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DiGiT: A Diffusion-based Modular Geophysical Toolkit for On-device Multi-modal Data Generation
Get PDFFull-wave inversion (FWI), as a fundamental scientific approach to deducing unknown or unobservable subsurface properties, holds significant value in geophysics applications. Traditional FWI methods rely on physics-driven approaches that demand substantial computational resources. Recently, with the breakthroughs in machine learning (ML) and the prevalence of AI for science, data-driven approaches have been applied to FWI, showing promising results. However, as these applications often necessitate deployment in diverse regions with remote and extreme environments, localization of ML models on edge devices becomes imperative. A promising approach involves leveraging Generative AI models and governing wave equations to generate paired training data, including geophysical measurements (i.e., seismic waveform) as data and corresponding velocity maps as labels for model fine-tuning. However, the limited resources on edge devices pose significant challenges to achieving high software efficiency and low latency. In this paper, we present a toolkit, namely DiGiT, a diffusion-based modular geophysical toolkit platform. One key component is a library of decomposed modules from the widely used geophysical designs. Benefiting from the flexibility of combining modules, we composite a toolkit for the generation of on-device diffusion-based paired geophysical training data. The toolkit includes a 1-in-2-out network structure and diffusion model distillation, both of which can significantly reduce the computational time. Experiments on the OpenFWI dataset show that the DiGiT toolkit can generate paired seismic waveform and velocity map in seconds, which is over 100 × speedup compared with the sequential execution of the diffusion model and the wave equation-based forward modeling
Homologous Recombination Is Associated with Enhanced Anti-Tumor Innate Immunity and Favorable Prognosis in Head and Neck Cancer
Get PDFBackground/Objectives: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy, often diagnosed at advanced stages with poor survival outcomes. Homologous recombination (HR), a major DNA double-strand break (DSB) repair pathway, safeguards genomic stability via error-free repair. While HR deficiency has been well established as a driver of genomic instability and tumorigenesis in several cancer types, the role of HR in HNSCC remains relatively understudied. Methods: Here, we analyzed the expression patterns of key HR proteins in HNSCC and investigated their association with clinical parameters, DNA methylation, immune cell infiltration, and patient survival outcome. Results: Surprisingly, our results demonstrate that HR factors are consistently upregulated in HNSCC, in both HPV-positive and HPV-negative groups. Survival analysis identified many HR factors, including ATM, BRCA1, BRCA2, PALB2, LIG1, RPA1, and RPA2, as potential prognostic biomarkers for better overall survival. Interestingly, we observed a significant correlation between HR protein overexpression and immune cell infiltration in HNSCC, suggesting a potential immunomodulatory role of HR proteins. To experimentally validate this association in both HPV-positive and -negative cell lines, we showed that MRE11 and RAD51 overexpression in HNSCC cells led to increased phosphorylation of IRF3 and STAT1, indicating activation of the cGAS/STING-mediated innate immune signaling. Conclusion: Together, our findings provide a comprehensive overview of the HR pathway in HNSCC, highlighting the dual role of HR proteins in both genomic maintenance and immune regulation. The consistent upregulation of HR proteins, their association with disease progression, and potential immunogenic effects underscore their promise as diagnostic/prognostic biomarkers and therapeutic targets in HNSCC
Nutritional Support for Gastrointestinal Cancer Patients: New (and Old) Frontiers in Management, a Narrative Review
Get PDFMalnutrition in patients with gastrointestinal (GI) cancers can be the result of functional and/or anatomical changes in the alimentary tract, secondary to malignancy or oncologic therapies. Understanding the underlying mechanisms of malnutrition in these patients is imperative in providing appropriate interventions that can not only improve quality of life for these individuals, but also improve their tolerance of oncologic treatment and progression towards remission or cure. In this narrative review, we address common nutritional deficiencies associated with GI malignancies, including pancreatic, biliary, and hepatic cancers. Furthermore, we address common issues related to these deficiencies and causes of nutrition barriers as they relate to organ malfunction or surgical alterations of anatomy. Recommendations for counseling, dietary modifications, nutritional supplements, and pharmacologic interventions are provided based on individual barriers and the vital role of multidisciplinary care is highlighted. Additionally, we highlight novel techniques, such as the role of psychosocial care, prehabilitation, digital health, and machine learning, which can improve nutritional outcomes, provide patient-directed care, and improve risk stratification for this complex and multifaceted issue that faces patients diagnosed with GI cancers
