Design Strategies for Luminescent Titanocenes

Abstract: Complexes of d0 transition metals with photoactive ligand-to-metal charge-transfer (LMCT) excited states have recently shown significant promise as photocatalysts involving earth-abundant metals.  Arylethynyltitanocenes of the type Cp2Ti(C2R)2 (where R = ferrocene or an aryl substituent) have recently been investigated for their C2R-to-TiIV LMCT states.  The first example of a TiIV complex with an emissive (FP ~ 10–4) ligand-to-TiIV LMCT state in RT fluid solution is Cp2Ti(C2Ph)2.  However, this complex undergoes photodecomposition with a high quantum yield (Frxn = 0.99). Coordination of CuX between the alkyne ligands to give Cp2Ti(C2Ph)2CuX (X = Cl or Br) has been shown to significantly increase the photostability, but such complexes are not emissive in RT solution.  The mechanisms for photodecomposition and nonradiative decay have been investigated and have led to design strategies for luminescent titanocenes.  Based on these strategies, we have developed titanocenes with increased photostability, and whose luminescence is visible to the naked eye in room-temperature fluid solution.

Bio: Paul obtained his B.S. in Chemistry from Furman University in 1986 and his Ph. D. from Stanford University in 1991.  Following postdoctoral studies at Colorado State University, he accepted a one-year adjunct teaching position at Occidental College in Los Angeles before beginning a tenure track position at San Jose State University in 1996. In 2004, he moved back to his alma mater, Furman University. Over his career, he has secured nearly $3 million in external funding for support of undergraduate research in his group and the chemistry department.  Since beginning his independent career with undergraduate researchers, he has published nearly 40 peer-reviewed research articles (mostly with undergraduate coauthors) and two patents. He is the recipient of the Henry Dreyfus Teacher-Scholar Award (2003), the South Carolina Governor’s Award for Excellence in Scientific Research (2020), and the Council on Undergraduate Research ChemCUR Outstanding Mentorship Award (2022). When not in the classroom or laboratory, he enjoys competing on the tennis courts, honing his BBQ skills, and trying to learn guitar.

FRIDAY, APRIL 21, 2023

The Poster Session will be held from 5:00 – 7:00pm in the 3rd floor lobby of the Chemistry Building.  The meeting will begin at 7:00pm in room Gilmer 390. 

Posters may be set up after 3:00pm on Friday, April 21st in the 3rd floor lobby of the Chemistry Building.  The presentation surfaces will provide you with a 4′ wide poster area.  Feel free to leave your poster up until after the ACS program.  Keep your text simple, in large letters, and to the point. Complete sentences are not required. People do not like to read a lot of words; they want to know what the main points are.  You should be available for discussion with viewers for the 5:00-7:00 p.m.

To participate in this year’s poster session, please submit:

• Title, authors, and school affiliation by 12pm, Monday, April 17th. The author list should include the mentor’s name.  Please bold the names of those attending.
• Abstracts by e-mail attachment (preferrable in .doc or .docx format) to Cindy Knight at csk3a@virginia.edu.

Format of Abstract:

Title in bold face with sentence capitalization. Names of authors with last name first in regular text. Affiliations including department. Be sure mentor is included.

Blank line

Abstract in regular text. Limited to 200 words.

Notes:

For GPS purposes, please use 70 Chemistry Dr. as the address.  Please note that our parking lots are accessed from Whitehead Road.  You will be ticketed if parking here prior to 5pm without a permit.

Pizza will be available for a $8.00 fee ($4.00 for High School Students). Soft drinks will be free. Reservations required for those having pizza.

We look forward to seeing you. If you have any questions call Cindy Knight at (434) 924-7995 or e-mail her at csk3a@virginia.edu.

Previous section meetings 

A series of new compounds, MAr2 (M = Ge, Sn, or Pb; Ar = terphenyl ligands) display structures and structural trends that are counter-intuitive with regard to steric effects. These trends are also reflected in their spectroscopic properties and in their reaction chemistry. It was found that the presence or absence of substituents at apparently-remote sites on the ligands can exert a large influence on the course of the reactions, as well as on the structural characteristics of the group 14 element environment. Their reactions with a range of olefins and carbon monoxide, which showed unexpected trends, will be shown. In addition, the reactions of the related subvalent hydrides, ArMH, with a range of olefins and alkyne molecules, as well as the unexpected compounds that are formed, will be presented. A notable feature of their behavior is their ability to induce unexpected isomerizations in the olefin substrates. Finally, it is proposed that many of the peculiar properties of the compounds is related to the presence of dispersion force interactions of their ligand substituents.

Engineered nanoparticles are increasingly being incorporated into devices and products across a variety of commercial sectors – this means that engineered nanoscale materials will either intentionally or unintentionally be released into the ecosystem. The long-term goal of the presented work is to understand the molecular design rules that control nanoparticle toxicity using aspects of materials science (nanoparticle design, fabrication, and modification), analytical chemistry (developing new assays to monitor nanotoxicity), and ecology (monitoring how nanoparticles enter and accumulate in the food web through bacteria and how these nanoparticles influence bacterial function). Taken together, these data suggest that careful consideration of engineered nanoparticle surface chemistry will likely allow design of safe and sustainable nanoscale materials.

ABSTRACT

Antisense Oligonucleotide Therapeutics for Neurological Diseases

Antisense oligonucleotides (ASOs) are synthetic, chemical modified nucleic acid analogs designed to bind to RNA by Watson-Crick base paring and upon binding, modulate the function of the targeted RNA. There are a variety of mechanisms by which ASOs can modulate RNA function dependent on the chemical design of the ASO, the type of RNA and where on the RNA the ASO is designed to bind. Both protein coding, as well as non-coding RNAs, can be targets of ASO based drugs, significantly broadening therapeutic targets for drug discovery compared to small molecules and protein-based therapeutics. The recent approval of nusinersen (Spinraza™) as a treatment for spinal muscular atrophy (SMA) and inotersen (Tegsedi) for polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR)  validates the utility of antisense drugs for the treatment of neurological  diseases. A summary of the progress, lessons learned and future challenges applying antisense technology for neurological diseases will be provided.

Friday, April 19, 2024

The Poster Session will be held from 5:00 – 7:00pm in the 3rd floor lobby of the Chemistry Building.  The meeting will begin at 7:00pm in room Gilmer 390. 

Posters may be set up after 3:00pm on Friday, April 19th in the 3rd floor lobby of the Chemistry Building.  The presentation surfaces will provide you with a 4′ wide poster area.  Feel free to leave your poster up until after the ACS program.  Keep your text simple, in large letters, and to the point. Complete sentences are not required. People do not like to read a lot of words; they want to know what the main points are.  You should be available for discussion with viewers for the 5:00-7:00 p.m.

To participate in this year’s poster session, please submit:

• Title, authors, and school affiliation by 12pm, Monday, April 15th. The author list should include the mentor’s name.  Please bold the names of those attending.
• Abstracts by e-mail attachment (preferable in .doc or .docx format) to Cindy Knight at csk3a@virginia.edu.

Format of Abstract:

Title in bold face with sentence capitalization. Names of authors with last name first in regular text. Affiliations including department. Be sure mentor is included.

Blank line

Abstract in regular text. Limited to 200 words.

Notes:

For GPS purposes, please use 70 Chemistry Dr. as the address.  Please note that our parking lots are accessed from Whitehead Road.  You will be ticketed if parking here prior to 5pm without a permit.

Pizza will be available for a $8.00 fee ($4.00 for High School Students). Soft drinks will be free. Reservations required for those having pizza.

We look forward to seeing you. If you have any questions call Cindy Knight at (434) 924-7995 or e-mail her at csk3a@virginia.edu.

Previous section meetings 

The functions of nucleotides and nucleic acids involve their interactions with cellular proteins.  In this presentation, I will discuss about our recent efforts toward the development and applications of quantitative proteomic methods for unbiased, proteome-wide discovery of proteins that can recognize unique secondary structures of DNA. I will also discuss our recent development of targeted quantitative proteomic methods for interrogating ATP- and GTP-binding proteins at the entire proteome scale. The application of these methods for uncovering novel targets of clinically used kinase inhibitors and for revealing novel drivers and suppressors for melanoma metastasis will also be presented. Through this presentation, I hope to illustrate that quantitative proteomics constitutes a power tool for discovering novel nucleic acid- and nucleotide-binding proteins and for revealing their functions in cells.

The design and engineering of protein catalysts that carry out rare or non-natural chemistry remains a challenging contemporary goal. However, enzymes are inherently limited by their chemical composition, i.e. the reagent pool that exists in nature and the amino acids and cofactors that form their physical and catalytic core. Because of this limitation, the majority of chemical transformations developed by synthetic chemists remain, at least to our knowledge, biologically inaccessible. Biological cofactors and prosthetic groups, including heme, provide a convenient means for natural proteins to increase their range of chemical transformations. Synthetic catalysts, similar to heme, demonstrate a wealth of chemical transformations, including metallocarbene insertion reactions, through mechanisms similar to native P450 catalysis; however, these reactions do not exist in biology due to the lack of the necessary ingredients in the cell or surrounding environment. By supplementing cytochrome P450s with non-natural reagents we have been able to demonstrate that a variety of natural enzyme scaffolds are capable of carrying out reactions, including the carbene-mediated cyclopropanation of olefins, not previously observed in the natural world. Moreover, as adaptable, genetically encoded systems, the activity and product regio- and stereochemical profiles of these catalysts can be tuned through mutation. We have shown that this non-natural chemistry can be applied for fine chemical synthesis, or even adapted to modify native P450 substrates. We have gone on to show that cytochrome P450s can be evolved for the incorporation of alternative metalloporphyrin scaffolds. By combining non-natural cofactor engineering with an increase in reagent diversity, we are generating orthogonal protein systems that deliver function not available to heme containing proteins.

Eric Brustad is a proud native of Indianapolis, Indiana. He graduated from Purdue University (W. Lafayette, IN) in 2002 receiving B.S. degrees in Chemistry and Biology as well as a B.A. in French. As an undergraduate, he began his research career in bioorganic chemistry under the mentorship of Jean Chmielewski. In the fall of 2002, he joined The Scripps Research Institute to carry out graduate research under the direction of Peter G. Schultz. His thesis work examined applications of unnatural amino acid mutagenesis to expand protein function. Dr. Brustad moved to the California Institute of Technology in December of 2008 as a Ruth Kirschstein postdoctoral fellow where he joined the group of Frances H. Arnold. While at Caltech, Dr. Brustad applied directed protein evolution to engineer proteins for non-natural catalysis or biosensing applications. In 2012, Eric joined the Department of Chemistry and the Carolina Center for Genome Sciences at the University of North Carolina at Chapel Hill. His research program focuses on combining chemical, biological and evolutionary approaches to expand the capabilities of living cells.  His honors include the Barry M. Goldwater Scholarship (2002), a Ruth L. Kirschstein National Research Service Award (2009), a DARPA Young Faculty Award (2013), and an NSF Career Award (2015).

The field of chemical neurobiology is providing insights into the molecules and interactions involved in neuronal development, sensory perception, and memory storage. In this talk, I will describe the development of chemical tools to understand how glycosaminoglycans contribute to neuroplasticity – the ability of the brain to adapt and form new neural connections. By combining synthetic organic chemistry, biochemistry, cell biology, and neurobiology, we have shown that specific sulfation motifs within these polysaccharides regulate signaling events that underlie processes such as axon regeneration, synaptic plasticity, and the formation of neural circuits.  

Cyclopropanone derivatives have long been regarded as unusable and elusive synthetic intermediates, mainly owing to their prominent ring strain and kinetic instability. In this work, we report the enantioselective synthesis of sulfonylcyclopropanols, shown to be modular and versatile synthetic equivalents of the corresponding cyclopropanone derivatives. These reagents were found to smoothly react in a variety of reaction manifolds, including organometallic 1,2-addition affording cyclopropanols, nitrene chemistry to access chiral β-lactams, nickel-catalyzed C–C activation to cyclopentenones, as well as olefination chemistry as a general platform to chiral alkylidenecyclopropanes and other substituted cyclopropanes. Moreover, we have shown that these sulfonylcyclopropanols can also behave as ‘electrophilic homoenolate’ equivalents, effectively acting as ring-opened 2- or 3-carbon linchpin reagents depending on the reaction conditions. This work constitutes the first general enantioselective route to cyclopropanone equivalents, thus unlocking a number of novel synthetic disconnections relevant to a variety of chemical industries.

Friday, April 11, 2025

The Poster Session will be held from 5:00 – 7:00pm in the 3rd floor lobby of the Chemistry Building.  The meeting will begin at 7:00pm in room Gilmer 390. Learn more

Hydrolases are enzymes that often play important roles in many common human diseases such as cancer, asthma, arthritis, atherosclerosis and infection by pathogens. Therefore tools that can be used to dynamically monitor their activity can be used as diagnostic agents, as imaging contrast agents and for the identification of novel classes of drugs. In the first part of this presentation, I will describe our efforts to design and synthesize small molecule probes that produce a fluorescent signal upon binding to tumor associated protease targets. We have identified probes that show tumor-specific retention, fast activation kinetics, and rapid systemic distribution making them useful for real-time fluorescence guided tumor resection and other diagnostic imaging applications. In the second half of the talk, I will present our recent advances using chemical probes to identify novel protease and hydrolase targets in pathogenic bacteria. This work has led to new imaging agents for Mycobacterium tuberculosis and the identification of novel virulence factors in Staphylococcus aureus that have the potential to be targeted with small molecules as a therapeutic strategy.

