The 2019 Graduate Research Symposium was held on Tuesday, March 19, 2019 and featured original research undertaken by graduate and professional students across Washington University in St. Louis. A full list of presenters is available below.

2019 Graduate Research Symposium Awards

Engineering Awards

  • 1st Prize: Rich Li – Biomedical Engineering
  • 2nd Prize: Eugene Kim – Energy, Environmental & Chemical Engineering
  • 3rd Prize: Ke Song – Mechanical Engineering and Materials Science

Professional Schools Awards

  • 1st Prize: Maya Williams – Social Work
  • 2nd Prize: Brinda Gupta – Olin Business School
  • 3rd Prize: Roger Wong – Social Work

Sciences Awards

  • 1st Prize: Madeline King – Data Analytics and Statistics
  • 2nd Prize: Jessica Nicosia – Psychological & Brain Sciences
  • 3rd Prize: Hyo-Jung Jeong – Movement Sciences

Arts and Humanities Awards

  • 1st Prize: Lacy Murphy – Art History and Archaeology

2019 Presenters

Punn Augsornworawat – Biomedical Engineering

Reversal of Diabetes with Engineered Islets Derived from Pluripotent Stem Cells

Type I Diabetes (T1D) is an autoimmune disorder associated with the destruction of pancreatic β-cells leading to loss of insulin production, causing patients to have dysregulated blood glucose levels that can result in ketoacidosis and death if left untreated. Insulin injections are the most well-known method for controlling diabetes, but these patients still suffer from long-term health complications. β-cell replacement therapy is a potential long term solution for curing T1D. While human islet transplantation from deceased donors has had some success in the clinic, these operations are extremely limited due to shortage in donor islets. Human pluripotent stem cells can be expanded virtually unlimitedly and have the potential to differentiate into any cell types, thus making them a promising source for β-cells.
To address the practical utilization of stem cell (SC) derived islets, we characterized and evaluated the functional features, specifically glucose stimulated insulin secretion (GSIS). These SC Islets secrete a substantial amount of insulin and exhibit both first phase and second phase GSIS. Restoration of normoglycemia has been achieved when these SC Islets were transplanted into diabetic mice.

Katlin Bentley – Psychological & Brain Sciences

Can you tell I’m hiding my feelings? Judging expressive suppression through nonverbal behavior

People can accurately judge expressive suppression use during interpersonal interactions, but it remains unclear what nonverbal behaviors are displayed when suppressing (beyond neutral facial expressions) and if judges tend to focus on valid cues when assessing suppression or a combination of valid and invalid ones. We examine suppression judgments following stranger interactions to determine which behaviors are associated with actual and perceived suppression use. Suppression is expected to be linked to behaviors signaling low engagement and avoidance of closeness, although regulators may periodically leak brief emotional cues. Participants (N=178) were filmed discussing a negative event with a stranger. One partner was randomly assigned to suppress, exaggerate, or naturally express emotion (control), while the other partner was always in the control condition. We coded face, body, and conversation cues to identify behaviors relevant to self, partner, and independent observer suppression judgments. By examining the behaviors exhibited during expressive suppression and whether these cues relate to self- and partner-rated suppression use, our findings advance our understanding of how people assess emotion regulation and where misperceptions may arise.

Tayte Campbell – Division of Biology & Biomedical Sciences

Captivity humanizes the chimpanzee and gorilla gut microbiome and resistome

Dysbiotic gut microbiota have been associated with various auto-immune disorders and increased susceptibility to bacterial infections. Animals in captivity are subjected to different diets, environments, levels of human contact, and medical treatments than their wild counterparts. These factors may lead to changes in the gut microbiome that are detrimental to host health. Understanding changes in the gut microbiome of endangered species is especially important as animals are bred and rehabilitated to increase wild populations. In this study, we aim to identify changes in the gut microbiome and resistome that occur in captivity for two endangered species, Chimpanzees and Western Lowland Gorillas. We predict that captivity will result in lower microbial diversity and lead to an increased load of antibiotic resistant genes in the gut microbiome of captive apes compared to wild apes. To contextualize microbiome changes in non-human primates (NHPs), we compared NHP gut microbiomes to humans living near the wild apes. We analyzed fecal samples from wild chimpanzees and gorillas in the Goualougo Triangle region of Nouabalé-Ndoki National Park and from humans living just outside the park in the Republic of the Congo. We also collected samples from captive apes in the St. Louis Zoo and the Lincoln Park Zoo in Chicago. 16S metagenomic sequencing results indicate that captivity increased the gut microbiome diversity, with captive apes having higher diversity than both wild apes and humans. Using shotgun metagenomics, we found that captivity and antibiotic treatment dramatically increased antibiotic resistance gene (ARG) diversity and abundance in chimpanzees with 3.6-fold more unique ARGs and 14.2-fold increased ARG abundance (RPKM). Gorillas showed milder increases with captivity resulting in 56% and 67% increases in ARG diversity and abundance, respectively. Through functional metagenomic selections we identified a novel antibiotic resistance gene conferring resistance to colistin, which is considered an antibiotic of last resort by the World Health Organization (WHO). We also found DNA contigs including ARGs and mobile elements with high similarity between wild, captive, and human libraries indicating shared resistance genotypes and possible ARG transfer between hosts. These findings highlight the impact of captivity and antibiotic treatment on non-human primates and implicate non-human primate microbiomes as a reservoir of antibiotic resistance genes.

Shin Ru Cheng – School of Law

A Legal and Economic Analysis on Mandatory Data Sharing

In the era of big data, consumers are at the risk of being overcharged because giant companies that monopolized data-driven markets can exclude competitors from entering markets and thus, charge a monopoly price. This risk is particularly acute in developing countries due to the lack of a powerful antitrust law system. Therefore, ways of maintaining healthy competition in the data-driven market is one of the hottest issues today. The main research question of this research is to figure out what regulatory framework is best suited to regulate the big data companies’ abuse of its dominant position.
This research argues that mandatory data sharing is the most economical way to promote competition between dominant firms that already have tons of raw data and smaller firms that have creative ideas, but lack a solid data base. By sharing data, smaller firms are able to compete with dominant firms and, in turn, innovate in ways that big firms refuse to but are beneficial to consumers. Besides, because of sharing data with other companies, the big data companies receive royalties from them which can cover part of costs of big data collection.
To support this argument, the research conducts an economic analysis of the law to evaluate three possible solutions: traditional antitrust regulation, mandatory data sharing, and data nationalized. In the first part, this research illustrates “competition law”, “nationalization” and mandatory data sharing’s” effects on competitive market and social welfare by building economic models. In the second part, the proposed research collects empirical evidence to examine whether the ability of collecting and analyzing big data provides companies with market power or causes entry barrier. The evidence includes but is not limited to Google’s business model in search engine market, video marker (YouTube), and advertising market. In the last part, I will examine whether the three models can recover the deadweight of current unregulated big data market.
The anti-competitive problems caused by Google and other big data companies have strongly attract attention from antitrust authorities of the US, the EU, Japan, South Korea and other countries. For example, the EU enacted the General Data Protection Regulation in 2018, in order to regulate the application of big data in business. Therefore, the result of this research can provide law makers in the US, Taiwan and other countries with an insight to enact a comprehensive framework.

