18525 research outputs found
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ANALYTICAL DESIGN OF ENERGETICALLY PASSIVE MECHANISMS
No full textEnergetically passive devices are rigid and complaint mechanisms that can amplify force as well as store and release energy with specific timings and forces. Designing a compliant mechanism for a given task, i.e “inverse design” of unpowered mechanisms, can be done numerically using topology optimization. However, topology optimization is computationally intensive and time consuming, and may not be guaranteed to find a near optimal design. Here we use approximation theory and the property that compliant mechanisms can be modeled by a scalar potential energy function to provide an approximate analytical solution to the inverse design of passive mechanisms. Using the proposed method, we created novel multi-stable mechanical
structures which can (i) store energy like a spring with an unusual torque -deflection curve that decreases as the deflection angle is increased, (ii) store energy like a spring that has three equilibrium lengths of equal
potential energy like three valleys of the same depth, and (iii) store energy like a spring but with three equilibrium lengths of increasing potential energy like a staircase
Insights from the Memory B Cell Repertoire: Molecular Motifs of Viral Reactivity
No full textThe B cell compartment of the adaptive immune system plays a critical role in the generation of antibodies in a variety of immune settings. As humans, we experience repeated exposure to viral antigens through infection and vaccination, resulting in the generation of diverse, and largely unique, antigen-specific antibody repertoires. Despite years of antibody discovery research, however, a detailed mapping of the similarities and differences of antibody responses to different pathogens at the repertoire level is lacking. In this dissertation, using the LIBRA-seq technology, we generated a large dataset of antibody-antigen pairs against twenty viral antigens representing diverse pathogens of biomedical significance. Analysis uncovered virus-specific patterns in variable gene usage, gene pairing, somatic hypermutation, as well as the presence of convergent antiviral signatures across multiple individuals. Our results indicate that, for B cell receptors originating from different individuals but leveraging an identical combination of heavy and light chain germline genes, there is a specific CDR3 identity threshold that defines whether these B cells may share the same antigen specificity, providing experimentally grounded criteria for defining public antibody clonality. Deeper characterization of select antibodies against respiratory syncytial virus (RSV), human metapneumovirus (hMPV), and human parainfluenza virus type 3 (hPIV3), revealed several potently neutralizing antibodies, enhancing our understanding of the sites of viral vulnerability on hPIV3 as well as our understanding of the genetic and structural determinants of cross-reactivity between RSV and hMPV. Elucidation of the fundamental rules governing antibody-antigen interactions can lead to transformative new approaches for the development of antibody therapeutics and vaccines against current and emerging viruses
Immunostimulatory Head and Neck Cancer-associated Fibroblasts Promote T Cell Activation via Prostaglandin E2 and Predict Immunotherapy Response
No full textThe extensive heterogeneity of cancer-associated fibroblasts (CAF) has precluded rigorous understanding of their immunoregulatory role in the head and neck tumor microenvironment (TME). To investigate the relationship between CAF and the immune environment in head and neck cancer, we leveraged protein activity inference tools to analyze single-cell RNA sequencing of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients pre- and post-treatment with the αPD-1 therapy, nivolumab. From this analysis, we identified a novel CAF population predictive of patient response to αPD-1 therapy. Upon further investigation, we discovered that this novel CAF population was able to elicit features associated with enhanced CD8+ T cell function, namely the reduction of PD-1+TIM-3+ exhaustive phenotypes and induction of CD103+NKG2A+ tissue-resident memory phenotypes and cytotoxicity. Due to their unique ability to stimulate T cells in this manner, we termed this novel CAF population T cell-stimulating CAF (tsCAF). In efforts to elucidate the mechanism behind this pro-inflammatory function, we determined that tsCAF secrete prostaglandin E2 to alter CD8+ T cell behavior. However, tsCAF will only secrete PGE2 following T cell-mediated NFkB activation in tsCAF demonstrating crosstalk between T cells and CAF in the head and neck TME. This pro-inflammatory crosstalk between CAF and T cells further contributes to the idea of immunoregulatory pleiotropy among CAF and highlights the importance of distinct CAF subsets in regulating immunotherapy response in human HNSCC
No Country Other Than Thise: Stories
No full textThis collection of seven short stories explores grief, toxic masculinity, and homesickness. In the opening story, “Prophecy,” a young man and his fiancé learn astrology in order to try to escape the xenophobia and toxic masculinity that rule the man’s household. In “Long Sleeves,” two teenage girls in Dubai sneak away to a New Year’s party, only to find that their relationship is forever changed as the night unfolds. In stories titled “Citizen” and “The Bridal Set,” characters who have long-ago renounced Mumbai as their home return for final romps through their hometowns, once again encountering the ghosts within it. In “Study Abroad” and “Those Days,” young women living in contemporary America revisit the violence they have experienced or witnessed at the hands of men, attempting to navigate their own stories and how to tell them to other women, in warning or in solidarity. No Country Other Than This traverses Mumbai, Dubai, and some major American cities, including Houston and Los Angeles. The stories take readers from living rooms to ice skating rinks to laborer’s accommodations, confronting the hidden effects of patriarchy, globalism, as well as portraits of love and power. The women and men in these stories look for ways in which to create new or better lives for themselves while they wrestle with the rigid limitations of patriarchy. Confronted by moments of change or remembering, the characters in these stories look to their pasts in order to better understand themselves, their loved ones, and their present moments