Tumor biology and access to care and metastatic breast cancer outcomes
Get PDFPurpose To understand how access to care influences metastatic breast cancer burden (MBC) while accounting for molecular tumor characteristics, and identify interventions to reduce metastatic disease burden. Methods The Carolina Breast Cancer Study is a population-based cohort with invasive breast cancer (diagnosed 2008–2013). Both de novo metastasis (stage IV at diagnosis) and distant recurrence were evaluated (12 years of follow-up. Tumor data were from medical records, pathology reports, and RNA expression data. Social variables and access to care were from participant surveys. Generalized linear models were used to estimate associations of biological and access characteristics with MBC; Cox models were used to estimate recurrence hazards. Results 464/2998 patients (15.5%) had MBC (n = 109 de novo; n = 355 recurrent). MBC was associated with grade 3 vs 1 (odds ratio (OR) = 4.15, 95% CI: 2.60, 6.99), LumB vs LumA (OR = 2.08, 95% CI: 1.48, 2.90), and high vs low PAM50 risk of recurrence score (OR = 4.45, 95% CI: 2.93, 6.99) vs. non-MBC. MBC was associated with Black race (Hazard ratio (HR) = 1.66, 95% CI: 1.32, 2.11), poverty (HR = 1.47; 95% CI: 1.09, 1.99), and low education (HR = 1.48, 95% CI: 1.03, 2.13). Controlling for healthcare access (screening, regular care, delayed treatment, and community healthcare) attenuated associations with metastasis for poverty and education, but had lesser effects on race associations. Conclusions Disparities in MBC burden persist after adjustment for individual- and community-level healthcare access. Reducing burden of MBC in Black women necessitates simultaneous targeting of biological and access to care factors. Supplementary Information The online version contains supplementary material available at 10.1007/s10549-025-07881-6
Analyzing the Reliability and Precision of Fast-Pitch Softball Kinematics Using Markerless Motion Capture
Get PDFThere is limited research the kinematics of the softball pitching motion, especially with markerless motion capture. Objective: Determine the test-retest and intersystem reliability of OpenCap when analyzing stride length, knee flexion, trunk flexion, trunk lateral flexion, and trunk rotation at stride leg foot contact. Participants: 9 softball pitchers with college pitching experience. Methods: This study examined the test-retest and intersystem reliability with which OpenCap can measure kinematics in a softball pitching motion. Subjects completed 2 sessions of 5 successful fastballs measured by two OpenCap systems running concurrently. Results: Variables were measured with moderate to excellent reliability with ICC values ranging from 0.614-0.987. All variables were significant (p<0.05) except for test-retest reliability of trunk rotation. Conclusion: The results illustrate that OpenCap can be used to reliably measure some kinematic variables during a softball pitching motion. This technology could be used for injury prevention and performance enhancement. More research needs to be done to determine the full extent of its use.Master of Art
Triggering-Effect Models for Multi-Type Recurrent Events and Biased Coin Randomization for Biomarker-Stratified Multiarm Trials
Get PDFMulti-type recurrent events frequently arise in lifetime data analysis. It is reasonable to assume that previously occurred events can trigger more events to come, either of homogeneous or heterogeneous categories. Previous work has focused on non-linear triggering models when there is only a single event type. We propose a general Cox-type structure for modeling the triggering effects among multiple types of events. In Chapter 2, we introduce the general structures of the triggering-effect models for single-event data and multi-type event data. We derive partial likelihood estimators and establish the consistency and asymptotic normality of the estimators, as well as provide plug-in variance estimators. We develop an algorithm to efficiently compute the partial likelihoods, gradients, and Hessian matrices of the models. We demonstrate a good performance of the methods through a series of simulation experiments. The models are applied to a cohort of patients with Li-Fraumeni syndrome (LFS) to analyze the triggering effects between breast cancers versus non-breast cancers. In Chapters 3, we introduce the frailty extension of the triggering-effect models to adjust for cluster effects and unobserved heterogeneity. We use the penalized partial likelihood approach to set up the estimation and inference procedures. We derive the penalized partial likelihoods for the main parameters of interest, and the profile likelihood for the variance parameters. We derive corresponding estimation procedures, and adjust the inference methods accordingly. We develop a two-loop algorithm to implement the estimation process. Simulation experiments are carried out to demonstrate the feasibility of proposed methods. We apply the models to LFS data to investigate the family heterogeneity among patients. In Chapter 4, as a separate topic, we describe how to implement a biased coin design to achieve the desired allocation ratios across interventions and between the number of biomarker-positive and biomarker-negative participants assigned to each intervention. We discuss about how the algorithm performs in terms of the balance of covariates prevalence and the situation of crossover studies. We simulate several scenarios to illustrate the proposed method with the randomization algorithm implemented in the Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) trial.Doctor of Philosoph
