For years, scientists have been baffled by the imbalance between matter and antimatter in the universe. The properties of the neutrino, a subatomic chargeless particle, may ultimately help us explain this anomaly. Double beta decay takes place in an atomic nucleus, and it occurs when two neutrons spontaneously transform into two protons, emitting two electrons and two antineutrinos in the process. However, if the neutrino is its own antiparticle, the antineutrinos could annihilate each other, so that the two electrons are emitted with no balancing emission of antimatter. This is a postulated process known as “neutrinoless double beta decay.” The MAJORANA Demonstrator, a collection of germanium detectors, allows us to search for this creation of matter in a laboratory setting. However, there are naturally occurring background processes, such as gamma rays, which closely resemble that of the creation of matter. In order to accurately distinguish one process from the other, we must understand them extremely well. The Demonstrator relies heavily on the use of simulation software, called Geant4, in order to predict the occurrence of gamma ray backgrounds. Geant4 previously generated the gamma rays’ directions isotropically, but many sequences of gamma emission are emitted in correlated directions. We contributed new code that uses the computation of associated Legendre polynomials to correctly generate the gamma emission directions. This code used a recursive algorithm that was too slow for general use. A speedup was attempted using a cache, meaning it stored computations to avoid repetition. However, the cache was implemented inefficiently and incorrectly. Improved caching should speed up calculations. If it is insufficient, we will unwrap the recursive algorithm into a generative for-loop. For gamma emissions with extremely large angular momenta, the code may still be too slow. In that case, we will explore asymptotic formulae to speed up computations even further.

Memory formation, or plasticity, is the brain’s ability to change and adapt in response to new information through altering the strength and effectiveness of communication at the synapse. Synaptic plasticity plays a major role in the brain’s capacity to incorporate past experiences into stored memories and it has become one of the most intensively researched subjects in neuroscience. Neuroscientists typically evaluate synapse function using enriched, homogenized preparations of synapses, called synaptosomes. However, synaptosome preparations contain a mix of neuronal and non-neuronal contamination along with active and inactive synapses that are impossible to separate, making it difficult to draw specific conclusions about synapse activity. To address these challenges and understand the molecular mechanisms behind synaptic plasticity, my lab has developed a synaptic TAG- an engineered protein that localizes to recently active synapses. The TAG construct, containing an extracellular CD4 protein whose expression is driven by activity-dependent regulatory elements, will be electroporated into the developing motor cortex of mice in utero. The mice will later be trained to run on a rotarod, a test commonly used to assess motor learning. After the mice have learned this task, the differences in their synapses will be evaluated by sectioning and staining the motor cortex with fluorescent antibodies. The number of distinct fluorescent TAGs on the synapses on a given number of neurons will be counted through confocal imaging. My hypothesis is that I will see an increase in the number of TAGs on the synapses of a trained mice, which will demonstrate that the TAG is synaptic in vivo and activity dependent. The completion of this experiment will allow my lab to identify learning-associated proteins using magnetic cell sorting, mass spectrometry, and RNA sequencing. Understanding learning-associated protein interactions will shed light on how their malfunctions contribute to Autism Spectrum Disorders or neuropsychiatric disorders.

Is the neutrino its own anti-particle? This is a question physicists do not have the answer to, but if a process known as neutrinoless double-beta decay were observed then it could be said with certainty that the neutrino is indeed its own anti-particle. In an attempt to search for said process, researchers at UW have joined forces with researchers from a number of other institutions to form the group known as LEGEND (Large Enriched Germanium Experiment for Neutrinoless Double-Beta Decay). The source used for this experiment that undergoes double beta-decay is Germanium-76. This source is also used for the detector itself. When a beta decay happens in the detector a pulse proportional to the energy of the electrons emitted is produced. If these electrons have all the energy available from the decay, then it will be known that no neutrinos are present. What makes things tricky is that if this process occurs it does so with a half-life greater than 10²⁶ years. Thus, counting rates for this process will be very low, and very low backgrounds will be needed to effectively carry out the experiment. Currently at UW we are working on developing pulse rejection techniques that will allow us to get rid of unwanted background events that our detectors measure. The project I'm presenting on involves aiming a collimated alpha source at our detector, and the goal is to develop techniques that allow us to reject pulses resulting from alpha decays. A number of other collimated sources are also aimed at the detector in order to study rejecting the pulses that they give rise to. In order to help design this experiment I am running simulations in the Geant4 based application “g4simple” to determine collimator dimensions and materials that will work best for different radiation sources.

