentrations of CCL18/PARC (Pulmonary and Activation Regulated Chemokine) in both spent dialysate and serum from patients receiving long term peritoneal dialysis. The long term clinical outcome of these patients has been followed up prospectively in our West London Peritoneal Dialysis Study. Interim analysis showed that patients had high concentration of CCL18 in dialysate or serum are more likely to develop EPS or technique failure requiring changing over to haemodialysis treatment.

Title: Development of a Novel DNA Vaccine Targeting Macrophage Migration Inhibitory Factor and Its Efficacy on Murine Models of Inflammatory Diseases
Dr. Shin Onodera, Assistant Professor, Department of Sports Medicine and Joint Reconstruction Surgery, Hokkaido University Graduate School of Medicine, Japan

Dr. Shin Onodera was graduated from Hokkaido University School of Medicine, Sapporo, Japan in 1988 to be given his M.D. degree. He was also awarded his Ph.D. degree from Hokkaido University Graduate in 2001. In this year, he joined the Department of Orthopaedsics, Hokkaido University Hospital as a staff orthopedicist. He was appointed as Assistant Professor of the Department of Orthopaedsics, Hokkaido University Hospital in 2002. He then became Assistant Professor of the Department of Sports Medicine and Joint Reconstruction Surgery in 2005. Since 2007, he has also been acting as a research consultant of Napa Jenomics, a Japanese company engaged in the development of novel drug delivery system for the delivery of antisense oligonucleotides, siRNA, and DNA vaccines. Currently, Dr. Onodera's major areas of interest include: (1) the development of anti-cytokine vaccine for the prophylaxis and therapeutics of inflammatory diseases, (2) in vivo bioimaging of bone and joint diseases including arthritis and particle-induced osteolysis, and (3) the use of beta-D-glucan as DNA/RNA carrier.

A large amount of information exists on the testing of small molecules in rodent models. This knowledge includes distribution characteristics, membrane penetration, pharmacokinetics and toxicity. However, biologicals such as antibodies or peptides have raised a challenge to their development teams. These proteins or protein-like molecules behave quite differently compared to small molecules. Protein-based biologicals tend to be highly target specific, which therefore produce fewer side effects, with higher molar activity. However, the comparatively large size of antibodies negatively effects their distribution in the animal, and cell membrane penetration, thus slowing down delivery to the target.

Title: Pre-clinical Development of a Bi-functional, Cancer Cell Homing, PKC Inhibitory Peptide for the Treatment of Head and Neck Cancer
Dr. Quintin Pan, Associate Professor, Director, Head and Neck Oncology Research Program, Otolaryngology-Head and Neck Surgery, the Ohio State University Comprehensive Cancer Center, USA

His research is focused on the genetic determinants of aggressive head and neck cancer to identify new “druggable” genes for the development of novel molecular-targeted anti-cancer therapeutics. Dr. Pan's laboratory has designed and developed a peptide therapeutic with two functional components to allow for the selective delivery of a PKC e inhibitor to tumor cells in vitro and in vivo . It is expected that this work will lead to the development of novel PKC e inhibitory peptidomimetics for the treatment of head and neck cancer.

Title: Fibrillar Protein rVP1 Induces Ovarian Cancer Cell Apoptosis via Integrin Signaling
Dr. Shu-Mei Liang, Deputy Director, Agricultural Biotechnology Research Center, Academia Sinica, Taiwan

Professor Shu-Mei Liang is currently the Deputy Director of Agricultural Biotechnology Research Center and Director of Office of Public Affairs, Academia Sinica. She received her doctorate in Biochemistry at University of Arkansas for Medical Sciences in 1978. Before joining Academia Sinica in 1998, Prof. Liang worked at biopharmaceutical companies such as Biogen S.A., and North American Vaccines, Inc., and also at FDA, USA. When she was at Biogen, she developed a simple and scalable novel process for isolating recombinant IL-2 which was successfully transferred to GSK. She also directed a team at North American Vaccines to produce recombinant porin conjugated vaccines which were then acquired by Baxter.

