Day 3 :
- Systems Biology | Bioinformatics | Bioengineering | Bioimaging
Location: Experience II
Jagiellonian University, Poland
Laval University, Canada
Jagiellonian University, Poland
Title: Regulation of oxidative phosphorylation during work transitions and bioenergetic background of mitochondrial diseases
Time : 09:00-09:20
Bernard Korzeniewski has completed his PhD and Postdoctoral studies from Jagiellonian University. He has published more than 75 papers in reputed journals.
It was proposed that the main mechanism responsible for the regulation of the cell bioenergetic system in skeletal muscle and heart during work transition is each-step activation (ESA) of all oxidative phosphorylation (OXPHOS) complexes, NADH supply and glycolysis in parallel with the activation of ATP usage (actomyosin-ATPase and Ca2+-ATPase) by Ca2+ ions. A widely-validated computer dynamic model involving this mechanism is able to explain numerous, frequently apparently unrelated to each other, properties of the system behavior under various conditions. Computer simulations demonstrate that in intact working skeletal muscle metabolite (PCr, ADP, Pi) concentrations and cytosolic pH begin to change significantly at much higher OXPHOS (complex) activities than the respiration rate (VO2). Consequently, it is postulated that inborn deficiencies of particular OXPHOS complexes and entire OXPHOS as well as ESA dysfunction can lead to mitochondrial myopathies not by compromising mitochondrial VO2 and oxidative ATP production per se, but through increase in cytosolic Pi, ADP and H+ concentrations. This increase can account for such mitochondrial myopathy syndromes as muscle weakness, exercise intolerance (exertional fatigue) and lactic acidosis.
University of Pittsburgh School of Medicine, USA
Time : 09:20-09:40
Vanathi Gopalakrishnan is a tenured Associate Professor of Biomedical Informatics in the School of Medicine at the University of Pittsburgh and has a PhD in Computer Science. She has secondary appointments in the Intelligent Systems Program and the Department of Computational and Systems Biology. She directs the PRoBE Laboratory for Pattern Recognition from Biomedical Evidence. Her research involves predictive modeling from big biomedical datasets with a focus on transforming imaging and biomarker data into actionable knowledge to enable precision medicine and translational bioinformatics. She is a Guest Editor for a special edition on Biomedical Informatics in the journal data.
Molecular profiling data from scientific studies aiming for early detection and better management of diseases such as cancer has accumulated at rates far beyond our abilities to efficiently extract knowledge of value to the practice of precision medicine. A major challenge is that these data are often generated using multiple high-throughput technologies giving rise to panomics data such as gene expression and DNA methylation for the same or related classification task. In this talk, I will present novel computational methods and tools that are being developed in my laboratory for the integrative modeling of panomics data to improve disease state classification from related molecular profiling studies. We are extending the novel Transfer Rule Learning (TRL) methods that were previously developed to deal with sparse data from biomarker profiling studies, by automatically learning classification rules from one dataset, transferring that knowledge and using it when learning rules from a related dataset. The extensions include methods for knowledge transfer using ontological or taxonomic hierarchies along with classification rule learning. Preliminary results from collaborative studies involving biomarker profiling data for the early detection of lung cancer and microbiome data for infectious disease classification will be presented.
Freie Universität Berlin, Germany
Time : 09:40-10:00
Max Von Kleist has an undergraduate background in Bioinformatics and holds a PhD in Mathematics, which he has completed in 2009 at the Hamilton Institute, National University of Ireland. After a short Postdoctoral phase at the Freie Universität Berlin (2010-2011), he gradually built up an own research group. He has published over 30 papers to date.
RNA has long been believed to mainly serve as a blueprint for proteins. However, a large diversity of so called non coding RNAs has been discovered lately to regulate virtually all cellular processes. Characterizing functional domains and structure-function-relationships in RNA is a major challenge as classical experimental approaches are time-consuming and require substantial investigator expertise. To overcome these obstacles we recently developed MIME which coupled to a bioinformatics analysis pipeline implemented in the cross-platform software MIMEAnTo allows to identify domains and structures in RNA that are important for its function. In MIME, target RNAs are randomly mutated, selected by function, physically separated and sequenced using next-generation sequencing (NGS). Consequently, quantitative effects of mutations at every nucleotide position are recovered. While the location of function-disrupting mutations in the RNA allows identifying binding domains, permitted patterns of mutations reveal the functional role of each nucleotide. Moreover, through co-variation analysis it is possible to de novo model the structure of the RNA that is associated with the analyzed function.