The nematode C. elegans is a common model organism for investigating cellular aging mechanisms and there is an extensive database of known genes which influence their lifespan. Protein kinases are regulatory enzymes which function in the cell as molecular switches. Here we use RNA interference to disrupt 11 classes of protein kinases to determine their role in 10 different C. elegans mutant backgrounds known to affect aging. With the included controls this involved over 120 individual lifespan experiments. In order to perform this many experiments we used a custom robotics platform called the Wormbot, a novel, high-throughput technique for measuring worm lifespans that our laboratory developed. We present here the results from 120 combinations of longevity mutants and inhibited protein kinases. The findings of this study may identify biochemical pathways or interactions which may play a role in the regulation of human aging or development of age related disease.

The endothelial to mesenchymal transition (EndMT) has been identified as a key part of organ development as well as many disease pathways. EndMT is characterized by endothelial cells, which make up the inner lining of blood and lymphatic vessels and are adhesive and non-migratory, gaining mesenchymal markers and invasive, migratory behaviors. This overall change in phenotype is normal in embryonic development where EndMT is linked to development of organs but has also been linked to numerous diseases in adults including cerebral malformations, Alport nephropathy, fibrosis, heart disease, and bronchopulmonary dysplasia. Whereas it appears that EndMT does not discriminate by organ, it does by sex. The diseases mentioned previously have a significantly higher incidence in males. To understand the role that sex plays on the EndMT pathway, human neonatal pulmonary cells with a gestational age of 18 to 19 weeks from three female and three male donors were routinely cultured and monitored for changes in phenotype. Using angiogenesis sprouting assays, western blot protein analysis and immunostaining, we collected quantifiable data on the reversibility of the EndMT process in each donor. We found that cells from male donors had lower plasticity, characterized as shifting between the two phenotypes, and generally existed in an endothelial state until pushed into a mesenchymal phenotype through a stressor. Female cells were more likely to shift between phenotypes regardless of conditions and exhibited more angiogenic potential, suggesting a heightened ability to transition between phenotypic states. Future experiments include placing cells in environments with differing stressors to mechanistically determine what drives EndMT processes and monitoring cells with time-lapse imaging to quantify the dynamics of the transition.

Fluctuating temperature patterns due to climate change could negatively impact the survival of species whose sex is determined by environmental cues rather than genetic factors. Species whose sex is determined by ecological cues or social interactions fall under the Environmental Sex Determination (ESD) category, while the Genetic Sex Determination (GSD) category includes species whose sex is determined by genotype at conception. There are numerous published examples of teleost fish species that rely on ecological factors for sex determination, but no studies have explored the extent to which the annual killifish Austrofundulus limnaeus, a species without sex chromosomes, relies on ESD. A. limnaeus inhabit ephemeral ponds in Venezuela, South America that experience extreme daily fluctuating temperatures. Climate change could affect this delicate lifecycle by disrupting seasonal temperature patterns that alter sex ratios or exposure to temperatures beyond their tolerance range. Therefore, it is essential to determine what impact temperature and social interaction may have on sex determination in developing A. limnaeus. To explore ESD, A. limnaeus larvae were exposed to constant temperatures of 20 and 30°C, and a daily fluctuating temperature regime from 20-30°C from hatching until the display of secondary sexual characteristics. Some fish were grown in isolation while others were grown in small groups. Fish grown in isolation at 30°C exhibited female-biased sex ratios with 64% developing as females whereas 69% in 20°C and 61% in fluctuating temperatures exhibited male-biased sex ratios. Ongoing experiments are being conducted to explore the possible interaction between temperature and social cues for determining the sex in this species. A. limnaeus has a relatively higher tolerance to fluctuating temperatures due to their ephemeral pond environment, and thus represents an opportunity to explore how even the most tolerant of species may respond to global climate change, especially in the context of ESD.