“Leveraging Chemoproteomic Tools to Drive Discovery in Chemical Biology”

Abstract: Despite tremendous advances and powerful tools from the human genome project, our understanding of the human proteome is uneven at best. In fact, estimates suggest that we know almost nothing about some 30-35% of human proteins, while less than 5% have been successfully prosecuted in drug discovery programs. Across the landscape of protein-targeting small molecules, covalency has re-emerged as a favorable route to achieve selective, potent, and durable protein modulation. Here I will describe our efforts to develop and use chemoproteomic tools to streamline characterization of covalent compounds. Exemplary data for both well-established and emergent target families in the functional proteome will be presented along with new avenues for reagent and analytical method development.

Professional Biography: Jarrod Marto, Ph.D., is a Principal Investigator at the Dana-Farber Cancer Institute in the Department of Cancer Biology and an Associate Professor of Pathology at Brigham and Women’s Hospital and Harvard Medical School. Since 2006 Dr. Marto has served as Director of the Blais Proteomics Center at Dana-Farber and more recently launched the Center for Emergent Drug Targets. Dr. Marto is internationally recognized for his expertise in the development and use of state-of-the-art mass spectrometry and other bioanalytical techniques to understand how genomic alterations as well as the activity of chemical probes or clinical drugs manifest at the level of individual proteins, signaling pathways, or other compartments throughout the functional proteome. Dr. Marto has authored nearly 200 peer-reviewed papers across the fields of bioanalytical chemistry, scientific instrumentation, mass-informatics, chemical biology, and cancer cell signaling. In addition, he is a founding member of Entact Bio and serves on the SAB of 908 Devices. Dr. Marto earned his Ph.D. in analytical chemistry with Alan Marshall at The Ohio State University and went on to postdoctoral studies with Don Hunt at the University of Virginia. Dr. Marto joined the faculty at Dana-Farber in 2004.

The Department of Chemistry's Graduation Ceremony will be held at 2:00pm, Saturday, May 17th, 2025! Click here for details

Abstract

Microfluidic methods provide a promising path to mimicking human organ function with applications ranging from fundamental biology to drug metabolism and toxicity. The vast majority of these systems use dissociated, immortalized, or stem cells to create two and three-dimensional models in vitro. While these systems can provide valuable information, they are fundamentally incapable of recreating the three-dimensional complexity of real tissue. As a result, an important gap exists between in vitro models and in vivo systems. To address this gap, we have begun combining microfluidic devices with ex vivo tissue slices or explants to recreate model systems that capture the cellular diversity of real tissue and bridge the gap between in vitro models and in vivo systems. In this presentation two systems will be discussed. The first uses a high-density electrode array equipped with microfluidic flow to image chemical release profiles from living adrenal slices. The second uses a 3D printed microfluidic device with removable inserts to hold and perfuse fluids over intestinal tissue, enabling generation of differential chemical conditions on either side of this important barrier tissue.

Charles Henry, Stuart Tobet, David Dandy, Tom Chen

Colorado State University

This lecture will describe recent developments in our efforts to develop low-molecular weight catalysts for asymmetric reactions.  Over time, our view of asymmetry has ebbed and flowed, with foci on enantioselectivity, site-selectivity and chemoselectivity.  In most of our current work, we are studying issues of enantioselectivity as a prelude to extrapolation of catalysis concepts to more complex stereochemical settings where multiple issues are presented in a singular substrate.  Moreover, we continuously examine an interplay between screening of catalyst libraries and more hypothesis-driven experiments that emerge from screening results.  Some of the mechanistic paradigms, and their associated ambiguities, will figure strongly in the lecture.

Scott J. Miller was born on December 11, 1966 in Buffalo, NY. He received his B.A. (1989), M.A. (1989) and Ph.D. (1994) from Harvard University, where he worked with David Evans as a National Science Foundation Predoctoral Fellow.  Subsequently, he traveled to the California Institute of Technology where he was a National Science Foundation Postdoctoral Fellow with Robert Grubbs until 1996. For the following decade, he was a member of the faculty at Boston College, until joining the faculty at Yale University in 2006.  In 2008, he was appointed as the Irénée duPont Professor of Chemistry.

Professor Miller’s research program focuses on catalysis. His group employs strategies that include catalyst design, the development of techniques for catalyst screening, and the application of new catalysts to the preparation of biologically active agents.  Three current interests are (a) the selective functionalization of complex molecules, (b) the exploration of analogies between synthetic catalysts and enzymes and (c) the discovery of effective antibiotics despite increasing resistance.

Scott Miller’s awards and honors include: National Science Foundation CAREER Award (1999), Alfred P. Sloan Research Fellowship (2000), Camille Dreyfus Teacher-Scholar Award (2000), Arthur C. Cope Scholar Award of the American Chemical Society (2004), Yoshimasa Hirata Memorial Gold Medal of Nagoya University (2009), National Institutes of Health MERIT Award (2011), Fellow of the American Association for the Advancement of Science (2012), American Chemical Society Award for Creative Work in Synthetic Organic Chemistry (2016), Member, American Academy of Arts and Sciences (2016), Max Tishler Prize, Harvard University (2017).

Professor Miller has served in number of capacities for public and private organizations.  For example, he recently completed a term on the National Institute of General Medical Sciences Advisory Council, convened by the Director of the National Institutes of Health.  He now serves as Editor-in-Chief of The Journal of Organic Chemistry.

Challenges and Opportunities in Chemical Separations with Porous Materials

Porous materials such as metal-organic frameworks have been extensively studied for applications in gas-adsorption, catalysis, and chemical separation (to name a few). With particular focus on separations, one of the long-term goals in my research program is to implement porous materials in real-world applications. For the research team to be successful, it is critical to address these challenges from a top-down approach. Factoring in issues such as partial pressure, overall gas composition, and regeneration need be at the forefront of the research. With that in mind, the presentation will explore how porous materials can be designed to address the challenges associated with chemical separations.

Imaging tools have revolutionized our understanding of living systems by enabling researchers to “peer” into tissues and cells and visualize biological features in real time.  While powerful, these probes have been largely confined to monitoring cellular behaviors on a microscopic level.  Visualizing cellular interactions and functions across larger spatial scales—including those involved in cell migration to distant tissues, immunosurveillance, and other biological processes—remains a daunting task.  My research group is developing general toolsets to image such macroscopic cellular networks and behaviors, and our efforts are focused in two areas: generating novel bioluminescent probes and developing new bioorthogonal chemistries for imaging in vivo.

Atherosclerosis is an inflammatory disease of the arterial wall driven by macrophages and other immune cells. Olfactory receptors (OLFRs) are G-protein coupled receptors expressed primarily in olfactory epithelium and are responsible for the sense of smell. OLFRs expressed in multiple extra-nasal tissues have been implicated in diverse biological processes. Here we show that mouse vascular macrophages express many olfactory receptors including Olfr2 (also known as I7), a receptor for octanal. They also express Rtp1, Rtp2, Adcy3, Gnal and the cyclic nucleotide-gated ion channel subunits Cnga1, 2, 3, 4 and Cngb1, accessory molecules needed for Olfr signaling and trafficking. Ligation of Olfr2 and its human orthologue (OR6A2), expressed in human atherosclerotic plaque and in human monocyte-derived macrophages, activates the NLRP3 inflammasome and, in synergy with LPS, induces secretion of IL-1α and β. Knocking out Olfr2 and Nlrp3 in mouse or knocking down OR6A2 in human macrophages abolishes IL-1β secretion in response to octanal. Mouse and human blood plasma contain micromolar levels of octanal, which are positively correlated with cholesterol and triglyceride levels. Boosting octanal levels exacerbates and knocking out Olfr2 significantly reduces atherosclerosis in the aortic arch and root. Our findings suggest that inhibitors of OR6A2 are promising targets for drug development to prevent and treat atherosclerosis-based cardiovascular diseases. 

The Nanoliter Lab: Droplet Microfluidics for Screening and Sensing

Manipulating samples as droplets within microfluidic devices has emerged as an interesting approach for chemical analysis and screening. In segmented flow, one embodiment of this technology, nanoliter samples are manipulated in microfluidic channels as plugs separated by an immiscible fluid, such as air or fluorinated oil. These plugs serve as miniature test-tubes in which reactions can be performed at high throughput. Microfluidic tools have been developed to split, dilute, extract, and filter such plugs at rates >10 samples/s. We have developed methods to analyze plug content by electrophoresis and mass spectrometry (MS). A natural application of this technology is for high throughput screening. By coupling droplet manipulation with MS detection, it is possible to greatly reduce reagent consumption and eliminate the need for fluorescent labels or coupled reactions. The technology and application to screens of deacetylase reactions and protein-protein interactions will be presented. A more involved screening allows for monitoring reactions of enzyme variants to identify new biocatalysts. Droplet technology can also be used for chemical monitoring or sensing applications. In this approach samples emerging from a miniaturized sampling device are segmented for later analysis. We have used this method to monitor neurotransmitter dynamics in the brain. The technology and application to studies of neurotransmission in a Huntington’s disease models will be demonstrated. 

ABSTRACT

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. Our group focuses 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. To enhance the weak Raman scattering signal, we incorporate noble metal nanoparticles in our sensors, which when excited with a laser generate an oscillating electric field, referred to as the localized surface plasmon resonance (LSPR), at the surface of the nanoparticles. The molecules of interest are adsorbed to the nanoparticle surface, and the Raman scattered light is enhanced by the LSPR of the nanoparticles. 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 low concentration detection of neurotransmitters in the micromolar (µM) to nanomolar (nM) concentration ranges with SESORS in a brain tissue mimic through the skull.

Abstract

This lecture will discuss the advent and development of new concepts in chemical synthesis, specifically the application of visible light photoredox catalysis to the discovery or invention of new chemical transformations.  This lecture will explore a strategy the discovery of chemical reactions using photoredox catalysis.  Moreover, we will further describe how mechanistic understanding of these discovered processes has led to the design of new yet fundamental chemical transformations that we hope will be broadly adopted.  In particular, a new catalysis activation mode that allows for the development of C–H abstraction and decarboxylative coupling reactions that interface with organometallic catalysis.

I will present recent work from my lab on the development and applications of magic-angle spinning solid-state nuclear magnetic resonance (NMR) techniques toward the structural and dynamic analysis of supramolecular protein and protein-DNA assemblies. The main topics will include: (1) new paramagnetic solid-state NMR methodologies for the rapid determination of three-dimensional protein structures and (2) studies of mammalian Y145Stop prion protein variants aimed at providing an atomic level structural basis for the phenomena of amyloid strains and cross-seeding barriers associated with these proteins. If time permits, I will also discuss our studies of the flexible histone N-terminal tail domains in large nucleosome arrays under experimental conditions corresponding to extended, folded and highly condensed chromatin.

Biosketch

Christopher Jaroniec received his B.S. degree in Chemistry from Kent State University in 1997 and his Ph.D. in Physical Chemistry from the Massachusetts Institute of Technology in 2003, where he was a National Science Foundation Graduate Research Fellow with Prof. Robert Griffin, and he was a Damon Runyon Cancer Research Foundation Postdoctoral Fellow with Dr. Ad Bax at the National Institutes of Health. He joined The Ohio State University as an Assistant Professor in 2006, was promoted to Associate Professor in 2011 and Professor in 2014, and named Evans Scholar in 2013. He currently also serves as the Vice Chair for Research and Administration in the Department of Chemistry and Biochemistry and the Director of the OSU CCIC Solid-State NMR Center, which houses multiple state-of-the-art high-field solid-state NMR instruments. Professor Jaroniec’s research in biomolecular solid-state NMR spectroscopy has been recognized by multiple awards including the NSF CAREER Award, the Eli Lilly Young Investigator Award in Analytical Chemistry, the Camille Dreyfus Teacher-Scholar Award, the Founders’ Medal from the International Council on Magnetic Resonance in Biological Systems, and the ACS Physical Division Early-Career Award in Experimental Physical Chemistry. He was also elected as Fellow of the American Association for the Advancement of Science and has held an Invited Visiting Professor position at Sorbonne Universités/Université Pierre et Marie Curie in Paris, France.

ABSTRACT

Antisense Oligonucleotide Therapeutics for Neurological Diseases

Antisense oligonucleotides (ASOs) are synthetic, chemical modified nucleic acid analogs designed to bind to RNA by Watson-Crick base paring and upon binding, modulate the function of the targeted RNA. There are a variety of mechanisms by which ASOs can modulate RNA function dependent on the chemical design of the ASO, the type of RNA and where on the RNA the ASO is designed to bind. Both protein coding, as well as non-coding RNAs, can be targets of ASO based drugs, significantly broadening therapeutic targets for drug discovery compared to small molecules and protein-based therapeutics. The recent approval of nusinersen (Spinraza™) as a treatment for spinal muscular atrophy (SMA) and inotersen (Tegsedi) for polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR)  validates the utility of antisense drugs for the treatment of neurological  diseases. A summary of the progress, lessons learned and future challenges applying antisense technology for neurological diseases will be provided.

ABSTRACT

Multi-component nanoparticles offer unique opportunities to combine different properties in a single construct, enabling both multi-functionality and the emergence of new synergistic functions. Synthesizing such multi-component nanoparticles requires simultaneous control over size, shape, composition, and structure, as well as interfaces and spatial arrangements. We have been developing two complementary strategies for synthesizing multi-component nanoparticles. The first approach involves heterogeneous seeded growth, where interfaces and asymmetry are introduced by sequentially growing new nanoparticles off of the surfaces of existing nanoparticles. Complex hybrid nanoparticles of a growing number of materials, configurations, and morphologies can now be synthesized. The second approach involves sequential partial cation exchange reactions, where interfaces and asymmetry are introduced by compositional modifications that are made within an existing nanoparticle. A growing library of complex heterostructured metal sulfide nanoparticles can now be rationally designed and then readily synthesized.