Taylor Dailing – School of Medicine

Identification of Factors that Impact Response to an Interactive Obesity Treatment Approach (iOTA) Adapted for use in Individuals with Severe Mental Illness (SMI)

Background
Behavioral weight loss interventions have limited effectiveness in patients with chronic severe mental illness (SMI), attributable in part to low treatment engagement. In our previous work, patients with SMI have indicated a preference for mobile health interventions to increase participation. Therefore, we tested the feasibility of delivering an interactive obesity treatment approach (iOTA), incorporating short message service (SMS) text messaging to supplement in-person health coaching.
Methods
Individuals with SMI between the ages of 16 and 75 underwent 12 weeks of treatment consisting of monthly 1:1 in-person visits for participants seen in the CMHC setting and monthly group sessions for participants seen in the Clubhouse setting. All participants received SMS-based health tips 5 days per week that were directly related to their goals. Participants were prompted once a week to respond via text with their weight and progress towards goals. The primary outcome of interest in this feasibility study was change in weight. In addition, we aimed to evaluate factors associated with the magnitude of the primary outcome. Based on prior work suggesting that psychiatric symptom severity and poor treatment engagement may be predictors of response, we evaluated illness severity and treatment engagement (measured by weekly text messaging response rate) as potential exclusion criteria.
Results
A total of 26 participants were recruited for the study (24% schizophrenia, 68% mood disorder). One participant dropped out and became ineligible due to active substance use. The mean age of the population was 48.5 years (SD=15.67); 60% were white and 60% female. A total of 8 participants met the exclusion criteria under evaluation (CGI >5 and response rate <80%). Using repeated measures ANCOVA, a significant interaction was observed between included/excluded participant group and time (F[1,23]=17.98, p<0.0001), explained by participants with lower symptom severity and criterion level engagement exhibiting a significant decrease in weight (F[1,16]=22.54, p<0.0001).
Conclusions
These results demonstrate the feasibility of delivering an adapted iOTA intervention to SMI patients receiving care in CMHC and Clubhouse settings, and suggest testable criteria for defining sufficient treatment engagement and psychiatric symptom severity.

Haley Dolosic – Education

Self-Assessment with Reading and Writing in French: Evidence from a Domestic Immersion Program

Individuals are increasingly seeking short-term immersive experiences to develop linguistic skills both abroad and at home, yet little previous research has examined reading and writing within such contexts (Author, et al., 2016). As researchers and educators pursue greater opportunities to encourage accurate self-diagnosis of strengths and weaknesses, much remains to be understood about how these capacities develop, particularly within domestic immersion contexts (Benson, 2013; Cotterall & Murray, 2009). With 46 adolescent students enrolled in a unique four-week French immersion summer camp, the present study examines the development of self-assessment capacities and French linguistic skills in terms of vocabulary, grammar, reading, and writing. Participants were fully immersed in French inside and outside of the classroom for their four-week program. Each completed both a pre-program and post-program test of their French involving tasks measuring their knowledge of French vocabulary grammar, and French reading and writing skills. Self-assessment instruments were adapted from a DIALANG framework aligned criterion-referenced measure (Brantmeier, et al., 2012). Using four advanced-level passages equated on complexity and length, students’ reading comprehension was measured via free recall, sentence-completion, and multiple-choice (Wolf, 1993). Writing was examined through two tasks: one storytelling task where students created a story using provided images and another letter writing task. These samples were analyzed using measures of complexity and length. Findings indicated that all learners demonstrated practical and statistically significant growth in their linguistic capabilities following this four-week program (p < 0.05). Further, students were able to self-assess with accuracy both before and after the program, providing self-assessments that aligned with performance. However, when examining these data with nuanced statistical methods to capture individual differences, preliminary analysis indicated wide variation for capabilities in self-assessment accuracy and linguistic development among individuals. Results will be discussed in correspondence to current understandings of individual learner differences and self-assessment.

Bisaiyo Fashemi – Division of Biology & Biomedical Sciences

The Decision Maker: The role of IFRD1 in urothelial plasticity and regeneration

The bladder urothelium forms a highly specialized watertight barrier to urinary wastes. The adult bladder offers an unusual example of tissue regeneration: although epithelial cells do not rapidly turn over under physiological conditions, they have an impressive capacity to regenerate tissue after injury. When challenged, adult urothelial cells are capable of completing the cell cycle as fast as embryonic bladder cells. Even more remarkable, depending on the modality of injury (chemical, infection) there appear to be two distinctive modes of urothelial regeneration. However, the key driver(s) of mode of regeneration choice has yet to be discerned. We have previously shown that in response to a urinary tract infection (UTI), the urothelial stem cell niche becomes activated and induces rapid restoration of the urothelium via BMP4-driven terminal differentiation. Whereas, chemical injury triggers intermediate-cell activation and regeneration, independent of the BMP4-signaling pathway. However, what directs this decision-making matrix is not understood. To better understand the regulatory pathways important for tissue regenerative response, we performed a large unbiased RNA-Seq screen. We identified interferon-related developmental regulator 1 (IFRD1), a transcriptional co-repressor, as a gene that is rapidly activated upon the induction of a UTI. Interestingly, aged mouse bladders have reduced IFRD1 expression, before and upon a UTI, and delayed regeneration. IFRD1 represses the activity of NF-κB p65 by enhancing the HDAC-mediated deacetylation of the p65 subunit, by favoring the recruitment of HDAC3 to p65. In fact, IFRD1 forms trimolecular complexes with p65 and HDAC3. IFRD1 appears to promote tissue regeneration and this ability may be reduced with age. Furthermore, uninjured IFRD1 -/- mice exhibit gross urothelial defects; the large superficial cells are eviscerated with an excess of vesicular bodies. Thus, we suggest IFRD1 plays a role in the decision-making matrix of urothelial regeneration and that IFRD1 plays a role in age-related decrease in regenerative capacity.

Brinda Gupta – Olin Business School

Tax-Time Saving Among EITC Recipients: Results of a Large-Scale Experiment Informed By Behavioral Economics

Low- and moderate-income (LMI) households lack sufficient liquid assets to address unexpected emergencies and dips in income. Receiving tax refunds is an opportunity for recipients of the Earned Income Tax Credit (EITC) to build emergency savings to help cope with these financial shocks. However, prior research has shown that EITC recipients use their tax refunds for several purposes, such as reducing unsecured debt and making large purchases, and save only small portions of their refunds.