ROLE OF A FLEXIBLE, ALLOSTERIC LOOP IN REGULATING PROTEIN ACTIVITY
Get PDFAllostery is a key driver of protein function and behavior in biological systems. While structure-based classical models and protein dynamics have greatly advanced our understanding of allostery, our knowledge of the underlying mechanisms of allosteric communication remains limited. This is evidenced by the ongoing challenges in engineering allosteric proteins and therapeutics, underscoring the need for deeper insights into the mechanisms governing allostery. Here, we investigate the allosteric protein chorismate mutase (CM), a homodimeric enzyme critical for the biosynthesis of aromatic amino acids. Although CM is differentially regulated by tryptophan and tyrosine through a shared pocket located over 25 Å from the active site, both TrpCM and TyrCM yield nearly identical NMR spectra corresponding to a “tense” T-state. TrpCM shows minor excursions into an excited state that aligns well with a “relaxed” R-state; however, it remains unclear whether this T-to-R pre-equilibrium is essential for CM function. In this work, we demonstrate that the R-state population in TrpCM can be substantially reduced by modifying buffer conditions. Lowering the salt concentration decreases the R-state population by more than half without significantly impairing enzymatic activity. Furthermore, we present a constitutively active CM variant fixed in the T-state without access to the R-state or other alternative microstates, suggesting that a pre-existing switching to the R-state may not be strictly required for catalytic activity. Subsequently, we demonstrate that a mutation within a structurally invisible and highly flexible loop, loop 11-12, located far from the active site, drastically alters CM’s activity landscape. Through paramagnetic labeling of the loop, we show that loop 11-12 undergoes transient excursions toward the active site only in the presence of the activator Trp, which binds over 20 Å away. Furthermore, employing a novel NMR approach, we show that loop 11-12 modulates CM’s electrostatics, potentially influencing charge distribution to optimize enzymatic activity. Our findings support a sophisticated allosteric process in which a flexible, distal loop is functionally coupled to both the effector binding region and the active site. This mechanism provides new insights into the diverse ways proteins achieve allosteric regulation and may contribute to understanding flexible regions in other allosteric systems.Doctor of Philosoph
Roosting birds link built structures to nutrient dynamics in human-altered coastal ecosystems
Get PDFCoastal birds are important biogeochemical vectors, redistributing nutrients within and between coastal environments. These inputs can enhance primary production, alter food web dynamics, and support the productivity of ecologically and economically valuable species. However, coastal habitat loss has increased bird reliance on built structures for roosting and nesting, reshaping where nutrients are deposited in nearshore habitats. In Chapter 1, I investigate how bird use of built structures changes with water level in a developed coastal setting, using biomass distribution data from a year-long set of transit surveys. Across all birds and individual functional groups (gulls/terns, shorebirds, wading birds, cormorants/pelicans), the proportion of biomass using built structures increases with higher water levels, suggesting even greater use as water levels rise. In Chapter 2, I estimate bird-derived nitrogen (N) and phosphorus (P) inputs at three farms using hourly camera trap monitoring and complementary metabolically informed nutrient loading models. N loading is on the scale of 4-58 kg N y-1 across sites and models, with farms exhibiting a sharp nutrient input peak during fall (September-November) driven by staging and migrating birds. When scaled as site-specific fluxes (g N m-2 y-1), these N inputs represent notable localized contributions that likely exceed other N sources such as biological fixation and atmospheric deposition. In Chapter 3, I assess the ecological consequences of these N inputs during fall migration using a before-after-control-impact (BACI) experiment to quantify isotopic (δ15N/δ13C) enrichment and trophic propagation in oyster-associated organisms. Relative δ15N enrichment is evident across multiple trophic levels post-migration, with fixed macroalgae and oyster tissue providing two distinct pathways for bird-derived N to enter the ecosystem. δ15N enrichment does not, however, scale proportionally with N input, indicating that other factors govern rates of localized incorporation. Collectively, this work highlights how coastal birds adapt to and utilize built structure in developed coastal ecosystems, and how these behaviors influence nutrient dynamics and ecosystem function. As human activities continue to reshape coastal environments, understanding the ecological consequences of bird use of the built structures will be essential for managing productive habitats where humans and birds can coexist.Doctor of Philosoph