Karen Lipkow was originally trained as a Molecular Biologist with undergraduate degree and research at the University of Konstanz, Germany and Rockefeller University, New York and has obtained his PhD degree from the University of Oxford, UK. For her Post doctorate at the University of Cambridge, she switched to computational biology. Since becoming a Group Leader in Cambridge, she is combining both computational and experimental approaches to study the mechanisms that shape cellular architecture. She is also an Editorial Board Member of the world's oldest scientific journal.
The questions of how genes are regulated remains fundamental even after many decades of intense study. Rather than just studying the linear, one-dimensional sequence of DNA to inform us about regulatory mechanisms, we can now investigate the complex 3-dimensional organization of whole genomes. It has become clear that this organization is non-random and highly dynamic. To address new questions in genome architecture, we are taking a systems biology approach, combining the bioinformatic determination of chromatin states with quantitative experiments and dynamic, stochastic models of whole genome organization. Comparing these results with our experimental data has led us to understand how biophysical properties of the chromatin fibre lead to significant and biologically relevant self-organization of the genome.
University of Southampton, UK
Title: MHC I and antigen selection: Immune system modeling integrates cellular function with structural plasticity
Time : 10:35-10:55
Jorn M Werner has received his PhD in Biochemistry from the University of Oxford and established his own research group at the University of Southampton in 2003. His interdisciplinary research group integrates structural biochemistry with cellular function using systems model approaches. He has published over 50 peer reviewed papers and is serving as an Editor for Science Reports as well as Frontiers in Structural Biology.
The control of the immune system plays a key role in both healthy and diseased states and the presentation of peptides at the surface of most nucleated cells by major histocompatibility complex class I molecules (MHC I) is crucial for eliciting or evading an immune response. Since the pool of surface presented peptides only presents a small sample of all possible peptides understanding their selection process is crucial for the development of treatments such as vaccines, which rely on the selection of specific peptides. The peptide selection process is mediated primarily by a weakly interacting multi-protein peptide loading complex (PLC) at the centre of which is the modulation of MHC class I conformation. To gain a better understanding of the mechanisms of peptide selection by MHC I, we developed computational systems models encoding distinct mechanistic hypotheses of PLC function. Using in vivo biochemical data we were able to infer that the system is under kinetic control and that a conformational intermediate of MHC I is significant for peptide selection. We investigate the molecular determinants of peptide selection using a combination of X-ray, NMR and biophysical techniques together with molecular dynamics simulations. Using this approach we show that peptide selector function correlates with protein plasticity rather than structure. This in turn was tested experimentally in vivo and extended to the PLC resident chaperone tapasin. By combining computational systems models with in-cell biochemical data and structural methods we identify a previously undetected correlation between protein plasticity and in vivo peptide selector function of MHC I, with implications for host defense and immunotherapy.
Texas A&M University, USA
Title: Investigating functional relationships of five critical genes present in the familial nonsynonymous loci with risk of having acute lymphoblastic leukemia
Time : 10:55-11:15
Erchin Serpedin has completed his specialization degree in Signal Processing and Transmission of Information from Ecole Superieure D’Electricite (SUPELEC), Paris, France, in 1992. He has received his MSc degree from the Georgia Institute of Technology, Atlanta, in 1992 and the PhD degree in Electrical Engineering from the University of Virginia, Charlottesville in 1999. He is currently a Professor in the Department of Electrical and Computer Engineering at Texas A&M University, College Station. He is the author of 2 research monographs, 1 textbook, 75 journal papers and 120 conference papers.
A recent whole exome sequencing of Acute Lymphoblastic Leukemia (ALL) revealed that common variations in particular non-synonymous homozygous variants affects disease risk. The present work researches into the functional consequences of the polymorphisms in the following genes: B3GALTL (rs1041073), GEN1 (rs16981869), CA9 (rs2071676), CHIT1 (rs2297950), CHRNB1 (rs17856697), ERBB2 (rs1058808) and ZNF207 (rs3795244). The Polyphen scores were evaluated using the residue changes due to missense variations and protein identifiers generated GlobPlots to predict inherent protein disorders and ProtParam provided the ‘instability indices’. Furthermore, metabolic pathways and protein networks were studied by Reactome Pathway Browser and String-db.
