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Testing of 10 W 445 nm Blue Diode on Laser-Based Additive Manufacturing of PEEK
No full textAdditive manufacturing with high-temperature polymers such as polyether ether ketone can create aerospace parts that are simultaneously structurally and thermally stable, and capable of functions like electromagnetic interference shielding when loaded with conductive fillers. Previous work showed that a 2W, 532 nm diode laser could melt—but not efficiently process—PEEK. This semester, that source was replaced with a 10 W, 445 nm blue diode whose shorter wavelength is better matched to PEEK’s absorption spectrum. After calibrating optical output versus drive current, a repeatable melt window was found near 2.6 A (≈ 9 W) and 0.83 mm/s. Relocation of the apparatus to a fume hood necessitated slightly higher power (2.7 A, ≈ 9.4 W) or lower speed (0.33 mm/s) but produced identical quality after two passes. High-speed IR videos acquired at \u3c 5 µs exposure resolved melt-pool geometry and temperature distribution in real time, while optical imaging highlighted surface topography. The upgraded system is now ready for integration with the powder-deposition system, positioning the project for further combined testing
Gender, Race, and Interruptions at Supreme Court Confirmation Hearings
No full textIn this research letter, we examine whether gender and racial bias affect interruption rates at one of the most visible events in American politics: US Supreme Court confirmation hearings. Using original data from 1939 to 2022, we find that male and white participants are more likely to interrupt women and person of color speakers, respectively, relative to male and white speakers. This finding holds for both senators and nominees as interrupters. Our results provide evidence that biased interruptive behavior occurs in even the most public and salient of political settings and that it can be mitigated (or intensified) by shared (or opposite) partisanship among speaking pairs. We also find interruption inequalities are not isolated to women as the interrupted, revealing that people of color in political and legal settings are subject to heightened rates of interruptions as well
Asset Building for All, Starting at Birth: Emergence of a Federal Policy and a Key Design Lesson
Get PDFA proposal in the 2025 tax-reconciliation bill would provide federal Child Development Account–like accounts for all children born between 2024 and 2028, with a provision enabling children born in 2028 or after to open accounts. This Policy Brief is designed to inform public debate about the legislation through a discussion of the evidence underpinning the most fundamental of many lessons learned from SEED for Oklahoma Kids, the Center for Social Development’s long-running, randomized experiment with Child Development Account policy: the need for a centralized savings-plan platform
Supporting Programmers Answering the Hard-To-Answer Questions Through the Use of Large Language Models
Get PDFProgrammers often face hard-to-answer questions when working on large-scale projects. Not only during team collaborations, but also during interruptions such as meetings, having to suddenly work on another project, or even just taking a break are major reasons these questions arise, as programmers have to regain the context, knowledge, and mental state to resume the work. Traditional text editors such as GitHub do provide a built-in history system, but they lack historical context behind the editing to answer such questions.
To address this issue, we developed an experimental extension, Code History, on Visual Studio Code (VS Code) in the hope of finding a way that enables programmers to make effective use of these subgoal-based histories to answer hard-to-answer questions. We have created this extension through a step-by-step process where one feature is built on top of another. We began with the interface design, where we created an interface that is intuitive for users. That created a solid foundation for the next mechanism of the extension in which the extension can generate subgoal summaries based on editing histories. In addition to displaying summarized user intentions, Code Histories also displays any web searches and links accessed by the programmers during the time when they were working on the subgoal. Lastly, we have integrated large language models (LLMs) such as ChatGPT and Gemini to improve the user’s experience by letting the programmer search for a specific piece of history. Rather than being conversational, the LLMs are used to retrieve and filter relevant subgoal histories in response to the users’ questions/commands. With the help of Code History, programmers can now access contextualized histories and answer questions about the code that would otherwise be difficult to answer through a list of history alone.
