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Enhancing Aerosol Scattering Measurements: Performance Evaluation and Quality Assurance of AirPhoton Integrating Nephelometers in the Surface Particulate Matter Network
No full textIntegrating nephelometers are key instruments for quantifying aerosol light scattering, a fundamental parameter governing the direct radiative effect of aerosols on climate and visibility, and for interpreting satellite observations of aerosol optical depth. The AirPhoton integrating nephelometer quantifies aerosol light scattering by measuring total scattering from the sample air and subtracting a clean-air reference that represents Rayleigh scattering, instrument wall scattering, and detector background noise. Measurement accuracy depends on rigorous calibration and regular performance evaluation to account for instrumental drift and environmental influences. This study presents a field performance evaluation of the AirPhoton integrating nephelometer within the global Surface Particulate Matter Network (SPARTAN), focusing on sensor stability and long-term clean-air reference baseline drift. Calibration experiments were performed at the SPARTAN laboratory at Washington University in St. Louis. Field evaluations were performed using blue (463 nm) scattering measurements from three SPARTAN sites: Rehovot (Israel), Sherbrooke (Canada), and Melbourne (Australia), each representing distinct climatic regimes and aerosol loadings. Blue (463 nm) scattering data were analyzed in detail, given its higher sensitivity to fine aerosol particles. Across all sites, the forward and backward blue (463 nm) reference sensor signals demonstrated stable long-term values, with a coefficient of variation consistently below 5%. A small seasonal variability observed was primarily driven by temperature-dependent sensor response. Clean-air reference baseline drift exhibited strong dependence on both aerosol loading and precipitation intensity and frequency. At the Rehovot site, characterized by high dust concentrations and a distinct wet season, the baseline remained stable during the dry months (May-October) but increased rapidly from October to January with the onset of rainfall. This increase is attributed to condensation of water vapor inside the nephelometer and enhanced particle deposition on interior surfaces, which becomes more pronounced when aerosol concentrations are high and humidity promotes particle adhesion. Frequent short-duration spikes in daily blue (463 nm) clear air reference scattering were observed during the rainy season, reflecting episodic condensation that subsequently evaporated. At Sherbrooke, where aerosol levels are lowest, the clean-air baseline remained nearly constant year-round, with only a modest rise during winter months (November-March), likely related to snowfall events. Spikes occurred throughout the year but were smaller in magnitude during winter due to lower rainfall and lower absolute humidity. Melbourne exhibited intermediate behavior, with baseline drift following the annual rainfall cycle and spike magnitudes reflecting its moderate aerosol burden and higher absolute humidity. This study recommends recalibrating the nephelometer when the moving-median clean-air baseline exceeds 20% of the 30-day moving average of ambient scattering and flagging days as invalid when the average scattering during the clean-air reference period exceeds 10% of ambient levels. This study provides new insights into environmental influences on nephelometer clean-air reference baseline drift and establishes site-specific patterns that can inform recalibration intervals. These findings improve the reliability and quality assurance of nephelometer scattering measurements within SPARTAN, supporting more accurate aerosol optical characterization for interpretation of satellite observations and aerosol modeling
Integrating Large Language Models and Single-Cell Omics Analysis for Target Discovery in Pancreatic Ductal Adenocarcinoma
No full textThe elucidation of cell-type–specific signaling networks is central to understanding pancreatic ductal adenocarcinoma (PDAC) and to nominating mechanistically grounded therapeutic targets. We present a Text-to-Target framework that integrates large language models (LLMs) with single-cell omics to couple literature-derived hypotheses to cell-type–resolved expression evidence. Using publicly available datasets, we construct malignant ductal epithelial and lineage-matched acinar meta-cell cohorts from PDAC and perform differential expression analysis to obtain a robust catalogue of disease-associated transcriptional changes. In parallel, an ensemble of LLMs is prompted in a schema-constrained manner to retrieve cell-type–specific