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Investigating the Consequences of Conjugated and Secreted ISG15 on Coronavirus Pathogenesis
Full text linkCoronaviruses have evolved a breadth of mechanisms to antagonize host innate immune responses. One widely studied mechanism is the ability to deconjugate ISG15 from target proteins in a process called deISGylation, which is catalyzed by the papain-like protease (PLP) domain of viral non-structural protein (nsp) 3. Since PLP activity is required for viral replication, it has been challenging to generate an infectious virus with a PLP that maintains protease activity but has lost deISGylase activity. In this study, we generated a chimeric MHV-A59 with its PLP2 domain replaced with that of the human coronavirus HKU1, which has been documented to have minimal deISGylase activity in vitro. By using this virus, we determined that the deISGylase activity is critical for inhibiting the IFN-response in primary macrophages and promoting robust viral replication. Importantly, we also report that without deISGylase activity, the chimeric virus is highly attenuated in vivo and is more rapidly cleared from infected mice compared to MHV-A59. Accordingly, we found that at earlier stages of infection, MHV-HP2 induces a higher IFN response in the liver, providing a potential mechanism for the rapid clearance of the deISGylase-deficient coronavirus. These results document the critical role of viral deISGylase activity as a key contributor to innate immune evasion during coronavirus infection. We also investigated the ability of ISG15 to be secreted from the cell in response to coronavirus infection. The mechanism of ISG15 secretion was unknown. Here, we report that ISG15 is secreted from inflammasome-activated macrophages via gasdermin D (GSDMD) pores on the plasma membrane, mirroring the unconventional secretory pathway used by IL-1β and IL-18. Secretion of ISG15 is negated by deletion of GSDMD. It is also inhibited by treatment with the small-molecule pan-caspase inhibitor zVAD-fmk, the FDA-approved drug disulfiram, the caspase-1 inhibitor VX-765, and the NLRP3 inhibitor MCC-950, all of which block GSDMD pore formation. This study paves the way for investigating how extracellular ISG15 contributes to viral pathogenesis. Finally, we interrogated the effects of extracellular ISG15 on coronavirus replication and activation of the innate immune response through the addition of recombinant ISG15 (rISG15) to macrophages. By analyzing changes in gene expression and cytokine release in BMDMs treated with rISG15 and comparing them to IFN-driven responses, we determined that extracellular ISG15 has antiviral and proinflammatory effects during MHV-infection that is distinct from the IFN response. This study contributes to our understanding of how coronavirus infection drives inflammation within the infected host
Characterizing the Role of the FAK-HIF1a-CTGF Axis in Hepatocellular Carcinoma
No full textHepatocellular carcinoma (HCC) is a deadly cancer, and there is a pressing need to identify novel therapeutic targets. Our lab characterized focal adhesion kinase (FAK) as a driver of HCC, where FAK is required to induce HCC in mouse models. In HCC, 16% of patients harbor an amplification of the PTK2 gene, and these patients have decreased survival. Because of its role in tumor promotion, FAK has been investigated as a therapeutic target, however these therapies show little clinical efficacy. We hypothesize that selectively treating patients with high levels of FAK will significantly benefit from FAK-targeting therapeutics, however there are currently no known biomarkers for FAK. We used a proteolysis-targeting chimera (FP) to degrade FAK in vitro and showed significant growth inhibition following treatment. RNA-seq of FP-treated cells showed connective tissue growth factor (CTGF) was significantly downregulated. CTGF is secreted from cells and can be detected in serum, making it a suitable biomarker candidate. We confirmed the downregulation of CTGF following FP treatment at the mRNA, intracellular protein level, and secreted protein level. Overexpression of FAK led to an increase in intracellular and secreted CTGF protein levels. To assess CTGF alone in HCC, we used an shRNA knockdown and found that shCTGF significantly inhibited cell growth in vitro and in vivo. RNA-seq of shCTGF cells showed an increase in SKP2 and a decrease in p27. Furthermore, we showed that HIF1 mediates the regulation of CTGF by FAK. Using immunohistochemistry of HCC patient tumor samples, we saw a strong correlation between FAK and CTGF protein. Using the DEN/CCl4 murine model, FAK knockout attenuated tumor formation, and in wild type mice, an increase in serum CTGF levels was seen as tumors progressed. Finally, serum collected from patients at high risk for developing HCC suggest CTGF can be used as a marker for tumor formation for tumors with high FAK expression. Overall, FAK promotes the expression and secretion of CTGF, which promotes HCC. FAK is a promising therapeutic target in HCC, and identification of CTGF as a downstream target of FAK suggests CTGF as a treatment-indicating biomarker for FAK in HCC patients