Spontaneous Formation of Oligomers and Fibrils in Large-Scale Molecular Dynamics Simulations of the Alzheimer’s Peptides

Protein aggregation is associated with serious and eventually-fatal neurodegenerative diseases including Alzheimer’s, Parkinson’s and the prion diseases.  While atomic resolution molecular dynamics simulations have been useful in this regard, they are limited to an examination of either oligomer formation by a small number of peptides or analysis of the stability of a moderate number of peptides placed in trial or known experimental structures. We describe large-scale molecular dynamics simulations of the spontaneous formation of fibrils by systems containing large numbers of peptides. The simulations are fast enough to enable us to follow the steps in the aggregation process from an initial configuration of random coils to oligomers and then to proto-filaments with cross-β structures. In simulations of Aβ17-42 peptides, we uncovered two fibrillization mechanisms that govern their structural conversion from disordered oligomers into protofilaments.  We also investigate the influence of crowding agents on oligomerization and fibrillization for Aβ16-22. Simulations are conducted which allow examination of the impact of naturally-derived inhibitors (resveratrol, curcumin, vanillin, and curcumin) on the oligomerization and fibrillation of A β17-36. Finally, we describe simulations of human, mouse and Syrian Movies of the aggregation process on a molecular level will be shown.

ABSTRACT

Public and private investments in energy storage have created a 100 billion dollar industry, and this industry is now converging on grid-scale applications due to the urgent need for resource conservation and our ever-increasing global demand for energy. Redox flow batteries (RFBs) are one method for grid-scale energy storage, being used for peak-shaving and renewable energy incorporation into the grid. Our lab has been using molecular structure as one method to influence electrolyte performance metrics such as Coulombic efficiency, charge-recharge cycling, and voltage window. This talk will describe the work in our lab that focuses on molecular design to address these specific issues in nonaqueous redox flow battery electrolytes.

Abstract

Research and development of materials and strategies for real-time, amperometric sensors and biosensors with potential in-vitro or in-vivo applications for clinically relevant physiological agents continues to be a relevant scientific endeavor.  Within this field of study, a large number of reports continue to focus on enzyme-based glucose detection because it serves both as a well-understood fundamental model system and as a clinically relevant sensing goal for diabetics.  It is, however, relatively rare that the same strategies and materials utilized for glucose sensing prove to be robust and versatile enough to be readily adapted to different target molecules with clinical relevance.  It follows then that a significant achievement would be the demonstration of a strategy and the use of materials that offer this type of versatility while maintaining superior performance toward a molecule with bioanalytical implications and possible medical applications.  Our work explores layer-by-layer (LbL) strategies for amperometric biosensor and sensor designs, where each layer or material within the composite film, including the incorporation of different nanomaterials, is functional with respect to sensing sensitivity and/or selectivity.  Additionally, this research also involves sensor development toward practical and effective clinical usage where the LbL strategies must be successfully adapted and miniaturized to needle or wire electrodes that can potentially function in vitro as a bedside device, within catheters for continuous, real-time measurements, or as an in vivo implant operating in biological media and physiologically relevant concentrations.     Fundamental studies proceed with a glucose model system before adapting the strategy and materials to specifically targeted clinical measurements including early detection/monitoring for sepsis, pregnancy-induced hypertension, and prostate cancer among others.   

Membrane Partitioning by and for Cell Wall Synthesis

Diffuse, sidewall patterning of cell wall peptidoglycan synthesis by the actin homolog MreB enables model organisms like Escherichia coli and Bacillus subtilis to maintain rod shape. Mycobacteria are also rods but grow from their poles and lack MreB. It is unclear how mycobacteria establish and propagate rod morphology. My lab has investigated the roles of the essential, cytoskeletal-like protein DivIVA (Wag31) and of inner membrane partitioning in polar growth and envelope assembly. Our work with the model organism M. smegmatis suggests that the membrane-cell wall axis is a self-organizing system in which DivIVA-directed cell wall synthesis organizes the inner membrane, and an organized inner membrane in turn makes cell wall synthesis more efficient and precise. These findings complement what has been reported for eukaryotic cell membranes, which can be partitioned by pinning to cytoplasmic structures such as the actin cytoskeleton and to external structures like extracellular matrix and cellulose. They are also congruent with the literature on model lipid bilayers, which can be phase separated by adhesive forces.

ABSTRACT 

Computers and algorithms are now sufficiently powerful that many complex molecular processes can be simulated at atomic resolution.  Yet it remains challenging to describe dynamics when processes are stochastic and proceed by multiple pathways.  In this talk, I will illustrate these issues with simulations of insulin dimer dissociation, which serves as a paradigm for coupled (un)folding and (un)binding.  Then I will present recent work that we have done to advance methods for efficiently estimating kinetic statistics and systematically learning complex reaction mechanisms from molecular dynamics data.

Abstract:

Various natural products, such as taxol, morphine and vancomycin, play a prominent role in medicine due to their ability to modulate biological targets critical to human disease. Our lab has two natural product inspired synthetic medicinal chemistry programs, driven by the structural complexity of indole alkaloids and the biological function of phenazine antibiotics. Each program aims to address major biomedical problems, including: (1) enhancing the chemical diversity of screening libraries used to drive drug discovery in high throughput screening campaigns and (2) the discovery of small molecules capable of targeting and eradicating surface-attached bacterial biofilms. Our first program aims to rapidly generate diverse and complex compounds, which can be accessed through short synthetic sequences motivated by the dramatic alteration of the inherent complex ring system of indole alkaloids. From these efforts, we have generated a library of >200 complex and diverse small molecules, which are producing an array of interesting hit compounds in diverse disease areas. Our second program aims to target bacterial biofilms, which contain specialized persister cells that are metabolically dormant and demonstrate tolerance towards every class of conventional antibiotic currently available. Biofilms are the underlying cause of chronic and recurring bacterial infections. Our lab has discovered that the marine phenazine antibiotic 2-bromo-1-hydroxyphenazine is a tunable molecular scaffold that provides access to highly potent antibacterial agents that are able to eradicate drug-resistant and antibiotic-tolerant bacterial biofilms. 

Metal-Ligand Multiple Bonds: Catalytic Dehydrogenation of Volatile Alkanes, Methane Olefination, and Super Bases

Abstract. Converting natural resources such as methane and ethane, the main components of natural and shale gas, into more value-added materials under mild conditions and using base metals, is one of the main objectives in my research program. I will start by presenting the reactivity of a transient titanium alkylidyne (PNP)Ti≡CtBu (pincer PNP = N[2-P(CHMe2)2-4-methylphenyl]2–), specifically how this species forms and engages in intermolecular C-H activation and functionalization reactions.  Such a system can dehydrogenate methane, and react with C2-C8 alkanes selectively by activating at the a- and b-positions. In the case of linear alkanes C4-C8, we only observe formation of the terminal olefin adduct.  A new catalytic cycle for transfer dehydrogenation of alkanes will be also introduced in addition to unique platforms to form kinetically stable Ti=CH2 moieties (titanium methylidene) that are relevant to our proposed catalytic cycle. I will also discuss a new transformation involving the room temperature conversion of methane to an olefin using a titanium alkylidene in cooperation with a redox-active ligand and how it compares to an electrophilic iridium system that can convert methane to ethylene with the aid of a phosphorus ylide reagent. The last component, if time permitted, will present the synthesis and reactivity of group 4 transition metal nitrides and how one can tune the basicity of the nitride ligand by shifting down the group. 

ABSTRACT

This presentation will describe our recent application of Frustrated Lewis Pairs (FLPs) to gain access to inorganic methylene EH2 complexes (E = Group 14 element) and their use to deposit bulk metal films from solution.[1] This will be followed by a highlight of our studies on anionic N-heterocyclic olefin (NHO) ligands, leading to rare examples of acyclic two-coordinate silylenes (R2Si:). I will also describe the ability of our silylenes to activate strong homo- and heteroatomic bonds under mild conditions.[2]

[1] For reviews of EH2 complexes, see: E. Rivard, Chem. Soc. Rev. 2016, 45, 989-1003.

[2] a) M. M. D. Roy, E. Rivard, Acc. Chem. Res. 2017, 50, 2017-2025; b) C. Hering-Junghans, P. Andreiuk, M. J. Ferguson, R. McDonald, E. Rivard, Angew. Chem., Int. Ed. 2017, 56, 6272-6275; c) M. M. D. Roy, M. J. Ferguson, R. McDonald, Y. Zhou, E. Rivard, Chem. Sci. 2019, 10, 6476-6481.

ABSTRACT

Main group Lewis acids for applications in catalysis and anion transport

Research in the Gabbaï group has been dedicated to the synthesis and study of Lewis acidic main group compounds with the development of applications in molecular recognition and catalysis as the ultimate goals.  This seminar will highlight a series of recent results obtained in pursuit of these goals.  The first part of the presentation will focus on the chemistry of antimony- and carbon-based Z-type ligands and their demonstrated ability to modulate the catalytic reactivity of adjacent metal centers.  The second part of the presentation will show how boron and antimony-based Lewis acids can be deployed in aqueous media to effectively transport a range of anions across phospholipid bilayers in artificial vesicles as well as in live cells.

Abstract:   

Access to global public healthcare is impacted by many technical, economic, and social factors. It is widely recognized that the resources required to deliver and improve global public health are currently constrained.  A powerful way to increase access is to lower the cost of products and services that have already proven to be effective.  Currently, the cost of producing a wide range of pharmaceutical products is higher than it needs to be. The mission of Medicines for All (M4All) is to transform active pharmaceutical ingredient (API) processes in order to reduce medication cost and improve patient access.  To fulfill this objective, M4ALL has developed a set of core principles for API process development, which is derived from fundamental elements of process intensification that are commonly known but often neglected. These principles have been applied to several global health drugs yielding dramatic improvements in chemical efficiency. The development of novel heterogeneous cross-coupling that support this effort will also be presented.

Manipulating Main Group Elements with Transition Metal Isocyanides

Abstract: Transition metal complexes supported by encumbering m-terphenyl isocyanides are adept platforms for the stabilization of unusual molecular species. It has recently been reported that an iron complex featuring two m-terphenyl isocyanide ligands can support a terminal boron monfluoride (BF) ligand. This simple 10e– molecule is isoelectronic to carbon monoxide, but possesses vastly different electronic structure properties. In this presentation, the electronic features of metal-coordinated BF are discussed. In addition, the reactivity properties coordinated BF are detailed, with an emphasis on reactions where BF is the primary chemical protagonist. Highlighted are a series of reactions between the BF complex and nucleophilic substrates. In certain cases, nucleophiles are shown to displace fluoride from BF to generate new boron-containing ligands. These reactions are compared and contrasted with transformations where fluoride remains bound to the boron atom. Also presented are reactions between transition metal isocyanide anions and other substrates that generate uncommon metal-bound main group species.

ABSTRACT

Specific Inhibition of Heparanase by Glycopolymers for Cancer and Diabetic Therapeutics

Heparanase has been illustrated to regulate aggressive tumor behavior and to play important roles in autoimmune diabetes. Heparanase cleaves polymeric heparan sulfate (HS) molecules into smaller chain length oligosaccharides, allowing for release of angiogenic growth factors promoting tumor development and autoreactive immune cells to reach the insulin-producing b cells. Interaction of heparanase with HS chains is regulated by substrate sulfation sequences, and only HS chains with specific sulfation patterns are cleaved by heparanase. Therefore, heparanase has become a potential target for anticancer and antidiabetic drug development. Several molecules have been developed to target heparanase activity, but only carbohydrate molecules have advanced to clinical trials. However, the carbohydrate-based heparanase inhibitors are heterogeneous in size and sulfation pattern leading to nonspecific binding and unforeseen adverse effects, thus halting their translation into clinical use.

Our group has recently discovered that the sulfation pattern of pendant disaccharide moiety on synthetic glycopolymers could be synthetically manipulated to achieve optimal heparanase inhibition. We have determined that glycopolymer with 12 repeating units was the most potent inhibitor of heparanase (IC50 = 0.10 ± 0.36 nM). This glycopolymer was further examined for cross-bioactivity, using a solution based competitive biolayer interferometry assay, with other HS-binding proteins (growth factors, P-selectin, and platelet factor 4) which are responsible for mediating angiogenic activity, cell metastasis, and antibody-inducedthrombocytopenia. The synthetic glycopolymer has low affinity for these HS-binding proteins in comparison to natural heparin. In addition, the glycopolymer possessed no proliferative properties towards human umbilical endothelial cells (HUVEC) and a potent antimetastatic effect against 4T1 mammary carcinoma cells. Furthermore, our recent results illustrated that treatment of cultured mouse pancreatic b cells with heparanase significantly reduced their survival. In stark contrast, the b cells treated with heparanase plus the synthetic glycopolymer exhibited a survival rate comparable to the b cells treated with the vehicle PBS. In addition, we treated insulin-secreting human pancreas islets with heparanase in the presence or absence of the glycopolymer inhibitor. Alcian blue staining of HS contents indicated that the the glycopolymer inhibitor protected the human islets from destruction of extracellular HS contents caused by elevation of heparanse. The extracellular HS contents play important roles in preserving pancreas β cell function and protecting β cells from destruction by heparanase.

Characterization of copper intermediates in enzymes and other catalysts that attack strong C-H bonds is important for unraveling oxidation catalysis mechanisms and, ultimately, designing new, more efficient catalytic systems. New insights into the nature of such intermediates may be obtained through the design, synthesis, and characterization of copper-oxygen complexes. Two key proposed examples contain [CuO2]+ and [CuOH]2+ cores, which have been suggested as possible reactive intermediates in monocopper enzymes such as lytic polysaccharide monooxygenase. Recent progress toward the characterization of the structures and properties of complexes with these cores that feature the same supporting ligand will be described, and detailed comparisons of their kinetics in reactions with C-H and O-H bonds will be discussed. Notable differences in their PCET reaction pathways with para-substituted phenols has been discovered that shed new light on the fundamental chemistry of these important core structures.