targets, pathways, and mechanistic annotations from the biomedical literature. After normalization and quality control, LLM outputs are intersected with PDAC meta-cell DEGs to define an LLM-supported DEG set, which serves as the interface between text priors and omic evidence. We then perform pathway-level integration using over-representation analysis augmented by three LLM-aware scores that quantify pathway recall, expression-weighted activation, and directional concordance, yielding an overall ranking of signaling axes. This integrated analysis recapitulates canonical PDAC modules such as KRAS–MAPK and PI3K–AKT–mTOR, highlights angiogenic and immune checkpoint programs, and elevates replication stress and DNA damage response pathways, including ATR- and PARP-associated circuits, as high-confidence candidates. More broadly, the study demonstrates how this framework can standardize heterogeneous omics and textual knowledge into a unified computational pipeline, enabling reproducible, mechanism-oriented target and pathway discovery in PDAC and, in principle, other complex diseases
Functional Characterization of ABCC8 Mutations Potentially Linked to the Transition from Hyperinsulinemic Hypoglycemia to Diabetes
No full textATP-sensitive potassium (KATP) channels, composed of the SUR1 and Kir6.2 subunits encoded by the ABCC8 and KCNJ11 genes, are critical regulators of membrane excitability and insulin secretion in pancreatic β-cells. Gain-of-function (GOF) mutations in these genes cause neonatal diabetes mellitus through impaired insulin secretion and persistent hyperglycemia, whereas loss-of-function (LOF) mutations lead to congenital hyperinsulinism (CHI) with hypoglycemia due to β-cell hyperexcitability. I have addressed a paradoxical form of maturity-onset diabetes of the young (MODY) arising from KATP mutations, in which patients transition from CHI to glucose intolerance later in life. My experiments indicate that many KATP mutations associated with later onset diabetes (MODY) are LOF, thereby significantly expanding the cohort of patients affected by this form of MODY
The Indoorsman
No full textThe Indoorsman is a memoir in essays depicting the experience of a Puerto Rican growing up right on the cusp of the analog and digital worlds. The information age transformed his insular island life, granting access to other worlds from the comfort of his computer, however, it also led to a chronic addiction he is constantly rehabilitating. On these islands of enchantment, the writer grapples with the seductive nature of the internet and its encroachment on everyday life. The tropical cyborg that emerges exists in between worlds, navigating online and offline spaces, Puerto Rico, USA, monolingual and bilingual environments, degrowth/hypercapitalism, urbanism/ruralism, indoors/outdoors. The collection centers identity, personas, integration, isolation, assimilation, media literacy, ecocriticism, surfing the webs of contemporary life logged on and off. The events take place in the nineties, before and after dialup access, all the way to present day interfacing with natural landscapes and virtual worlds. Equal parts incisive, sardonic, romantic, and irreverent, The Indoorsman is a living, evolving creative/critical text that will exist as a physical book and a digital humanities project. It bends genre, weaves disciplines and plays with multimedia, delineating the struggle of decolonization and relapses of its protagonist on this complex world
Jim Crow Medicine: Race in JAMA, 1883-1982
No full textUsing a historical approach I examined race discourse within the Journal of the American Medical Association (JAMA) between 1883 and 1982 to better understand how race concepts connect to the production of medical knowledge and ignorance; how they influenced the production of legal and medical policy; how they related to the production and maintenance of health injustice; and how oppressions and injustices are interrelated. I found a clear differentiation between Jim Crow era and post-Jim Crow race discourse. Jim Crow era race discourse was characterized by a nested, bio-nationalist construct of race, an explicit commitment to White supremacy, a sense of racialized professional responsibility that included sometimes explicit disinterest in and resentment toward Black patients, and enthusiastic advocacy for race-informed policy, especially eugenics. Notions of race quality and improvement are tightly related to ableism, including sanism, and to heterosexist and cissexist views of women as reproducers. Post-Jim Crow race discourse largely treats race as an obvious, fundamental division of human bodies but lacks explicit justification; it does not explicitly confront or acknowledge earlier white supremacy, ableism, or sexism
