Gaute Einevoll, Ph.D.
Professor of Physics, Department of Mathematical Sciences & Technology, Norwegian University of Life Sciences (UMB)
Multiscale modeling of cortical network activity: Key challenges
Gaute T. Einevoll Computational Neuroscience Group, Norwegian University of Life Sciences, 1432 Ås, Norway; Norwegian National Node of the International Neuroinformatics Coordinating Facility (INCF)
Several challenges must be met in the development of multiscale models of cortical network activity. In the presentation I will, based on ongoing work in our group (http://compneuro.umb.no/ ) on multiscale modeling of cortical columns, outline some of them. In particular,
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Combined modeling schemes for neuronal, glial and vascular dynamics [1,2],
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Development of sets of interconnected models describing system at different levels of biophysical detail [3-5],
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Multimodal modeling, i.e., how to model what you can measure [6-12],
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How to model when you don’t know all the parameters, and
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Development of neuroinformatics tools and routines to do simulations efficiently and accurately [13,14].
References:
- L. Øyehaug, I. Østby, C. Lloyd, S.W. Omholt, and G.T. Einevoll: Dependence of spontaneous neuronal firing and depolarisation block on astroglial membrane transport mechanisms, J Comput Neurosci 32, 147-165 (2012)
- I. Østby, L. Øyehaug, G.T. Einevoll, E. Nagelhus, E. Plahte, T. Zeuthen, C. Lloyd, O.P. Ottersen, and S.W. Omholt: Astrocytic mechanisms explaining neural-activity-induced shrinkage of extraneuronal space, PLoS Comp Biol 5, e1000272 (2009)
- T. Heiberg, B. Kriener, T. Tetzlaff, A. Casti, G.T. Einevoll, and H.E. Plesser: Firing-rate models can describe the dynamics of the retina-LGN connection, J Comput Neurosci (2013)
- T. Tetzlaff, M. Helias, G.T. Einevoll, and M. Diesmann: Decorrelation of neural-network activity by inhibitory feedback, PLoS Comp Biol 8, e10002596 (2012).
- E. Nordlie, T. Tetzlaff, and G.T. Einevoll: Rate dynamics of leaky integrate-and-fire neurons with strong synapses, Frontiers in Comput Neurosci 4, 149 (2010)
- G.T. Einevoll, F. Franke, E. Hagen, C. Pouzat, K.D. Harris: Towards reliable spike-train recording from thousands of neurons with multielectrodes, Current Opinion in Neurobiology 22, 11-17 (2012)
- H. Linden, T Tetzlaff, TC Potjans, KH Pettersen, S Grun, M Diesmann, GT Einevoll: Modeling the spatial reach of LFP, Neuron 72, 859-872 (2011).
- H. Linden, K.H. Pettersen, and G.T. Einevoll: Intrinsic dendritic filtering gives low-pass power spectra of local field potentials, J Computational Neurosci 29, 423-444 (2010)
- K.H. Pettersen and G.T. Einevoll: Amplitude variability and extracellular low-pass filtering of neuronal spikes, Biophysical Journal 94, 784-802 (2008).
- K.H. Pettersen, E. Hagen, and G.T. Einevoll: Estimation of population firing rates and current source densities from laminar electrode recordings, J Comput Neurosci 24, 291-313 (2008).
- K. Pettersen, A. Devor, I. Ulbert, A.M. Dale and G.T. Einevoll. Current-source density estimation based on inversion of electrostatic forward solution: Effects of finite extent of neuronal activity and conductivity discontinuities, Journal of Neuroscience Methods 154, 116-133 (2006).
- G.T. Einevoll, K. Pettersen, A. Devor, I. Ulbert, E. Halgren and A.M. Dale: Laminar Population Analysis: Estimating firing rates and evoked synaptic activity from multielectrode recordings in rat barrel cortex, Journal of Neurophysiology 97, 2174-2190 (2007).
- LFPy: A tool for simulation of extracellular potentials (http://compneuro.umb.no)
- E. Nordlie, M.-O. Gewaltig, H. E. Plesser: Towards reproducible descriptions of neuronal network models, PLoS Comp Biol 5, e1000456 (2009).