Title: A Novel HSP27-Targeted Heptapeptide for Overcoming Chemo- and Radioresistance
Dr. Yun-Sil Lee, Chief, Division of Radiation Effect, Korea Institute of Radiological and Medical Science, South Korea

Heat shock protein 27 (HSP27) is highly expresed in human lung and breast cancer tissues and induces to cell death against various stimuli. We developed the heptapeptide of PKCdetla-V5 region, sensitized cancer cells through its interaction with HSP27, thereby sequestering HSP27. This heptapeptide may provied a novel strategy for selective nuetralizing of HSP27, which resulted in abolishing HSP27-mediated radio- and chemoresistnace.

The molecular and cellular mechanisms underlying the memory deficits in Alzheimer's disease are increasingly thought to be associated with faulty processing of APP. Following our earlier findings that it is possible to use the tripeptide RER (NH2-D-Arg-L-Glu-L-Arg-COOH, derived from the external domain of APP) to rescue memory in animal models, we report here that the diasteromeric (D/L) form of the acetylated tripeptide RER protects against A? induced memory loss for a passive avoidance task in young chicks and enhances retention for a weak version of the task when injected peripherally up to 12 hr prior to training.

Title: A Novel Protein in Chick Retina Exhibits Bifunctional Activities: Glutamine Synthetase and Glutamate Decarboxylase
Dr. Nison Sattayasai, Associate Professor in Biochemistry, Faculty of Science, Khon Kaen University, Thailand

The protein was determined for its purity and characterized for its identification using SDS-PAGE, 2D-gel electrophoresis and LC-MS/MS. The purified protein was identified as a glutamine synthetase with four isoforms. Enzymatic reaction followed by paper chromatography confirmed the protein identification. The protein catalyzed the synthesis of glutamine from glutamate in the presence of ammonium ion and ATP. Interestingly, prolonging reaction time, γ-aminobutyric acid (GABA) was then detected in the reaction mixture. Reaction started with glutamate and glutamine, in the presence or absence of ammonium ion and ATP, GABA could be detected immediately in the reaction mixture. The results suggested that the 42 kDa biotin-coupled protein also exhibited glutamate decarboxylase activity. Both activities were inhibited by avidin. The 42 kDa biotin-coupled protein, therefore, is a bifunctional enzyme which behaves as both synthetase and carboxylase. Concerning the function of glutamate in the retina as a neurotransmitter and a neurotoxin, this enzyme may help balancing between glutamate and GABA in neural tissues.

The amyloidogenic protein, amyloid b peptide (A b) is composed of 40 or 42 amino acids and is a critical component in the etiology of the neurodegenerative Alzheimer disease (AD). A b is prone to aggregate and forms amyloid fibrils progressively in vivo and in vitro . A b 40 and 42 differed by 2 residues at the C-terminus posses different biochemical and physiological properties. A b 42 aggregates faster and is the main composition of senile plaques found in AD brains. Despite sporadic AD, familial AD containing autosomal mutation in A b (Flemish A 21G, Dutch E22Q, Artic E 22G, and Iowa D23N) causes early onset of AD. In addition, specific aggregates designated as spherical oligomers are considered as the toxic entity. Therefore, understanding the initial stages in the aggregation is pivotal to develop methods for prevention oligomer formation.

Title: Experimental Approach for Growth Inhibition of Human Malignancies by the Highly Efficient Transporter-mediated Anti-tumor Peptide Delivery System
Dr. Eisaku Kondo, Associate Professor, Department of Pathology, Okayama University Graduate School of Medicine, Japan

Upon completion of his doctorate in Department of Pathology at the Okayama University, Japan in 199 2, he started working as an instructor at the Dept. of Pathology there, where he proceeded basic cancer research mainly focusing on B-cell lymphomagenesis with molecular pathological methods such as mRNA in situ hybridization and so on. He was assigned for an associate professor of the department of Pathology, Okayama University Medical School in 2006, and he is still developing the research of medical technology for a future peptide-based therapy with a continued effort.