The Floquet Stability of Two-Bladed Teetering Rotors in Forward Flight
No full textThis report presents a comprehensive analysis of the flap mode stability for a two-bladed teetering rotor using Floquet theory, focusing on the parameter space defined by the advance ratio (μ) and lock number (). The study employs numerical integration to compute the monodromy matrix and Floquet multipliers over a grid of μ from 0 to 3.0 and γ from 0 to 20. Key findings include distinct regions of instability where the maximum magnitude of the Floquet multipliers (|ρ|_{\max}) exceeds 1, primarily at higher μ values. Instability boundaries are identified, revealing two primary unstable lobes: one at lower (approximately 1.0–12.0) starting around μ ≈ 1.5, and another at higher (≥14) with onset at progressively lower μ (decreasing from ≈2.9 to 2.6). Eigenvalues are predominantly real in unstable regions and complex in stable ones, consistent with divergencetype instabilities
The Effect of Fascicular Elastin on the Mechanical and Functional Properties of Healthy, Damaged, and Healing Tendon
No full textMechanical properties of tendon are highly influenced by structural protein composition and microscopic sub-structures. Within the largest subunit of tendon, the fascicle, the role of the elastin protein remains understudied despite impressive extensibility and fatigue resistance of its resulting elastic fibers. While previous work catalogued contributions of fascicular elastin across tendon type and species, the anticipated effects of elastin in fatigue and healing have not yet been explored. While previous knockout mouse models showed that disruption of elastic fibers led to altered mechanical properties (e.g., increased linear modulus), these models depended on heterozygous elastin deficiency or indirect knockout of proteins related to elastic fibers. Thus, opportunities for in vivo studies were limited, since remaining elastin could possess inherent bioactivity even with elastic fiber disruption. To this end, a novel murine model of local elastin knockout Prx1Cre+;Elnfl/fl was developed. Tendons from Prx1Cre+;Elnfl/fl mice were examined and found to share similarities with previous models, but with increased sensitivity to previously unknown elastin contributions. Results differed by tendon type, with linear modulus increases in energy-storing tendons (i.e., Achilles or AT) and decreases in positional tendons (i.e., tibialis anterior or TB). Next, fatigue- xiii to-failure testing was performed, where Prx1Cre+;Elnfl/fl tendons had decreased fatigue life and increased energy loss in early cycles. Elastin knockout resulted in increased AT strain accumulation throughout testing and variable effects on damage accumulation by tendon type, as measured by collagen hybridizing peptide (CHP) assay and collagen fiber kinking (with development of custom image processing software). A subsequent study applied 50% fatigue failure to functionally distinct tendons followed by subsequent stress relaxation (SR) and ramp-to-failure testing. Mechanical properties were observed to be reduced after cycling, though no differences in damage accumulation by genotype were measured, suggesting that evidence of damage likely emerges in the second half (i.e., 50- 100%) of fatigue testing. While differences in ramp properties between genotypes were no longer apparent for sub-failure fatigue tendons, SR properties were altered in Prx1Cre+;Elnfl/fl tendons. Moreover, elastin was shown to modulate dynamic fiber engagement during AT cycling, which persisted post-rupture as quantified by the spread of fiber orientations. These results suggested that elastin may rely on different underlying mechanisms to impact mechanics depending on tendon type. Lastly, the role of elastin in post-rupture healing was investigated in Prx1Cre+;Elnfl/fl mice through unilateral partial AT transection and treatment injections (tropoelastin, saline, or no injections). Notably, we found non-injected Prx1Cre+;Elnfl/fl mice exhibited worse functional (i.e., gait) outcomes than all other groups, as measured by high-speed video and a custom automated DeepLabCut/Python pipeline. Moreover, non-injected Prx1Cre+;Elnfl/fl tendons alone exhibited significant tendon lengthening and contralateral imbalance between multiple mechanical properties. While injection of any kind modulated some morphological and mechanical properties, saline injections produced more unintended effects (e.g., tendon thickening) than tropoelastin. xiv Overall, this study has shown that the presence of elastin impacts tendon health at multiple levels, including improved mechanics, fatigue resistance, and recovery following injury. This work provides multiple novel insights that are impactful on their own but also lay the foundation for future research to optimize elastin-informed treatment strategies to limit tendon degeneration and increase healing following injury