K. Satyamoorthy, Ph.D.
Director, Life Sciences Centre, Manipal University, India
Epigenetic Changes due to DNA Methylation in Human Epithelial Tumors
Extensive global hypomethylation in the genome and hypermthylation of selective tumor specific suppressor genes appears to be a hallmark of human cancers. Data suggests that hypermethylation of promoter region in genes is more closely related to subsequent gene expression; contrary to gene-body DNA methylation. The intricate balance between these two may contribute to the progressive process of development, differentiation and carcinogenesis. Epigenetic changes encompass, apart from DNA methylation, chromatin modifications through post-translational changes in histones and control by miRNAs. At the genome level, effects from these are compounded by copy number variations (CNVs) which may ultimately influence protein functions. From clinical perspective, changes in DNA methylation occur very early which are reversible and are influenced by environmental factors. Therefore, these can be potential resource for identifying therapeutic targets as well as biomarkers for early screening of cancer. Our current efforts in profiling genome wide DNA methylation changes in oral, cervical and breast cancers through DNA methylation microarray analysis has revealed number of alterations critical for survival, progression and metastatic behavior of tumors. Bioinformatics and functional analysis revealed several key regulatory molecules controlled by DNA methylation and suggests that DNA methylation changes in several CpG islands appear to co-segregate in the regions of miRNAs as well as in the CNVs. We have validated the signatures for methylation of CpG islands through bisufite sequencing for essential genes in clinical samples and have undertaken transcriptional and functional analysis in tumor cell lines. These results will be presented.
Nader Pourmand, Ph.D.
Director, UCSC Genome Technology Center,University of California, Santa Cruz
Biosensor and Single Cell Manipulation using Nanopipettes
Approaching sub-cellular biological problems from an engineering perspective begs for the incorporation of electronic readouts. With their high sensitivity and low invasiveness, nanotechnology-based tools hold great promise for biochemical sensing and single-cell manipulation. During my talk I will discuss the incorporation of electrical measurements into nanopipette technology and present results showing the rapid and reversible response of these subcellular sensors to different analytes such as antigens, ions and carbohydrates. In addition, I will present the development of a single-cell manipulation platform that uses a nanopipette in a scanning ion-conductive microscopy technique. We use this newly developed technology to position the nanopipette with nanoscale precision, and to inject and/or aspirate a minute amount of material to and from individual cells or organelle without comprising cell viability. Furthermore, if time permits, I will show our strategy for a new, single-cell DNA/ RNA sequencing technology that will potentially use nanopipette technology to analyze the minute amount of aspirated cellular material.
Kal Ramnarayan, Ph.D.
Co-founder President & Chief Scientific Officer, Sapient Discovery, San Diego, CA, USA
A cost-effective approach to Protein Structure-guided Drug Discovery: Aided by Bioinformatics, Chemoinformatics and computational chemistry
With the mapping of the human genome completed almost a decade ago, efforts are still underway to understand the gene products (i.e., proteins) in the human biological and disease pathways. Deciphering such information is very important for the discovery and development of small molecule drugs as well as protein therapeutics for various human diseases for which no cure exists. As an example, with more than 500 members, the kinase family of protein targets continues to be an important and attractive class for drug discovery. While how many of the members in this family are actually druggable is still to be established, there are several ongoing efforts on this class of proteins across a broad spectrum of disease categories. Even though in general the protein structural topology might looks similar, there are issues with respect selectivity of identified small molecule inhibitors when, the lead molecule discovery is carried out at the ATP binding site. As an added complexity, allosteric modulators are needed for some of the members, but the actual site for such modulation on the protein target can not resolved with uncertainty. In this presentation we will describe a bioinformatics and computational based platform for small molecule discovery for protein targets that are involved in protein-protein interactions as well as targets like kinases and phosphatases. We will describe a computational approach in which we have used an informatics based platform with several hundred kinases to sort through in silico and identify inhibitors that are likely to be highly selective in the lead generation phase. We will discuss the implication of this approach on the drug discovery of the kinase and phosphatase classes in general and independent of the disease category.
Manzoor K, Ph.D.
Professor, Centre for Nanoscience & Molecular Medicine, Amrita University
Targeting aberrant cancer kinome using rationally designed nano-polypharmaceutics
Manzoor Koyakutty, Archana Ratnakumary, Parwathy Chandran, Anusha Ashokan, and Shanti Nair
`War on Cancer’ was declared nearly 40 years ago. Since then, we made significant progress on fundamental understanding of cancer and developed novel therapeutics to deal with the most complex disease human race ever faced with. However, even today, cancer remains to be the unconquered `emperor of all maladies’. It is well accepted that meaningful progress in the fight against cancer is possible only with in-depth understanding on the molecular mechanisms that drives its swift and dynamic progression. During the last decade, emerging new technologies such as nanomedicine could offer refreshing life to the `war on cancer’ by way of providing novel methods for molecular diagnosis and therapy.