The purpose of this study was to assess the hypothetical probability that EITC recipients would defer a portion of their refund for six months if offered savings bonuses like those proposed in bills recently introduced in Congress (H.R. 4236, S.2797), and to examine whether these savings preferences varied by the size of expected refunds.

The study sample was comprised of tax filers who were eligible for the EITC, expected to receive a federal income tax refund, and completed an online survey (N = 3,941) as part of a larger tax-time savings initiative during the 2016 tax season. To assess deferral preferences, survey respondents were asked whether they would be willing to defer 20% of their expected refund for six months (i.e., to ensure they had money to use later in the year) and were randomly assigned to see one of three deferral conditions – no deferral bonus, a 5% bonus, or a 10% bonus. Linear probability modeling was used to examine preferences as binary outcomes across the three randomized conditions. Preferences were also analyzed across refund quantiles.

Only 21% of respondents in the no bonus condition said they would hypothetically defer a portion of their refund for six months, yet most respondents in the 5% (70%) and 10% (80%) bonus conditions said they would. Respondents had 49% and 59% increased probabilities of deferring 20% of their refunds for six months when hypothetically offered 5% and 10% bonuses (p < .001), respectively, compared to an offer of no bonus, all other things being equal. These probabilities rose steadily across refund quantiles.

Despite many intended uses of their tax refunds, EITC recipients are willing to save a portion of their refunds, which can help build emergency savings and help lower risk for material hardship. This willingness rises dramatically with the offer of modest savings bonuses, which supports key provisions of congressional bills and suggests that refund saving can be widely stimulated with modest incentives.

Suyash Harlalka – Biomedical Engineering

Enhanced Synchronous Neural Activity During Virtual Reality(VR) Learning

The hippocampus is required for many types of learning and memory but little is understood
about how the activity dynamics of individual neurons or circuits are transformed into memories. We are studying this question using in vivo recording and activity manipulation techniques that allow us to target cells with high specificity and resolution. We use in vivo two-photon recording to stably record the same neurons over weeks during virtual reality (VR) learning. As a complementary technique, we use in vivo electrophysiology to identify memory consolidation through replay events.

Hyo-Jung Jeong – School of Medicine

Effects of Diabetes, Age, and Load on Foot and Ankle Kinematics during Heel Rise Task

Background: Diabetes mellitus, peripheral neuropathy (DMPN) and aging contribute to foot and ankle movement dysfunction that leads to impaired walking and balance. Heel rise (HR) task is commonly used to assess foot and ankle dysfunction that can be performed in two different load conditions (50% and 100% body weight; BW). However, effect of DMPN, age, and load on foot and ankle kinematics during HR task is unknown.

Objective: To determine the effects of DMPN, age, and load on foot and ankle kinematics during HR task.

Methods: We studied 40 participants with DMPN [mean (SD), age: 66.0 (6.5) y/o, body mass index (BMI): 32.7 (5.9) kg/m2], 12 old controls participants age and BMI matched [age: 65.1 (5.5) y/o, BMI: 32.7 (5.7) kg/m2], and 12 young control participants BMI matched [age: 26.3 (2.7) y/o, BMI: 30.1 (6.3) kg/m2]. Forefoot and rearfoot plantarflexion (PF) excursion were collected by a 3-D motion analysis system. Each participant performed single-limb HR (SLHR; 100% BW) and double-limb HR (DLHR; 50% BW).

Results: (1) Forefoot PF excursion: People with DMPN showed 56% lower excursion than young controls [mean (standard error): 7° (1.0°) vs 16° (1.9°); p < 0.01] across tasks. Forefoot PF excursion in DMPN and old controls [7° (1.0) vs 11° (1.9°); p = 0.21] and old and young controls were not significantly different [11° (1.9°) vs 16° (1.9°); p = 0.20]. SLHR was 53% lower than DLHR [7° (1.0°) vs 15° (1.1°); p < 0.01] across all groups. There was no significant interaction effect (p = 0.08). (2) Rearfoot PF excursion: People with DMPN showed 26% lower excursion than old controls [17° (0.9°) vs 23° (1.6°); p < 0.01] and 35% lower excursion than young controls [17° (0.9°) vs 26° (1.6°); p < 0.01]. Old and young controls were not significantly different [23° (1.6°) vs 26° (1.6°); p = 0.56). SLHR was 20% lower than DLHR [20° (0.9°) vs 25° (0.9°); p < 0.01] across all groups. The difference of rearfoot PF excursion between SLHR and DLHR in DMPN group is 57% greater compared to the young controls [mean difference (standard error): -10° (1.8°); p = 0.01].

Conclusion: Foot and ankle PF excursions were affected by older age with DMPN and load, but neither age or DMPN alone. Similarly, the reduction in ankle PF excursion with increasing load was affected by older age with DMPN, not age or DMPN alone. Further study is recommended to determine the relationships of HR task performance to walking and balance in people with DMPN.

Eugene Kim – Energy, Environmental & Chemical Engineering

Recombinant and Synthetic Production of Repetitive Mussel Foot Proteins with Enhanced Underwater Adhesion

Mimicking the adhesive capabilities of nature’s marine organisms offers interesting possibilities. For example, mussels strongly adhere to a variety of surfaces by secreting byssal threads that contain mussel foot proteins (Mfps). Recombinant production of Mfps presents an attractive route for preparing advanced adhesive materials. Out of the seven known types of Mfps, Mfp5 is of particular interest because it is spatially localized on the distal end of the mussel’s byssal thread plaque, implying its crucial role in surface adhesion, and it has the highest density of 3,4-dihydroxyphenylalanine (DOPA) and lysine residues, which are essential for strong underwater adhesion. In this study, we used synthetic biology strategies to recombinantly synthesize Mfp5, along with Mfp5 oligomers that contain two or three consecutive, covalently-linked Mfp5 sequences named Mfp5(2) and Mfp5(3). We studied the effect of chain length on Mfp underwater adhesion using both colloidal probe atomic force microscopy and quartz crystal microbalance analysis. Our results demonstrated a clear positive correlation between Mfp5 molecular weight with underwater adhesive properties, including the force of adhesion, work of adhesion, protein layer thickness, and recovery distance. For cure times of 200 seconds, DOPA-containing Mfp5(3) displayed a force of adhesion (201 ± 36 nN/µm) and work of adhesion (68 ± 21 fJ/μm) higher than those of previously reported Mfp-mimetic adhesives. The synthesis approach utilized in this study highlights the power of synthetic biology in preparing protein-based materials that are difficult to synthesize by other approaches. The results can be used as generalizable design principles for future engineering of protein-based underwater adhesives.