Elucidating the Role of the Synovial Matrix in Drug Transport and Disease
No full textThe synovium is a thin, multi-layered tissue that envelops the diarthrodial joint and regulates molecular transport between the intra-articular (IA) joint space and systemic circulation; it also drives inflammation during joint pathology. Local drug delivery to the IA space is appealing for its efficacy in targeting disease of localized joints such as osteoarthritis. However, benefits of IA drug delivery are hindered by rapid clearance through the synovium, warranting investigations of solute--matrix interactions in trans-synovial solute diffusion as well as pathological changes to the synovial matrix to enhance models of IA drug transport. This dissertation first explores the effect of molecular weight (MW) on solute diffusion through porcine and human synovial explants as a model of IA drug clearance. Here, a previously established multiphasic finite element model (FEM) of synovium was combined with an unsteady diffusion experiment in vitro that mimicked a bolus drug delivery to the joint space. Concentration profiles of neutral solutes measured experimentally over time were numerically matched to those predicted by the FEM and fitted to a first-order exponential decay, yielding an effective diffusivity and a time constant that correlated well with each other after controlling for sample thickness. Experimental data also agreed with MW-dependent IA clearances previously reported in the literature. These are the first reports of intrinsic solute diffusivities through synovium, which form the foundation for understanding trans-synovial solute transport. The second aim of the dissertation builds upon the first by adapting the FEM of synovium to accommodate charged solutes, allowing for measurement of the effective diffusivity of anionic, cationic, and neutral dextrans of two MWs (4 kDa and 20 kDa) through human explants. Another prerequisite was the inclusion of the fixed charge density of synovium, which was reported here for the first time and found to be negligible, orders of magnitude lower than that of other soft tissues. Based on FEM predictions and exponential fitting of experimental clearance data, both charge and MW contributed to solute diffusivity. Cationic charge accelerated solute diffusion, one of the first findings related to charged solute--matrix interactions in synovium. In the third aim of the dissertation, collagen-induced arthritis (CIA) was established in rats as a platform for characterizing the collagen morphology and mechanical properties of diseased synovium. Optical tissue clearing, second harmonic generation microscopy, and the gray-level co-occurrence matrix (GLCM) were combined, promoting image texture analysis of full-thickness z-stacks of healthy and CIA rat synovium. GLCM-derived texture parameters suggested the presence of thicker and less organized collagen fibers in CIA synovium. Additionally, nanoindentation data showed that CIA synovial explants are softer than non-degenerate ones, particularly in the intimal layer. This work included the first quantitative assessment of collagen fibers in synovium that bolster our understanding of synovial architecture during pathology; it also presented moduli that can be used to further refine models of drug transport through diseased synovium. The work presented in this dissertation further elucidates the role of the synovial matrix in both drug transport and disease. These findings will enhance not only future complex models of drug transport to better guide the rational design of IA therapeutics for treating arthritis, but also our fundamental understanding of the pathology of synovium
Selective Binding of Amino Acids by Clay Minerals and Altered Rocks in Prebiotic Systems
No full textMineral-water partitioning provides a mechanism for the selection and concentration of simple organic compounds, such as amino acids, into the adsorbed phase prior to prebiotic evolution into more complex bio-macromolecules. Smectite and serpentine clays are the major alteration phases expected for early Earth and planetary systems. These clays vary in structure and composition, properties which influence their reactivity. Smectites, in particular, could have been effective at concentrating amino acids in early aqueous environments due to their high surface area (i.e., large number of reactive sites), permanent negative structural charge, and high cation exchange capacity. Serpentines, on the other hand, do not have hydrated interlayers and have negligible structural charge, so they should