Chemical and Biochemical Engineering
Co-authors: Dr. Mikael Nilsson (PI, Department of Chemical and Biochemical Engineering), Dr. George Miller (Department of Chemistry)
Radioactive lanthanides have become an important imaging, diagnostic and therapeutic tool in the medical field. For example, the neutron rich samarium isotope of Sm-153 has been proven to have desirable characteristics for treatment of bone cancer. However, for medical purposes, the radioactive lanthanide isotope must be produced at high specific activity, i.e. low concentration of inactive carrier, so they are both beneficial for therapy and the concentration of the metal ions does not exceed the maximum sustainable by the human body. The objective of our research is to produce radioactive lanthanides with high specific activity in a small-scale research reactor using the Szilard-Chalmers method. The Szilard-Chalmers process is a method to separate radioactive ions away from a bulk of non-radioactive ions by neutron capture. Our preliminary experimental results show a decrease of 34% in the amount of lanthanide needed for a typical medical procedure. We propose an innovative experiment setup to instantaneously separate the radioactive recoil product formed during irradiation from the bulk of non-radioactive ions. The instant separation prevents the recoiled radioactive nucleus from reforming its original bonds with the target matrix and chemically separates it from the non-radioactive target matrix, resulting in a carrier free radiolanthanide with increased specific activity. We will present methods for preparation and synthesis of the material used for irradiations and the results of enrichment factors and extraction yields in radioactive lanthanide solutions.
This research project is important due to its potential contribution to both the diagnostic and therapeutic medical field. Developing and optimizing methods for producing high-specific activity radioisotopes has a number of valuable outcomes and applications such as (but not limited to): 1. Local production of small amounts of radioisotope for the local medical school and research labs to incorporate in research areas such as labeling studies and synthesis of radiolabeled drugs. 2. Larger facilities to scale up our methods and supply these radioisotopes for medical application.
Alzheimer’s disease (AD) is a neurodegenerative disease that is currently affecting 5.2 million Americans. Almost all of the patients are elders age 65 and older. But about 5% of AD patients have early-onset AD, where they have a genetic predisposition toward developing AD at a much younger age, decades earlier than the common AD patient. Surprisingly, as AD is the 6th leading cause of death, there are no treatments, cures, or even preventive measures available. The severity of this lack of medical care is detailed in the latest 2012 World Health Organization’s report, in which AD is viewed as a priority for global public health.
The hallmark of AD is the accumulation of amyloid plaques in the brain, which consist of fibrillar aggregates of amyloid-β (Aβ). Instead of these insoluble fibrils, the soluble aggregates of Aβ have been implicated as the toxic species of interest. The pathogenesis of these soluble Aβ higher-order assemblies (Aβ oligomers) is not well understood. Likewise, there is little structural information on these toxic Aβ oligomers. Understanding their structures is indispensable for elucidating Aβ’s pathogenesis. Unfortunately, their structural elucidation is complicated by Aβ’s innate propensity to self-associate and aggregate into multiple species. This property makes the isolation, purification, and subsequent characterization of these Aβ oligomers difficult. There is a pressing need to establish chemical models that can mimic the molecular interactions of Aβ oligomers, but are much easier to manipulate and study.
My Ph.D. thesis research in Dr. James Nowick’s laboratory in the Chemistry department utilizes a macrocyclic, peptide-based chemical model aiming to identify the atomistic structures of these elusive Aβ oligomers by using high-resolution structural elucidating techniques. I design these chemical models to contain the Aβ sequence, so they can imitate Aβ’s molecular interactions. Most importantly, they also contain a N-methylated amino acid derivative that suppresses the aggregation caused by Aβ’s ability to self-associate. Specifically, I utilize my Aβ-derived chemical models to study oligomers of Aβ familial mutants. I aim to elucidate and then compare their structures with the native Aβ peptide to identify any structural differences that may attribute to the different physical properties exhibited by the Aβ familial mutants. My research will ultimately contribute the much-needed structural information on Aβ oligomers. This information will generate a greater understanding of these oligomeric structures, and will enable scientists in academia and industry to better devise a strategy to develop therapies for Alzheimer’s disease.