In the present talk, we discuss our approaches to target critically aberrant cancer kinases using rationally designed polymer-protein and protein-protein core-shell nanomedicines. We have used both genomic and proteomic approaches to identify many intimately cross-linked and complex aberrant protein kinases behind the drug resistance and uncontrolled proliferation of refractory leukemic cells derived from patients. Small molecule inhibitors targeted against oncogenic pathways in these cells were found ineffective due to the involvement of alternative survival pathways. This demands simultaneous inhibition more than one oncogenic kinases using poly-pharmaceutics approach. For this, we have rationally designed core-shell nanomedicines that can deliver several small molecules together for targeting multiple cancer signalling. We have also used combination of small molecules and siRNA for combined gene silencing together with protein kinase inhibition in refractory cancer cells. Optimized nanomedicines were successfully tested in patient samples and found enhanced cytotoxicity and molecular specificity in drug resistant cases.
Nano-polypharmaceutics represents a new generation of nanomedicines that can tackle multiple cancer mechanisms simultaneously. Considering the complexity of the disease, such therapeutic approaches are not simply an advantage, but indispensable.
Acknowledgements:
We thank Dept. of Biotechnology and Dept. Of Science and Technology,Govt. of India for the financial support through `Thematic unit of Excellence in Medical NanoBiotechnology’ and `Nanomedicine- RNAi programs’.
Andrey Panteleyev, Ph.D.
Vice Chair, Division of Molecular Biology, NBICS Centre-Kurchatov Institute, Moscow, Russia
The system of PAS proteins (HIF and AhR) as an interface between environment and skin homeostasis
Regulation of normal skin functions as well as etiology of many skin diseases are both tightly linked to the environmental impact. Nevertheless, molecular aspects of skin-environment communication and mechanisms coordinating skin response to a plurality of environmental stressors remain poorly understood.
Our studies along with the work of other groups have identified the family of PAS dimeric transcription factors as an essential sensory and regulatory component of communication between skin and the environment. This protein family comprises a number of hypoxia-induced factors (HIF-alpha proteins), aryl hydrocarbon receptor (AhR), AhR nuclear translocator (ARNT), and several proteins implicated in control of rhythmic processes (Clock, Period, and Bmal proteins). Together, various PAS proteins (and first of all ARNT – as the central dimerization partner in the family) control such pivotal aspects of cell physiology as drug/xenobiotic metabolism, hypoxic and UV light response, ROS activity, pathogen defense, overall energy balance and breathing pathways.
In his presentation Dr. Panteleyev will focus on the role of ARNT activity and local hypoxia in control of keratinocyte differentiation and cornification. His recent work revealed that ARNT negatively regulates expression of late differentiation genes through modulation of amphiregulin expression and downstream alterations in activity of EGFR pathway. All these effects are highly dependent on epigenetic mechanisms such as histone deacetylation. Characterisation of hypoxia as a key microenvironmental factor in the skin and the role of HIF pathway in control of dermal vasculature and epidermal functions is another major focus of Dr. Panteleyev’s presentation.
In general, the studies of Dr. Panteleyev’s laboratory provide an insight into the PAS-dependent maintenance of skin homeostasis and point to the potential role of these proteins in pathogenesis of environmentally-modulated skin diseases such as barrier defects, desquamation abnormalities, psoriasis, etc.
![Delegate Talk: Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies on Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK 1 inhibitors @ Sathyam Hall | Vallikavu | Kerala | India](http://www.amritabioquest.org/conference/2013/wp-content/uploads/sites/2/2015/02/bicb.jpg)
Rajasekhar Chekkara, Venkata Reddy Gorla and Sobha Rani Tenkayala
Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies on Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK 1 inhibitors
Polo-like kinase 1 (PLK1) is a significant enzyme with diverse biological actions in cell cycle progression, specifically mitosis. Suppression of PLK1 activity by small molecule inhibitors has been shown to inhibit cancer, being BI 2536 one of the most potent active inhibitor of PLK1 mechanism. Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies were carried out for a set of 54 compounds belonging to Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK1 inhibitors. A six-point pharmacophoremodel AAADDR, with three hydrogen bond acceptors (A), two hydrogen bond donors (D) and one aromatic ring (R) was developed by Phase module of Schrdinger suite Maestro 9. The generated pharmacophore model was used to derive a predictive atom-based 3D quantitative structure-activity relationship analysis (3D-QSAR) model for the training set (r2 = 0.88, SD = 0.21, F = 57.7, N = 44) and for test set (Q2 = 0.51, RMSE = 0.41, PearsonR = 0.79, N = 10). The original set of compounds were docked into the binding site of PLK1 using Glide and the active residues of the binding site were analyzed. The most active compound H18 interacted with active residues Leu 59, Cys133 (glide score = −10.07) and in comparison of BI 2536, which interacted with active residues Leu 59, Cys133 (glide score = −10.02). The 3D-QSAR model suggests that hydrophobic and electron-withdrawing groups are essential for PLK1 inhibitory activity. The docking results describes the hydrogen bond interactions with active residues of these compounds. These results which may support in the design and development of novel PLK1 inhibitors.