Evaluating a New Master's Entry Program in Nursing Using the CIPP Model
Get PDFMaster’s Entry in Nursing Practice (MEPN) programs are an emerging model in pre-licensure nursing education, requiring evaluation of institutional readiness, stakeholder needs, and alignment with national standards before implementation. At the University of North Carolina at Chapel Hill (UNC– CH) School of Nursing, this Doctor of Nursing Practice project used the Context, Input, Process, Product (CIPP) evaluation framework to assess readiness for a proposed MEPN program. Faculty surveys (n=10), faculty focus groups (n=8), current ABSN student focus group (n=6), ABSN alumni survey (n=4), and semi-structured interviews with MEPN graduates from peer institutions (n=5) were conducted. Data were analyzed using qualitative content analysis in ATLAS.ti guided by a nine-subcode coding framework, supplemented by benchmarking of five peer MEPN programs and validation of proposed terminal program outcomes using a Content Validity Index rubric. Findings indicated that faculty expressed enthusiasm for program innovation and graduate-level teaching but identified workload management, instructional design support, and protected time for curriculum development as critical needs. ABSN students emphasized communication challenges, curriculum rigor, and the importance of balancing adult learner responsibilities, while alumni highlighted delivery format, program cost, and institutional prestige as influential factors. MEPN graduates described advantages and pressures associated with being perceived as “advanced,” while also noting uncertainties in role clarity and preparedness for leadership. Benchmarking confirmed that the proposed UNC–CH MEPN program is consistent with peer institutions, and faculty validation confirmed that terminal program outcomes are fully aligned with national standards and institutional mission. Based on these findings, recommendations include prioritizing faculty development and workload transparency, establishing clear communication strategies, supporting adult learner needs, and clarifying the professional role of MEPN graduates. Collectively, this project confirmed institutional readiness for MEPN program implementation and identified targeted resource gaps that must be addressed to ensure program success.Doctor of Nursing Practic
CONSIDER THE CONTEXT: CHARACTERIZING STIMULUS DEPENDENT GENETIC EFFECTS IN HUMAN NEURAL PROGENITOR CELLS
Get PDFGWAS-implicated common genetic variants associated with complex brain traits and neuropsychiatric disorders primarily reside in non-coding regions. Functionally characterizing these variants is challenging because their regulatory effects are often context-dependent, becoming apparent only in specific cell types, developmental windows, or in response to stimulus. Studying variants in static, bulk post-mortem tissues obscure this crucial context-specificity. To address this, we utilized a "Gene-by-Environment (GxE) in a dish" approach, leveraging a large, genetically diverse cohort of primary human neural progenitor cells (hNPCs), a relevant fetal-stage context for cortical development. We performed multi-omic profiling, RNA-sequencing (RNA-seq) for gene expression and ATAC-sequencing (ATAC-seq) for chromatin accessibility, across disease-relevant contexts. These included stimulation of the fundamental neurodevelopmental Wnt signaling cascade and exposure to psychiatric medications Valproic Acid (VPA) and Lithium Chloride (LiCl). This interrogation successfully revealed thousands of genetic detected only under stimulated conditions. Many of the Wnt-stimulated eGenes were novel when compared to aggregated bulk-tissue cohorts, demonstrating that context is a crucial consideration in understanding genetic architecture. Furthermore, the Wnt-responsive regulatory quantitative trait loci (rQTLs) demonstrated significant colocalization with GWAS risk loci for schizophrenia and autism spectrum disorder (ASD), providing mechanistic insights. The analysis of Gene-by-Treatment (GxT) interactions with VPA identified genetically mediated alterations in key pathways, such as folate metabolism, associated with inter-individual variability in cognitive traits. In parallel, analysis of LiCl identified genetic variants influencing hNPC proliferation that colocalized with risk for bipolar disorder, establishing a molecular mechanism for differences in drug response. These findings provide a functional basis for developing targeted therapeutics and pharmacogenomic strategies to mitigate side effects or improve clinical outcomes in patient populations. We also generated a pilot genetic resource exploring the cellular responses to additional contexts, including maternal immune activation (MIA), signaling pathways, and estradiol. This further demonstrates the utility of context-dependent genetic mapping and provides targets for future, focused exploration. This research establishes a robust methodology and a comprehensive multi-omic resource to bridge the critical gap between genetic association and complex phenotypes. Our findings unequivocally reinforce that context is an essential layer of information required to fully understand genetic contributions to neurodevelopmental and neuropsychiatric disorder risk.Doctor of Philosoph