Bloodborne pathogens are wide spread and can pose risks to health care workers and vulnerable patient populations alike. Conventional diagnostic tests for bloodborne pathogens are costly and time intensive, so fast, affordable, and sensitive diagnostic methods are needed that can be performed under low-resource conditions by untrained personnel. Microfluidic self-digitization technology, developed in the Chiu Laboratory, provides the foundation for such low-cost diagnostics. As undergraduates, we work on the fabrication and optimization of cheap, robust devices used to load samples, as well as dPCR of samples required to detect diseases. As part of a larger research endeavor, we are developing a portable instrument that, in combination with our proprietary microfluidic chip technology, will expand rapid diagnostics to low-resource settings around the world. Expanding diagnostics for bloodborne pathogens will both help prevention as well as monitoring treatment of patients already infected.

Autism spectrum disorder (ASD) are a group of neurodevelopmental disorders characterized by impairments in social interaction and repetitive behaviors. One of the most common mutations leading to ASD is 15q11-q13 duplication, a CNV mutation where extra copies of a chromosomal region are expressed. The major gene within this region is ube3a. My lab has generated a mice model with increased copies of this gene and demonstrated a novel deficit in the mTOR/AKT signaling pathway. Other mice models of autism have exhibited deficits in this pathway and have rescued behavioral deficits with a drug, rapamycin. Rapamycin is an inhibitor of a key protein of the mTOR/AKT pathway suggesting a similar behavioral rescue could be observed with ube3a transgenic autism model mice. Rapamycin is administered to ube3a transgenic mice to normalize deficits in social interaction and repetitive behavior, two main behavioral hallmarks of autism. Mice are assessed using a three-chamber social interaction and repetitive self-grooming test. Successful behavioral rescue by rapamycin would be seen as increased social interaction and decreased repetitive grooming, similar to behaviors seen in wild type control mice. This would suggest that therapeutic treatment of the mTOR/AKT signaling pathway could be a viable target for patients with 15q11-q13 duplication.

New Caledonia is a French collectivity in the South Pacific that transitioned from colony to territory in the 1940’s, like many other former French colonial holdings. However, unlike other overseas territories of France, New Caledonia has been on an unofficial transition towards decolonization that began in 1998 with the Nouméa accords, stipulating a vote to take place in twenty years that would decide whether or not the islands would remain French. Despite a slim loss for independence when this long-awaited vote took place last year in November 2018, future referendums to challenge this decision are on the horizon. The objective of this research is thus to understand why the situation in New Caledonia is so different from that of other French territories. In particular, how do contemporary issues in the archipelago and the question of race complicate the decolonization process? To effectively answer this question, this study will analyze academic literature comprising subjects on foundational postcolonial theory, New Caledonian history, and race in the French–controlled South Pacific. Peculiarities of New Caledonia include its relatively late colonization compared to other French territories and the fact that the native society residing on the island continues to hold a strong presence. These factors along with a turbulent past may explain in part why New Caledonia finds itself in a slow process of decolonization. However, rich mineral reserves and the rise of neocolonialism may also complicate this event. Ultimately, this research hopes to bring a better understanding of New Caledonia to a wider public while serving as a foundation for continuing conversations around neocolonialism and efforts to combat it in the French territories and elsewhere.