Madeline King – Data Analytics and Statistics

Modelling the allocation of pediatric intensive care retrieval teams in England and Wales

Background Following centralisation of UK paediatric intensive care units in 1997, specialist paediatric intensive care retrieval teams (PICRTs) were established to transport critically ill children from district general hospitals (DGHs). The current location and catchment area of PICRTs covering England and Wales are based on historical referral patterns. National quality standards specify that PICRTs should reach the patient bedside within 3 hours of accepting a referral.
Objective To determine what proportion of demand for PICRT services in England and Wales can be reached within 3 hours and to explore the potential coverage impact of more stringent ‘time to bedside’ standards.
Methods We used mathematical location–allocation methods to: (1) determine the optimal allocation of DGHs to current PICRT locations to minimise road journey time and calculated the proportion of demand reachable within 3 hours, 2 hours, 90 min, 75 min and 1 hour and (2) explore the impact of changing the number and location of PICRTs on demand coverage for the different time thresholds.
Results For current (and optimal) location of 11 PICRTs, 98% (98%) of demand is reachable within 3 hours; 86% (91%) within 2 hours; 59% (69%) within 90 min; 33% (39%) within 75 min; and 20% (20%) within 1 hour. Five hospitals were not reachable within 3 hours. For the 3-hour standard, eight optimally located PICRT locations had similar coverage as the current 11 locations.
Conclusions If new evidence supports reduction in the time to bedside standard, many more hospitals will not be adequately covered. Location–allocation optimisation is a powerful technique for supporting evidence-based service configuration.

Abhilasha Kumar – Psychological & Brain Sciences

Mapping Direct and Conceptual Knowledge Using 5018-word Network and Spatial Word Representations

There is currently some controversy regarding whether humans use a localized, network-based word representation or represent word meaning in a high-dimensional space. We compared and contrasted 5 different models of representing semantic knowledge (5018-word directed and undirected step distance networks, an association-correlation network as well as LSA and word2vec spatial representations) to predict semantic priming performance in two behavioral tasks. In Experiment 1, response latencies for relatedness judgments for word-pairs followed a quadratic relationship with network path lengths and spatial cosines, replicating and extending a pattern recently reported by Kenett, Levi, Anaki, and Faust (2017) for an 800-word Hebrew network. In Experiment 2, response latencies to identify a target word through progressive demasking showed a linear trend for network path lengths and cosines, suggesting that simple association networks can capture distant semantic relationships. Model comparisons indicated that spatial models and correlation networks are less sensitive to direct associations between distant concepts and more likely driven by higher-level conceptual relationships. Current research is focused on establishing the predictive power of each semantic model in an ecologically valid word-association game.

Isidro Landa – Psychological & Brain Sciences

Subterranean homesick blues: Mood regulation and relationship quality as predictors during college

Recent theorizing has implicated affect regulation as central to the experience of homesickness. Conceptualized as grief due to losing social connections with close others when relocating, homesickness is associated with poor emotional and social adjustment. The present study examined how mood regulation and relationship quality—at home and in college—predict homesickness and negative affect among college students (N = 168). We assessed 16 mood regulation strategies as well as relationship quality each week over the first college term. As predicted, time-lagged multilevel analyses demonstrate that avoidance-oriented strategies were helpful in the short-term (the following week), but chronic avoidance (across the college term) predicted higher levels of homesickness. Approach-oriented regulatory strategies did not predict homesickness, however. Relationship quality demonstrated differential main effects at the between-person level but did not predict fluctuations in homesickness from week-to-week. Across the college term, closer ties at home predicted greater homesickness whereas closer ties in college predicted lower homesickness. Notably, there were distinct effects of mood regulation for homesickness compared to negative affect. The present study is among the first to examine effects of mood regulation on homesickness longitudinally, suggesting it is important to consider the type of regulation strategies being used as well as the time scale.

Rich Li – Biomedical Engineering

The role of canonical Wnt signaling in cardiac development, disease, and electrophysiology

Several inherited arrhythmias, including Brugada syndrome and arrhythmogenic cardiomyopathy, primarily affect the right ventricle and can lead to sudden cardiac death. Among many differences, right and left ventricular cardiomyocytes derive from distinct progenitors, prompting us to investigate how embryonic programming may contribute to chamber-specific conduction and arrhythmia susceptibility. We show that developmental perturbation of Wnt signaling leads to chamber-specific transcriptional regulation of genes important in cardiac conduction that persists into adulthood. Transcriptional profiling of right versus left ventricles in mice deficient in Wnt transcriptional activity reveals global chamber differences, including genes regulating cardiac electrophysiology such as Gja1 and Scn5a. In addition, the transcriptional repressor Hey2, a gene associated with Brugada syndrome, is a direct target of Wnt signaling in the right ventricle only. These transcriptional changes lead to perturbed right ventricular cardiac conduction and cellular excitability. Ex vivo and in vivo stimulation of the right ventricle is sufficient to induce ventricular tachycardia in Wnt transcriptionally inactive hearts, while left ventricular stimulation has no effect. These data show that embryonic perturbation of Wnt signaling in cardiomyocytes leads to right ventricular arrhythmia susceptibility in the adult heart through chamber-specific regulation of genes regulating cellular electrophysiology.

Kristina Maxwell – Biomedical Engineering

Rapid Reversal Of Diabetes After Transplantation Of Human Beta Cells From Patient IPS Cells With CRISPR Correction

Stem cell-derived β (SC-β) cells are a powerful tool for disease modeling, drug screening, and cell therapy. Specifically, induced pluripotent stem (iPS) cells allow us to study many patient-specific forms of diabetes without ethical concern, providing an unlimited cell source with great potential as an autologous cell therapy, removing the need for heavy immunosuppression. Monogenetic forms of diabetes, including Wolfram Syndrome (WS), are a clear application of SC-β cell technology; as primary human β cells are rare and mouse models do not recapitulate the disease accurately therefore little is known about disease progression. WS patients suffer from diabetes mellitus and neurodegeneration as children caused by an autosomal recessive pathogenic variance in WFS1 causing endoplasmic reticulum (ER) stress, which is implicated in many forms of diabetes. Therefore, we reprogrammed WS patient fibroblasts into iPS cells and corrected the disease-causing sequence with CRISPR/Cas9 for disease modeling in vitro and to determine cell therapy potential in vivo. After differentiation with our 6-stage protocol, we performed single cell RNA sequencing of over 10,000 cells. Enrichment analysis and PCA alongside human pancreatic and diabetic islet datasets revealed unedited WS cells generated 10 clusters with multiple non-pancreatic cell types, including neural, epithelial, and muscle tissues, whereas the corrected WS cells produced 7 clusters of nearly purely endocrine cells, including β-like, α-like, and δ-like cells. Unedited WS SC-β cells had reduced total insulin content and glucose stimulated insulin secretion (GSIS) compared to corrected WS SC-β cells. Corrected WS SC-β cells achieve dynamic function in response to glucose stimulation similar to primary human islets in vitro, demonstrating their maturity and projected cell therapy success in vivo. β cell genes (NKX6-1, MAFA, INS) had lower expression while ER stress associated genes (CHOP, BiP, ATF6α, MANF) were elevated in compared to corrected WS SC-β cells. Furthermore, transplantation of corrected WS SC-β cells rapidly alleviated diabetes in STZ-induced diabetic mice, 10 days after transplantation. However, the unedited WS SC-β cells were unable to regulate blood glucose, delivering significantly less human insulin to the diabetic mice. This platform allows for the study of human diabetes pathology and is an enabling technology for drug screening and cell replacement therapy.