The goal of this thesis is to enable us to test the hypothesis that question-based interfaces for sub-goal histories will better support programmers in answering hard-to-answer questions than the commonly available supports today. Pilot studies have suggested that, with some minimal alteration to the test format and interface design, we will be able to move on to the user testing phase
How New Lawyers Value Law School Experiential Training
Get PDFWhile the legal academy continues to debate the appropriate role of experiential training in preparing graduates for practice, one group consistently embraces its value: newly-licensed lawyers. In repeated surveys over the past twenty years, early career lawyers, as well as experienced attorneys, report that law clinic, externship, and simulation courses play an important role in legal education. The research summarized herein demonstrates that newly-licensed lawyers highly value their law school experiential courses, deem them important in their transition to practice, and believe their legal education did not sufficiently prepare them for practice
Ten Years and Ten Miles: Reflecting on Ferguson
Get PDFThis Essay serves as the introduction to a symposium on the ten-year anniversary of Michael Brown\u27s death in Ferguson, Missouri and the subsequent protests and uprisings across the country. The authors look back on the past decade—their own experiences and our experiences as a nation—to consider the impacts of the Ferguson uprisings and the landscape of criminal justice and racial justice advocacy, scholarship, and teaching today. In this Essay, I provide a brief introduction to the Volume and essays that follow. In Part I, I situate the Ferguson uprisings in the broader context of activism responsive to racial injustice in the U.S. criminal system. In Part II, I describe the essays that follow. Finally, in Part III, I offer a few words on the twenty-fifth anniversary of the Washington University Journal of Law & Policy, and the importance of this Volume in continuing the journal’s mission
A Role for the Actin Cytoskeleton and Plastin-3 in Osteoblast Mineralization and Mechanosensation
Get PDFThe great diversity in actin network architectures and dynamics is exploited by cells to drive fundamental biological processes including cell migration, intracellular trafficking, and cell division. One such system that relies on the actin cytoskeleton to fulfill its physiological function are osteoblasts, which are mesenchymal lineage bone cells that promote bone formation through depositing a collagen scaffold and subsequently promoting mineralization of this matrix. A number of factors are known to drive osteogenic differentiation of pre-osteoblast cells including extracellular matrix cues such as substrate stiffness, which are primarily detected via mechanosensitive machinery linked to the actin cytoskeleton. Disruptions to β-actin, actin cytoskeletal dynamics, and actin-associated proteins have all been shown to disrupt both osteoblast physiology at the cellular level as well as the integrity of bone structure in model systems. This emphasizes that careful tuning of actin filament dynamics is required for osteoblast differentiation and function, which thus raises the question of how actin-binding proteins contribute to these processes. In this work, we take two approaches to explore the significance of regulatory mechanisms governing actin cytoskeleton dynamics. In the first part of this work, we directly compare how processing and modification of the N terminus of β-actin affects intrinsic polymerization dynamics and its remodeling by actin-binding proteins that are essential for cell migration. In the second part of this work, we investigate the role of plastin-3 (PLS3) in osteoblast physiology. PLS3 is a calcium-sensitive actin-bundling protein that has recently been linked to the development of childhood-onset osteoporosis, however, the underlying mechanism remains elusive. To investigate the role of PLS3 in osteoblasts, we generated MC3T3-E1 pre- osteoblast cells that are stably depleted of PLS3. Comparison of osteogenic differentiation in control and PLS3 knockdown cells reveals that depletion of PLS3 does not alter the first stage of osteoblast differentiation in which a collagen matrix is deposited, but severely affects the subsequent mineralization of that matrix. Osteogenic differentiation heavily relies on mechanosensitive pathways including those linked to focal adhesions to drive mineral deposition. We observed PLS3 prominently localizes to focal adhesions (FAs) and that depletion of PLS3 rendered osteoblasts unresponsive to changes in ECM stiffness. More specifically, our results reveal pre-osteoblasts depleted of PLS3 exhibit similar cell sizes, FA lengths, and number of FAs when plated on soft (6 kPa) versus stiff (100 kPa) substrates in contrast to control cells, which showed an increased in each of these parameters when plated on 100 kPa substrates. Defective cell spreading of PLS3 KD cells on stiff substrates could be rescued by expression of wildtype PLS3, but not by expression of three PLS3 mutants that were identified in patients with early-onset osteoporosis and that have aberrant actin-bundling activity. Altogether, our results show that actin-bundling by PLS3 is part of the mechanosensitive mechanism that promotes osteoblast mineralization and thus begins to elucidate how PLS3 contributes to the development of bone defects such as osteoporosis
