Digital Commons Network^™

Life-Extending Interventions Do Not Necessarily Result In Compression Of Morbidity: A Case Example Offering A Robust Statistical Approach, Deependra K Thapa, Wasiuddin Najam, Erik S Parker, Xi Rita Wang, Daniel L Smith, Ufuk Beyaztas, James F Nelson, Steven N Austad, Gary A Churchill, David B Allison

Children’s Nutrition Research Center Staff Publications

Despite extensive research on life-extending interventions, rigorous statistical techniques to determine their impact on compression of morbidity (CoM) are rarely used. We present a case example of an analytical method for examining the effect of life-extending dietary interventions on CoM by comparing the rates of decline in vitality and survival toward the end of life. Using data from previous experimental studies in mice, we calculated the average rate of vitality decline by fitting exponential decay models to individual vitality trajectories and compared this rate with the rate of survival decline estimated from Cox proportional hazards model. The results showed that, …

Rethinking The Centrality Of Brain Areas In Understanding Functional Organization, Benjamin Yost Hayden, Sarah R Heilbronner, Seng Bum Michael Yoo

Faculty, Staff and Students Publications

Parcellation of the cerebral cortex into functionally modular brain areas is foundational to cognitive and systems neuroscience. Here, we question the central status of brain areas from the perspectives of neuroanatomy and electrophysiology. We argue that the major ostensible determinants of brain function, such as cytoarchitecture and connectivity, seldom produce convergent parcellations. Brain areas themselves are just one of several equally important organizing principles; others include macroscale gradients, distributed networks, layers, columns and patches. We further argue that the evidence for a close correspondence between areal parcellation and cognitive function is weaker than is generally supposed. Indeed, many important cognitive …

Cancer Vaccine Targeting Mutated Gnaq-Expressing Uveal Melanoma, Vitali Alexeev, Mizue Terai, Sergei Koshkin, Olga Igoucheva, Takami Sato

Department of Medical Oncology Faculty Papers

Background/Objectives: Uveal melanoma (UM) is the most common intraocular malignancy in adults. Although brachytherapy of the primary tumor provides an approximate 80% five-year survival, with time, nearly half of patients experience predominant liver metastases. It was proposed that malignant cells migrate early and stay dormant as they adapt to the liver microenvironment. We propose that cancer vaccine-mediated activation of UM-targeted immunity in primary UM patients could prevent progression of metastatic disease from dormant cells or malignant seeds. Thus, this study explored DNA vaccination as a measure to educate the immune system to recognize the most common UM-associated Q209L tumor driver …

Preoperative Malnutrition Is Associated With Increased Postoperative Complications Following Lumbar Fusion: A Propensity-Matched Analysis, Ali Mehaidli, Muaaz Wajahath, Jad Lawand, Omar Abdalla, Lorenzo Deveza, Noah Hodson, Ryan J Berger, Kevin Taliaferro

Faculty, Staff and Students Publications

Background: Lumbar fusion (LF) is a common surgical intervention for degenerative spinal conditions but carries significant short- and long-term risks. Preoperative malnutrition, characterized by low serum albumin or leukocyte counts, impairs wound healing and increases susceptibility to infection, yet its influence on LF outcomes remains underexplored. This study evaluates the association between preoperative malnutrition and long-term postoperative outcomes following LF.

Methods: Adult patients undergoing LF between 2003 and 2023 were identified in the TriNetX US Collaborative Network. Malnutrition was defined as serum albumin < 3.5 g/dL or leukocyte count < 1,500/mm3 within 1 year preoperatively. A 1:1 propensity score match was performed for demographics, comorbidities, surgical approach, and body mass index (BMI), yielding two cohorts (n=20,693 each). Ninety-day and 5‑year postoperative outcomes were compared using hazard ratios (HRs) with 95% confidence intervals (CIs).

Results: Malnourished patients experienced significantly higher 90‑day rates of transfusion (8.4% vs. 4.5%; HR 1.87, 95% CI: …

Development Of Dirofilaria Immitis Adult Worms In Nsg Mice, Detection Of Parasite-Derived Microrna And Comparative Analysis Of Laboratory Isolates, Mohini Nakhale, Jessica A. Hess, Ellie Oliver, Nathan M. Ryan, Kirsten Mallon, Omair Sultan, Elinor Willis, Esha Banerjee, Enrico Radaelli, Charles-Antoine Assenmacher, Michael Povelones, Duncan Wells, Russ Morphew, Jennifer Willingham-Lane, Christine Henderson, John Harrington, Paul Mcveigh, David Abraham

Department of Surgery Faculty Papers

Global efforts to control heartworm disease are challenged by increasing drug resistance and inadequate early detection methods, which hinder the effective diagnosis and treatment of Dirofilaria immitis infection. This study presents an in vivo model for investigating D. immitis development and host-parasite interactions. The growth and migration of the D. immitis JYD-34 isolate were analyzed in immunodeficient NSG mice over 177 days, revealing parasite migration to the heart and lungs, which mirrors infection dynamics in the natural canine host. Pathophysiological examination of host tissues revealed early adult-stage worms elicited minimal inflammation. However, with chronicity, mild pulmonary hemosiderin accumulation was observed. …