Generality as an Interaction between Recombinative Generalization and Derived Relational Responding
No full textRecommendations for achieving generalized instructional outcomes often overlook the capacity for generative learning. We sought to demonstrate how decontextualized and logically organized instruction would lead to derived and contextually appropriate recombinative generalization and arbitrarily applicable relational responding (AARRing) in multiple contexts. Study stimuli (noun-verb combinations) were arranged in a 3x3 matrix, and individual components were arranged based on assigned arbitrary equivalence classes. Three children with developmental and intellectual disabilities (ages 9-11) participated in this project. We first established individual relations between toys and corresponding signs in American Sign Language. For participants who did not engage in compound responding (noun-verb combinations), training was provided in combinations on the diagonal of the matrix. Following the successful derivation of untrained compound stimuli (recombinative generalization), we provided equivalence-based instruction for component parts, teaching relations between signs and arbitrary stimuli. Following instruction, all participants engaged in derivative responding, providing evidence of AARRing for component parts, AARRing for compound stimuli, and AARRing the context of a game. This outcome demonstrates how teaching simple relations can result in learning that manifests across contexts
thornado-Hydro, xCFC: A Discontinuous Galerkin Hydrodynamics Solver for General Relativisitc Core-Collapse Supernova Simulations
No full textModeling core-collapse supernovae (CCSNe) has been an on-going effort since the 1960s. Despite advances in physics theory, physics experiments, and technology, consistent, multi-dimensional CCSN explosions are still difficult to achieve, and a consensus is yet to be reached regarding what physics is required. Here, we present the status of a novel simulation code, thornado, which aims to simulate the neutrino-radiation kinetics and the stellar hydrodynamics of CCSNe using high-order discontinuous Galerkin methods under the extended conformally flat condition (xCFC), an approximation to GR. Specifically, we show the progress in implementing a solver for the general relativistic (GR) hydrodynamics equations and we show results from several test problems designed to demonstrate the abilities and capabilities of the code. This includes evolving a Kelvin–Helmholtz instability problem, a multi dimensional blast wave, and the adiabatic collapse, bounce, and post-bounce phases of a realistic progenitor. These simulations are performed in parallel with MPI and with adaptive mesh refinement via a coupling to AMReX, a software framework designed for exascale systems. This adiabatic collapse test also demonstrates the coupling of thornado to Poseidon, a hybrid spectral finite-element xCFC metric solver that is also designed with an eye toward simulating CCSNe. We also analyze the performance of the solver with both strong- and weak-scaling tests. As a science application of our code, we show results from a study of the effects of GR on the standing accretion shock instability, a hydrodynamical instability that manifests in, among other scenarios, CCSNe
Defective Mitochondrial and Peroxisomal Fission Dynamics Impair Neurogenesis
No full textMitochondrial and peroxisomal dynamics driven by DRP1 are integral to many cellular functions. Mutations in DRP1 lead to a devastating neurodevelopmental disease known as encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1), which presents with a spectrum of symptoms including developmental delay, seizures, and microcephaly. To interrogate the molecular mechanisms by which DRP1 mutations lead to developmental defects, we used induced pluripotent stem cell (iPSC)-derived models with patient mutations in different domains of DRP1. Given that EMPF1 patients present with a spectrum of neurodevelopmental abnormalities, we differentiated iPSCs into neural progenitor cells and neural organoids. DRP1 mutant neural progenitor cells express lower levels of critical identity transcription factors, such as PAX6 and TBR2. Intriguingly, neural organoids with mutations in the stalk domain of DRP1 take on a choroid plexus identity instead of following a cortical development trajectory. Our results show that EMPF1 associated DRP1 mutations lead to metabolic dysregulation, which may cause changes in neural cell fate during early corticogenesis. Understanding these mechanisms will give insight into the role of mitochondrial and peroxisome dynamics in neurodevelopment, as well as the mechanisms underlying the rare disease EMPF1
Inhibition of the cGAS/STING Pathway for the Treatment of Colitis and Other Inflammatory Diseases
No full textThe cGAS/STING pathway is of paramount importance in healthy immune function due to its role in antiviral and antitumoral immunity. However, chronic or aberrant overactivation of cGAS/STING can cause tissue damage and cell death, leading to serious autoimmune disorders and inflammatory diseases. Thus, STING pathway inhibition in the inflamed tissue may be a viable therapeutic strategy. This work explores the use of nanoparticle carries and albumin hitchhiking to block cGAS/STING signaling in order to illicit a therapeutic effect in a murine model of colitis.