ABSTRACT

Carbon dioxide is an attractive C1 synthon in chemical synthesis due to its abundance, obtainability, non-toxicity, and inherent renewability. However, it has been undervalued and underutilized for the synthetic installation of carboxyl functionality because of its unreactive nature, owing to its inherent thermodynamic stability and kinetic inertness. Traditionally the carboxyl group is accessed by organic chemists through redox manipulation and protection/deprotection reactions or through the use of strong nucleophiles that have limited functional group tolerance. By fixing carbon dioxide with unsaturated organic molecules through C–C bond formation, rapid and redox-economic synthesis of carboxylic acids and their derivatives can be realized. Nevertheless, these transformations remain rare, are poorly understood, and generally limited to more energetic alkyne substrates. The Popp Research Group uses methodological and mechanistic approaches to expand the versatility and usefulness of transition metal-catalyzed reductive olefin carboxylation. Two approaches that will be discussed in this seminar are transfer hydrometallation–carboxylation and hetero(element)carboxylation. Recent mechanistic work will be presented on an iron-catalyzed variant of the former reaction class that has revealed new details, and possibly new opportunities, for this poorly understood class of reaction. The latter manifold was only recently extended by our group to include olefins (vinyl arenes) for the first time (ACS Editors’ Choice–Org. Lett. 2016, 18, 6428). The mild method uses redox-neutral copper catalysis and a single atmosphere of CO2 to obtain boron-functionalized α-aryl carboxylic acids, including novel functionalized-NSAIDs such as bora-ibuprofen and bora-naproxen. Recent progress toward the preparation of new bora-olefin compounds, subsequent synthetic elaboration of the carbon-boron bond, and complementary experimental/computational studies to improve our mechanistic understanding of the reaction will also be presented.

Rising atmospheric concentration of CO2 is forecasted to have potentially disastrous effects on the environment from its role in global warming and ocean acidification.  Converting CO2 into valuable chemicals and fuels is one of the most practical routes for reducing CO2 emissions while fossil fuels continue to dominate the energy sector.  In the past few years our group has investigated the catalytic reduction of CO2 using a combination of kinetic studies, in situ characterization and density functional theory calculations.  In this talk we will present several examples on (1) CO2 conversion by thermocatalysis, (2) CO2 reduction by electrocatalysis, and (3) simultaneous upgrading of CO2 and shale gas. We will use these examples to highlight the importance of using fundamental chemical engineering principles to guide the selection of reaction conditions and catalyst compositions.

ABSTRACT

Islets of Langerhans are the endocrine portion of the pancreas responsible for maintaining glucose homeostasis via the regulated secretion of numerous hormones, most notably insulin and glucagon. Defects in the secretion of these hormones are associated with a number of metabolic diseases, including diabetes and the metabolic syndrome. The ability to measure these glucose-regulating peptides with high time resolution and sensitivity is necessary to fully resolve the secretion dynamics of these factors and to understand how they change at various disease stages.

In this talk, a number of analytical strategies our group has developed which enable monitoring of secretion with high time resolution will be discussed. These assays include multi-color electrophoretic affinity assays, electrochromatographic separations for small molecule transmitters, and fluorescence anisotropy immunoassays. A number of these assays have been integrated into microfluidic systems to enable monitoring of secretions as a function of time. Select applications of these devices will also be discussed including how groups of islets can coordinate their secretion in vivo into pulses that are necessary for proper glucose utilization.

ABSTRACT

Lipids represent a rich model system for understanding how nature maintains cellular architecture (membrane building blocks), bioenergetics (energy stores), and communication (secondary messengers) through fine adjustments in enzyme metabolism. Embedded within lipid structures is chemical information that define their metabolic fate and function. Elucidating structure-function relationships of lipids in biological systems has been traditionally challenging because of the massive structural diversity of lipids in nature and lack of tools to selectively probe their function in vivo. I will describe efforts from my group to use chemical biology and mass spectrometry to gain fundamental insights into diacylglycerol (DAG) biology and the translational potential of modulating DAG pathways in inflammation and immuno-oncology.

ABSTRACT

Interstellar space is replete with molecules, ranging from the very simple (e.g. molecular hydrogen), to more complex and exotic species such as the cyanopolyynes (e.g. HC9N). However, young star-forming regions in particular demonstrate the richest chemistry observed outside the solar system, and are host to many molecules that are familiar from the terrestrial chemistry lab, including alcohols, aldehydes, esters and ethers; it is still a matter of debate how much of this interstellar material can survive intact to the planet-formation stage and beyond. Recent millimeter-wavelength spectral observations of high-mass star-forming regions, using the new ALMA telescope, have identified a range of new, and yet more complex molecules, whose formation mechanisms are just beginning to be fully explored. Diffusive chemistry on cold dust-grain surfaces and the energetic processing of the resultant ice mantles seem to play a critical role for many.

I will outline the chemical and physical processes that take place in interstellar clouds and star-forming cores, and will discuss new astronomical observations of organic molecules. I will also show how new chemical kinetics simulations, combined with astrophysical spectral-emission models, can help us understand both the chemistry of star formation, and the laboratory experiments that aim to reproduce its conditions.

Elucidating Proton-Coupled Electron Transfer Mechanisms Underpinning the Catalytic Generation of Renewable Fuels

The conversion of energy-poor feedstocks like water and carbon dioxide into energy-rich fuels involves multi-electron, multi-proton transformations. In order to develop catalysts that can mediate fuel production with optimum energy efficiency, this complex proton-electron reactivity must be carefully considered. Using a combination of electrochemical methods and time-resolved spectroscopy, we have revealed new details of how molecular catalysts mediate the reduction of protons to dihydrogen and the experimental parameters that dictate catalyst kinetics and mechanism. Through these studies, we are revealing opportunities to promote, control and modulate the proton-coupled electron transfer reaction pathways of catalysts.

ABSTRACT

The renaissance that has occurred in main group chemistry over the last several decades has been largely driven by the realization that very low oxidation state p-block compounds can be stable species at ambient temperature, given the right ligand environment. Increasingly, such compounds are being shown to possess "transition metal-like" reactivity patterns in small molecule activations, and associated catalytic synthetic transformations.[1] In late 2007 we extended this field to the s-block with the preparation of the first room temperature stable molecular compounds containing magnesium-magnesium covalent bonds, viz. LMgMgL (L = bulky guanidinate or b-diketiminate, e.g. 1).[2] We have subsequently shown that the unique properties these species possess lend them to use as versatile reducing agents in both organic and inorganic synthetic protocols.[3] The products of such reactions are often inaccessible using more classical reducing agents. In this lecture an overview of what has been achieved with these remarkable reagents will be given, with an emphasis placed on the preparation of unprecedented examples of low oxidation state/low coordination number metal-metal bonded complexes involving metals from the s-, p- and d-blocks, e.g. 2-4.[4] The further chemistry of these highly reactive systems will also be discussed, as will our efforts to incorporate magnesium(I) dimers into catalytic cycles.[5]

REFERENCES

[1] Power, P. P. Nature 2010, 463, 171.

[2] Green, S. P.; Jones, C.; Stasch, A. Science 2007, 305, 1136.

[3] Jones, C. Nature Rev. Chem. 2017, 1, 0059.

[4] Bonyhady, S.J.; Collis, D.; Holzmann, N.; Edwards, A.J.; Piltz, R.O.; Frenking, G.; Stasch, A.; Jones, C. Nature Comm., 2018, 9, 3079.

[5] (a) Boutland, A. J.; Carroll, A.; Lamsfus, C. A.; Stasch, A.; Maron, L.; Jones, C. J. Am. Chem. Soc. 2017, 139, 18190; (b) Yuvaraj, K.; Douair, I.; Paparo, A.; Maron, L.; Jones, C. J. Am. Chem. Soc., 2019, 141, 8764.

White phosphorus (P4) has been the traditional entry point into phosphorus chemistry. The thirteenth element to have been isolated, it can be oxidized with elemental oxygen or chlorine, or reduced in a variety of ways. We investigated its reduction using early transition metal systems and breakdown to produce complexes with terminal metal-phosphorus triple bonds. Such terminal phosphide complexes possess nucleophilic phosphorus atoms, paving the way to new phosphorus-element bonded systems. This opened the door to the study of reactive diphosphorus molecules, the naked P2 molecule being otherwise a high-temperature species. Subsequently, it proved possible to deliver P2 into organic molecules using photochemical “cracking” of white phosphorus, the P2 serving as an effective dienophile with 1,3-dienes. An alternative pathway to the generation of unsaturated, P-containing reactive intermediates is through the use of anthracene as a delivery platform as illustrated for aminophosphinidenes, the interstellar molecule HCP, and diphosphorus. The raw material serving as a phosphorus source for global agriculture is not white phosphorus, but rather apatite in phosphate rock. White phosphorus is made in the legacy “thermal process”, accounting for ca. 5% of global phosphate rock consumption but ca. 30% of the energy utilized in phosphate rock upgrading. Now we are seeking routes to value-added phosphorus chemicals that leverage the “wet process”, in which phosphate rock is treated with sulfuric acid en route to phosphoric acid and phosphate fertilizers. 

Prebiotic Astrochemistry in the "THz-Gap"

Small reactive organic molecules are key intermediates in interstellar chemistry, leading to the formation of biologically-relevant species as stars and planets form.   These molecules are identified in space via their pure rotational spectral fingerprints in the far-IR or terahertz (THz) regime.  Despite their fundamental roles in the formation of life, many of these molecules have not been spectroscopically characterized in the laboratory, and therefore cannot be studied via observational astronomy.  The reason for this lack of fundamental laboratory information is the challenge of spectroscopy in the THz regime combined with the challenge of studying unstable molecules.  Our laboratory research involves characterization of astrophysically-relevant unstable species, including small radicals that are the products of photolysis reactions, organic ions formed via plasma discharges, and small reactive organics that form via O(1D) insertion reactions.  Our observational astronomy research seeks to examine the chemical mechanisms at play in a range of interstellar environments and to identify chemical tracers that can be used as clocks for the star-formation process.  In this seminar, I will present recent results from our laboratory and observational studies that examine prebiotic chemistry in the interstellar medium.  I will discuss these results in the broader context of my integrative research program that encompasses laboratory spectroscopy, observational astronomy, and astrochemical modeling.

Abstract.

Molecular clouds of gas and dust pervade our galaxy, and are the birthplaces of stars and planets.  The temperature, density, and radiation conditions inside these clouds make them unique chemical laboratories for studying both fundamental reactions and the evolution of the molecular complexity that seeds primitive planets.  We have recently discovered a new regime of unexpected low-temperature aromatic chemistry in these sources that has far-reaching implications on the lifecycle of carbon in the universe.  These detections are demanding new analysis techniques to extract the maximum information content from increasingly large and complex datasets both observationally and in the laboratory.  Here, I will discuss novel applications of signal processing and analysis in both arenas.  Observationally, we are using Bayesian approaches combined with matched filtering techniques, while in the laboratory, we are conducting reaction screening analyses to try to understand the content and evolution of this new carbon chemistry in space.  I will describe the results of our new observational analysis techniques, as well as outline several new methods we have developed for rapidly screening complex chemical mixtures in the laboratory using pump-probe rotational spectroscopy in a (semi-)automated fashion to enable new molecular discovery.

Organic micropollutants, such as pesticides and pharmaceuticals, have raised concerns about negative effects on ecosystems and human health. These compounds are introduced into water resources by human activities, and current wastewater treatment processes do not remove them. Activated carbons are the most widespread adsorbents used to remove organic pollutants from water, but they have several deficiencies, including poor removal of relatively hydrophilic micropollutants, inferior performance in the presence of naturally occurring organic matter, and energy intensive regeneration processes. I will describe polymers based on β-cyclodextrin, an inexpensive, sustainably produced derivative of glucose, that binds these emerging contaminants from water. We also recently modified our original polymer design to target perfluorinated alkyl substances such as PFOA and PFOS, which are environmentally persistent and associated with negative effects at trace concentrations.

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ABSTRACT

In the "bottom-up" approach, materials and devices are constructed from molecules capable of assembling themselves by principles/methods of molecular recognition. Although well-defined assemblies can be engineered by exploiting various noncovalent interactions, there are limited methods in the literature regarding the design and analysis of self-guiding molecules for materials application in which there is a strategic integration of the self-assembling motif.  The principal research conducted in the Watkins Group encompasses fundamental studies towards understanding the molecular assembly of complex systems as it relates to overall performance. Reported are design guidelines towards novel building blocks for functional materials—specifically those for applications in optoelectronic devices and biomaterials. The multi-step synthesis of these building blocks is discussed.  Spectroscopic analysis, as well as characterization via transmission electron microscopy (TEM) and X-ray crystallography of the molecular components and their resulting supramolecular assemblies, reveal materials possessing properties that are comparable to—even surpass—those commonly reported in the literature.  Results of this study will be employed towards further research in novel molecular components capable of yielding high performing materials.

ABSTRACT

Alzheimer’s disease remains a major unmet medical need representing a huge societal burden and a difficult event in the lives of patients and families. Current treatments do not offer hope for disease altering outcomes and recent attempts to bring forward new therapies have proven largely unsuccessful. This presentation will review two programs at Bristol-Myers Squibb spanning two therapeutic targets and two drug structural classes, or modalities: Small molecules and antisense oligonucleotides (ASOs). Efforts to improve the stereospecific synthesis of an important class of ASOs will be described.

Abstract: 

Access to global public healthcare is impacted by many technical, economic, and social factors. It is widely recognized that the resources required to deliver and improve global public health are currently constrained.  A powerful way to increase access is to lower the cost of products and services that have already proven to be effective.  Currently, the cost of producing a wide range of pharmaceutical products is higher than it needs to be. The mission of Medicines for All (M4All) is to transform active pharmaceutical ingredient (API) processes in order to reduce medication cost and improve patient access.  To fulfil this objective, M4ALL has developed a set of core principles for API process development, which are derived from fundamental elements of process intensification that are commonly known but often neglected. These principles have been applied to several global health drugs yielding dramatic improvements in chemical efficiency. The development of novel and highly efficient heterogeneous catalysts for cross-coupling reactions that support this effort will also be presented.