High purity germanium (HPGe) detectors are an important technology in several leading experimental searches for dark matter and neutrinoless double beta decay. Understanding the interaction of various types of radiation on the different surfaces of HPGe detectors is essential to developing methods to reject unwanted signals from radioactive background sources. I have taken a leading role in the construction and use of the Collimated Alphas, Gammas, and Electrons (CAGE) test stand at the University of Washington, whose goal is to evaluate the response of an HPGe detector to different types of radiation on its various surfaces. CAGE is a vacuum cryostat with an internal system of motors that move a radiation source while keeping the detector active. It requires the operation of a liquid nitrogen cryostat, vacuum pump, temperature sensors, and various radioactive sources, all of which must be integrated into a single data acquisition (DAQ) system. We are currently constructing this system, fabricating and installing parts, and are planning to take initial data with the HPGe detector in the summer. In this talk I will present the current status of the CAGE detector, as well as preliminary data from radiation signals in the detector.

Here at the University of Washington we are characterizing one ton of NaI[Tl] crystal scintillator detectors for use in the COHERENT project. NaI[Tl] scintillating crystals detectors work by producing photons from the kinetic energy of charged particles passing through the scintillating material. COHERENT aims to detect coherent elastic neutrino-nucleus scattering, a novel interaction between neutrinos and matter that was first observed less than two years ago. It employs a large scale of scintillator detectors in order to record these events at an appreciable scale. Our characterization campaign allows us to group crystals with similar outputs by voltage which will determine the setup of our detectors once at ORNL. During this characterization, the crystals exhibited behaviors that correlated with the ambient temperature of the lab. The temperature dependence was first noticed during voltage gain characterization tests taken at different times of the day in the uncontrolled temperature environment of our lab. We expect the gain of our crystals to fit to a curve function, which breaks down if data is taken at different times of the day. The goal of this study is to understand the impact of temperature dependencies on our characterization campaign, and in particular to derive a relationship between voltage gain and temperature. I will present the data gathered toward this goal, and also our larger body of data on the relationship between light yield, voltage gain, peak resolution, and waveform rise time, as well as the techniques used to re-characterize previous crystals gain curve based on the derived relationship from this study.

Wireless power transfer has many applications, from powering biomedical implants to wireless sensors. For more practical use, however, several challenges must be overcome, such as a lack of efficiency and power leakage to other nearby electronics. These issues become especially difficult to tackle with a moving receiver. To combat these problems, an array of magnetically coupled coils was designed. Previous work has shown the capabilities of this system when one coil of the array is supplied with power. In this work, I explore the possible benefits of having two coils in the array driven with power instead, studying the interaction between the different coils. By adjusting parameters such as the phase relationship between the two transmitters’ signals, we aim to optimize power delivery to specific targets and simultaneously minimize leakage to other areas. I tested different configurations of the system in a series of experiments and analyzed measured data to determine which setup is most favorable. Afterwards, I evaluated the efficiency of the configuration compared to the previous single-transmitter case. This provides better insight into how the coils in the array magnetically interact with one another, which will inform future design decisions. It can also eventually lead to better solutions for delivering high power to selected targets within a given space. This can create flexible, efficient, and safe wirelessly charged electronic implants for a variety of biomedical applications, enabling further research in the field and the development of novel solutions.

Twenty-seven years ago, the movie Indochina debuted and brought up interesting questions about the direction and future of France's colonies. Almost three decades later, the continuing presence of France's colonies and influx of immigrants to France from countries known formerly as Indochina also raise questions about the effects of colonialism, especially pertaining to immigrant identities both past and present. This essay examines the lasting legacy of French colonization on the Vietnamese diaspora through both a literary analysis of Linda Lê's novel Les Trois Parques, which offers an observed history of Vietnamese restaurant workers and scholars and their agency regarding the fight against colonization, as well as a sociological exploration of a study conducted on the success of international students' integration into French universities. Additionally, the paper seeks to illustrate the significance of cultural amnesia —the assimilation into a new culture by rejecting one's former identity — as well as the benefits and motivations that may have guided first-generation immigrants to do so instead of rebelling and continuing their cultural traditions. 