Drew McLaughlin – Psychological & Brain Sciences

Task-evoked pupillary response for completely intelligible accented speech

Speech perception under adverse conditions, such as those caused by noise in the environment or a speaker’s accent, can be cognitively demanding. For second language- (L2-) accented speech, mismatches between the speech patterns of an L2-accented speaker and a listener can result in poorer understanding and reduced intelligibility (i.e., fewer words in the speech stream can be correctly identified). However, it remains unclear whether completely intelligible L2-accented speech imposes greater cognitive load (defined here as the degree to which cognitive resources are recruited at a given moment to meet processing demands) than native speech. In the current study, we used pupillometry to examine cognitive load during the perception of completely intelligible, Mandarin Chinese-accented English speech and standard American-accented English speech. Results from two experiments showed greater and more rapid pupillary response (indicating greater cognitive load) for L2-accented speech than native speech. Additionally, participants subjectively rated the L2-accented speaker as more effortful to understand than the native speaker. Consistent with an executive recruitment account for accented speech, these findings indicate that mismatches between the systematic speech patterns of a speaker and a listener require greater cognitive load to process—even when recognition accuracy is at ceiling.

Lacy Murphy – Art History and Archaeology

Bryan Page’s Mutated Bodies: Transgressing Physical and Conceptual Borders

The abject. Located at the border of inexistence and hallucination, it is a space where meaning collapses and the self and other are no longer discernible. Therein lies all that is perverse and transgressive: shit, vomit, blood… The abject repulses us, and yet, it attracts us as well. We stare in wonder at its horrible power. This is precisely what is experienced by the viewers of recent work by Bryan Page, a Saint Louis-based artist. In his practice, Page creates images and videos of chill-inducing masses of flesh, bone, and muscle by digitally splicing disparate body parts together. These digital mutants, which lack facial features, appear familiar yet unfamiliar, attractive yet repulsive, and transgress the rigidity of borders and rules by disturbing the fixity of identity, system, and order.
As the stability of physical and conceptual borders are transformed and eroded in an increasingly globalizing and digital world, Page’s work brings to the fore essential questions about identity, belonging, and wholeness. In a time of mass displacement and migration, how are our notions of national borders changing? What new anxieties are emerging with increased intermingling of the world population? With the growing pervasiveness of technology in everyday life, now more than ever, individuals navigate the world digitally. We do much of our buying, selling, learning, socializing, and even dating online. Where do the boundaries of the self even begin and end in the digital age? Does the self really end at the bounds of the physical body? Or is at least part of the self now located in the digital universe as well? If so, what would our digital selves look like? Would they appear grotesque like Page’s technologically engineered, mutated forms?
Although Page’s mutant bodies appear to be a threat because of their displeasing appearance, entered into the realm of art, the unaesthetic is aestheticized. The ability to transform the abject through art reveals the abject as culturally constructed. It is, in fact, specifically the status of the mutant bodies as art that enables this examination of taboo and convention. Page’s mutated bodies therefore illustrate that the borders that dictate what is legal/illegal, aesthetic/unattractive, or acceptable/unacceptable are, in fact, permeable, thereby suggesting the possibility of cultural renovation and exposing the fragility of the symbolic order.

Jessica Nicosia – Psychological & Brain Sciences

The Effects of Motivation on Mind-Wandering

Mind-wandering is the phenomenon of intentional or unintentional shifts of attention from the task at hand to unrelated thoughts and feelings and evidence suggests that mind-wandering is pervasive, and often deleterious to task performance, in our everyday lives. A perplexing pattern of results suggesting that older adults mind-wander less than younger adults has become the focus of a considerable number of studies. While research on mind-wandering has rapidly increased over the past decade, few studies have investigated how best to ameliorate the adverse effects that mind-wandering has on sustained attention and vigilance. In the current paradigm, we investigate the effects of task-motivation and framing on mind-wandering propensity in younger and older adults and whether these manipulations may serve as techniques to reduce mind-wandering and improve vigilance in our everyday lives.

Christopher Pacia – Biomedical Engineering

A cost-effective magnetic resonance-focused ultrasound system for blood-brain barrier opening and biomarker release in porcine model

Although blood-based liquid biopsy is a promising non-invasive method to detect biomarkers from various cancers, limited progress has been made for brain tumors, at least partly due to hindrance of tumor biomarker release into the peripheral circulation by the blood-brain barrier (BBB). In our previous study, we demonstrated the feasibility for focused ultrasound-enabled brain tumor liquid biopsy (FUS-LBx) in mouse models. The objective of this study was to develop a FUS system for FUS-LBx application in a large animal model. A stereotactic frame was designed to stabilize the head of anesthetized piglets. A magnetic resonance (MR)-compatible FUS transducer was used for FUS treatment. Software was developed to target a specific brain location with MR guidance. FUS sonication was performed after intravenous injection of microbubbles. After treatment, contrast-enhanced MR images were acquired to evaluate BBB permeability. Blood was collected and brain-specific biomarkers were analyzed using enzyme-linked immunosorbent assay. A stereotactic frame was designed to stabilize the head of anesthetized piglets. A magnetic resonance (MR)-compatible FUS transducer was used for FUS treatment. Software was developed to target a specific brain location with MR guidance. FUS sonication was performed after intravenous injection of microbubbles. After treatment, contrast-enhanced MR images were acquired to evaluate BBB permeability. Blood was collected and brain-specific biomarkers were analyzed using enzyme-linked immunosorbent assay. Contrast-enhanced T1-weighted MR images confirmed BBB opening. The concentration of brain-specific biomarkers, GFAP, MBP, and S100B, increased respectively by a factor of 2.5, 4, and 3 after FUS treatment compared with before. This integrated system allowed precise BBB disruption to enhance brain-specific biomarker release into the bloodstream. This study established a tool for FUS-LBx in large animals, which can be translated to the clinic for diagnosing various brain cancers.