Studying Cell Signaling in Complex Environments Using Open Microfluidics

Small molecule and protein signals provide a rich vocabulary for cellular communication. To better understand signaling processes in both normal and disease states, we have developed new open microfluidic platforms that accommodate the culture of multiple cell types in microfabricated compartments while allowing soluble factor signaling between cell types. Our microscale culture systems allow a 10- to 500-fold reduction in volume compared to conventional assays, enabling experiments with limited cells from patient samples. Furthermore, our devices are open, pipette accessible, interface with high resolution microscopy, and can be manufactured at scale by injection molding, increasing translation to collaborators in biological and clinical labs without chemistry and engineering expertise. Finally, this talk will highlight recent results using open microfluidic principles to develop novel strategies to 3D print hydrogels for biological and materials science applications.

ABSTRACT

The past 40 years of astrochemistry has showed that unusual molecules readily form in extreme interstellar environments. One of these interesting settings is the material lost from stars in their final stages. Here gas-phase material is ejected from the hot stellar photosphere, often at high velocities, and rapidly cools to create molecules and dust grains under competing thermodynamic and kinetic conditions. Using a combined program of high-resolution laboratory spectroscopy and astronomical observations, we have been investigating the chemistry of stellar ejecta. Measurements of rotational spectra of small, metal-bearing molecules using millimeter-wave and Fourier transform microwave methods have been conducted, such as simple oxides and dicarbides. Molecular-line observations have shown that some of these exotic species are present in circumstellar material, defying thermodynamic predictions, including such highly refractory molecules as VO and FeCN. At the very late stages of stellar evolution, the planetary nebula phase, a wide variety of carbon-containing molecules appear to be present, ranging from CCH and c-C3H2 to C60, despite the presence of very high ultraviolet radiation fields. The chemical formation of this wide variety of chemical compounds will be discussed, including a novel mechanism for fullerene production in circumstellar environments.

Photoredox and Electrochemical Methods for C-N Bond Forming Reactions

C-N bonds are ubiquitous in medical, pharmaceutical, and natural products. Therefore, it is important to develop synthetic procedures that both effectively form C-N bonds and incorporate sustainable principles. These principles include the use of renewable energies sources such as sunlight, utilization of abundant transition metal catalysts, and increasing the atom economy of the reactions. Along these lines, we have utilized dual photoredox system capable of accessing diaryl amines, amines containing aliphatic groups, and tertiary amines nickel catalysis to perform aryl-amine cross-coupling reactions. Until very recently this class of C-N bond forming reactions were limited to Pd-catalyzed reactions. Our system is the first Ni-catalyzed reaction system capable of synthesizing diaryl amines, tertiary amines, and amines containing aliphatic groups. Mechanistic studies support an amine-radical-based reaction pathway that allows for the access to the range of products. Furthermore, we have developed an “anion pool” electrochemical method for the synthesis of N-substituted heterocycles. This base-free and transition-metal-free approach exhibits good atom economy and has proven widely applicable for the synthesis of substituted benzimidazoles.

Harnessing RNA Regulation to Direct Protein Evolution and Control Mammalian Gene Expression

I will present two recent technologies our group has developed that harness RNA regulation – one for basic science purposes and one for therapeutic development. First, I will describe new methods that use our RNA polymerase-based biosensors to harness evolution in order to probe the emergence of “selectivity” between biomolecular interfaces, in particular, protein-protein interactions (PPIs). Using a combination of high-throughput biochemical methods, ancestral reconstruction, and a new rapid evolution technology, we developed a model system involving the BCL-2 family of apoptotic regulatory proteins to probe fundamental evolutionary questions about PPIs and how selectivity (or not) emerges between them. In the second half of the talk, I will discuss therapeutic opportunities involving RNA regulation and “epitranscriptomics”. While RNA regulation offers exciting opportunities to create genetic therapies that are reversible and tunable, most current approaches rely on large, microbially-derived systems that pose clinical challenges. We developed the CRISPR/Cas-inspired RNA targeting system (CIRTS), a new protein engineering strategy for constructing programmable RNA regulatory systems entirely from human protein parts. The small size and human-derived nature of CIRTS provides a less-perturbative method for fundamental studies as well as a potential strategy to avoid immune issues when applied to epitranscriptomic therapies.

John M. Butler is an internationally recognized expert in forensic DNA analysis and holds a Ph.D. in analytical chemistry from the University of Virginia. He has written five textbooks on Forensic DNA Typing (2001, 2005, 2010, 2012, and 2015) and given hundreds of invited talks to scientists, lawyers, and members of the general public throughout the United States and in 26 other countries so far. In 2022, he co-authored a new book, Understanding Forensic DNA with Cambridge University Press, to improve public understanding of the field.  

Dr. Butler’s research, first conducted at the FBI Laboratory and now at the National Institute of Standards and Technology (NIST), pioneered the methods used today worldwide for DNA testing in criminal casework, paternity investigations, and many DNA ancestry assessments.  He has been honored in multiple White House ceremonies (2002 and 2015) for his work in advancing DNA testing.

In 2011, ScienceWatch.com named him the worldwide high-impact author in legal medicine and forensic science over the previous decade. A 2020 Stanford University analysis of eight million scientists published since 1960 put Dr. Butler as #7 (#1 from the United States) out of 10,159 researchers worldwide in the subcategory of legal medicine and forensic science. He has received the Gold Medal (2008) and Silver Medal (2002) from the U.S. Department of Commerce, the Scientific Prize of the International Society for Forensic Genetics (2003), the Paul L. Kirk Award from the American Academy of Forensic Sciences (2017), and the Magnus Mukoro Award for Integrity in Forensic Science from the NYC Legal Aid Society (2020).

Dr. Butler is a NIST Fellow (highest scientific rank at NIST) and Special Assistant to the Director for Forensic Science in the Special Programs Office. He served as the Vice-Chair of the National Commission on Forensic Science from 2013 to 2017. In 2019, he was elected the President of the International Society for Forensic Genetics, which has 1300 members in 79 countries. Dr. Butler and his wife have six children, all of whom have been proven to be theirs through the power of DNA testing.

Title for Graham Lecture (7 October 2022):

“Understanding Forensic DNA: Its Background, Capabilities, and Limitations”

DNA testing and forensic evidence play an important role in the criminal justice system. The media regularly reports on how DNA samples change the course of important investigations. This presentation will discuss the background of modern forensic DNA testing and links to the University of Virginia Department of Chemistry. The capabilities and limitations of DNA analysis will also be examined in the context of the 1998 Nature article titled “Jefferson fathered slave’s last child.”   

ABSTRACT

O-GlcNAc transferase (OGT) is essential for viability of all mammalian cells but no one knows why. OGT has two catalytic activities that take place in the same active site. In one, OGT attaches N-acetyl glucosamine to serine and threonine side chains of at least a thousand nuclear and cytoplasmic proteins. In the other, OGT cleaves a transcriptional co-activator involved in cell-cycle regulation. Because OGT is found in several stable protein-complexes, it is also proposed to act as a scaffolding protein. How do you dissect the cellular functions of an essential protein that has multiple biochemical activities and a thousand different substrates? I will argue that you need to start by understanding the chemistry –  mechanisms of catalysis and substrate recognition – so you can develop variants with some activities and not others. I will describe how we have done so and how we have used our knowledge to answer a fundamental question: What is the essential biochemical function of OGT for cell survival? I will also describe how we have developed and used a specific small molecule inhibitor of OGT to uncover an unexpected role in controlling RNA splicing.  

ABSTRACT

Selective trimerization of ethylene to produce 1-hexene is a commercially practiced process that yields valuable comonomer for linear low density polyethylene production. Several years ago, ExxonMobil chemists developed a family of chromium catalysts useful for ethylene trimerization, but a mechanistic understanding of the catalysis remained elusive. This talk presents a mechanistic proposal to explain the catalytic selectivity, supported by a computational exploration of proposed cycle. Results will be discussed in terms of geometric requirements for reaction and the fundamental steps involved in catalysis.

Abstract

Biological molecules rarely act alone. Instead, molecular complexes carry out a range of cellular functions from DNA repair to cell motility and protein folding. Dysfunction of complexes is implicated in numerous diseases. For example, altered cellular distributions of actin cytoskeletal protein monomers and complexes result in highly motile and invasive cancer cells. Such dysfunction arises biochemically, biophysically, or both. Biochemical and biophysical changes occur on the length and force scales of the complexes themselves—micro/nanoscale and ultra-low forces. Microscale tools, such as size-based electrophoretic (EP) cytometry protein separations, and piconewton-scale magnetic tweezers, can measure such small size and force changes respectively.

I will describe efforts to establish and apply microscale tools to study the function of diverse protein complexes. First, I will discuss the design of single-cell EP cytometry fractionation of actin complexes from monomers. The microscale device geometry achieves rapid, arrayed on-chip sample preparation and EP fractionation without perturbing complexes. Second, I will share how magnetic tweezers reveal that tension in Rad51-DNA protein complexes drives accurate DNA damage repair processes. Finally, we will explore the future of microscale biophysical and biochemical analysis of complexes, with a focus on chaperone protein complexes responsible for protein folding, which goes awry in Alzheimer’s disease. 

Inspiration from Fluorination:  Chemical Epigenetics Approaches to Probe Molecular Recognition Events in Transcription

Protein-protein interaction inhibitor discovery has proven difficult due to the large surface area and dynamic interfaces of proteins.  To facilitate the early lead discovery rate, I will first describe a rapid protein-based 19F NMR method for detecting protein-ligand interactions by screening low complexity molecules (fragments), drug-like molecules, and peptidomimetics. We have tested the sensitivity, accuracy, and speed of this method through screening libraries of small molecule fragments.  The advantages of using 3D-fragments for discovery of more selective hits for bromodomain-containing proteins will be specifically highlighted. In the second part of the talk, I will describe improvements in our method for the field of epigenetics targeting bromodomain and extra-terminal (BET) family proteins. These studies have led to a selective inhibitor for the first bromodomain of BRD4. Structure-based design has identified several new design rules for maintaining selectivity and potency.  Cellular efficacy in cancer and inflammatory model systems using this novel BRD4 inhibitor will be briefly described.  Finally, development of a new heterocyclic scaffold for the second bromodomain of BRD4 will be highlighted. The speed, ease of interpretation, and low concentration of protein needed for binding experiments affords a new method to discover and characterize both native and new ligands for bromodomains and may find utility in the study of additional epigenetic “reader” domains.

ABSTRACT

Advancing highly tunable synthetic materials to operate in an increasingly cooperative fashion with biological systems and the environment provides a compelling opportunity to expand the repertoire and enhance the performance of critically needed technologies.  To this end, we are developing new building blocks for polymer biomaterials so as to access to a breadth of thermomechanical properties and promote productive interactions with biological systems.  The first part of this talk will describe our research on mirror image peptide complexes, or ‘stereocomplexes’, as tunable, transient junctions in synthetic polymer biomaterials.  Varying the primary structure of the peptides and solvent conditions were found to markedly impact the secondary structure, which in turn determined the macroscale properties of polymer-peptide conjugates.  These junctions are envisioned as molecular ‘VELCRO®’ strips and are anticipated to impart a myriad of adaptive properties, including self-healing and shear thinning, useful for 3D printing-based manufacturing processes and targeting biological proteins, among other applications.  Another approach to engineer adaptive materials involves controlling degradation rates, and the second part of this talk will describe the synthesis, thermomechanical characterization, and degradation profiles of poly(β-amino ester) networks.  By adjusting monomer composition, networks were obtained with degradation times scales that spanned hours to months.  Synthetically accessible and highly tunable, this polymer platform offers enormous opportunities, from sacrificial template materials for biomanufacturing to commodity materials that degrade after their useful lifetime.  Ultimately, by intertwining concepts from small molecule and peptide chemistry with polymer science and engineering, we aim to advance polymer and peptide building blocks, and thereby contribute to next generation materials and technologies for healthcare and beyond.

This seminar will cover the recent advances in the design and fabrication of folding- and dynamics-based electrochemical biosensors. These devices, which are often termed electrochemical DNA (E-DNA), aptamer-based (E-AB), and peptide-based (E-PB) sensors, are fabricated via direct immobilization of a thiolated and methylene blue (MB)-modified oligonucleotide or peptide probe onto a gold electrode. Binding of an analyte to the probe changes its structure and/or flexibility, which, in turn, influences the electron transfer between the MB label and the interrogating electrode. These sensors are resistant to false positive signals arising from the non-specific adsorption of contaminants and perform well even when employed directly in whole blood, saliva, and other realistically complex sample matrices. Furthermore, because all of the sensing components are chemisorbed onto the electrode surface, they are readily regenerable and reusable. Our results show that many of these sensors have achieved state-of-the-art sensitivity while offering the unprecedented selectivity, reusability and operational convenience of direct electrochemical detection.

Incorporating Metal-Ligand and Metal-Metal Cooperativity into First Row Transition Metal Complexes with Applications in Catalysis

The formation and cleavage of chemical bonds in catalytic reactions relies on accessible two-electron redox processes that are often challenging for base metals such as first row and early transition metals. Metal-ligand and metal-metal cooperativity provide a potential solution to this challenge by enabling heterolytic bond cleavage processes and/or facilitating redox processes. Both strategies will be discussed, showcasing the many ways that metal-ligand and bimetallic cooperativity can operate and the methods by which cooperativity can be built into catalyst design. A tridentate pincer ligand featuring a reactive N-heterocyclic phosphido fragment is found to be both redox active and an active participant in bond activation across the metal-phosphide bond, with catalytic applications in alkene hydroboration. A tetradentate bis(amido)bis(phosphide) ligand has been coordinated to iron and it has been shown that the resulting complex can activate two σ bonds across the two iron-amide bonds in the molecule without requiring a change in the formal metal oxidation state. In the context of metal-metal cooperativity, phosphinoamide-linked early/late heterobimetallic frameworks have been shown to support metal-metal multiple bonds and facilitate redox processes across a broad range of metal-metal combinations and the resulting complexes have been shown to activate small molecules and catalyze organic transformations.