show distinct binding affinities based on adsorption to edge sites. However, the systematics of selective organic binding to clay minerals is poorly characterized in fluid compositions relevant to prebiotic systems. Therefore, the selective adsorption of amino acids to smectite and serpentine clays, as well as hydrothermally-altered rocks, was investigated through three experimental approaches. In the first study, the selective uptake and adsorption mechanisms of 10 amino acids (L-arginine, L-lysine, L-asparagine, L-tryptophan, L-serine, L-threonine, L-alanine, glycine, L-leucine, and L-glutamic acid) to the smectite montmorillonite were explored under varied fluid compositions (10 mmol/L NaCl or MgCl2) and pH (5 or 7). The amino acids studied had various R-groups (basic, acidic, amide, hydroxylic, aromatic, aliphatic, and none), which influenced their selectivity due to the amphoteric nature of amino acids in solution. The basic amino acids (L-arginine and L-lysine), which are predominantly cationic at pH 5 and 7, were selectively adsorbed to montmorillonite compared to other amino acids with their uptake minimally affected by changes in pH but substantially inhibited in the magnesium chloride fluid. This suggests that their adsorption was dominated by cation exchange into smectite interlayers. The adsorption mechanisms of the basic amino acids were characterized using attenuated total reflectance Fourier transform infrared spectroscopy and powder X-ray diffraction. Results indicated that L-arginine and L-lysine are intercalated within the montmorillonite at orientations parallel to the basal plane, with strong interactions between the protonated amino sidechain and the mineral surface. This observation further supports adsorption driven primarily through electrostatic interactions between amino acids and the negatively charged smectite surface. In the second study, the binding affinity of four amino acids with different chemical properties (L-arginine, glycine, L-threonine, and L-glutamic acid) to three smectites (montmorillonite, nontronite, and saponite), one serpentine (lizardite), and two altered rocks (diabase and dunite) was evaluated in 10 mmol/L NaCl at pH 5, 7, and 10. Adsorption varied among the clays and altered rocks due to varying properties of the single-phase clays and alteration products (i.e., mineral structure, composition, particle size layer charge, and location of the layer charge), as well as cations released from the clay and altered rock suspensions. Overall, the dominant clay (either smectite or serpentine) produced in the alteration assemblages controlled the adsorption of amino acids. The smectites and altered diabase showed strong affinity for L-arginine with the binding affinity weakly decreasing as the pH increased from 5 to 7 but strongly decreasing as the pH increased from 7 to 10. In contrast, the binding affinity of glycine, L-threonine, and L-glutamic acid weakly decreased as the pH increased. As a result, adsorption showed two co-occurring adsorption mechanisms universal to smectites: cation exchange of cationic amino acids within hydrated interlayers and baseline adsorption via surface complexation on edge sites. In contrast to the smectites, lizardite and altered dunite showed no relationship between the Langmuir constants and amount of cationic species in solution, instead displaying only baseline adsorption via surface complexation. Lizardite had higher affinity for L-arginine adsorption at pH 7 and 10, albeit much weaker than the smectites, whereas altered dunite showed binding affinities for L-glutamic acid equal to L-arginine at pH 7 and greater than L-arginine at pH 10. This deviation from lizardite likely occurred due to enhanced cation bridging to the octahedral sheet attributed to the release of Ca2+ from the dissolution of an alteration product in altered dunite. As a result, higher concentrations of divalent cations, especially Ca2+, could be important for enhanced adsorption of acidic (i.e., glutamic acid and aspartic acid) amino acids to serpentines in early environments, whereas competition with divalent cations for interlayer binding sites suppresses cation exchange of amino acids to smectites. In the third study, the selective uptake of 22 proteinaceous and non-proteinaceous amino acids (including four sets of L- and D-enantiomers) to seven smectites of varying Fe(III)-Mg-Al compositions and lizardite was evaluated in seawater. Two seawater fluids were used with initial amino acid concentrations of 210 and 730 nmol/L of each amino acid on average. Clay mineralogy affected selectivity patterns with adsorption normalized to glycine exhibiting selectivity that varied up to 100×, depending on the amino acid. The smectites showed strong