Rutgers University, USA
Time : 11:15-11:35
Daniel H Shain has completed his PhD from Colorado State University and Postdoctoral studies from the University of California, Berkeley. He has published more than 50 papers in reputed journals.
Adenosine 5’-trisphospate (ATP) is the universal currency of energy in living cells. We have determined that elevated ATP confers environmental stress resistance in disparate organisms. For example, glacier ice worms (Annelida) display atypically high ATP levels that paradoxically increase as temperatures decline, comparable with other cold-adapted taxa. By manipulating key targets in purine metabolism, we have generated strains of bacteria and algae with elevated ATP that are cold tolerant. The F1F0 ATP synthase complex is the primary producer of energy and is the most functionally conserved molecular machine across domains of life. We have identified two ice worm-specific accessory domains in subunits ATP6 and epsilon that likely enhance ATP production. We propose that manipulation of these targets will lead to translatable applications ranging from stress-resistant crops to the treatment of mitochondrial disease.
Federal University of Rio Grande do Sul, Brazil
Title: Conformational study of a mutated protein complex in xeroderma pigmentosum disease using molecular dynamics and residue interaction networks
Time : 11:35-11:55
Bruno Cesar Feltes is currently a PhD candidate in Cellular and Molecular Biology at the Federal University of Rio Grande do Sul, Brazil. His studies have been focused in bioinformatics with emphasis on systems biology, systems toxicology and systems pharmacology to answer biological questions related to developmental biology and aging mechanisms; he has published most of his works in these fields. Presently, he works with molecular dynamics simulations and network analysis applied to structural biology and diseases. His collaborations also extend to microarray and RNA-seq data analysis.
Xeroderma Pigmentosum (XP) is a rare autosomal recessive disorder caused by mutations in seven genes that codify Nucleotide Excision Repair (NER) pathway proteins, named XPA to XPG. As a result of this, XP patients produce mutant proteins that compromise DNA lesion removal, resulting in a broad range of pathological symptoms. However, little is known about XP proteins structure or how these mutations affect NER complex assembly. Thus, to understand how these mutations impact on XP proteins, we obtained DDB2(XPE)-DDB1 protein complex (DDB-complex) PDB data, since this complex is necessary for damage recognition in NER and performed multiple molecular dynamics simulations. Simulations were performed in triplicates for wild-type DDB2, DDB1 and DDB-complex, as well as for the naturally-occurring mutations found in XP, namely DDB2R273H, which impair DDB2 DNA binding and DDB2L350P, which affect the DDB-complex (all simulated alone and assembled with DDB1). We also applied dynamic Residue Interaction Networks (RINs) analyses to observe how these mutations impact on structurally important residues and communities formation over simulated periods and combined these results with systems biology analysis of RINs. Hence, it was possible to observe conformational differences between wild-type and mutated proteins/complex, such as reduced local flexibility, residues imperative for communication between communities, complex instability, structurally critical residues and loss or gain of communities. The combination of in silico analyses employed arises as a promising method for studying protein structure and could be assigned to other relevant investigations, such as small molecules impact on proteins and recombinant proteins design.
Tokyo Institute of Technology, Japan
Time : 11:55-12:15
Ken-ichro Ogawa has completed his PhD (Doctorate of Science) in 2011 from Tokyo Institute of Technology and was engaged in scientific pursuits as a Research Associate at Tokyo Institute of Technology from 2011 to 2012. He is currently an Assistant Professor in the Department of Computational Intelligence and Systems Science at Tokyo Institute of Technology. His research interests lie in the field of modeling embryogenesis of multicelluar organisms and embodied interaction in human communication.
Cell-to-cell communication in multicellular organisms is established through the transmission of various kinds of chemical substances. It is known that gene expression triggered by a chemical substance in individuals has stable spatial patterns despite the individual differences in concentration patterns of the chemical substance. This fact reveals an important property of multicellular organisms called “robustness”. Robustness has been conventionally accounted for by the stability of solutions of dynamical equations of chemical substances. However, any biological system is composed of autonomous elements, in which each element does not merely accept information on the chemical substance from the environment; instead, it accepts the information based on its own criteria for reaction. Therefore, this phenomenon needs to be considered from the viewpoint of cells. This study aims to explain theoretically the robust patterning of gene expression from the viewpoint of cells. For this purpose, we introduced a new operator for transforming a state variable of a chemical substance from an external coordinate system to an internal coordinate system of each cell. Then, this operator is applied to the simplest reaction diffusion model of the chemical substance. This extended model indicates that the robust patterning of gene expression against individual differences in concentration pattern of the chemical substance can be explained from the viewpoint of cells if there is a regulation field that compensates for the difference between cells seen in transformation. This result provides a new insight into the investigation of the mechanism of robust patterning in biological systems composed of individual elements.