Title: Design of Functional Peptide-nanoparticle Complexes for Applications in Medical Imaging and Targeted Drug Delivery
Dr. Bengt-Harald Jonsson, Professor, Division of Molecular Biotechnology, Department of Physics, Chemistry and Biology, Linkoping University, Sweden

Title: Mammalian Cell Cultures: How the Glycosylation Pattern Can be Influenced by Various Scale-up Methods
Dr. George Lovrecz, Principal Research Scientist and Project Leader, Molecular & Health Technologies, CSIRO, Australia

Dr George Lovrecz is a Senior Principal Research Scientist at CSIRO Molecular and Health Technologies with 25+ years experience in fermentation, specialising in mammalian cell cultures. His early projects involved the development of an on-line computer-linked control for bioreactors using novel techniques and the scale-up and GMP production of human growth hormone (hGH) at the University of New South Wales in conjunction with Commonwealth Serum Laboratories (CSL) and the Garvan Institute. Later he become responsible for the operation of the Recombinant Products Laboratories at UNSW. He joined CSIRO in 1995 as the Head of the Fermentation Group in Parkville. George provides expertise in the area of large-scale production, optimisation, development and characterisation of recombinant proteins for internal and external research collaborators such as programs from CSIRO, WEHI, LICR, PHI, Agenix, etc. He had an integral role in the development of a large-scale production system for mammalian cell receptor glycoproteins, as part of a collaborative effort. The resulting achievements of this work included the 3D structure of hIR and EGF receptor fragments the first published instance from this receptor family. George also has been involved in several patents/publications and teaching and training and various organisations.

Title: PER.C6® Technology: A Human Cell Line for Recombinant Protein Production at Extreme Levels
Dr. John H Chon, Director, Upstream Process Development, PERCIVIA PER.C6® Development Center, LLC., USA

Today's biopharmaceutical market requires manufacturing processes that are flexible, robust, cost-efficient, and deliver consistent product quality. A process that is capable of producing large amounts of the product quickly is valuable not only for preclinical and early-phase clinical material generation it also has great advantages in late-clinical and commercial manufacturing arena. PER.C6 cells are of a human cell line that has been used for years for production of vaccines. In the past few years, however, this cell line has become a popular platform for the production of recombinant proteins and monoclonal antibodies as well. Our research areas are focused on improving the yields of recombinant proteins by combination of PER.C6® cell line genetics, cell csulture medium optimization, and development of best practices to produce recombinant proteins in cell culture.

Coffee Break

We believe that the DVS-II may provide a valuable tool in constructing a combinatorial phage-displayed Fab library with large diversity which is readily applicable in isolation of desired antibody clones based upon the L chain promiscuity of antibodies in determining antigen-binding specificity, and the DVS-III provides a convenient way to achieve light chain shuffling with any given heavy chain, leading to the identification of optimal light chain counterparts, which ultimately leads to in vitro affinity maturation of an antibody molecule. In addition to creating a huge combinatorial Fab diversity with great ease, another unique advantage of our hierarchical approach using the DVS-II and DVS-III over a conventional one-phagemid system has is its versatility in that the same human H and L chain sub-libraries created in the DVS-II or DVS-III, respectively, that used for construction of a 'single pot' human antibody library can be utilized in guided-selection or chain shuffling of mAbs of non-human origin instantly.

Title: Flexible and/or Disordered Structures of Tandem Repeats in Proteins
Dr. Norio Matsushima, Professor of Division of Biophysics, Center for Medical Education, Sapporo Medical University, Japan

Tandem repeats occur in 14% of all proteins. The repeat unit lengths range from a single amino acid to more than 100 residues and the repeat number is sometimes over 100. Understanding the structures, functions, and evolution of these repeats is a significant goal in both proteomics and genomics. There are two general classes of tandem repeats in proteins. Some consist of globular domains, such as EF-hands, WD repeats, leucine rich repeats, and ankyrin; some of these domains associate to form helical structures. There are two subclasses of non-globular repeats. The first, such as collagen, form stable helices. The second, the focus of this review, are flexible and somewhat disordered both in vitro and in vivo.