Essays in Monetary Economics and Financial Frictions
Get PDFThis dissertation consists of three independent articles in the field of Macroeconomics. The first chapter investigates the implications of various Quantitative Tightening strategies, examining both implementation and announcement effects. We focus on the consequences for financial stability and real variables, particularly the impact of reintroducing government bonds to the market, the role of reserves demand and balance sheet costs of financial intermediaries during the unwinding process. We also explore the dynamics associated with announcement effects. We explore optimality and compare cases of commitment and discretion, as well as credibility and limited commitment. Our findings indicate that announcing QT with sufficient anticipation yields better macro-financial outcomes. While sales initially have a relatively short-term stimulative effect due to agents precautionary motives, negative implementation effects eventually arise. Announcing passive unwinding followed by conducting sales leads to lower welfare and higher output volatility. Optimal QE is aggressive and optimal QT is gradual. QT should be more gradual when the maturity of debt is higher and reserves demand is higher. Under the optimal dual policy with commitment, the output gap closes and fully stabilizes 12 quarters earlier than observed in the data. T he second chapter studies the corporate debt structure under both conventional and unconventional monetary policies. We provide empirical evidence that unconventional monetary policy increases the corporate debt-to-bank loans ratio, while expansionary conventional policy raises the share of bank loans in relative terms. We then build a quantitative model with households, a production sector consisting of both bank-dependent and non-bank-dependent firms, banks that provide loans, and funds that trade bonds. We show that a QE shock increases the corporate debt-to-bank loans ratio, while a decrease in the interest rate on reserves has the opposite effect. Finally, the third chapter studies the transmission of monetary policy in economies with high levels of informality and financial markets segmentation. We show evidence of a negative correlation between different indicators of financial inclusion and the size of the informal economy. Based on this stylized fact, we build a monetary model with “formal” and “informal” households featuring limited participation in financial markets as in Williamson 2008. The degree of interaction between the two types of agents in the goods markets determines the transmission of monetary policy from the financial sector to the rest of the economy. We show analytically that the optimal inflation rate is increasing in the size of the informal sector, for a given path of fiscal policy. We calibrate the model to Mexico and discuss various policy experiments
Validation of the National Institutes of Health Toolbox for Use in Phenylketonuria Clinical Trials: A Pilot Study
Get PDFBackground: Many individuals with phenylketonuria (PKU), a rare genetic disorder, find current treatments inadequate and believe new treatments must be developed (Brown, 2018). Although approvals of existing treatments have largely been based on decreases in phenylalanine (Phe) levels, the Food and Drug Administration (FDA) has indicated that instruments to assess functional outcomes are needed in future PKU clinical trials. The National Institutes of Health (NIH) Toolbox Cognition Battery (Toolbox) meets criteria that are crucial for such trials. Methods: Data from 58 individuals with early-treated PKU (aged 8–55 years) enrolled in an ongoing NIH-funded longitudinal study of hyperphenylalaninemia were used to provide an early step in validating use of the Toolbox in PKU clinical trials. Associations between Toolbox performance and performance on validation instruments were examined through linear regression modeling to demonstrate convergent validity. The Toolbox performance of our PKU sample relative to the normative sample was also examined to demonstrate Toolbox sensitivity to compromise in key domains of cognition in PKU. Finally, the association between Toolbox performance and most recent Phe level was examined through linear regression modeling to demonstrate Toolbox sensitivity to metabolic control. Results: Toolbox Total Cognition, Fluid Cognition, and Crystallized Cognition Composite scores were significantly