Crystal growth theory predicts that heterogeneous nucleation will occur preferentially at defect sites, such as the vertices rather than the faces of shape-controlled seeds. Platonic metal solids are generally assumed to have vertices with nearly identical chemical potentials, and also nearly identical faces, leading to the useful generality that heterogeneous nucleation preserves the symmetry of the original seeds in the final product. This presentation will discuss how this generality can be used to access stellated metal nanocrystals with high and tunable symmetries for applications in plasmonics. This presentation will also discuss the limits of this generality in the extreme of low supersaturation. A strategy for favoring localized deposition that differentiates between both different vertices and different edges or faces, i.e., regioselective deposition, will be demonstrated. Such regioselective heterogeneous nucleation was achieved at low supersaturation by a kinetic preference for high-energy defect-rich sites over lower-energy sites. This outcome was enhanced by using capping agents to passivate facet sites where deposition was not desired. Collectively, the results presented provide a model for breaking the symmetry of seeded growth and for achieving regioselective deposition.

Learning Objectives

•       Trends for isolation of monoclonal antibodies
•       Current  antibody reproducibility problem in academic institute
•       Antibody validation: Standards, policies, and practices 
•       A new mindset for affinity application, evaluation, and authorization
•       The advantages of recombinant antibody production methods over monoclonal and polyclonal antibody production methods.
•       Phage display antibody production be adapted to produce the characteristic desired in applications such as multiple epitope recognition, tissues, and phenotype functional antibodies. 
•       Learn about protein chemistry and conjugation of antibody and drug
•       Immobilize antibody onto different polymers, nanoparticles, liposome  

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

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.

This talk will address the development of three classes of graphene-based materials as (1) support for metal nanoparticle catalysts in heterogeneous catalysis, (2) sorbent materials for the removal of heavy metal ions from polluted water, and (3) photothermal energy converter materials for efficient solar water desalination.

In heterogeneous catalysis, we will discuss the superior catalytic activity of Pd nanoparticles supported on reduced graphene oxide (RGO) nanosheets for carbon-carbon cross-coupling reactions. Second, the enhanced catalytic activity for the Fe-based nanoparticle catalysts supported on graphene in the Fischer-Tropsch Synthesis of liquid transportation fuels will be presented. Finally, the superior catalytic activity and selectivity of Pd nanoparticles supported on a sandwich-type nanocomposite consisting of Metal-Organic Frameworks (MOFs) wrapped with thin RGO nanosheets for the biomass-refining of liquids derived from lignocelluloisc sources will be presented.

For the removal of heavy metals from water, we will discuss the development of chemically modified graphene-based adsorbents containing highly efficient chelating groups such as diamine, imino and thiourea for the effective extraction of the toxic metal ions mercury (II), lead (II) and arsenic (V) from wastewater.

For photothermal energy conversion, we will discuss the development of a new generation of highly efficient, flexible, low weight, highly porous and cost effective Plasmonic Graphene Polyurethane (PGPU) nanocomposite materials for solar steam generation through the efficient evaporation of water surface pools. The PGPU nanocomposites contain metallic nanoparticles that exhibit very strong solar absorption. The polyurethane (PU) foam provides a hydrophilic surface with abundant microporous structure, excellent thermal insulation properties, and facile and scalable synthesis. The high solar thermal evaporation efficiency, excellent stability and long-time durability make the PGPU nanocomposites excellent candidates for solar-steam-generation applications and seawater desalination.

This talk will provide an overview of our group’s work using both standard and atypical high-performance computational chemistry modeling to elucidate atomic scale reaction mechanisms of catalytic reactions. I will introduce our toolkit of in silico methods for accurately modeling (electro)catalytic reactions in solvating environments. I will then present how in silico methods can be used for predictive insights into chemical and material design. The talk will then highlight our progress in modeling 1) the complex Morita-Baylis-Hillman reaction, 2) inefficient amorphous TiO2 materials as anti-corrosion coatings, and 3) biomimetic CO2 reduction mechanisms.

The materials-by-design approach to the development of functional materials requires new synthetic strategies that allow for material composition and structure to be independently controlled and tuned on demand. Although it is exceedingly difficult to control the complex interactions between atomic and molecular species in such a manner, interactions between nanoscale components can be encoded, independent of the nanoparticle structure and composition, through the ligands attached to their surface. DNA represents a powerful, programmable tool for bottom-up material design. We have shown that DNA and other nucleic acids can be used as highly programmable surface ligands (“bonds”) to control the spacing and symmetry of nanoparticle building blocks (“atoms”) in structurally sophisticated materials, analogous to a genetic code for materials assembly. The sequence and length tunability of nucleic acid bonds has allowed us to define a powerful set of design rules for the construction of nanoparticle superlattices with more than 50 unique lattice symmetries, spanning over one order of magnitude of interparticle distances, with several well-defined crystal habits. Furthermore, this control has enabled exploration of sophisticated symmetry breaking processes, including the body-centered tetragonal lattice as well as the clathrate lattice, the most structurally complex nanoparticle-based material to date (>20 particles per unit cell). The nucleic acid bond can also be programmed to respond to external biomolecular and chemical stimuli, allowing structure and properties to be dynamically tailored. Notably, this unique genetic approach to materials design affords functional nanoparticle architectures that can be used to catalyze chemical reactions, manipulate light-matter interactions, and improve our fundamental understanding of crystallization processes.

ABSTRACT

The majority of FDA-approved drugs are small organic molecules, generally defined as having a molecular weight below 900 g/mol. The speed and reliability with which one can synthesize complex bioactive small molecules is a major limiting factor in the race to discover new drugs. As a consequence of this, a historical overreliance on a small number of highly robust synthetic methods has limited the diversity of chemical structures generally pursued as drug leads. A long-term goal of our research program is to develop new synthetic methods that fill significant current gaps in the organic chemist’s toolbox, in order to work towards eliminating synthetic considerations as a barrier to the discovery of new therapeutics. Two major areas of research will be presented: (1) The development of new strategies and new modes of catalysis for the direct, site-selective functionalization of C–H bonds, and (2) The development of new methods for the synthesis and selective modification of nitrogen-containing heterocycles, which are present in the majority of FDA-approved small molecule drugs.

Antimicrobial, cytolytic, and cell-penetrating peptides, often called membrane-active peptides, belong to a variety of structural classes, including, alpha-helical, beta-sheet, unstructured, and cyclic polypeptides, among others. Those peptides were intensely studied in the 1990s and early 2000s with the hope of opening the door for urgently needed new antibiotics. For about 15 years we have studied the kinetics and thermodynamics of their interactions with lipid vesicles with the hope of understanding the mechanism of their function. In general, these peptides bind to lipid bilayers and somehow disrupt or perturb them, causing flux of ions and molecules across the membrane, and also, in some cases, translocating themselves across the membrane. In this talk, I will discuss our efforts to understand the mechanisms of these peptides and what we have learned regarding the effect of sequence on their ability to translocate across the membrane. I will conclude with the examination of a very different case, the cyclic peptide daptomycin, which is one of the few in clinical use. This peptide appears to behave very differently from all other membrane-active peptides that we have studied.

Polymer Modified Carbon Fiber Microelectrodes and Multielectrode Arrays for Multiplexing Neurochemical Measurements

We have developed novel methods to detect neurotransmitters and their metabolites. Traditionally, carbon-fiber microelectrodes (CFMEs) have been utilized to detect dopamine, serotonin, and other important neurotransmitters. However, this method is limited due to a low sensitivity to detect physiologically relevant concentrations of these neurotransmitters. Polymer modified microelectrodes will be utilized to detect fast changes of neurotransmitters. Furthermore, novel electrode coatings and waveforms will also be utilized to detect several neurotransmitter metabolites such as 3,4-dihydroxy-benzeneacetaldehyde (DOPAL), 3-methoxytyramine (3-MT), and 3,4 dihydroxyphenylacetic acid (DOPAC). There is no current assay to detect metabolites of dopamine utilizing voltammetry. Through waveform modifications and polymer electrode coatings, we develop a novel method for dopamine metabolite detection utilizing fast scan cyclic voltammetry (FSCV), which will help differentiate the cyclic voltammograms of dopamine and dopamine metabolites through the shapes and positions of their respective cyclic voltammograms. Preliminary measurements have been made in zebrafish retina ex vivo. We have also developed multielectrode arrays (MEAs) for neurotransmitter detection with FSCV in multiple brain regions simultaneously. Parylene and silicon insulated CFME arrays measured neurochemicals in multiple brain regions simultaneously when coupled with multichannel potentiostats. Moreover, we have utilized techniques such as plasma enhanced chemical vapor deposition to deposit conductive carbon nanospikes onto the surface of existing metal multielectrode arrays to give them dual functionality as neurotransmitter sensors with FSCV in addition to being used primarily for electrical stimulation and recording. Other assays have shown the utility of electrodepositing carbon nanotubes and polymers such as PEDOT to coat metal arrays with carbon to give them dual sensing capabilities.

Increasingly, fluorescent tools are providing insight into the “dark matter” of the cellular milieu: small molecules, secondary metabolites, metals, and ions.  One of the great promises of such tools is the ability to quantify cellular signals in precise locations with high temporal resolution.  Yet this is coupled with the challenge of how to ensure that our tools are not perturbing the underlying biology and the need to systematically measure hundreds of individual cells over time.  The focus of research in the Palmer Lab is to develop fluorescent tools to illuminate and quantify biochemistry in living cells.  In addition to developing such tools, we strive to develop robust systematic analytical approaches for using sensors and fluorescence microscopy to carry out quantitative biochemistry at the single cell level.  Over the past 12 years our greatest effort has been in understanding the cell biology of zinc.  We have developed fluorescent sensors to map out the spatial distribution of zinc ions and quantify zinc dynamics in live mammalian cells.  These tools have allowed us to answer fundamental questions such as: where zinc is located in cells, how much is present in different kinds of cells, under what conditions zinc ions are dynamic, and how the zinc status of healthy cells differs from diseased cells.  Along the way, we have also established benchmark analytical approaches for using fluorescent sensors for quantitative biology and biophysics.  We have developed microfluidic cell sorting technologies to study and engineer fluorescent tools.  We have leveraged our expertise in fluorescent probes, single cell biology and live cell imaging to establish new methods for defining the complex dynamic interface between bacterial pathogens and host mammalian cells. And finally, we have started to expand our reach to develop chemical biology tools for labelling and tracking RNA in live cells.  This talk will provide a highlight of these research areas.

.

Dye-Sensitization for the Production of Electrical Power and Chemical Fuels from Sunlight

Gerald J. Meyer

Department of Chemistry,
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 27599-3290

E-mail: gjmeyer@email.unc.edu

Dye-sensitized solar cells have received considerable attention since the advent of mesoporous metal oxide thin films first described by Grätzel and O’Regan [1]. We have a fundamental interest in light driven interfacial electron transfer in these materials that is motivated by applications in electrical power generation and in solar fuels production [1,2]. Background on dye-sensitization and solar energy conversion will be provided that gives context for our most recent advances that suggest new directions for future research. An example includes the identification of a kinetic pathway for electron transfer from TiO2 to transition metal complexes with two redox active groups. [2,3] The distance between the two groups were held near parity yet electron transfer through an aromatic bridge that separated them was critically dependent on the degree of conjugation [3,4]. Electron transfer to acceptors positioned at variable distances from a conductive oxide surface revealed that the intrinsic barriers were dramatically decreased within the electric double layer [5]. Mechanistic study of core/shell oxide materials provided new insights into electron transport that were correlated with water oxidation efficiency [6]. Finally, an alternative approach to solar fuel production with small band gap semiconductors and tandem catalyst hybrids will be presented. This approach forms the basis of a new Department of Energy supported Solar Hub entitled the Center for Hybrid Approaches in Solar Energy to Liquid Fuels (CHASE) [7].       

References:

[1] “A Low- Cost, High Efficiency Solar Cell Based on the Dye- Sensitized Colloidal TiO2 Films” O’Regan, B.; Grätzel, M. Nature 1991, 353, 737.

[2] “Perspectives in Dye Sensitization of Nanocrystalline Mesoporous Thin Films” Hu, K.; Sampaio, R.N.; Schneider, J.; Troian-Gautier, L.; Meyer, G.J. J. Am. Chem. Soc. 2020, in press.

[3] “A Kinetic Pathway for Interfacial Electron Transfer from a Semiconductor to a Molecule” Hu. K.; Blair, A.D.; Piechota, E.J.; Schauer, P.A.; Sampaio, R.N.; Parlane, F.; Meyer, G.J.; Berlinguette, C.P. Nature Chem. 2016, 8, 853-859.

[4] “Kinetics Teach That Equilibrium Constants Shift Toward Unity with Increased Electronic Coupling” Sampaio, R.N.; Piechota, E.J.; Troian-Gautier, L.; Maurer, A.B.; Berlinguette, C.P., Meyer, G.J. Proc. Nat. Acad. Sci. USA 2018, 115, 7248-7253.

[5] “Kinetic Evidence that the Solvent Barrier for Electron Transfer is Absent in the Electric Double Layer” Bangle, R.E.; Schneider, J.; Conroy, D.T.; Aramburu-Troselj, B.M.; Meyer, G.J. J. Am. Chem. Soc. 2020, 142, 14940-14946. 

[6] “Electron Localization and Transport in SnO2/TiO2 Mesoporous Thin Films: Evidence for a SnO2/SnxTi1- xO2/TiO2 Structure” James, E.M.; Bennett, M.T.; Bangle, R.E.; Meyer, G.J. Langmuir 2019, 39, 12694-12703.