Title: Conformational Preferences of Bioactive Peptides Studied by Quantum-Chemical Methods
Dr. Young Kee Kang, Professor, Department of Chemistry, Chungbuk National University; Secretary General of Korean Peptide-Protein Society, South Korea

Upon completion of his doctorate in physical chemistry at the Korea Advanced Institute of Science and Technology in 1983, he joined the faculty at the Department of Chemistry, Chungbuk National University, Korea. Dr. Kang spent two years as a postdoctoral fellow with Dr. Harold A. Scheraga at Cornell University for 1985-1987, where he developed a method to calculate the hydration free energies of peptides and proteins during their conformational changes. After returning to Korea, he has interested in developing the parameters for the molecular force field and applied his methods to study the conformational preferences of bioactive peptides, especially in aqueous solution. In particular, he has focused on the cis-trans isomerization of prolyl peptide bond and the puckering of prolyl ring since 1990. He has also served as the president of the Korean Biophysical Society (2005-2006), a steering committee member of Asian Biophysical Association (2007-present), and the Secretary General of Korean Peptide-Protein Society (2006-present).

Title: Chemokine Peptide-mediated Migration Control of Osteoclast Precursors Visualized by in Vivo Bone Imaging: A Novel Point of Regulation for Osteoimmunology
Dr. Masaru Ishii, Associate Professor, Chief of Laboratory of Biological Imaging, Immunology Frontier Research Center (IFReC), Osaka University, Japan

Chemokines are a family of small cytokines, consisting of approx. 100-polypeptides. The major role of chemokines is to act as a chemoattractant to guide the migration of cells. Although a variety of chemokines have been shown to control cells of the immune system, chemokine-mediated control of other biological systems is less demonstrated. Here I show for the first time that chemokines, such as CXCL12 and sphingosine-1-phosphate (S1P), dynamically controls migration of osteoclasts, special cell types for destroying bone tissues, and thus regulates bone homeostasis.

Title: Simultaneous Qualitation and Quantitation of Peptides by Liquid Chromatography/ Mass Spectrometry with Electron Transfer Dissociation Technology
Dr. Chien-Chen Lai, Associate Professor, Institute of Molecular Biology, National Chung Hsing University, Taiwan

Title: Current Drug Discovery Approaches Using Molecular Diversity and Chemical Biology
Dr. Seung Bum Park, Associate Professor, Department of Chemistry, College of National University, Seoul National University, South Korea

Upon completion of his doctorate in bioorganic chemistry at Texas A&M University in 2001, Dr. Seung Bum Park extended his scientific training as a postdoctoral research fellow at Harvard University under the guidance of Prof. Stuart L. Schreiber (2001-2004). Then, he joined the faculty of Chemistry department at Seoul National University. His research interest is following: Diversity-Oriented Synthesis and Chemical Biology, Rational Designed Drug Discovery, Bioimaging and High Throughput Screening, Proteomics screening using small molecule microarray, and NanoBioTechnology (NBT) for smart drug delivery system.

Title: Inhibitory Effect of Oligopeptide on Cbl-b-mediated Ubiquitination and Degradation of IRS-1
Dr. Takeshi Nikawa, Professor, Department of Nutritional Physiology, Institute of Health Biosciences, the University of Tokushima Graduate School, Japan

The down-regulation of IGF-1 signaling by Cbl-b, a RING-type ubiquitin ligase, contributed to bone loss and skeletal muscle atrophy during unloading. Cbl-b ubiquitinated IRS-1, an important intermediate of IGF-1
signal transduction, and enhanced its degradation. Since Cbl-b deficient mice were resistant to muscle atrophy and osteopenia induced by unloading conditions, we hypothesized that inhibition of IRS-1
ubiquitination promised to prevent unloading-mediated bone loss and muscle atrophy. In this study, we found that a synthetic oligopeptide with specific amino acid sequences effectively inhibited the Cbl-mediated ubiquitination of IRS-1 (patent pending). We also suggest that specific oligopeptides may be available as potent inhibitors against ubiquitin ligases, which are the rate-limiting enzymes of the ubiquitin-proteasome proteolytic pathway.

Coffee Break

Recently, I have developed a ribosome display technology for in vitro selection of target binding peptides from artificial peptide library. By use of this technology, I actually isolated and characterized new peptides with specific affinities for proteins, metal ion, metal biomaterial, and chemical compound. In my speech, I will present the details of the original technology, functions of target binding peptides, and bio-applications of them.