Human alpha defensins, a component of the innate immune system, are small cationic peptides that possess antiviral activity against non-enveloped viruses. The effect of defensins on human adenoviruses (HAdV) is serotype-dependent, infection by some serotypes is enhanced while for others it is neutralized. Enhanced infection correlates with increased cell binding; however, the mechanism of increased binding is unclear. One hypothesis is that defensins mediate receptor-independent binding. Inhibitor studies support this hypothesis, although formal proof is still needed. To test this hypothesis, we used CRISPR/Cas9 lentivirus to knockout the primary receptor, coxsackie adenovirus receptor(CAR), in A549 lung cells. In order to vet these cell lines, they were infected with different HAdV serotypes that use either CAR or an unrelated molecule, sialic acid, as their primary receptors. As expected, the sialic acid-utilizing but not the CAR-utilizing serotype was able to infect the CAR KO A549 cells. We have used these cell lines in combination with integrin co-receptor inhibitors to measure binding and infection of wildtype and mutant adenoviruses in the presence and absence of defensins. These experiments allowed us to determine the extent to which defensin-mediated attachment and entry is receptor-independent.
 

Mouse adenoviruses (MAdVs) are non-enveloped double stranded DNA viruses. There are two different types of MAdVs with different tropisms or ability to infect particular cells or tissues. MAdV-1 infects macrophages and endothelial cells and causes encephalitis. MAdV-2 infects intestinal cells but causes no disease. Although, the MAdV fiber capsid proteins are important for attachment of the virus to host cells, it is not known if they are the major determinant of tissue tropism in the mouse. To address this question, I use recombination-mediated genetic engineering to make chimeric MAdVs, wherein I keep most of the genome of one strain but replace the fiber protein with that of the other strain. I then use transfection to introduce the DNA of the chimeric virus into a mouse cell line to allow the virus to replicate. I am currently designing and testing the proper chimeric fiber construct that will result in a replication-competent virus. Ultimately, I compare infection of the chimeric virus to that of the parent viruses in intestinal organoids, a tissue culture model that allows us to faithfully test tropism without the need for mouse studies. These experiments may reveal general principles of AdV tropism that will allow us to understand why different human AdVs cause disease in specific organs.

Mouse adenoviruses (MAdV), like human adenoviruses (HAdVs), have specific tissue tropisms. MAdV-1 infects macrophages and vascular endothelial cells, which can result in encephalitis, while MAdV-2 infects epithelial cells of the intestine but does not cause overt disease. The viral protein that determines MAdV tropism is unknown; however, for many viral families it is the viral attachment protein that is critical. For MAdVs, fiber is the viral attachment protein, and the receptors used by MAdV-1 and MAdV-2, although unknown, are distinct. To test whether MAdV receptor usage dictates tissue tropism, I constructed a MAdV-2 chimeric virus, replacing its fiber protein with that of MAdV-1 using a gene-editing recombination system. The chimera was used to infect a 3D culture model of the intestinal epithelium called “enteroids.” As expected, MAdV-1 does not replicate in enteroids and MAdV-2 does, consistent with their in vivo tropisms. Remarkably, the chimera replicated efficiently, indicating that the fiber protein is not the sole determinant of MAdV-2 intestinal tropism. Although fiber is not the main contributor to tropism, its interactions with host factors are still likely important for productive infection. A recent study identified N-acetylglucosamine (GlcNAc) as a specific ligand for MAdV-2 fiber. We have shown that GlcNAc is not the primary receptor for MAdV-2; however, binding to GlcNAc may aid in adhesion of MAdV-2 and penetration through the mouse intestinal mucus layer. To test this hypothesis, I mutated the GlcNAc interacting residues in MAdV-2 fiber to prevent GlcNAc binding. I am currently comparing the infectivity of this mutant virus to wild type MAdV-2 in both epithelial tumor cells and enteroids. Unlike tumor cell cultures, enteroids contain mucus-secreting goblet cells which will recreate the in vivo context more accurately. Together, these studies of MAdV may help us to understand why different HAdVs infect specific tissues.

