Spring 2022 Seminars

Seminar at 3:00-3:45 pm est and Questions 3:45-4:00

Sensing through the Skull: Developing Surface-Enhanced Spatially-Offset Raman Spectroscopy (SESORS) for in vivo Neurochemical Detection

Bhavya Sharma
Department of Chemistry, University of Tennessee, Knoxville

 

The brain is a complex organ, with billions of neurons and more than 30 distinct neurochemicals (possibly up to 100), involved in all aspects of a human life, including cognition, movement, sleep, appetite, and fear responses. For some neurological diseases/conditions, changes in neurochemical concentrations could be predictors of early onset disease or disease progression. While there are a variety of sampling techniques which can detect neurotransmitters in biofluids at low concentrations, these techniques often involve multi-step sample preparations coupled with long measurement times, and are not suited for in vivo detection. There is a need for the development of sensors for the detection of neurotransmitters that are selective, rapid, and label-free with little to no sample processing. We focus on the detection of biomarkers for neurological activity in biofluids and through the skull.

Our approach is to apply surface enhanced Raman spectroscopy (SERS), a highly specific and selective vibrational spectroscopy, for the detection of neurochemicals. Raman scattering is an inherently weak phenomenon. We incorporate the electric field generated at the surface of noble metal nanoparticles in our sensors to enhance the weak Raman scattering signal. SERS is surface selective, highly sensitive, rapid, label-free and requires little to no sample processing. We are developing SERS-based sensors for in vitro neurotransmitter sensing at physiologically relevant concentrations in biofluids. For in vivo detection, we combine SERS with spatially offset Raman spectroscopy (SORS), where Raman scattering spectra is obtained from subsurface layers of turbid media. We demonstrate detection of physiologically relevant concentrations of neurotransmitters in the micromolar (µM) to nanomolar (nM) concentration ranges with SESORS in a brain tissue mimic through the skull.

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Exotic Transformations of the Neutron

Dr. Leah Broussard, Wigner Fellow, Oak Ridge National Laboratory ([email protected])

One of the most interesting questions in all of science today is the origin of matter in the universe. Why is there matter but virtually no antimatter in the universe? What particles make up dark matter, comprising the majority of the matter in the universe? The neutron can be used to search for new phenomena that can explain both of these puzzles. If the neutron were observed to oscillate into its own antiparticle, that would give direct evidence of the mechanism by which the universe could have evolved to have the significant matter-antimatter asymmetry we see today. The neutron can also provide a unique portal to a dark sector, and transform directly into dark matter particles. A new program of searches has been launched at Oak Ridge National Laboratory to search for neutrons transforming into "mirror" neutrons, a proposed dark matter  candidate. A recent experiment at the Spallation Neutron Source has ruled out this mechanism as an explanation for the neutron lifetime anomaly, where there is a persistent disagreement between two techniques for measuring the neutron lifetime. This program will also provide opportunities for technical development which will inform future high-sensitivity searches for free neutron transformations into antineutrons, such as the proposed NNBAR experiment at the European Spallation Source.

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Structure-Based Insights into Control of Heme Biosynthesis

Breann Brown, Ph. D, Vanderbilt University School of Medicine

https://lab.vanderbilt.edu/brown-lab/

Protein assembly drives many aspects of cellular and mitochondrial physiology. We are interested in uncovering and characterizing the protein interactions that support proper heme biosynthesis. Heme is a critical biomolecule that carries out several functions in nearly all life forms, including humans where its most widely-known role is mediating oxygen transport in blood. It is imperative that heme production is tightly controlled as alterations in cellular heme levels can have drastic consequences for human health. The first and rate-limiting enzyme controlling heme biosynthesis is aminolevulinic acid synthase (ALAS). ALAS is conserved in a- proteobacteria and non-plant eukaryotes; there are two isoforms in vertebrates with mitochondrial protein ALAS2 being responsible for heme synthesis during erythropoiesis. There are two separate diseases that may result from one of over 90 mutations in the ALAS2 gene. Importantly, several disease-causing mutations are located in a eurkaryote-specific C-terminal extension, a region absent from bacterial ALAS enzymes. Certain mutations also result in an inability of ALAS2 to assemble with other proteins involved in separate metabolic pathways. we lack an understanding of how these mutations lead to a change in ALAS2 structure, and therefore, function. We seek to understand how ALAS interacts with accessory proteins as well as organism-specific differences in assembly that may alter regulation of heme production. Therefore, we use X-ray crystallography combined with biophysical and biochemical characterization of various eukaryotic ALAS enzymes to parse apart the role of this key regulatory region on eukaryote ALAS function. Our work is beginning to reveal key structure-function relationships between the orientation and molecular contacts mediated by the C-terminus and overall ALAS enzyme function, thus controlling heme biosynthesis.

Dr. Brown is currently an Assistant Professor of Biochemistry at the Vanderbilt University School of Medicine where her lab uses structural biology and enzymology to understand mechanisms of macromolecular assembly necessary for mitochondrial signaling and metabolism. She earned her B.S. in Chemistry from Duke University. She received her Ph. D. in Molecular Pharmacology and Physiology from Brown University with Dr. Rebecca Page where she investigated protein pairs that play a role in bacterial multidrug tolerance and chronic biofilm infections. She then completed her postdoctoral training at the Massachusetts Institute of Technology with Dr. Tania Baker where she used X-ray crystallography and biochemical techniques to study mechanisms of protein assembly in both bacteria and human metabolic systems.