ML Model to Better Identify Instances of Bullying Faced by Members of the LGBTQ+ Community
Full text linkCyberbullying poses a significant threat to online communities, with the LGBTQ+ community facing disproportionately higher rates of harassment. While existing cyberbullying detection systems have made progress in identifying general instances of online harassment, they often fail to capture the nuanced and context-dependent nature of LGBTQ+-targeted bullying. This thesis presents a novel approach to this challenge by developing SpectrumNet, an LGBTQ+-centric transformer-based model for cyberbullying detection. Our research was conducted in two phases. In Phase 1, we evaluated the effectiveness of pre-trained transformer models (RoBERTa, BERT, and GPT-2) in identifying LGBTQ+-related cyberbullying. Building on these findings, Phase 2 introduced SpectrumNet which integrates identity-aware attention mechanisms with hierarchical attention networks to understand the contextual nuances of LGBTQ+-targeted harassment better. The model was trained and evaluated on Instagram comments, demonstrating SpectrumNet\u27s superior performance in detecting LGBTQ+-specific harassment, with notable improvements in identifying subtle forms of bullying that traditional models often miss. This work contributes to the field of cyberbullying detection by introducing specialized architectural components designed specifically for identifying LGBTQ+-targeted harassment, potentially offering new directions for creating safer online spaces for marginalized communities
Early Social Experience and Biased Attention to Threat-Related Emotion in Infancy
Full text linkBy 7 months of age, infants typically develop a bias toward threatening facial expressions, such as fear and anger (Leppänen & Nelson, 2009; Leppänen et al., 2018; Peltola et al., 2009; 2013). However, individual differences in threat-related attention biases in adulthood are related to socioemotional functioning across a broad range of outcomes, including racial biases and psychological well-being. Links between attention and socioemotional development may begin in infancy, with prior evidence demonstrating that both maternal well-being and race may bias visual processing of emotional expressions (Morales et al., 2017; Vogel et al., 2017; Quinn et al., 2018; 2020). Thus, the current study aimed to examine the impact of two potential modulators of infant threat bias, maternal anxiety and racial and ethnic identity, on attention to emotional expressions. In pursuit of these aims, 40 mother-infant dyads participated in this study asynchronously online. Infants completed a preferential looking paradigm viewing pairs of own- and other-race faces expressing happy, angry, fearful, and sad emotion. Mothers completed measures of community and caregiving network diversity, depression, and anxiety. Results showed that infants were biased toward fearful expressions regardless of in- or out-group racial categorization, while race simultaneously biased attention to other negatively-valenced expressions (i.e., sad, angry). Maternal anxiety was uncorrelated with attention biases in our sample of 7-month-olds; however, experience-dependent shaping of emotion perception was observed through infant exposure to racial and ethnic diversity. These findings provide evidence of distinct responses to affect by in- and out-group racial categorizations by 7-months-of-age and has implications for the role of early experience in shaping visual attention biases for emotion
AI-Driven Systems in MTSS: Potential Opportunities and Challenges
No full textMulti-tiered systems and support (MTSS) offers a framework for schools to provide equitable learning opportunities. However, implementing MTSS with fidelity can be challenging due to limited resources that many schools experience. As a result, more educators are turning to artificial intelligence (AI) tools as a solution to resource limitations. This article examines how AI tools can strengthen MTSS, specifically, improvement to inclusive practices, data analysis, intervention implementation, progress monitoring, personalized learning, student engagement, and teacher efficiency. The article also examines potential risks related to using AI tools within MTSS such as ethical considerations, date security, data quality, bias potential, financial limitations, and professional development needs. Additionally, practice implications are provided to guide school psychologists in leading responsible AI implementation within MTSS frameworks
HOTLangBench, a Tiny Benchmark Suite for Higher-Order Statically Typed Languages
No full textThis work in progress aims to compare various HOT (higher-order and statically typed, a term coined by Phil Wadler) through reproducible course-grained, wall-time benchmarks. Our overall goals include simplicity, agility, and reproducibility.