selectivity for the cationic amino acids (arginine and lysine) in both seawater fluids. In contrast, lizardite showed strong selectivity for arginine and aspartic acid with weaker selectivity (i.e., lower adsorption) for lysine. Amino acid adsorption differed due to extrinsic and intrinsic properties of the minerals, such as clay-induced pH changes, layer charge, and particle size. In general, adsorption to smectites was controlled by the total layer charge and location of the layer charge for cationic amino acids, whereas clay-induced pH changes controlled adsorption of the anionic amino acids. This behavior demonstrates that cationic and anionic amino acids adsorb at different smectite binding sites consistent with adsorption through cation exchange within hydrated interlayers for cationic amino acids and surface complexation to edge sites for anionic amino acids. For the four sets of L- and D-enantiomers, chiral selectivity was negligible to weak among the clays, suggesting that clay mineral adsorption in realistic fluid matrices is unlikely to induce the substantial chiral selection needed to support the development of homochirality for terrestrial life. The results of this dissertation contribute to a fundamental understanding of the role of the smectite- and serpentine-water interface in the emergence of complex biochemistry on the prebiotic Earth and geochemical origin of life. These studies reveal that affinity and selectivity for basic amino acids is a consistent feature of prebiotically-relevant clay minerals and fluid compositions. The selectivity for basic amino acids to smectites (stronger) and serpentines (weaker) suggests that these amino acids are strongly retained by clays in prebiotic environments, likely skewing their detection in extraterrestrial samples and affecting amino acid migration, accumulation, and polymerization during fluid circulation in prebiotic environments. The affinity and selectivity of amino acids varied by up to 100× among different amino acids under varying conditions (i.e., fluid composition and pH), demonstrating that 100× variation in dissolved concentrations is required to create equal solid-phase concentrations of amino acids. This behavior may have enabled polymerization and biological utilization of arginine and lysine concentrated in the adsorbed phase despite their limited abiotic production. While fluid- and mineral-specific effects among other amino acids were weaker, amplification of these patterns during fluid flow provides a mechanism for generating distinct amino acid profiles in different environmental setting
Mitochondria Transfer-based Therapy for the Mitochondrial Disease Leigh Syndrome
No full textLeigh syndrome is a severe neurodegenerative disease caused by mutations affecting mitochondrial electron transport chain function, the most common of which impair complex I. Children with Leigh syndrome acquire symptoms of psychomotor regression, ataxia, failure to thrive, seizures, and typically die by the age of 3. There are no treatments for Leigh syndrome and disease pathophysiology is poorly understood. Recently, mitochondria transfer has been described as a method to provide metabolic support to cells with impaired respiratory function. However, the application of mitochondria transfer-based therapies to improve mitochondrial disease has not been explored. Here, I show that bone marrow transplant improves morbidity and mortality in the Ndufs4 KO mouse model of Leigh syndrome and led to widespread transfer of donor mitochondria to Ndufs4 KO acceptor cells. These findings were recapitulated via administration of isolated mouse mitochondria to Leigh syndrome mice, establishing novel therapeutic approaches leveraging mitochondria transfer for the treatment of mitochondrial diseases. I show that these therapies are associated with no change to immune cell composition or inflammatory cytokine production, suggesting healthy mitochondria are intrinsically non- immunogenic. I further explore the effect of complex I deficiency on mitochondrial function using multiplexed quantum sensing for the first time in mouse primary cells. Measurement of intracellular temperature revealed decreased temperature in Ndufs4 KO cells, which was improved by mitochondria transplant. Further, I show that mitochondria coordinate cellular temperature and magnetism in a manner dependent on complex I function. Finally, I provide preliminary evidence that this process is dysregulated in cells from patients with Leigh syndrome, suggesting this disease can be characterized as a thermomagnetic disorder. This work reveals potential new approaches for the treatment of Leigh syndrome and suggests that thermomagnetic regulation could be a novel therapeutic target for this disease