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Petit Institute Breakfast Club Seminar Series
Petit Institute Breakfast Club Seminar Series
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ItemThe Possible Origin of the Biochemical Function of Proteins and its Implications for the Origin of Life(Georgia Institute of Technology, 2020-03-10) Skolnick, JeffreyLiving systems have chiral molecules,; e.g., native proteins almost entirely contain L-amino acids. How protein homochirality emerged from a background of equal numbers of L and D amino acids is among many questions about life’s origin. The origin of homochirality and its implications are explored in computer simulations examining the stability, structural and functional properties of an artificial library of compact proteins containing 1:1, termed demi-chiral, 3:1 and 1:3 ratios of D:L and purely L or D amino acids generated without functional selection. Demi-chiral proteins have shorter secondary structures, fewer internal hydrogen bonds, and are less stable than homochiral proteins. Selection for hydrogen bonding yields a preponderance of L or D amino acids. Demi-chiral proteins have native global folds, including similarity to early ribosomal proteins, similar small molecule ligand binding pocket geometries, and many constellations of L-chiral amino acids with a 1.0 Å RMSD to native enzyme active sites. For a representative subset containing 550 active site geometries matching 457 (2) four (three) E.C digits, native active site amino acids were generated at random for 472/550 cases. This increases to 548/550 cases when similar residues are allowed. The most frequently generated sequences correspond to ancient enzymatic functions, e.g., glycolysis, replication, and nucleotide biosynthesis. Surprisingly, even without selection, demi-chiral proteins possess the requisite marginal biochemical function and structure of modern proteins, but were thermodynamically less stable. If demi-chiral proteins were present, they could engage in early metabolism, which created the feedback loop for transcription and cell formation.
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ItemHealth Analytics: From Data to Decision Making(Georgia Institute of Technology, 2020-03-10) Serban, NicoletaNicoleta Serban's research interests on Health Analytics span various dimensions including large-scale data representation with a focus on processing patient-level health information into data features dictated by various considerations, such as data-generation process and data sparsity; machine learning and statistical modeling to acquire knowledge from a compilation of health-related datasets with a focus on geographic and temporal variations; and integration of statistical estimates into informed decision making in healthcare delivery and into managing the complexity of the healthcare system.
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ItemLow-Energy Electron Interactions with Complex Biomolecules and Carcinogenesis(Georgia Institute of Technology, 2020-01-14) Orlando, Thomas M.
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ItemSurface Modified Cellulose Nanocrystals for Drug Polymorph Screening(Georgia Institute of Technology, 2020-01-11) Brettmann, BlairA major design consideration for active pharmaceutical ingredients (APIs) for oral drug delivery is the crystalline form of the API itself. The solubility, and thus bioavailability, depends greatly on the crystal structure and it is essential to select an appropriate polymorph that is stable over the shelf life of the drug and has acceptable solubility. However, due to the sensitivity of the polymorph formation to a variety of conditions, including solvent, temperature, impurities, mixing procedure, size of crystallizer, and more, it is challenging to control the crystallization and identify all the potential polymorphs that may form. Thus, improved techniques for screening and control are needed. Gel phase crystallization uses two methods to affect polymorph formation: particles within the gel provide a surface for heterogeneous nucleation and the pores within the gel allow for confined homogenous nucleation. By changing the surface of cellulose nanocrystals (CNCs), we can change the heterogenous nucleation sites and thus provide a variety of crystallization environments in one tool, valuable for a screening process. CNCs have a high surface area covered with readily-modifiable hydroxyl groups, which enable the production of CNCs with various surface functionalities. These surfaces can be used to form gels via network formation in organic solvents, which promotes API crystallization into a variety of different polymorphs. In this work, we develop supramolecular organogel systems based on CNC derivatives to be used as a favorable environment for crystallizing APIs. Using a variety of amines, including long-chain amines, diamines, and branched amines, we studied the network formation between oxidized cellulose molecules and the resulting API crystallizaiton. The high surface area of the nanocellulose provides a high concentration of interaction sites and the small size of the modified nanocellulose particles has interesting performance in promoting assembly and packing of the composite gel for use in crystallization screening.
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ItemDecoding Memory in Health and Alzheimer’s Disease(Georgia Institute of Technology, 2019-04-09) Singer, AnnabelleIn this talk I will discuss how neural activity goes awry in Alzheimer’s disease, driving specific frequencies of neural activity recruits the brain’s immune system, and new methods to drive rhythmic activity non-invasively. Spatial navigation deficits are one of the earliest symptoms of AD and the hippocampus is one of the areas first affected by the disease. First, I will describe how neural codes underlying memory-based spatial decisions fail in animal models Alzheimer’s disease (AD). Using a virtual reality behavior paradigm to record and manipulate neural activity in transgenic mice, the primary animal model of AD, we found deficits in hippocampal neural activity early in the progression of the disease. These deficits occurred in the same patterns of activity that we have found inform memory-guided decisions in a spatial navigation task. Next, I will discuss the effects of driving these patterns of activity in AD model mice. We found that driving gamma activity, the activity lacking in AD mice, mobilized the immune system to remove pathogenic proteins. Specifically, driving gamma recruited the primary immune cells of the brain, microglia, to alter their morphology and increase engulfment of beta-amyloid. Finally, I will discuss new non-invasive methods we are developing to drive rhythmic neural activity non-invasively. Ultimately, these discoveries could lead to new therapies for Alzheimer’s disease by driving specific patterns of neural activity to impact the disease at the cognitive, cellular, and molecular levels.