First, we formulated PLGA nanoparticles containing the cGAS inhibitor RU.521 and the STING inhibitor H-151, and we demonstrated the capacity of these STING-pathway inhibiting nanoparticles (SPINs) to inhibit cGAS/STING signaling in mouse and human macrophages and monocytes. Additionally, formulating these SPINs with a benzylated excipient polymer resulted in increased drug loading and extended drug release, while maintaining the inhibitory capacity.
To build upon this work, we designed and tested ROS-quenching poly(propylene sulfide) SPINs, which potently inhibit STING signaling and have a protective effect in oxidative in environments. We observed a trending decrease in STING-driven inflammatory signaling in the colons of mice with DSS-induced colitis when these SPINs were administered orally or rectally every-other-day. After increasing oral administration to daily and including an empty PPS control, we again observed trending decreases in decrease in STING-driven inflammatory signaling.
Finally, we explored albumin hitchhiking as an alternative drug delivery mechanism for colitis, which has never before been exploited for drug delivery in this disease context. We demonstrated that three different albumin-binders accumulate in the inflamed colon in the context of DSS-induced colitis: the albumin-binding dye Evans Blue, a Cy7-labeled albumin-binding nanobody, and a Cy5-labelled albumin-binding lipid-conjugated siRNA.
Overall, the work presented here introduces promising new strategies for STING pathway inhibition, which may be relevant for the treatment of many inflammatory diseases, including colitis. Herein, we have developed modular hydrolytic and ROS-quenching platforms to deliver small molecule STING pathway inhibitors, tested them in a murine model of colitis, and importantly, we have presented albumin hitchhiking as a hitherto unexplored drug delivery strategy for colitis
Think Smaller: Understanding Selenium Pathways in Metal Selenide Nanocrystal Synthesis
No full textAs nanochemistry grows as a field and the applications of nanomaterials emerge, the importance of understanding what happens in the reaction flask during synthesis—thinking smaller than the nanoscale level to the molecular level—has never been more important. Being able to track how the precursors are decomposing and affecting the resulting metal chalcogenide phase leads to more predictable and reproducible nanoparticle syntheses. The following dissertation outlines three mechanistic studies tracking selenium in the production of metal selenide nanoparticles. Diselenides were thoroughly investigated as they are important precursors in synthesizing metstable phases in nanochemistry. First, five hypotheses were explored for why diselenides experience much larger thermal movement in their chemical shift compared to monoselenides or selenols, including 1) rapid equilibrium to an isomer, 2) temperature dependent solute-solvent interactions, 3) shielding, 4) solvent effects, and 5) molecular twisting. Second, molecular pathways from diselenide precursors to all eight copper selenide phases were tracked and two mechanisms were proposed—a Chan-Lam like and hydrogen peroxide like mechanism. Finally, tunable selenoureas and a combination of solvents were explored in the synthesis of iron selenides. Mechanistic deconvolution is still in progress. Ultimately, this dissertation shows progress towards a mechanistic toolbox that can be applied when uncovering pathways in nanoparticle syntheses of metal selenides
Perceptions of Special Education Teachers and Board Certified Behavior Analysts on Self-Determination for Elementary-Aged Children with Complex Communication Needs
No full textSpecial education teachers and Board Certified Behavior Analysts play an important role in supporting the development of self-determination skills for children and youth with disabilities, including at the elementary level. This study used a web-based survey to evaluate the views of special education teachers and BCBAs on self-determination for elementary-aged children with complex communication needs. A total of 166 special education teachers and BCBAs participated. Special education teachers and BCBAs rated the importance of various domains of self-determination for children with complex communication needs and reported on the self-determination capacities and opportunities of individual children with complex communication needs that they served. Results indicated that special education teachers and BCBAs both reported high levels of importance for all domains of self-determination, with no significant differences between the two groups. However, when reporting on the capacities and opportunities of individual children, BCBAs’ ratings were significantly lower than special education teachers’ ratings. Children’s use of robust language-based communication systems (e.g., speech, sign, high-tech aided augmentative and alternative communication [AAC]) was found to be a significant factor associated with special education teachers’ ratings of students’ capacities and opportunities for self-determination, but not BCBAs. Implications for future research and practice are discussed, including those related to the need for practitioner support for creating goals that target self-determination