Co-authors: Hanna Lignell (California Institute of Technology), Monica Brady (Georgetown University), Sergey Nizkorodov (UCI)
Air pollution is a major contributor to human driven climate change. Molecules that are introduced into the atmosphere from either man-made or natural sources may undergo changes as they are exposed to sunlight. Our research is focused on how atmospheric conditions such as temperature and relative humidity will affect these changes. We are specifically interested in how long these pollutants will remain in the environment as well as how the molecules will change as a result of interactions with sunlight. Pollutants that have longer lifetimes in the atmosphere may survive long enough to be transported away from their sources (e.g., factories) and into the “cleaner” areas where people may live. It is important to understand how environmental conditions affect pollutant lifetimes so that we can better predict where they may end up and how they may affect human health. One type of pollutant that we are particularly interested in is aerosol particles, which are made up of a composite of various molecules. Exposure of the aerosol to sunlight would cause any light-sensitive molecules to degrade. These light-driven reactions are further complicated by the fact that aerosol particles are comparable in consistency to caramel. As the temperature and/or relative humidity is changed, the consistency will be altered, similar to how caramel becomes softer and thinner as it is heated. We hypothesize that molecules in a thick caramel-like material, such as an aerosol, will move more slowly. This will result in slower reactions, because molecules need to be able to move to react, including those induced by sunlight. We have found that as temperature is decreased, molecules tend to have longer lifetimes. The implications of these results are that pollutant molecules associated with aerosol particles may remain in the atmosphere for longer periods of time on cold, dry days and thus travel further from their source.
Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, have emerged as an epidemic among aging populations of developed nations. There are no cures or treatments to prevent or halt the progression of these diseases, which ultimately lead to death. Understanding the fundamental cause of these diseases is imperative to their prevention and to development of treatments.
The neurodegeneration observed in Alzheimer’s disease and Parkinson’s disease is thought to occur as a result of the accumulation of amyloid peptides and proteins in the brain. In Alzheimer’s disease, the peptide beta-amyloid (Aβ) aggregates to form fibrils that contain hundreds of thousands of Aβ peptides. Aβ fibrils form insoluble plaques in the brains of patients with Alzheimer’s disease, and were originally targeted as the toxic aggregate that causes neurodegeneration. However, poor correlation between plaque deposition and neuronal loss has shifted researchers attention to alternate assemblies of Aβ that exist en route to fibril formation termed ‘Aβ oligomers’ as the toxic species that causes neurodegeneration in Alzheimer’s disease.
Aβ oligomers are small soluble assemblies of Aβ made up of only a few Aβ peptides. Despite mounting evidence that links Aβ oligomers to neurodegeneration, atomic resolution structures of Aβ oligomers remain elusive. This critical gap in knowledge is the result of isolations and preparations of Aβ oligomers containing a heterogeneous, meta-stable mixture of different oligomeric assemblies, making determination of their atomic resolution structure seemingly impossible.
Our lab, among others, has simplified these issues by studying fragments of the full length Aβ peptide that are important in its assembly into aggregates. This approach has facilitated atomic resolution structural characterization of numerous oligomers of Aβ fragments by X-ray crystallography. These studies have afforded tremendous insight into the structural diversity of Aβ oligomers, and have allowed us to generate hypotheses about how Aβ oligomers form in solution and elicit their neurodegenerative effect.
My talk will focus on the approach and methodology our lab has developed to gain atomic resolution structural insight into these novel assemblies of Aβ. I will talk about the design of a chemical model system that enables these studies; and how our lab has used this system to see these otherwise unseeable Aβ aggregates. In addition, I will focus on how this research has challenged our understanding about amyloid peptide and protein assembly, and is pushing the field of neurodegenerative disease study in new directions.
Materials Science and Engineering
Co-authors: Craig L. Perkins (National Renewable Energy Laboratory), Matt Law (Department of Chemistry, UCI)
My research involves studying a material a bright yellow color compound called bismuth vanadium oxide(BiVO4). A while ago, the yellow color used to paint cars was lead-based(lead oxide to be specific). But due to toxicity of lead, it was replaced by BiVO4 due to its earth abundance and non-toxicity. My work involves using this material to split water molecules into hydrogen and oxygen by absorbing simply sunlight.
As part of my PhD, I have been involved in optimizing the electronic and catalytic properties of BiVO4. I can fabricate devices as large as 3 x 3″ by simply spin casting a viscous solution of bismuth and vanadium salts and heating the as-cast film to 475C for 15 minutes. The entire process from the making of the ink to the final device is completed in little more than an hour. These devices have demonstrated a record performance(over 5%) for solar-driven water splitting owing to their high catalytic and superior electronic properties when compared to those made by any other lab across the world. This is because I am able to control the way bismuth and vanadium atoms in these films are bonded to each other such that they mimic the catalyst in plants that are responsible for photosynthesis.
This work will pave the way ahead for a new method to rationally develop cheap and high efficiency systems to generate hydrogen directly from the sun.