[7] https://uncnews.unc.edu/2020/07/31/department-of-energy-funds-milestone-north-carolina-led-initiative-to-advance-solar-energy-research/

“Enhancing investigations of structure, function, and inhibition at the protein-membrane interface”

Abstract: 

Peripheral membrane proteins (PMPs) are water-soluble proteins that bind reversibly to membranes to perform function. Central to a variety of biological and disease processes, PMP functions are diverse, critical to life, and represent promising yet underutilized therapeutic targets. Despite their importance the functional, membrane-bound state of PMPs is typically poorly understood. Due to their relatively small size, the membrane protein revolution ushered in by cryo-EM has largely left PMPs behind. Detailed structural study is often constrained to the nonfunctional, water-solubilized state. While protein NMR is a promising method, a larger toolbox must be developed to improve the evaluation of PMPs in their membrane-bound state.

We have recently developed membrane-mimicking reverse micelles (mmRMs) as NMR-compatible models to house PMPs in their functional state. Use of mmRMs have been applied to a variety of human PMPs including glutathione peroxidase 4 (GPx4) and fatty acid binding protein 4 (FABP4). For these proteins, certain investigations of their structure, function, and interactions have been improved compared to other membrane models. New insight into high-resolution biological and disease processes gained here has revealed inhibitor design strategies for PMPs. We have applied traditional, aqueous state fragment-based inhibitor design (FBID) methods to the membrane anchoring p47phox-PX domain with promising results. However, for GPx4 and other similar PMPs, targeting the relevant membrane-bound state represents a greater challenge. Fragment screening is highly compatible with mmRMs, allowing GPx4 to be assessed in its functional state. A variety of fragments are revealed to bind in the protein-membrane interface, representing a pool of potential inhibitor building-blocks. Results have also revealed fundamental properties of fragments that bind within the protein-membrane interface, a relatively new mode of inhibition. The addition of mmRMs to the PMP toolbox promises to open new avenues of exploration an inhibition to improve our understanding of this essential category of proteins.

ABSTRACT

Two-dimensional (2D) materials with a thickness of a few nanometers or less can be used as single sheets, or as building blocks, due to their unique properties and ability to assemble into a variety of structures. Graphene is the best-known example, but several other elemental 2D materials (silicene, borophene, etc.) have been discovered. Numerous compounds, ranging from clays to boron nitride (BN) and transition metal dichalcogenides, have been produced as 2D sheets. By combining various 2D materials, unique combinations of properties can be achieved which are not available in any bulk material. The family of 2D transition metal carbides and nitrides (MXenes) has been expanding rapidly since the discovery of Ti3C2 in 2011 [1]. Approximately 30 different MXenes have been synthesized, and the structure and properties of numerous other MXenes have been predicted using density functional theory (DFT) calculations [2]. Moreover, the availability of solid solutions on M and X sites, control of surface terminations, and the discovery of ordered double-M MXenes (e.g., Mo2TiC2) offer the potential for synthesis of dozens of new distinct structures.

This presentation will describe the synthesis of MXenes by selective etching of layered ceramic precursors, including various MAX phases. Delamination into single-layer 2D flakes and assembly into films and 3D structures, as well as their properties will be discussed. Synthesis-Structure-Properties relations of MXenes will be addressed on the example of Ti3C2.

The versatile chemistry of the MXene family renders their properties tunable for a large variety of applications [3]. Oxygen or hydroxyl- terminated Menes, such as Ti3C2O2, have been shown to have redox capable transition metals layers on the surface and offer a combination of high electronic conductivity with hydrophilicity, as well as fast ionic transport [4].  This, among many other advantageous properties, makes the material family promising candidates for energy storage and related electrochemical applications [5], but applications in plasmonics, electrocatalysis, biosensors, water purification/ desalination and other fields are equally exciting. In particular, capacitive deionization and membrane desalination and purification will be addressed.

Dmitri V. Talapin
Department of Chemistry and James Franck Institute
University of Chicago, Chicago IL 60637, USA

Inorganic nanomaterials enabled impressive developments, both in the fundamental understanding of nucleation, growth and surface chemistry of inorganic solids, and in our ability to make functional materials for real-world applications. Nanocrystals and nanocrystal assemblies offer a versatile platform for designing two- and three-dimensional solids with tailored electronic, optical, magnetic, and catalytic properties. Unlike atomic and molecular crystals where atoms, lattice geometry, and interatomic distances are fixed entities, the arrays of nanocrystals represent solids made of “designer atoms” with continuously tunable properties.

I will discuss our recent developments in synthesis of inorganic nanostructures, from new semiconductor quantum dots to two-dimensional transition metal carbides, also known as MXenes. We are developing chemical approaches to electronically couple individual nanostructures into extended materials. These “modular” materials are explored as active components for electronic, light-emitting, thermoelectric and photovoltaic devices.

Abstract

Calcium is critical to a wide range of physiological processes, including neurological function, immune responses, and muscle contraction in the heart. Calcium-dependent signaling pathways driving these functions enlist a variety of proteins and channels that must rapidly and selectively bind calcium against thousand-fold higher cation concentrations. Frequently these pathways further rely on co-localization of these proteins within specialized subcellular structures to function properly. Our lab has developed multi-scale simulation tools to understand calcium homeostasis and its dysregulation at the molecular through systems levels. Applications include molecular simulations to predict protein-protein interactions, reaction-diffusion simulations that leverage high-resolution microscopy data and computer vision techniques to characterize morphological differences in cells important to their function. In this seminar, I will describe these tools and their applications to a calcium-dependent signaling pathway driven by calmodulin and calcineurin activation, which is important in cardiac development and hypertrophy.

The incorporation of main group elements into conjugated materials is known to result in unusual properties and to enable new functions.[1] In particular, the ability of tricoordinate boron to participate in p-delocalization can have a dramatic effect on the optoelectronic properties of conjugated materials by selectively lowering the LUMO orbital levels. The electron-deficient character of boron also enables the reversible formation of Lewis pairs (LPs) by interaction of Lewis acids with Lewis bases.

In our recent work, we have explored the incorporation of boron into conjugated oligomers, macrocycles, and polymers for optoelectronic applications.[2] We have also demonstrated that base-directed electrophilic aromatic C-H borylation provides an effective means to generate luminescent B-N containing conjugated materials with unusual properties such as self-sensitized singlet oxygen generation.[3]

On the other hand, the judicious decoration of polymers with organoborane Lewis acid sites can be exploited in sensory and stimuli-responsive materials, as well as the development of supported catalysts that rely on the ability of Lewis acids to activate small molecules.[4] In addition, we have discovered that “smart” dynamic materials can be generated by embedding both Lewis acid and base sites into polymer networks.[5]

In this talk I will discuss some of these discoveries and highlight their impact in diverse application fields ranging from organic electronic materials and chemosensors to reprocessible elastomers and supported catalysts.

References:

1. (a) Main Group Strategies towards Functional Hybrid Materials, T. Baumgartner, F. Jäkle, Eds. John Wiley & Sons Ltd, Chichester, 2018; (b) F. Vidal, F. Jäkle, Angew. Chem. Int. Ed. 2019, 58, 5846.
2. (a) B. Meng, Y. Ren, J. Liu, F. Jäkle, L. Wan, Angew. Chem. Int. Ed. 2018, 57, 2183; (b) N. Baser-Kirazli, R. A. Lalancette, F. Jäkle, Angew. Chem. Int. Ed. 2020, 59, 8689.
3. (a) K. Liu, R. A. Lalancette, F. Jäkle J. Am. Chem. Soc. 2019, 141, 7453; (b) M. Vanga, R. A. Lalancette, F. Jäkle Chem. Eur. J. 2019, 25, 10133.
4. (a) F. Cheng, E. M. Bonder, F. Jäkle, J. Am. Chem. Soc. 2013, 135, 17286; (b) F. Vidal, J. McQuade, R. A. Lalancette, F. Jäkle, J. Am. Chem. Soc. 2020, 142, DOI: 10.1021/jacs.0c05454; (c) H. Lin, S. Patel, F. Jäkle, Chem. Eur. J. 2020, submitted.
5. F. Vidal, J. Gomezcoello, R. A. Lalancette, F. Jäkle, J. Am. Chem. Soc. 2019, 141, 15963.

Biography

Frieder Jäkle is a Distinguished Professor in the Department of Chemistry at the Newark Campus of Rutgers University. He received his Diploma in 1994 and Ph.D. in 1997 from TU München, Germany, under the direction of Prof. Wagner. After a postdoctoral stint with Prof. Manners at the University of Toronto he joined Rutgers University in 2000. His research interests revolve around main group chemistry as applied to materials and catalysis, encompassing projects on organoborane Lewis acids, conjugated hybrid materials, luminescent materials for optoelectronic and sensory applications, stimuli-responsive and supramolecular polymers. He is the recipient of an NSF CAREER award (2004), an Alfred P. Sloan fellowship (2006), a Friedrich Wilhelm Bessel Award of the Alexander von Humboldt Foundation (2009), the ACS Akron Section Award (2012), the Boron Americas Award (2012) and the Board of Trustees Research Award at Rutgers University (2017). In 2019 he was named a Fellow of the American Chemical Society. He has served on the editorial advisory boards of several journals, including Macromolecules, ACS Macro Letters, and Organometallics.

ABSTRACT

A summary of studies on the total synthesis and evaluation of the vancomycin family of glycopeptide antibiotics, their ligand binding pocket redesign to address the underlying molecular basis of resistance, and their subsequent peripheral tailoring to address the emerging public health problem of vancomycin resistance will be presented.

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The worldwide opioid crisis has occasioned efforts to develop new opioids for both existing uses (pain control) as well as new indications (itch, addiction). We have focused on the discovery of compounds able to selectively activate one of the two main intracellular pathways associated with the kappa opioid receptor. This type of activity, called “functional selectivity” or “ligand bias”, has the potential to segregate many of the ultimate biological effects of therapeutic opioids.

This project is an effort of a multidisciplinary, multi-institutional team led by the speaker and Professor Laura Bohn of the Scripps Research Institute.[1,2] It began with the development of a speculative library for screening against a range of potential biological targets based on a known but underexplored isoquinolinone synthesis. Applying this chemistry to library synthesis led to a hit compound that stoked our interest in biased ligand discovery, ultimately leading to the discovery of Triazole 1.1, a strongly biased KOR agonist with a fascinating in vitro and in vivo profile. These efforts and recent results will be described.

[1] Bohn, L.M.; Aubé, J. ACS Med. Chem. Lett, 2017, 8, 694–700.

[2] Brust, T. F.; Morgenweck, J.; Kim, S. A.; Rose, J. H.; Locke, J. L.; Schmid, C. L.; Zhou, L.; Stahl, E. L.; Cameron, M. D.; Scarry, S. M.; Aubé, J.; Jones, S. R.; Martin, T. J.; Bohn, L. M. Biased Agonists of the Kappa Opioid Receptor Suppress Pain and Itch Without Causing Sedation or Dysphoria. Sci. Signal. 2016, 9, ra117.

Jeffrey Aubé attended the University of Miami, where he did undergraduate research with Professor Robert Gawley (with whom he later co-authored the graduate text “Principles of Asymmetric Synthesis”, currently in its second edition). He received his Ph.D. in chemistry in 1984 from Duke University, working with Professor Steven Baldwin, and was an NIH postdoctoral fellow at Yale University with Professor Samuel Danishefsky. From 1986 until 2015, he held a faculty position in the Department of Medicinal Chemistry at the University of Kansas. In 2015, he retired from KU and moved to the University of North Carolina, where he is an Eshelman Distinguished Professor in the Division of Chemical Biology and Medicinal Chemistry. In addition to holding a joint appointment in the Department of Chemistry, Aubé is a member of the Center for Integrative Chemical Biology and Drug Discovery and the Lineberger Cancer Center.

Aubé’s research interests lie in the chemistry of heterocyclic compounds and their applications to problems in medicinal organic chemistry. The lab’s interests in bioorganic chemistry include collaborations in the area of opioid pharmacology (with Laura Bohn), steroid biosynthesis inhibitors (with Emily Scott), and in the discovery of anti-Mtb agents (with Carl Nathan). Aubé served as the principal investigator of the Chemical Methodology and Library Development Center program at Kansas as well as a specialized chemistry lab in the NIH’s Molecular Libraries Initiative.

Aubé has been honored for his research and scholarship by his receipt of awards from the American Chemical Society (including the Arthur C. Cope Scholar Award and the Midwest Award, bestowed by the St. Louis Section of the ACS) and for teaching (including the university-wide HOPE Award and the Kemper Fellowship for Teaching Excellence at KU). He is a fellow of both the American Association for the Advancement of Science and the American Chemical Society.

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The complexity and specificity of many forms of signal transduction require spatial microcompartmentation and dynamic modulation of the activities of signaling molecules, such as protein kinases, phosphatases and second messengers. In this talk, I will focus on cAMP/PKA, PI3K/Akt/mTORC1 or Ras/ERK signaling pathways and present studies where we combined genetically encoded fluorescent biosensors, advanced imaging, targeted biochemical perturbations and mathematical modeling to probe the biochemical activity architecture of the cell.

Dr. Jin Zhang received her PhD in Chemistry from the U. Chicago.  After completing her postdoctoral work at University of California, San Diego (UCSD), she joined the faculty of Johns Hopkins University School of Medicine in 2003. She was promoted to Professor in 2013. In 2015 she moved back to UCSD and is currently a Professor of Pharmacology, Bioengineering and Chemistry & Biochemistry. Research in her lab focuses on developing enabling technologies to probe the active molecules in their native environment and characterizing how these active molecules change in diseases including cancer. Professor Zhang is a recipient of the NIH Director’s Pioneer Award (2009), the John J. Abel Award in Pharmacology from ASPET (2012), the Pfizer Award in Enzyme Chemistry from ACS (2012), and the Outstanding Investigator Award (2015) from NCI. She was elected as a Fellow of AAAS in 2014 and a Fellow of AIMBE in 2019.