Title: Development of a Microwave-assisted Synthesizer for Polymer Supported Peptide Synthesis, and Its Application
Dr. Hiroki Shimizu, Research Institute of Genome-based Biofactory, Hokkaido Center, National Institute of Advanced Industrial Science and Technology (AIST), Japan

Microwave has well known as an effective heating tool and recently applied for chemical synthesis. Nevertheless this situation, we have focused on microwave non-thermal effect in the synthetic chemistry field, especially in peptide and carbohydrate syntheses. Based on our studies, we have developed a new semi-auto synthesizer which can be applied for polymer supported peptide synthesis as being able to control a reaction temperature rigidly and shake a reaction flask effectively. By use of this machine, we have synthesized some of bio-active peptides as ten, fifteen and thirty amino acid residual peptides easily and effectively, and even a sixty nine amino acid residual protein, verotoxin1 B subunit, is on the target of our chemical synthesis.

Title: Intracellular Signal-Responsive Gene Regulation System for Cancer Cell-Specific Gene Therapy by Using New Class of Peptide-Polymer Conjugate
Dr. Yoshiki Katayama, Professor, Department of Applied Chemistry, Faculty of Engineering, Kyushu University, Japan

fter back to Dojindo Labs in 1991, Dr. Yoshiki Katayama then joined the faculty of Kyushu University. A t first, he pioneered a new technology for SNP analysis or biosensors for the detection of cyclic nucleotide ( Katayama et al. 200 0 ). From 1999-2002, he accomplished the research project of JST (PRESTO) for the research of intracellular signal-responsive DDS (Katayama et al. 2001, 2002). This technology is capable of signal-responsive drug release or gene activation. This work was developed by the next project of JST (CREST) from 2004-2008. The concept was successfully applied to living cell and animals and established a new concept of DDS (J-H. Kang et al 2008, J. Oishi et al. 2006 etc). He also developed a new peptide array for comprehensive analysis of intracellular signals or repid screening system of such signals using gold nanoparticles (K. Inamori et al. 2008, J. Oishi et al. 2007). He is now professor in Kyushu University from 2003.

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Title: Molecular Hiving Technology Bringing a New Innovation to Peptide Based Therapeutics
Mr. Yusuke Kohno, Director, Department of Business Development, Jitsubo Co., Ltd., Japan

Mr. Kohno is appointed as a Director of b usiness development at Jitsubo Co., Ltd. in Jul y 2007. He re ceived his Msc and Bsc in Organic chemistry from Tokyo University of Agriculture and Technology in 2002 on efficient peptide synthesis with thermomorphic solvent system. For 3 years f rom 2002 to 2005, he was with DIC Corporation as a chemical specialist focusing on the process developmen t of the biomaterials and macro molecular for industry use. And then he was invited to join Jitsubo in 2005 and dedicated himself to establish Molecular Hiving? platform in collaboration with Tokyo university of Agriculture and Technology. In last 2 years he made up a number of collaborations with academia, biotech and pharmaceutical companies as a business development

Title: Endomorphins: Potent Anti-inflammatory Drugs in Arthritis
Dr. David S. Jessop, Department of Medicine, University of Bristol, UK

Dr. Jessop was awarded his PhD from the University of London in 1988 for endocrine studies performed at St Bartholomew's Hospital. Since then he has worked at Westminster Hospital, London, and the University of Bristol in the UK. He was the first to identify the novel opioid peptides endomorphins in the mammalian immune system and demonstrate their anti-inflammatory activities. His current interests are the synthesis of endomorphins in immune cells and the therapeutic application of these compounds, and their long-acting analogues, to the treatment of arthritis. Dr Jessop was awarded an honorary Professorship in Neuroimmunology by the Hong Kong Polytechnic University in 2004.

Title: Conopeptide to Drug: Structure and Activity Studies Central to the Development of Xen2174
Dr. Andreas Brust, Reasearch Manager Chemistry, Xenome Limited, Australia

Dr. Andreas Brust obtained his Ph.D. degree in organic chemistry from the Technical University of Darmstadt ( Germany ). His work was focused on the synthetic evaluation of the use of carbohydrates as renewable resource for the chemical industry; Postdoctoral research into the biosynthesis of sponges including synthesis ( 14 C -labeled), isolation and structural determination of marine natural products at the University of Queensland braught him to Australia. In 2002 he joined Xenome Ltd.. As Research Manager (Chemistry) he is part of Xenome's Drug Development Team working closely with pharmacology and preclinical development.