Robert Potter – Division of Biology & Biomedical Sciences

Novel Gardnerella genomospecies detected in the setting of bacterial vaginosis

Gardnerella vaginalis is one of the causative agents of bacterial vaginosis however defying Koch’s postulates it can also be isolated from the vagina of healthy women. One explanation of this observation could be the existence of G. vaginalis strain types with different pathogenic potential. Consistent with this, genomic efforts to study G. vaginalis identify 4-6 clades. However, pairwise average nucleotide identity analysis between these genomes indicates that multiple species may erroneously be annotated as G. vaginalis. Despite this result, a robust taxonomic investigation on the 100+ G. vaginalis genomes available has not been performed.
To address this gap in knowledge, we gathered 103 publicly available genomes from NCBI annotated as G. vaginalis. We then performed comprehensive taxonomic and phylogenomic analysis to quantify the number of species annotated as G. vaginalis, the similarity of their core-genes, and the differential burden of their accessory genes. We additionally gathered publicly available metatranscriptome reads of women with bacterial vaginosis to determine if the newly delineated genomospecies are present in symptomatic individuals and to identify conserved features of G. vaginalis expression during pathogenesis.
We found that 9 different genomospecies are annotated as G. vaginalis (termed GV01-GV09). 4 of the genomospecies are previously recognized as different clades of “G. vaginalis” however 5 are newly reported. The genomospecies can be readily distinguished by the phylogeny of their shared genes and burden of accessory genes. The accessory genes include genomospecies specific proteins involved in carbohydrate degradation and acetoin utilization, suggesting differentiation into different niches within the vagina, supporting the idea of variable pathogenic potential for bacterial vaginosis. Importantly, we determined that 3 of the new genomospecies are identified as abundant contributors to the Gardnerella specific metatranscriptome in 4/20 bacterial vaginosis samples. When we combined the metatranscriptome information across samples we found conserved features of Gardnerella transcription during bacterial vaginosis, including expression of protein synthesis genes and known virulence factors (ie. vaginolysin). These results have important implications for future efforts to understand the evolution of the Gardnerella genomospecies, host-pathogen interactions of the genomospecies during bacterial vaginosis, and metagenomic inves

Cole Pruitt – Chemistry

Neutron Skins from a Dispersive Optical Model Analysis

The nuclear optical model was developed in the 1950s and 60s in part to explain neutron total cross section data in a simple, intuitive way.
Since then, regional and global optical models have been developed for a wide variety of projectiles (p, n, alpha, heavy ion, etc), but they often lack sufficient connection to formal many-body methods.
In addition, as phenomenological objects, optical models are only as good as the data they are based on. Given the paucity of high-energy proton reaction cross section and neutron total cross section data in the literature,
their usefulness typically diminishes beyond 100 MeV. This poster connects newly-measure isotopic neutron total cross sections and new developments in the Dispersive Optical Model (DOM), which extends traditional optical models to the negative energy domain by enforcing a dispersion relation.
This improved DOM generates predictions for the neutron skins of O18, Ca48, Ni58, Ni64, Sn112, and Sn124 to help constrain the density dependence of the nuclear symmetry energy.

Gerry Sann Rivera – Chemistry

Siderophore-antibiotic conjugates: Hydrolysis and drug release mechanism

There is an increasing urgency to discover new and innovative solutions to combat antibiotic resistant bacteria. Bacteria have evolved rapidly in the past few decades to resist various antibiotic treatments, leading to an increased death toll. In order to solve this problem, it is necessary to have a clear understanding of the mechanisms bacteria undergo in order to thrive in a host environment. One of these ways is by obtaining specific transition metals in a metal-deficient environment. The pathway highlighted here focuses on the iron acquisition pathway, with the utilization of small secondary metabolites called siderophores. Siderophores have an interesting feature that allows them to chelate metal with multiple ligands leading to high iron-binding affinities of up to 1050.

Sideromycins are siderophore-antibiotic conjugates that are found in nature due to the competitive environment between different bacteria and the scarce nutrients available. Sideromycins act as a “trojan horse” which the host bacteria releases into the environment, and any competing bacteria that scavenges the siderophore in an attempt to obtain its iron would also uptake the conjugated antibiotic. Once inside the cell, the antibiotic is then cleaved off through a hydrolysis mechanism. The work centers on elucidating the mechanism to try and understand when the antibiotic is cleaved off. A variety of trihydroxamate siderophore methyl esters with varying chain lengths in their apo- and holo- form were screened and monitored for the rate of hydrolysis via analytical HPLC and 1H NMR. The hydrolysis rates observed supports the theory that the shorter the end chain length between the hydroxamate and the ester, the faster hydrolysis occurs. The holo- form hydrolyzes much faster than the apo- form, supporting evidence that iron release triggers hydrolysis once inside the cell. Salmycin hydrolysis was tested through agar diffusion assays against S. aureus, showing that apo-salmycin hydrolysis occurs very slowly. This suggests that hydrolysis of the antibiotic probably occurs after iron is released from the siderophore, allowing for a stable complex up until the siderophore is inside the competing bacterial cell.

Helen Robinson – Social Work

Collective Impact and Community Engagement: Lessons Learned from the Field

The case study method was use to explore highlights seven community engagement strategies and eleven corresponding lessons learned emanating from a Collective Impact (CI)-informed, university-community research partnership attempting to support positive youth development (and prevent youth gang involvement) in a small metropolitan community located in the Southeast U.S. city (Yin, 2014). The case example pronounces the critical role of university-community research partnerships and the importance of preparing social work students in effective community practice. Specific community engagement strategies utilized within this case example are provided and demonstrate how such strategies allowed for emergent learning across stakeholders at various places on the intervention continuum, provided time and resources for cross-sector learning, and worked to (re)build once-tenuous relationships between community members and larger institutional partners. In addition, lessons learned illustrate specific structured means for community-based, experiential and service-learning opportunities for social work students that supports mezzo- and macro-level practice skill development.

Min Kyung Shinn – Physics

Assembly and Binding of E. coli SSB C-terminal Tails to RecOR Proteins

The E. coli RecO protein is a recombination mediator protein (RMP) involved in the RecF pathway of homologous recombination, and it is one of at least 15 different proteins that are known to interact with the last 9 amino acids of the intrinsically disordred C-terminal tails of E. coli single-stranded DNA binding (SSB) protein during DNA replication, recombination, and repair. Whereas structures of RecOR complexes from other organisms have been determined, they show different RecO/RecR stoichiometries. Furthermore, crystal structures of the E. coli RecOR complex are not available. We therefore are investigating the functional oligomeric states of E. coli RecO and RecR, and the stoichiometry of the RecOR complex using analytical ultracentrifugation and isothermal titration calorimetry. E. coli RecR had previously been reported to form a dimer, but we find that it is in a dimer-tetramer equilibrium that is sensitive to pH with lower pH stabilizing the tetrameric species. In fact, we find that the RecR tetramer is the form that binds RecO with a minimal stoichiometry of one RecO per RecR tetramer. We have also examined the effect on RecO-RecR interactions of the binding of RecO to the intrinsically disordered SSB tail.