Abstract

Research in the Wang group aims to answer fundamental questions that lie at the interface of chemistry and biology. This talk will present her group’s recent efforts in developing new amination chemistry and strategies toward design and discovery of novel nitrogen-containing molecules for molecular labeling, imaging tools, and new antipsychotics. 

Many disease states are characterized by molecular level changes that occur before detectable symptoms have begun to manifest. In order to maximize treatment outcomes it is essential to accurately detect such alterations at an early stage. Chemical probes designed to selectively image such molecular processes have the potential to not only aid in disease diagnosis but can also provide unique insights into disease progression. As an important step toward these goals we have developed a palette of activatable probes for photoacoustic imaging and apply these to visualize changes in the tumor microenvironment. Briefly, photoacoustic imaging is a state-of-the-art technique that generates ultrasound signals from light, which can be detected and converted into high-resolution 3D images. Since sound scattering is three orders of magnitude less than light in tissue, photoacoustic imaging can be employed to image up to 8 cm in depth while achieving micron resolution. To image deeper regions of the body in real-time, we have recently developed the first activatable ‘smart bubbles’ for ultrasound imaging. Like our photoacoustic probes, smart bubbles respond selectively to a disease property to provide signal enhancements via enhancement of their echogenic properties. In this seminar, we will discuss the strategies employed to construct both photoacoustic and ultrasound probes, as well as highlight notable examples from our laboratory.      

Brief Bio:

Professor Chan received his BSc degree in chemistry from the University of British Columbia in 2006 and his PhD from Simon Fraser University (Prof. Andrew Bennet) in 2011. For his graduate research, he received the Boehringer Ingelheim (Canada) Doctoral Research Award for the top Canadian thesis in the areas of organic and bioorganic chemistry. From 2011-2014 he was a Human Frontiers Science Program Postdoctoral Fellow at the University of California, Berkeley (Prof. Christopher Chang). In the fall of 2014 he joined the faculty at the University of Illinois, Urbana-Champaign.

Abstract

Oxygen is a master regulator of many cellular processes. In tissues, gradients of oxygen and nutrients extend radially from blood vessels. The gradients in these diffusion-dominated environments increase greatly when a blood vessel is occluded, or in the case of the tumors when the rate of proliferation outpaces the rate of vascularization. The extent of hypoxia in tumors has been correlated with cancer aggressiveness, drug resistance, and invasiveness. Gradients of oxygen are also believed to direct cellular invasion from the solid tumor mass to neighboring healthy tissue.

Despite the pivotal role that oxygen plays in tumor biology, there are a limited number of in vitro assays able to quantify cellular morphology, gene- and protein-expression, or drug sensitivities in well-defined oxygen gradients. Due to the lack of experimental tools, many studies compare cellular differences at a single normoxic (21% O2) and hypoxic (~0.2% O2) condition. Monolayer cultures are also commonly used in these normoxia-hypoxia comparisons. These experiments provide a simplified view of oxygen-mediated regulation, overlooking the importance of gradients by exposing cells to a single oxygen and nutrient concentration. Evaluating a limited number of oxygen tensions has led to the inadequate interpretation that cellular responses to oxygen are a binary phenomenon, eliciting a particular hypoxic phenotype or not.

We are developing a 3D culture platform utilizing paper-based scaffolds to prepare tissue- or organ-like structures. We are able to engineer extracellular environments with specific oxygen or nutrient gradients and to tease apart the nuanced responses of cells in gradients of different steepness and shape. In this talk, I will highlight the paper-based culture platform as well as other technologies we are developing to address three long-standing questions in tumor biology. First is the role that oxygen gradients play in directing cellular movement. We have recently shown that oxygen is a chemo-attractant in diffusion-dominated environments, and are exploring what additional extracellular conditions (e.g., gradient steepness, the presence of overlapping nutrient gradients) promote this directed invasion. Second is the oxygen-mediated mechanisms through which hypoxic cells become drug resistant. In particular, we use invasion assays and tumor-like structures to evaluate the relationship between oxygen tension, active resistance (upregulation of drug efflux pumps), and passive resistance (altered metabolism or halted proliferation). Third is the relationship between hypoxia and hormone responsiveness in estrogen receptor alpha-positive (ER+) breast cancers.

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Life is sustained through a delicate balancing act of the immune system, a complex network of molecular and cellular interactions from which health or disease can emerge.  Despite a long catalogue of the cells and signaling proteins in this system, traditional experimental approaches have struggled to explain how they are organized in organs such as the lymph node to dynamically protect against infection, cancer, and autoimmunity.  The overarching goal of my laboratory is to develop bioanalytical methods to visualize where, when, and how cells interact during immunity and inflammation, to inform the development of immunotherapies. In this talk, I will describe the development of (1) hybrids of microfluidics with live immune tissues, to study local dynamics in the lymph node and multi-organ immunity, and (2) novel, spatially resolved analyses of the activity of cells and proteins in living tissue.  I also will give a preview of the future, with our work towards better understanding the organization of the lymph node by building one from cells, matrix elements, and proteins.  

On the Nature of the Entropic Bond

Entropy is typically associated with disorder; yet, the counterintuitive notion that particles with no interactions other than excluded volume might self-assemble from a fluid phase into an ordered crystal has been known since the mid-20th century. First predicted for rods, and then spheres, the thermodynamic ordering of hard shapes by nothing more than crowding is now well established. In recent years, surprising discoveries of entropically ordered colloidal crystals of extraordinary structural complexity have been predicted by computer simulation and observed in the laboratory. Colloidal quasicrystals, clathrate structures, and structures with large and complex unit cells typically associated with metal alloys, or obtained in systems of interacting nanoparticles, can all self-assemble from disordered phases of identical particles due solely to entropy maximization. In this talk, we show how entropy alone can produce order and complexity beyond that previously imagined, both in colloidal crystal structure as well as in the kinetic pathways connecting fluid and crystal phases. We show how entropic forces can be directional and introduce the concept of the entropic bond. We introduce a new theory of entropic bonding and show how methods used by the quantum community to predict atomic crystal structures can be used to predict entropic colloidal crystals.

ABSTRACT

The rapid development of novel energy technologies has decreased renewable electricity prices significantly over the past decade. This foreseen cheap electricity has motivated significant research interest in the development of electrified pathways for chemical and fuel production. Compared to traditional chemical processes driven by fossil energy, electrochemical processes are often more environmentally friendly, can operate under relatively mild conditions, and can also be coupled with renewable electricity sources at remote locations. Recently, efforts have been devoted to the development of CO2 electrolysis devices that can be operated at industrially relevant rates; however, limited progress has been made, especially for valuable C2+ products. In this presentation, I will present our recent work on nanoporous copper as a CO2 reduction catalyst and its integration into a microfluidic CO2 flow cell electrolyzer. The CO2 electrolyzer exhibited a current density of 653 mA/cm2 with a C2+ product selectivity of ~62% at an applied potential of -0.67 V (vs. reversible hydrogen electrode). The highly porous electrode structure facilitated rapid gas transport across the electrode-electrolyte interface at high current densities. Further investigations on electrolyte effects revealed that the surface pH value was substantially different from the pH of bulk electrolyte, especially for non-buffering near-neutral electrolytes when operating at high currents.

In addition to CO2 electrolysis, CO electrolysis has also been reported to yield enhanced multi-carbon (C2+) Faradaic efficiencies up to ~55% but only at low reaction rates. This is due to the low solubility of CO in aqueous electrolytes and operation in batch-type reactors. In a recent study, we constructed a high-performance CO flow electrolyzer with a well-controlled electrode-electrolyte interface that can reach total current densities up to 1 A/cm2 together with improved C2+ selectivities. Computational transport modelling and isotopic C18O reduction experiments suggest that the enhanced activity is due to a higher surface pH under CO reduction conditions, which facilitated the production of acetate. At optimal operating conditions, we achieved a C2+ Faradaic efficiency of ~91% with a C2+ partial current density over 630 mA/cm2. Further investigations show that maintaining an efficient triple-phase boundary at the electrode-electrolyte interface is the most critical challenge to achieving a stable CO/CO2 electrolysis process at high rates.

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We are excited to announce that the 2024 American Chemical Society - Division of Organic Chemistry Graduate Research Symposium (GRS) will take place at the University of Virginia on July 25-28, 2024. Please mark your calendars. The application/nomination process deadline is on March 11, 2024. See you in Charlottesville, Virginia!

#2024ACSGRS P. Andrew Evans Brett Fors Jason Chruma

https://lnkd.in/g7yQWgQb

Abstract

The increased emergence of bacterial resistance over the past two decades has greatly reduced the effectiveness of nearly all clinical antibiotics, bringing infectious disease to the forefront as a dire threat to global health. To combat these infections, new antibiotics need to be rapidly discovered, and bacterial natural products have reemerged as an abundant source of novel bioactive molecules. Herein, the isolation and evaluation of over 400 bacteria from bulk and rhizosphere soil native to western North Carolina and the southwestern U.S. in a novel and robust liquid-based high-throughput antagonism assay against Staphylococcus aureus and Escherichia coli is presented. Over 300 bacterial species were screened in monoculture, and 12% and 15% were found to produce antibiotics capable of ≥30% growth inhibition of Staphylococcus aureus or Escherichia coli respectively. 69 of those bacteria were subjected to 16s rRNA sequencing and found to be majority Pseudomonas (30%) and Serratia (17%) bacteria, and Aquitalea, Brevundimonas, Chryseobacterium, Herbaspirillum, and Microbacterium bacteria, which are currently not known to be antibiotic producers. More than 10 producing bacteria have been subjected to large scale culture and extraction techniques to isolate the produced antibiotic. One of those, a Pseudomonas sp., was found to produce the natural product pseudopyronine B, and we have further improved the antibiotic activity of this natural product through SAR evaluation of the alkyl side chains.

We will be meeting in Chem 204 from 2-3pm to discuss the following papers:

(1) “Color-blind or racially conscious? How college science faculty make sense of racial/ethnic underrepresentation in STEM” by Tatiane Russo-Tait

(2) “Evading Race: STEM Faculty Struggle to Acknowledge Racialized Classroom Events” by Gretchen P. King, Tatiane Russo-Tait, and Tessa C. Andrews

Please join us for an open and honest discussion about the findings and underlying themes of this research! Students, postdocs, faculty, and staff are all welcome. There are still open slots for volunteers to present in the following months as well! Check out the link below for more details.

Thanks,

Sophie Cook
Graduate Student
Pompano Lab
she/her/hers

More info on the journal club:  Following a successful first meeting in May, 2023, we have extended the DEI journal club to a monthly meeting held on the last Wednesday of each month from 2-3pm! This monthly journal club aims to discuss peer-reviewed papers about DEI in STEM across a wide range of topics (e.g. STEM disparities across race, gender, disability, faith, sexuality, etc.). All students, postdocs, staff, and faculty are invited and welcome. Please join us for any or all sessions to learn more about issues that are new to you, and to add your voice on issues you have experience with. We invite anyone to bring your own topic and perspective. This is a volunteer opportunity: You can sign up to lead the conversation in future meetings! Just like for any other paper presentation, no prior expertise is needed. You can learn as you go and help others do the same. To see the schedule, list of ideas for topics, and sign up sheet, click the link below -- just a few slots remain in 2023!  

https://docs.google.com/spreadsheets/d/12rRA15Bi1qihtcwICaJujZEqsqTKgRE-8BFTCyKvNMI/edit?usp=sharing

If you have any questions, please contact Jon Zatorski (jmz3gm) and Sophie Cook (src3qd), the current organizers of this series.

Abstract

Oxidation and reduction reactions are crucial to the synthesis of organic chemicals, and they also provide the basis for energy production. Electrochemistry is the archetypal method for the removal and delivery of electrons in oxidation and reduction reactions, but electrochemical processes face numerous challenges. Most of the important redox processes involving organic molecules and energy-related small molecules (e.g., H2, O2, CO2, N2) feature the addition or removal of an even number of electrons and protons: 2e–/2H+, 4e–/4H+, 6e–/6H+. Such reactions are not well suited for a direct electrochemical processes, and catalysts are required to enable these reactions proceed with high efficiency and controlled selectivity. This talk will present our recent efforts to develop electrochemical transformations and electrocatalytic methods inspired by biological energy transduction and enzymatic redox processes. Specifically, we take advantage of electron-proton transfer mediators (EPTMs) that couple the movement of both electrons and protons. These mediators avoid unfavorable charge separation associated with independent electron and proton transfer steps, and they introduce new mechanistic pathways to achieve electrode-driven redox reactions. Quinones and organic nitroxyls are especially promising EPTMs, as they mediate hydrogen-atom or other proton-coupled electron transfer reactions with molecules or catalysts in solution, and then are capable of efficient regeneration via proton-coupled electron-transfer at an electrode. These mediator concepts and their use in electrocatalytic reactions will be illustrated through a series of case studies related to chemical synthesis (alcohol oxidation, C–H functionalization) and energy conversion (the oxygen reduction reaction).

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Cells are poised to respond to their physical environment and to chemical stimuli in terms of collective molecular interactions that are regulated in time and space by the plasma membrane and its connections with the cytoskeleton and intracellular structures. Small molecules may engage specific receptors to initiate a transmembrane signal, and the surrounding system efficiently rearranges to amplify this nanoscale interaction to microscale assemblies, yielding a cellular response that often reaches to longer length scales within the organism. A striking example of signal integration over multiple length scales is the allergic immune response. IgE receptors (FceRI) on mast cells are the gatekeepers of this response, and this system has proven to be a valuable model for investigating receptor-mediated cellular activation. My talk will describe our efforts with quantitative fluorescence microscopy and modeling to investigate the poised, “resting state” of the plasma membrane and how signaling, initiated by an external stimulus and mediated by specific receptors, is regulated and targeted within this milieu.