University of Wurzburg, Germany
Time : 12:15-12:35
Susanne Franziska Fenz has studied Physics in Wurzburg and Heidelberg. She has received her PhD in 2009 from the University of Bonn, Germany. As a Post-doctoral fellow she moved to Leiden University in the Netherlands to work on single-molecule fluorescence microscopy of living cells. Her current interests include biomimetics, cell adhesion and diffusion in crowded membranes as well as super-resolution microscopy.
Recent developments in super-resolution microscopy made it possible to resolve structures in biological cells at a spatial resolution of a few nm and observe dynamical processes with a temporal resolution of ms to µs. However, the optimal structural resolution requires repeated illumination cycles and is thus limited to fixed cells. For live cell applications substantial improvement over classical Abbe-limited imaging can be obtained in adherent or slow moving cells. Nonetheless, to our knowledge a large group of cells, intrinsically fast moving flagellates could not yet be addressed with super-resolution microscopy. These include pathogens like trypanosomes, the causative agents of sleeping sickness in humans and Nagana in cattle. Attempts to immobilize these cells include drug treatment or embedding in agarose or gelatin gels. However, these methods either have unwanted side effects or are not sufficient for super-resolution imaging because they do not efficiently suppress the flagellar beat. Here, we present a novel hydrogel embedding and quantify its biocompatibility and immobilization efficiency. We characterize both the cells and the gel with respect to their autofluorescence properties and find them suitable for single-molecule fluorescence microscopy (SMFM). We apply SMFM to track individual Atto647N-labeled membrane proteins on the surface of immobilized trypanosomes and achieve a localization precision of 30 nm and a temporal resolution of 25 ms.
Tokyo Institute of Technology, Japan
Title: Fabrication of high biocompatible Pt-nylon and Pt-silk composite materials by supercritical carbon dioxide-assited metallization method
Time : 13:25-13:45
Tso-Fu Mark Chang has received his BSc in Chemical Engineering from the University of Toronto (2004), MS in Chemical Engineering from National Tsing Hua University (2007) and PhD in Materials Science and Engineering from Tokyo Institute of Technology (2012). He is currently an Assistant Professor of Precision and Intelligence Laboratory at Tokyo Institute of Technology. His research interests include pressure and solvent effects on reactions in supercritical CO2 and characterization of the materials fabricated in supercritical CO2. He has published more than 50 papers in reputed journals.
As the medical technology advances, the next-generation healthcare devices are urgently demanded. Implantable and wearable medical devices are the latest applications over the decades. Nickel, copper and aluminum are widely used in aforementioned medical devices because of the simple process and low cost, however, adverse reactions such as allergies and Alzheimer's disease might take place due to the releasing of the metal ions. A biocompatible electronic material, thus, becomes the most urgent demand. Platinum is considered to be the most promising material owing to its irreplaceable biocompatibility. Moreover, nylon and silk are the common materials used in clothes. The combinations of Pt with nylon and silk textiles are considered to be promising candidates for the medical devices. Electroless plating can put these composite materials into practice and further achieves homogeneous metallized-surface due to the low deposition rate. Typical electroless plating consists of pretreatment to clean and roughen the surface, catalyzation to embed the catalysts as a nucleation site into the substrate and the plating step for the metallization. In spite of the dominance of Pt, electroless plating of Pt remains less studied due to the difficulties in controlling the catalyzation step in the electroless plating process. An up-to-date technique of supercritical carbon dioxide (sc-CO2) assisted catalyzation is practiced in this study to overcome the instinct difficulty of Pt metallization. With the help of the sc-CO2, the Pt catalyst can be inlaid into the textile structure and uniform Pt coatings can be deposited on the textile.