As the only bus that runs from the University District to Mount Baker across Seattle’s Eastside, the 48 provides a unique perspective on accessibility. Through a research paper, and map of the 48’s route I analysed the access to various forms of economic and social capital, such as grocery stores, schools, medical centers, and community centers. Access to forms of economic and social capital were analyzed through their relative proximity to the 48 bus route, or the walking distance from homes in the Central District. The purpose of my project was to start a conversation about the access provided by the 48 bus, and to create a map and record of what is in the quickly changing Central District, as well as Mount Baker and Capitol Hill neighborhoods relative to the 48. All to ask where can the 48 take you? With the Mount Baker Transit Center and University of Washington as end caps, all of the destinations in between mark different issues Seattle faces such as development of single family homes, food deserts, and access to community centers. Focused through the perspective provided by public transportation a new perspective is provided on these issues through the lens of public transportation.

Neurodegenerative diseases, such as Alzheimer’s (AD), Parkinson's, and Huntington’s, affect millions of people. In AD, prior studies indicate the formation and accumulation of amyloid-beta proteins may play a crucial role in the pathology of the disease. The Herpes Simplex Virus (HSV-1) encodes an alkaline nuclease (UL12.5) known to cause degradation of the mitochondrial genome. HSV-1 infection has been previously associated with AD brain pathology. We hypothesize that UL12.5 activity in the brain may predispose an individual to amyloid-beta aggregation and AD neuropathology. Here, we controlledl the amyloid-beta protein aggregation using a degron attached UL12.5, which is induced by the plant hormone auxin through a molecular signaling pathway known as auxin-inducible degron. We have engineered an auxin UL12.5-degron construct in order to precisely control the temporal and cell type expression of UL12.5 in Caenorhabditis elegans (C.elegans). This construct was microinjected into the worms and by using auxin, we controleld the expression of UL12.5 and tested its effects on amyloid-beta and Huntington protein aggregation. Here, we have elucidated the relationship between HSV-1 infection, UL12.5 expression, and neurodegenerative disease which may form the basis of novel treatments.

Studying zebrafish embryos allows us to understand features of vertebrate embryonic development. Neuro-mesodermal progenitor cells at the very posterior end, or tailbud, of an embryo are bipotential. This is because the presence or absence of Wnt signaling commits them to either neural or mesodermal fate. Directed by environmental cues, mesodermal cells exit the tailbud, migrate anteriorward, and become somites, structural segments from which muscles differentiate. The Kimelman lab has found that Tbx16/Spadetail, a major driver of mesodermal morphogenesis, downregulates Arhgap29 and Arhgap35, members of Rho family GTPase activating proteins. This suggests Arhgap29 and Arhgap35 may be involved in mesodermal cell movement. My work in the lab is focused on finding out what roles these two genes play. I used heat shock promoter hsp70 to overexpress Arhgap29 and Arhgap35 in transgenic fish lines. Previously, our lab showed that sustained Arhgap35 affected somite morphology, and that sustained Arhgap29 also decreased the number of somites. In my experiments, I carried out in-situ hybridization in wild-type, Arhgap29- and Arhgap35-expressing embryos to examine genes regulating specification/differentiation of muscle cells and genes involved in transmembrane cell adhesion. I will present data on cell tracking and cell protrusions collected from Arhgap29- and Arhgap35-expressing embryos. These results will help me compare cell migration between Arhgap-expressing and wild-type embryos. The purpose of these analyses is to understand how these two proteins control cell movement in the embryo. In the future, I will continue to investigate cellular mechanisms underlying vertebrate posterior elongation.