Chemical and Materials Physics
Co-authors: Roxanna Ochoa, Krysten Jones, Naomi Morrissette, Jennifer Prescher
Intracellular pathogens present a serious threat to human health as they can be difficult to detect and can artfully evade many host defenses. Among the most prevalent of these intracellular pathogens is Toxoplasma gondii, a parasite that infects one-third of the world’s population. In recent years, T. gondii has been discovered to express and secrete unique glycoproteins within host cells. These biomolecules likely interact with host signaling proteins and other networks to ensure parasite survival, but the extent of these interactions and their downstream physiological consequences remain unknown. To begin to examine these features, we aimed to profile the repertoire of T. gondii’s glycoproteins using a chemical reporter strategy. This strategy involves the metabolic incorporation of unnatural glycan building blocks endowed with unique chemical handles (i.e., “chemical reporters”) into target glycoproteins. Following incorporation, T. gondii’s tagged glycoproteins can be specifically detected in a second step utilizing highly selective (i.e., bioorthogonal) probes. Using this strategy, we found that the metabolic labeling of T. gondii’s glycoproteins was both dose- and time-dependent, and did not compromise parasite viability. We further identified a large, diverse set of glycosylated proteins in the parasite, including some previously unannotated proteins likely involved in modulating host-parasite interactions. Further biochemical evaluation of these glycoproteins will provide a more detailed understanding of host-parasite communications and can help develop new diagnostics and therapeutics for parasitic infections.
Neurodegenerative diseases such as Parkinson’s disease are an epidemic among aging populations; nearly one in one hundred adults over the age of sixty will be afflicted with Parkinson’s disease. There are no known treatments to cure or halt the progression of the disease. Understanding the fundamental causes of Parkinson’s disease is imperative to prevent and treat this neurodegenerative disorder.
There is strong evidence that the molecular events leading to Parkinson’s disease involves the aggregation of the protein alpha-synuclein into plaques, termed Lewy bodies, in the brain. It has become strikingly apparent in recent years that the Lewy body aggregates of α-synuclein are not the toxic agent in Parkinson’s disease; rather a transient species that exists in route to the plaques appears to be the culprit. These species are now known as soluble oligomers of alpha-synuclein. There is a critical knowledge gap in our understanding of the biochemical and biophysical properties that enable these oligomers to cause the neurodegeneration associated with the disease. This lack of understanding is due to the transient and heterogeneous nature of the oligomers; regardless, a detail structure characterization of these species would be transformative to our understanding of Parkinson’s disease.
My lab has championed an approach that simplifies the issue of heterogeneity and instability of toxic oligomers that results form working with full-length proteins such as alpha-synuclein. Namely, we have found that using small fragments of these proteins has allowed us to study their assembly at atomic resolution. These structures provide snap shots of the invisible oligomers and allow us to generate hypotheses about their modes of action on neurons.
My research involves the study of a fragment of alpha-synuclein that has been demonstrated to be crucial to the oligomers’ assembly. Through the use of X-ray crystallography, I characterized an oligomer formed by this fragment of alpha-synuclein. I have been able to demonstrate that this fragment is capable of killing human neuronal cells; further, I have observed that this fragment’s toxicity is directly related to its ability to assemble into the oligomer, echoing the properties of full-length α-synuclein. The X-ray crystal structure I solved could serve as a model with which we can began to understand the detailed atomic mechanisms that result in the development of Parkinson’s disease. This structure is the first and only atomic resolution insight we have into the neurotoxic oligomers and could be transformative to our understanding of Parkinson’s disease.
Kimberly D. Edwards (Chemistry Lecturer, UCI)
A visual aid teaching tool, the DanceChemistry video series, has been developed to teach fundamental chemistry concepts through dance. These educational videos present chemical interactions at the molecular level using dancers to represent molecules. The DanceChemistry videos help students visualize chemistry ideas in a new and memorable way. This project involves students, staff, and instructors in both the chemistry and dance department and provides a platform for a diverse set of people to work together. Students that participate in these videos play an active role in their own education while providing a visual teaching aid for their peers to use. These videos also give graduate students who are interested in pursing a career in teaching an opportunity to create an educational tool for their own future use. I surveyed 1200 undergraduate chemistry students who watched my videos in class; the students who watched the videos scored 30% higher on a short quiz than their classmates who did not see the video. Greater than 75% of the students said they would like to learn the chemistry concept using these videos. The DanceChemistry videos are broadly disseminated for free on YouTube; this broad distribution enhances the infrastructure for education at secondary schools and provides underserved communities in science with free instructional videos that can be used to improve scientific understanding from a creative viewpoint.