Sofia Smith – Chemistry

Bioinspired Aerobic Oxidation Chemistry using High-Valent Nickel Species

Nickel catalysts have been widely employed in the catalysis of C–C and C–heteroatom bond formation reaction. Using a modified pyridinophane ligand, oxidation of Ni(II) complex with O2 or H2O2 produces several high-valent nickel species, followed by C–C and C–O bond formation. Cyclic voltammetry and EPR studies show the ability of oxidizing the Ni(II) complex. With cryo-ESI-MS, high-valent Ni-oxygen species were detected, and a mechanism using O2 was proposed. Using an asymmetric pyridinophane ligand with one electron withdrawing group in the axial position has proven to be the sweet spot of stability vs reactivity for the formation of C–C and C–O bond formation. The work allows for the study of the relative reactivity of C–C and C–O bond formation, which has important applications in organic chemistry and exhibit bioinspired aerobic oxidation chemistry.

Ke Song – Mechanical Engineering and Materials Science

Hip Joint Reaction Force Contributions to Acetabular Edge Loading in Dysplastic Hips: A Subject-Specific Musculoskeletal Modeling Study

Labral tears in developmental dysplasia of the hip (DDH) may be related to abnormal loads at the acetabular edge. Thus, quantifying in-vivo edge loads can help us clarify the reasons for labral tears. Using image-based musculoskeletal models, we developed new analyses to project hip joint reaction forces (HJRF) on DDH and healthy acetabula for estimation of edge loads in gait. Compared to healthy, HJRF in DDH were higher, and closer to the acetabular edge. As a result, higher edge loads were projected on the DDH acetabula. The findings support risks of labral tears in DDH and may help inform clinical treatments.

Marta Stojanovic – Psychological & Brain Sciences

Exercise Engagement and Long-term Changes in Brain Structure and Cognitive Functioning

Past research suggests that exercise engagement may play a protective role against cognitive and brain decline with aging. Although the effect of exercise engagement on regional brain structure and cognitive functioning in older adults has been studied at a point in time, the longer-term effect of exercise engagement has been less examined. The current study examined whether individuals with higher baseline exercise engagement exhibit less longitudinal change in regional brain structure and cognitive functioning than individuals with lower baseline exercise engagement. Another goal was to examine whether APOE genotype, a genetic risk factor for AD, influences the effect of exercise on longitudinal changes. Individuals who were clinically normal at baseline were administered a questionnaire on their physical exercise engagement over the prior 10-year period. 238 individuals had serial MRI collected to examine regional brain structure, and 327 individuals underwent multiple neuropsychological assessments of cognitive functioning. We observed significant change in regional brain structure over time, with both volume and thickness decreasing. Longitudinal decline was also observed for cognitive functioning, including for semantic memory, episodic memory, processing speed, and working memory. However, the level of baseline exercise engagement did not affect long-term change in regional brain volume and thickness, or cognitive performance, with the exception of processing speed. APOE genotype did not influence the effect of exercise on structural changes or cognitive decline, again with the exception of processing speed. These results suggest that physical exercise engagement may be limited as a moderator of changes in regional brain structure and cognitive functioning over time.

Benjamin Sumlin – Energy, Environmental & Chemical Engineering

Multiwavelength Optical Properties of Light Absorbing Organic Aerosol

Atmospheric aerosols alter the Earth’s energy balance by absorbing and scattering solar radiation, contributing to atmospheric heating and cooling, respectively. Between 20-90% of the global aerosol burden are carbonaceous aerosols, which have been recognized by the Intergovernmental Panel on Climate Change as important drivers of radiative forcing. Carbonaceous aerosols are broadly divided into two types: black carbon (BC) and organic carbon (OC). BC, which is often called soot or elemental carbon, absorbs strongly throughout the solar spectrum, varying inversely with wavelength, and is well-studied.
Radiative transfer models typically assume OC is purely light scattering and exhibits zero absorption. However, “brown carbon” (BrC) is a class of light absorbing OC that has received increasing attention in recent years as a strong contributor to atmospheric absorption of solar radiation, especially in the near-UV and visible wavelengths. This strong near-UV absorption imparts a brownish-yellowish color, which is the basis for the name. BrC is emitted predominantly from the low-temperature, flameless smoldering phase of biomass burning, or is created in the atmosphere by secondary processes such as photooxidation of gas-phase precursors. If the contribution to light absorption by BrC aerosols is neglected in climate models, then cooling due to scattering offsets the warming contribution by BC, resulting in a net negative direct forcing effect (cooling) for biomass burning emissions.
Data on the near-UV and short-wavelength visible optical properties of BrC remains scarce. This poster describes the development, calibration, and characterization of the multiwavelength Integrated Photoacoustic-Nephelometer (mIPN), an in-situ, real-time, contact-free instrument designed primarily for field use to measure BrC light absorption and scattering at four wavelengths. mIPN, and its application to BrC optical properties in both laboratory and real-world settings.

Hui Wang – Physics

Noninvasive Electromyometrial Imaging of Uterine Contractions: Robustness under Noise

Available techniques to monitor uterine contractions are invasive or lack sufficient spatial resolution to reveal where contractions originate, how contractions propagate, and whether preterm contractions differ between women who do and do not progress to preterm delivery. Recently, electromyometrial imaging (EMMI) was developed to non-invasively assess uterine electrical activation. EMMI employs magnetic resonance imaging to obtain subject-specific body-uterus geometry and captures uterine electromyographic data from up to electrodes on the abdomen. EMMI generates maps of electrical activity on the entire three-dimensional (3D) uterine surface. Here, we sought to determine whether EMMI could robustly image uterine electrical activity in the presence of electrical noise contamination. We used a hybrid experimental-simulation approach to model the effects of fnoise contamination caused by environmental noise. Our data indicate that EMMI can accurately image uterine electrical activity in the presence of clinically relevant noise. Thus, EMMI can be clinically translated to non-invasively image 3D uterine electrical activation in pregnant women.