predictive of scores on comparable Wechsler Abbreviated Scale of Intelligence Indices. The Toolbox Executive Function Composite was significantly predictive of scores on the Cambridge Neuropsychological Test Automated Battery and on the Conners Continuous Performance Test. Our PKU sample exhibited significantly lower scores than normative samples, as well as a higher proportion of scores in the clinically elevated range (i.e., one standard deviation or more below the mean of the normative sample), on the Toolbox Total Cognition, Fluid Cognition, and Executive Function Composites. Conclusion: Consistent with our hypotheses, the Toolbox demonstrated good convergent validity with established cognitive assessments and demonstrated sensitivity to compromise in key domains of cognition in PKU. Contrary to our hypothesis, there was no demonstrable relationship between Toolbox performance and most recent Phe level. Overall, our results support consideration of the Toolbox for use in PKU clinical trials
Targeting Nonsense-Mediated RNA Decay in Splicing Factor Mutant Myeloid Malignancies
Get PDFApproximately 50% of patients with myelodysplastic syndromes (MDS) (which frequently progresses to secondary acute myeloid leukemia [AML]), 60% of chronic myelomonocytic leukemia (CMML) and 20% of de novo AML harbor heterozygous somatic mutations in spliceosome genes. We and others have shown that mutations in spliceosome genes U2AF1, SF3B1, SRSF2 and ZRSR2 cause alterations in RNA splicing, leading to production of numerous aberrant RNAs. Interestingly, spliceosome mutant cells are more sensitive to genetic alterations or drugs that further perturb RNA splicing, compared to wild-type cells. The sensitivity of spliceosome mutant cells to further perturbations in RNA splicing raises the possibility that mutant cells may be vulnerable to accumulation of dysregulated transcripts. A large portion of alternatively spliced RNAs caused by spliceosome gene mutations or splicing modulator treatment are nonsense mRNAs that harbor premature termination codons (PTCs). These nonsense mRNAs, which may cause deleterious effects if translated, are normally degraded by a RNA surveillance pathway called nonsense-mediated RNA decay (NMD). The prevalence of nonsense mRNAs in cancer cells with spliceosome mutations leads us to hypothesize that these mutant cells may be more sensitive to NMD attenuation. In support of this idea, we have previously shown that cultured cancer cells expressing mutant spliceosome factors exhibited heightened sensitivity to NMD disruption. Using two pre-clinical mouse models, in my thesis research, we show that transformed and non-transformed primary mouse cells expressing splicing factor mutant U2AF1S34F are preferentially sensitive to inhibition of the kinase SMG1 (SMG1i), a key regulator of NMD. Importantly, we show that SMG1i treatment extended the overall survival of mice harboring splicing factor mutant leukemic cells compared to the vehicle control treated mice. We also demonstrated that SMG1 inhibition in vivo causes R-loop accumulation, a RNA:DNA hybrid with a displaced single strand of DNA, and increased DNA damage in the cells. These findings were also validated in a human cell line-derived AML model in vivo in mice. Importantly, the sensitivity of mouse and human cells that express splicing factor mutant U2AF1S34F could be rescued by RNase H1 overexpression, an enzyme that degrades RNA:DNA hybrids, suggesting that R-loops are a major mechanism of the synthetic lethality between altered RNA splicing and NMD inhibition. In our effort to further explore the mechanisms underlying the synthetic lethality between spliceosome mutations and NMD inhibition, we performed a series of RNA sequencing experiments and found that SMG1i treatment led to distinct alternative pre-mRNA splicing and expression changes in genes involved in the unfolded protein response (UPR) and DNA repair pathways. Interestingly, we also identified that increased expression of PTC-containing isoforms in ATR and RAD51 occurred after U2AF1S34F or SMG1i treatment, resulting in reduced protein expression. This observation nominates these genes as potential vulnerabilities to target in splicing factor mutant cells in combination with SMG1i. Indeed, we found that splicing factor mutant cells were more sensitive to pharmacologic inhibition of ATR or RAD51 (ATRi and RAD51i, respectively) in combination with SMG1i than splicing factor wild-type cells. The combination of SMG1i with either ATRi or RAD51i likely further induces R-loop accumulation, causing increased DNA damage and cell apoptosis. The identification of a unique vulnerability of cancer cells with spliceosome mutations to NMD inhibition suggests a new approach to treat these cancers. Our results have laid a strong foundation for testing the therapeutic potential of SMG1 inhibitors as a monotherapy or in combination with ATRi or RAD51i in cancers with spliceosome gene mutations