Contextual word representations derived from large-scale neural language models are successful across a diverse set of natural language processing (NLP) tasks, suggesting that they encode useful and transferable features of language. To shed light on the linguistic knowledge they capture, we study the representations produced by several recent pretrained contextualizers (variants of ELMo, the OpenAI transformer LM, and BERT) with a suite of sixteen diverse probing tasks. We find that linear models trained on top of frozen contextual representations are competitive with state-of-the-art task-specific models in many cases, but fail on tasks requiring fine-grained linguistic knowledge (e.g., conjunct identification). To investigate the transferability of contextual word representations, we quantify differences in the transferability of individual layers within contextualizers, especially between recurrent neural networks (RNNs) and transformers. For instance, higher layers of RNNs are more task-specific, while transformer layers do not exhibit the same monotonic trend. In addition, to better understand what makes contextual word representations transferable, we compare language model pretraining with eleven supervised pretraining tasks. For any given task, pretraining on a closely related task yields better performance than language model pretraining (which is better on average) when the pretraining dataset is fixed. However, language model pretraining on more data gives the best results.

2-deoxy-ATP (dATP) is a nucleotide used in DNA synthesis and its presence has been seen to improve the magnitude and rate of contractions in heart muscle cells. However, levels of dATP are naturally low in mature cells. As an attempt to develop a novel treatment for heart failure, methods to increase the expression of ribonucleotide reductase (RNR), a key enzyme in the production of dATP are being investigated. RNR is regulated by ubiquitin-proteasome degradation of the small subunit of RNR, the Rrm2 subunit. We constructed a variant version in which two regions were changed to prevent ubiquitination. This new variant should lead to higher levels of RNR in cardiomyocytes, which also indirectly increases levels of dATP. Our preliminary results show a successful increase in levels of both RNR protein and dATP in cultured neonatal rat cardiomyocytes. Although levels of RNR and dATP were increased, the level present in our cultured samples are much higher than expected for adult rat and mice cells. Therefore, we are currently testing this RNR variant in vitro in cultured adult rat cells, as well as in vivo in aged adult mice. These models are more representative of a therapeutic use. Preliminary results have been promising toward identifying a more effective method of increasing dATP levels for improving cardiac function.

Mycobacterium tuberculosis (Mtb) is a bacterium that can cause both latent Mtb infection (LTBI) and tuberculosis disease (TB). LTBI affects one quarter of the world’s population of those who are LTBI positive, 5-10% develop TB disease which left untreated can be fatal. Most individuals who are highly exposed to Mtb develop LTBI and show positive results for the tuberculin skin test (TST) or interferon-g release assay (IGRA). The Hawn lab has followed a cohort of Ugandans with heavy exposure to Mtb within the household but test negative by the TST and IGRA tests and define these individuals as Mtb 'resisters'. The presence of these Mtb ‘resister’ genes suggests a possible pathway for host directed therapies. Using transcriptomic profiling to compare the ex vivo Mtb response in LTBI and resister monocytes, several candidate resister genes were identified. We hypothesized that these candidate resister genes modulate antimicrobial functions through an effect on pro-inflammatory cytokine secretion which restricts Mtb growth. Individual ‘resister’ genes were inactivated by CRISPR/Cas9 gene editing in THP-1 cells and then differentiated into macrophage-like cells prior to various stimulations. Macrophage signaling pathways were stimulated with LPS (Toll-like Receptor 4 (TLR4)), PAM3 (TLR2/1) as well as with whole cell lysate from Mtb. I measured pro-inflammatory cytokine secretion in supernatants after 24h (IL-6, IL-1b, and TNF-a). We identified two genes, SETDB1 and NFIL3_03, that may differentially regulate pro-inflammatory cytokines compared to the control THP-1 cells. By uncovering the function of these genes, we hope to better understand how Mtb infections can result in variable immunopathogenesis.