Laval University, Canada
Time : 13:45-14:05
Mahmoud Rouabhia is a full Professor at the Faculty of Dentistry of Laval University. He is a Senior Scientist in the field of Immunology, Cell Biology and Tissue Engineering. He has obtained his PhD in France, followed by a Postdoctoral training for four years in Canada. His research interest includes wound healing under chemical and physical stimulations that include growth factors but also electrical stimulation, stem cell differentiation for tissue regeneration, the interaction between host & oral microorganisms related to the oral cavity, the role of local innate immunity reducing oral infections, etc. He has more than 130 pair reviewed scientific publications. He is the Editor/Co-editor of three books. He has published over 15 book chapters/review articles and two patents.
Electrical stimulation (ES) in its various forms has been shown to promote wound healing by increasing the migration of keratinocytes and macrophages, enhancing angiogenesis and stimulating dermal fibroblasts. Delivery of ES to the wound can be through biocompatible conductive biomaterials such as conductive membranes made of 5% polypyrrole (PPy) and 95% polylactide (PLA), as well as an electronic system that enables cells to be cultured on the surface of the conductors and then electrically stimulated. One of the key cells in wound healing is fibroblast contributing to extracellular matrix synthesis and interaction with epidermal cells thus contributing to wound closure. Fibroblast activities during wound healing were reported to be modulated by multiple agents including ES. However, the underline molecular mechanisms are not clear and the approach to apply electrically activated fibroblasts to assist skin wound healing needs to be explored. With this conference, we will be presenting cell response/cell signaling pathway following exposed to ES; demonstrating the advantages of ES on in vitro and in vivo skin tissue regeneration. To generate original data related to ES promoting wound healing we used a sophisticated conductive membrane that combines polylactide (PLLA) or polyester fabrics (PET) with polypyrrole (PPy) as a conductive polymer. With these conductive membranes, we demonstrated that both continuous and pulsed ES-induced fibroblast adhesion and proliferation. Furthermore, ES promoted fibroblasts to myofibroblast differentiation confirming what has been reported previously. Interestingly, the myofibroblast phenotype acquired following ES can be transferred to daughter cells. The effects of ES on human fibroblasts lead to an increased production of TGFβ1 by activating ERK and NF-κB signaling pathway. The ES-modulated fibroblasts adequately interacted with keratinocytes leading to a well-structured EHS tissue expressing basement membrane (BM) glycoproteins, including laminin and type IV collagen. Tissue organization was superior under 200 mV/mm of ES compared to 50 mV/mm. This confirms the previously reported study suggesting that exogenous ES maintains the ex vivo epidermal integrity and cell proliferation of a human skin explants. Following 20 and 30 days of grafting, the newly regenerated skin was well vascularized, showing BM formation through laminin and type IV collagen secretion and was wholly formed by the implanted human cells. In conclusion, we demonstrated that electrically activated fibroblasts interacted with keratinocytes leading to in vitro/in vivo well-structured engineered skin. This study thus provides an innovative way to use electrically activated cells for skin regeneration and wound repair.
National Taiwan University of Science and Technology, Taiwan
Title: Synthesis of molybdenum disulphide (MoS2 ) gadolinium complex with core shell structure used as in vivo MRI
Time : 14:05-14:25
Rajeshkumar Anbazhagan has completed his Master’s degree from Annamalai University and studying PhD in National Taiwan University of Science and Technology, Taiwan. He has published 2 papers in reputed journals.
In this paper, water soluble core shell molybdenum disulphide (MoS2) gadolinium complex was synthesized and used as in vivo MRI contrast agents. Briefly, monolayer MoS2 nanosheets were exfoliated with help of thioglycolic acid (TGA) as stabilizing agents by room temperature stirring followed by the sonication in water. Subsequently, luminescent MoS2 quantum dots with sustained fluorescence emission, which were fabricated through hydrothermal treatment of exfoliated MoS2 and could be utilized as cell biomarkers. These primary in vitro cell imaging results proved the biocompatibility of the nanomaterials, it could be used as in vivo imaging candidate in future. Therefore, we develop core-shell molybdenum disulfide and gadolinium complex, as an alternative in vivo MRI candidate. The synthesized core-shell contrast agents’ exhibits enhanced paramagnetic property; compared to commercial gadolinium contrast agents core-shell MoS2 chelate has 4.5-times longer water proton spin-lattice relaxation time (T1); as well as lowered toxicity, extended blood circulation time, increased stability and desirable excretion characteristic. Transmission electron microscopy (TEM) proved core-shell nanoparticles 100 nm in size. These findings suggest that the synthesized nanomaterials possess high potential as a positive contrast agent for the enhancement of MRI imaging.