There is currently only one benchmark, but it brings out substantial performance differences among the various languages and platforms. It uses function composition and other higher-order constructs to build a pipeline of transformations, along with a brute-force iteration that is computationally expensive for input files specifying large ranges as function domains. We currently include versions in Modern C++, C#, Go, Haskell, Kotlin, Modern (stream-based) Java (24), OCaml, Scala 3, and Swift.
It is easy to add versions of this benchmark in other languages not yet covered, and we plan to make it easy to add other algorithms to be benchmarked across languages
Practitioners’ perspectives on preventing environmental gentrification in Chicago, Illinois, USA
No full textPollution cleanup, green space creation, and other improvements to environmental quality in cities are important to urban sustainability. However, because they occur within a political economic context characterized by structural racism, urban greening initiatives can intentionally or unintentionally reproduce racial, economic, and social inequities through environmental gentrification. We explored possibilities for improving environmental quality without displacing or excluding long-term residents including people of color, the poor, and members of other marginalized groups. We conducted in-depth, semi-structured interviews with community organizers, environmental justice advocates, urban planners, housing specialists, and others who held deep expertise through their lived and professional experience in relevant fields in Chicago, Illinois. Five interrelated themes emerged through inductive analysis of the interview data that offer guidance for leaders of environmental improvements: (1) co-construct knowledge and share decision-making power, (2) design inclusive community engagement that centers marginalized voices, (3) implement multi-issue interventions, (4) disrupt structural racism and other causes of disparities, and (5) coordinate policies and programs across local, state, and federal scales. These findings reinforce and extend established knowledge about the need to design inclusive, community-driven, intersectional, multi-scalar environmental decision-making processes that help disrupt the systemic drivers of environmental injustice to achieve equitable outcomes
“A bond as strong as a lock and chain”: Youth of color in low-income communities use photovoice to theorize developmentally nurturing processes of their cross-age mentoring programs
No full textYouth of color experiencing low-income in the United States face multiple human rights violations: over-policing, community violence, racial discrimination, and insufficient voice in the programs and policies that impact their current and future lives. To accomplish transitional justice, participatory processes are needed that elicit youths’ cultural strengths and wisdom about themselves, their social conditions, services they find helpful, and why those services are helpful. This study highlights findings from a photovoice that elicited youths’ perspectives about a crossage mentoring out-of-school-program. Responding to “What does mentoring mean to you?” 147 youth took photographs in their communities and wrote narratives about the photographs’ meanings. The research team, including youth co-researchers, conducted a thematic and content analysis of the participants’ narratives. Youth were highly articulate about the specific program elements that would uplift their peers, and why those elements are impactful. Through qualitative analysis of youths’ photographs and narratives, this study reveals the youths’ “folk theories” about their program’s mechanism of action. Youth described mentoring as a nurturing family, friendship, community, care, love, acceptance, trust, communication, and vulnerability. They thoughtfully described culturally relevant “folk theories” of how cross-age mentoring fosters children\u27s development, counteracting stressful high-burden contexts. Analyzing youths’ metaphors for the nurturing process in cross-age mentoring indicated how much they valued caring for each other, creativity, and supporting positive life trajectories for each other while overcoming poverty and discrimination. When offered opportunities for creative self-expression such as photovoice, youth can be insightful partners in resisting the downward pull of human rights violations and theorize interventions and nurturing processes that develop their resilience
Give People Money: The Effect of Perceived inequality in Everyday Life and Previous Cash-Transfer Programs on Support for Universal Basic income