Maya Williams – Social Work

School-to-Prison Pipeline: Education Policy, Reform, and Social Action

The school-to-prison-pipeline is a phenomenon that removes predominately African American and Latino students from schools through exclusionary discipline. Harsh disciplinary measures, in schools across the United States, can be observed through increased detentions, suspensions, and expulsions that target minority students. This phenomenon leads to minority students’ increased contact with law enforcement while funneling them into the criminal justice system, which is a national issue. Unfortunately, minority students are often targeted by zero tolerance policies, which is one of the direct causes of dropout. According to the National Center for Juvenile Justice, in 2014, the school dropout rate for minority youth in juvenile detention centers was higher than dropout rates for White youth between 44-47%. As a result, impacted students lose a disproportionate amount of instructional time and educational opportunities. In turn, youth who dropout are eight times more likely to be institutionalized than students who receive a high school or college education.
Missouri school districts have been impacted by the school-to-prison pipeline as well, which has severe consequences for students of color. Therefore, this presentation will compare four Missouri school districts. This research study will specifically highlight the discipline incidents and suspension rates in the following school districts: Clayton, Ferguson-Florissant RII, Hazelwood, and Ladue. This presentation will emphasize the disproportionate discipline policies used in districts where African Americans predominately attend school, compared to school districts that have a majority Caucasian American student attendance. Racial and discriminatory incidents in Missouri such as the Michael Brown case, The Stockley verdict, and Class E felonies will be explored to understand their impacts on the schooling experiences of minority students.
Finally, this presentation will explain how academic work can be applied to the real world through existing opportunities through policy reform. Scholars will learn about micro and macro level changes to intervene on this issue with the support of educators and community partners to improve the quality of the United States’ education system. Ultimately, social action is required to inform policy makers of culturally sensitive and non-discriminatory policies to promote the education of all youth. This presentation will inform scholars of education policy and reform.

Roger Wong – Social Work

Strategies for the recruitment and retention of African Americans in Alzheimer’s disease and dementia clinical research: A systematic review

Background:
African Americans have the highest risk for Alzheimer’s disease among all racial groups, but remain underrepresented in clinical research. The synthesis of the diverse methods to increase African American participation in Alzheimer’s research is absent in the current literature, which is essential considering inclusion of minorities is mandated in federally-funded clinical research to address racial health disparities in Alzheimer’s disease.

Objectives:
This study aimed to identify effective strategies to recruit and retain African Americans in Alzheimer’s disease and dementia clinical research.

Methods:
A systematic review was conducted in December 2017 using five databases: CINAHL, EMBASE, MEDLINE, PsycINFO, and Scopus. Studies that implemented recruitment or retention strategies for African Americans in Alzheimer’s disease or dementia clinical research were included. Four investigators extracted study data using an instrument adapted from the extraction checklist in the Cochrane Handbook, and assessed study quality using the Effective Public Health Practice Project Quality Assessment Tool.

Results:
Among the 2,613 studies screened, 18 met inclusion criteria. Included studies focused predominantly on recruitment, whereas few studies described retention strategies. A wide variety of recruitment and retention strategies were reported including community outreach and mass marketing, however, few strategies were formally evaluated.

Conclusions:
Our findings suggest there is a high need for researchers to incorporate evidence-based strategies when recruiting and retaining African Americans in Alzheimer’s disease clinical research. Alternatively, studies utilizing novel strategies should be evaluated to assess their effectiveness. Additional research is especially needed to identify promising strategies to improve African American retention in Alzheimer’s disease research.

Jiang Zhu – Division of Biology & Biomedical Sciences

The Role of Valosin-Containing Protein (VCP) in Seeding of Prion-like Proteins

One of the hallmarks of neurodegenerative diseases is protein aggregation, such as β-amyloid, tau, α-synuclein and etc. Accumulating evidence suggested that those proteopathic proteins own seeding property, that the protein can travel through brain network and template the new aggregation as “seed”. But the precise mechanism of the intracellular seeding remains elusive. Recently, the FRET assay enables us to investigate the factors that participate in the conversion of this intracellular conversion with high resolution. We aim to find genes that involve in this process. VCP is a versatile protein in protein homeostasis and its mutations were discovered in multiple neurodegenerative diseases, including Frontotemporal dementia and ALS, and in a few cases of Parkinson’s. VCP mutations characterized in our lab have impaired ELDR function. We propose that VCP-dependent ELDR plays a safeguard role on preventing the conversion of prion-like protein in cytoplasm. Our data show that both VCP inhibitor and disease mutations are sufficient to exacerbate the conversion of α-synuclein and tau via FRET. The similar result was recapitulated in hippocampal neuron, in which both VCP knockdown and VCP mutation knock-in show increasing α-synuclein aggregation. Those converging results support VCP as an important protein for intracellular seed conversion.

Lifei Zhu – Biomedical Engineering

Focused Ultrasound-Enabled Brain Tumor Liquid Biopsy (FUS-LBX) And Parameter Optimization

Glioblastoma multiform (GBM) is the most common primary brain tumor and one of the deadliest of all cancers. Direct surgical tissue biopsy to determine tumor molecular profiles is associated with potential complications such as hemorrhage and infection. Meanwhile, repeated tissue biopsies using surgical interventions to assess treatment response and recurrence may not be feasible given the increased risk for complications and morbidity. Blood biomarkers have significant potential applications in early detection and management of brain cancer. However, the tumor biomarker release into the bloodstream is hindered by the blood-brain barrier. The objective of this application is to develop the focused ultrasound-enabled liquid biopsy (FUS-LBX) technique to noninvasively increase the concentration of biomarkers in the blood and investigate the effects of FUS acoustic pressure on the tumor biomarker release efficiency and brain injury to optimize the FUS-LBx technique.

Two glioblastoma tumor models (U87 and GL261) were developed by intracranial injection of respective enhanced green fluorescent protein (eGFP)-transduced glioblastoma cells. Microbubbles were injected systemically to the mice through the tail vein, followed by FUS sonication with acoustic pressures of 0.59 MPa, 1.29 MPa, 1.48 MPa, 2.10 MPa, and 3.34 MPa. FUS was targeted at the center of the tumor under the guidance of MRI. Blood samples of 500–800 µL were collected from the heart and prepared for quantitative polymerase chain reaction (qPCR) analysis of eGFP mRNA. Contrast-enhanced MR images were acquired before and after the FUS treatment.

eGFP mRNA was detectable in the FUS-treated mice with all pressure levels and undetectable in the untreated mice (maximum cycle number set to 40). The circulating levels of eGFP mRNA were 1,500–4,800 fold higher in the FUS-treated mice than that of the untreated mice for the three acoustic pressures. Hemorrhage associated with FUS at 0.5 MPa was significantly lower than that with higher acoustic pressures and not significantly different from the control group. MRI analysis revealed that post-sonication intratumoral and peritumoral hyperenhancement was linearly correlated with the level of FUS-induced biomarker release and the extent of hemorrhage.

FUS-LBx may offer an enabling technique for image-guided, noninvasive, and regionally-specific brain tumor liquid biopsy. Safely and effectiveness can be achieved through parameter optimization.