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ItemEmergence of Genetic Complexity in Clonal Populations Evolving in the Lab: Implications for Cancer and Chronic Infectious Disease(Georgia Institute of Technology, 2018-10-09) Rosenzweig, FrankA bacterial population that initially consists of a single clone can evolve into a population teeming with many, whether or not the surrounding environment is structured, and whether or not resource levels are constant or fluctuating. Emergence of genetic complexity, measured as functional information, has been variously attributed to balancing selection, clonal interference and/or clonal reinforcement arising from either antagonistic or synergistic interactions among evolving lineages. Using a combination of theory and experiment, we seek to define the boundary conditions under which one causal mechanism prevails over another. These investigations illuminate the process of adaptive evolution in other populations that originate as a single clone: those that give rise to cancer and those that bring about chronic infectious disease.
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ItemTesting Thousands of Nanoparticles in Vivo(Georgia Institute of Technology, 2017-11-28) Dahlman, James E.
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ItemRedrawing the Global Map of Drug Discovery Science: Hopes and Challenges in South Africa(Georgia Institute of Technology, 2017-10-10) Pollock, AnneThis talk draws on material from Anne Pollock's second book, forthcoming, provisionally titled Synthesizing Hope: Matter, Knowledge, and Place in South African Drug Discovery.
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ItemLearning Neural Crest Migration at the Interface of Cell and Extracellular Matrix(Georgia Institute of Technology, 2017-04-11) Nie, ShuyiUnderstanding how cells migrate during embryonic development: The fundamental question we are trying to answer is how the coordinated cell movements are regulated during animal development. Different groups of cells move to different locations in a growing embryo to give rise to specific tissue and structures. It is a very complex process since the “ground” cells travel on is also undergoing constant rearrangement and growth. We use neural crest as a model to study the mechanisms of cell migration during embryonic development. The neural crest is a vertebrate innovation, comprised of highly migratory stem-like cells that give rise to multiple tissue and structures, including craniofacial bones and cartilages, connective tissue in the heart, enteric nervous system in the gut, and pigment cells all over the skin. Defects in their proliferation, migration, differentiation, or survival lead to numerous diseases and birth defects, including craniofacial and heart malformations as well as different types of cancer. Ongoing studies aim to uncover how neural crest cell migration is regulated from several prospectives: at the level of cytoskeletal machinery, at the interface between cell and extracellular matrix, and at the level of gene transcription. We hope to understand how neural crest cells achieve such extraordinary migratory abilities, and whether such knowledge can be extended to study cancer metastasis.
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ItemGene Based Neuromodulation(Georgia Institute of Technology, 2017-03-14) Boulis, NicholasNicholas Boulis, M.D. is a Functional Neurosurgeon with significant expertise in the field of gene transfer to the nervous system. Dr. Boulis' Gene and Cell Therapy Translational Laboratory pursues advanced biological treatments for neurological disorders, including Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig's disease) and Spinal Muscular Atrophy (SMA). Over the last two decades, growing knowledge about the underlying causes of these diseases, as well as the protective effects of special proteins, has given rise to hope for the development of therapies. Dr. Boulis' laboratory specializes in the therapeutic application of the genes for these proteins. Within the Boulis laboratory, the genes for neural growth factors and antiapoptotic intracellular proteins are inserted into the DNA of genetically engineered viruses. These viruses, which have been rendered safe through the removal of their native genes, can be used to transfer therapeutic genes into diseased tissue. A variety of vectors are currently being tested in both neuronal cell cultures and in animal models for MND. In parallel, the Boulis laboratory has focused on the development of tissuespecific targeting strategies. These approaches are designed to deliver molecular therapeutics to an anatomically defined site of interest. Much of this effort has concentrated on motor neuron-specific gene delivery. Finally, Dr. Boulis has focused on the development of techniques for safe and accurate injection of stem cells into the human spinal cord. Research in the Boulis laboratory tests basic principles while providing tools for clinical translation. Techniques/assays applied in the lab include: neuronal cell cultures, rodent transgenic colonies, surgery in rodents (mice and rats), locomotor behavior assays in rodents, surgery in large animals {pigs and monkeys), histology, etc. With proof-of-principle in the laboratory and Dr. Boulis' expertise in neurosurgery, the laboratory creates a unique resource for the development and clinical translation of these concepts.