No full textEconomic inequality is a global concern with many adverse consequences for people across class divides. These consequences vary in scope—from negative effects on individual’s physical, mental, and social health to large-scale economic shifts which result from climate change (Galbraith & Hale, 2008; Hiesh & Pugh, 1993; Kaplan et al., 1996; La Ferrara & Alesina, 2000; Solt, 2008; Vilhjalmsdottir et al., 2016; Wilkinson & Pickett, 2007). Policy solutions meant to address the negative effects of economic inequality include government redistribution of wealth. Universal Basic Income (UBI), a specific and actionable policy of government redistribution, is a promising method of economic inequality alleviation (Gibson, 2018). However, not all people, politicians or otherwise, see economic inequality as a problem (Bobzien, 2019). As a result, many may see no need for government redistribution, let alone UBI (Choi, 2021). This proposal is interested in 1) the mechanisms underlying an individual’s perception of objective and subjective economic inequality, 2) attitudes toward the value of decreasing economic inequality, and 3) the support or opposition to policies seeking to reduce economic inequality—specifically Universal Basic Income. Prior work on the relationship between perceived economic inequality, personal tolerance for inequality, and support for redistribution provides evidence that experience with or exposure to inequality on a day-to-day basis predicts one’s tolerance for inequality (García-Castro et al., 2019). This in turn may motivate one to support policies to reduce economic inequality (Garcíaix Sánchez et al., 2018). In Study 1, I propose a replication of these studies with the goals of 1) providing evidence toward the replicability and reliability of the relationship between these variables, 2) expanding generalizability through conducting this experiment with a U.S. population, and 3) using support for the specific, actionable policy of Universal Basic Income as the dependent variable. In Study 2, I propose a method of intervention to increase support for UBI across political ideologies using personal experience with government redistribution as an intervention method
Drawing the Curtain: A Grounded theory Analysis of the Conceptualizations of Culture, Ethnicity and Race in Professional Training Materials for Child Life Certification
No full textObjectives: Certified Child Life Specialists (CCLS) are pediatric healthcare professionals primarily working in hospital settings to support children and families in navigating the developmental challenges of hospitalization, illness, and enduring medical treatment. Recognizing the presence of racial and ethnic health disparities, coupled with the field’s notable lack of diversity (98% White female), the child life workforce is increasingly acknowledging the undeniable evidence that discriminatory behaviors adversely affect a child’s life and well-being. As advances in the social sciences increasingly reveal that discrimination functions as a socially transmitted disease in a child\u27s life, I predict that the failure of child life certification materials to prepare CCLSs to identify racial bias in clinical practice risks perpetuating discriminatory healthcare practices. Such practices may lead affected children to observe, experience, and internalize racism. This, in turn, can result in numerous harmful effects, including poor health outcomes and the development of maladaptive behaviors that persist throughout a child’s lifespan. To mitigate these impacts, it is crucial to systematically address the role of discrimination in shaping child life outcomes and to ensure that future child life professionals are thoroughly prepared to actively engage in societal antiracism. Methods: Anchored in Garcia Coll and colleagues’ (1996) integrative model of child development, a qualitative, grounded-theory research design was employed to examine how cultural constructs were conceptualized in the professional training materials recommended for mastery in child life certification. A total of 14 documents were reviewed, with the analysis identifying limited segments of text addressing the social constructs under study: “culture,” “ethnicity,” and “race,” as well as emerging concepts aimed at alleviating discrimination through professional training. Results: There were a total of 87 out of 2017 pages (.04%) that mentioned the constructs in this study. Results demonstrate that the cultural-deficit model is deeply embedded in the historical narratives of the child life field, a perspective which attributes a child’s maladaptive development to his/her culture rather than to failures or limitations of the education and training system or to prevalent socio‐positional factors. A discussion on how to draw the curtain on higher-level concepts in professional training materials across the pediatric healthcare continuum is offered, ultimately channeling the child life infrastructure into a direction of critical consciousness and improved cultural praxis