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Pushing the Boundaries of Carbon Acidity, One pKa Unit At a Time

Paul A. Deck, Ph. D., Virginia Tech

Ordinarily, we don’t think of C-H bonds as acids.  But synthetic organic chemistry allows us to place C-H bonds into a wide variety of structures and thereby modify their reactivity.  For example, malonitrile (NC-CH2-CN) and pentanedione (CH3COCH2COCH3) are acidic because they have electron-withdrawing groups to stabilize their conjugate bases.  Their acidities (pKa = 10.2 and 13.3, respectively) are remarkable when one considers that the compound on which they are based (methane) is about the weakest carbon acid (pKa > 50) that one can imagine!

We thought it made more sense to start with a hydrocarbon that is already fairly acidic on its own.  Cyclopentadiene (pKa = 15.8) is a good choice because its conjugate base is stabilized by aromaticity, and because it is possible to attach up to five electronegative substituents.  Our most acidic cyclopentadiene derivative presently stands at pKa = −6.0.  In this presentation I will describe how we make our cyclopentadiene derivatives and how we measure their acidities.  I will also explain the limitations of our acidity determinations and describe some possible applications of our strongest carbon acids.  Finally I will describe our plans to push to ever-lower pKa values until we have made – and characterized – the strongest neutral carbon acids known.

The third son of two chemists, Paul Deck grew up in suburban Detroit.  He earned his B.S. in Chemistry, from Hope College (Holland, Michigan) in 1987 and his Ph.D. from the University of Minnesota in 1993, working with P. G. Gassman.  Paul then spent two years postdocking at Northwestern University, working with T. J. Marks.  At Northwestern, Paul met his wife, Dr. Carla Slebodnick, who is also a professor at Virginia Tech – she runs the Chemistry Department’s X-ray crystallography lab.  Paul has received several awards including National Science Foundation graduate and postdoctoral fellowships, the NSF Career Award, the Research Corp. Cottrell Scholarship, the ACS E. Ann Nalley Award for Regional Volunteer Service, as well as premium teaching and service awards within his department and the VT College of Science Certificate of Teaching Excellence.  When he is not teaching or working with his students in the lab, Paul enjoys cooking, woodworking, reading, and especially music (Paul is an amateur jazz pianist and classical violinist and violist).  Paul and Carla have two daughters, ages 19 and 15.

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Rapid Synthesis of Topologically Complex Molecules with Tungsten Dearomatization Agents

Dean Harman, Ph.D., Department of Chemistry, University of Virginia

https://sites.google.com/view/the-harman-lab-uva/home

The development of a new pharmaceutical agent often requires screening thousands of compounds. Such compounds are typically derived from high-throughput syntheses, which tend to focus on simple transformations. For this reason, so called “flat” compounds, made from aromatic rings coupled together, predominate medchem libraries. However, molecules in these libraries stand in contrast to most naturally occurring, biologically active compounds, which have well-defined three-dimensional structures, rich in carbon stereocenters, adapted for specific and selective interactions with receptors. Since more complex molecules are better able to optimally fill space in their binding sites, molecular complexity strongly correlates with clinical success. Thus, a limited scope of synthetic methods used in discovery chemistry has led to an overpopulation of certain types of molecular shapes and properties to the exclusion of others. The challenge is to generate new classes of compounds with both diversity and complexity in a manner that is accessible to medicinal chemists. Such methodologies would open new, more prolific chemical space for exploration in both traditional SAR studies and the generation of fragment libraries. This talk describes an approach to building cyclohexanes with multiple stereocenters derived from simple benzene precursors. The otherwise inert benzene scaffold is chemically enabled through its dihapto-coordination to a tungsten complexing agent. In this seminar, we will discuss the ability of {WTp(NO)(PMe3)} to activate aromatic molecules toward electrophilic addition and nucleophilic addition reactions with a high degree of regio- and stereochemical control. 

Transition Metal Catalyzed Hydroarylation of Olefins:  New Catalysts for Alkyl and Alkenyl Arenes

Brent Gunnoe, Ph.D., Department of Chemistry, University of Virginia

https://gunnoelab.virginia.edu/

The selective catalytic functionalization of C–H bonds of hydrocarbons remains one of the foremost challenges facing synthetic chemists. For example, alkyl and alkenyl arenes are produced on a scale of billions of pounds per year. Current commercial catalysts (e.g., Friedel-Crafts catalysts or zeolites) for arene alkylation are based on acid-mediated olefin activation. New catalysts that operate by a different pathway that involves transition metal-mediated C–H activation followed by olefin insertion into metal-aryl bonds offer potential advantages. The presentation will focus on the development and study of new transition metal catalysts for arene alkylation and alkenylation based on molecular complexes of Ru, Rh, Pd and Pt with an emphasis on new Rh catalysts that convert arene, olefin and Cu(II) carboxylates to alkenyl arene with high selectivity and turnovers. 

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