Two Lysosomal Genes Atp13a2 And Gba1 Interact To Drive Neurodegeneration, Mingxue Gu, Jinghan Zhao, Mingxi Deng, Guang Lin, Xueyang Pan, Wenwen Lin, Mengqi Ma, Jinyong Kim, Seul Kee Byeon, Akhilesh Pandey, Lara M Lange, Chad A Shaw, Jonggeol Kim, Joanne Trinh, Christine Klein, Oguz Kanca, Joshua M Shulman, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Background: Parkinson’s disease (PD) is a genetically complex disorder in which combinations of heterozygous risk variants may contribute to pathogenesis. Many PD risk loci encode lysosomal genes, such as GBA1, a common and potent risk factor, conferring at least a 5-fold increase. However, the mechanisms of GBA1 penetrance remain poorly understood.

Methods: Using Drosophila melanogaster, we performed a genetic interaction screen of lysosomal storage disorder (LSD) genes to identify dominant modifiers of Gba1b (fly homolog of GBA1). Age-dependent locomotor assessments, electroretinograms (ERG), transmission electron microscopy (TEM) analyses and quantification of dopaminergic (DA) neurons were used to assess …

Use Of Electrocardiograms To Identify Coronary Artery Disease: Cross-Validation Of An Artificial Intelligence Model, Michael Leasure, Indu Poornima, Adam Butchy, Utkars Jain, Devin Vasoya, Michael Warnick, Brent Williams, John Rehder, Prahlad Menon, Veronica A. Covalesky, Gary S. Mintz

Department of Medicine Faculty Papers

BACKGROUND: The current gold standard for the diagnosis of coronary artery disease (CAD) is invasive angiography; however, it is an invasive procedure. Therefore, we developed an artificial intelligence model designed to predict significant CAD from a resting digital 12-lead electrocardiogram (ECG).

OBJECTIVES: This retrospective study assessed the model's ability to predict clinically significant CAD in a patient population presenting for coronary angiography.

METHODS: From 2019 to 2021, 16,476 patients had a resting 12-lead digital ECG recorded within 90 days prior to coronary angiography. The artificial intelligence model was developed using 10-fold cross-validation methodology. Clinically significant disease was defined as angiographic …

Downregulation Of Slc40a1 Leads To Iron Accumulation In Fibrotic Lung Fibroblasts, Quanjin Dang, Chaoqun Huang, Yurong Liang, Akshaya Surendran, Dharanya Muthiah, Kishore Vaddadi, Sankha Hewawasam, Tingting W Mills, Lin Liu

Faculty, Staff and Student Publications

Iron is an essential nutrient for almost all organisms. However, excess iron generates reactive oxygen species and causes tissue injuries. Iron is implicated in idiopathic pulmonary fibrosis (IPF). In this study, we examined iron accumulation in fibrotic lung fibroblasts and the underlying mechanisms. We hypothesize that the downregulation of Solute Carrier Family 40 Member 1 (SLC40A1) results in iron accumulation in lung fibroblasts of IPF patients. Using a Prussian Blue iron staining, we found that iron accumulated in the fibrotic region of the lungs from IPF patients and bleomycin- and asbestos-induced lung fibrosis mice. Iron was partially co-localized with the …

The Origin Of Hepatocellular Carcinoma Depends On Metabolic Zonation, Jason Guo, Roger Liang, Andrew Chung, Zhijie Li, Boyuan Li, Eric Chen, Lin Li, Jingjing Wang, Meng-Hsiung Hsieh, Ivy Xiangyi Fang, Benjamin Kroger, Yunguan Wang, Min Zhu, Xiongzhao Ren, Greg Mannino, Yuemeng Jia, Yonglong Wei, Stephen Moore, Daniel J Siegwart, Stephen S Chung, Zixi Wang, Tripti Sharma, Suman Komjeti, Yi Han, Purva Gopal, Guanghua Xiao, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

The origin of cancer is poorly understood because premalignant cells are rarely followed in their native environments. Although the spatial compartmentalization of metabolic functions is critical for proper liver function, it is unknown whether cancers arise from some zones but not others and whether there are metabolic determinants of cancer risk. Zone-specific, mosaic introduction of Ctnnb1 (catenin beta 1) and Arid2 (AT-rich interaction domain 2) mutations, commonly co-mutated genes in hepatocellular carcinoma (HCC), in mouse models showed that position and metabolic context determine clone fates. Ctnnb1/Arid2-driven cancers were much more likely to arise in zone 3. The …

Kdm4a Promotes Nepc Progression Through Regulation Of Myc Expression, Celia Sze Ling Mak, Ming Zhu, Jie Fu, Xin Liang, Xiaoxuan Wang, Fei Yuan, Feng Wang, Anh G Hoang, Xingzhi Song, Peter Shepherd, Derek Liang, Jessica Suh, Jordan Contreras, Thisawin Dang, Cindy Yan, Brandon Figueroa, Mathias Mazzocco, Athena Luo, Bijeta Pradhan, Jiwon Park, Mirrah Bashir, Miao Zhang, Eric Metzger, Roland Schüle, Abhinav K Jain, Ellen Karasik, Daniel Frigo, Barbara A Foster, Min Gyu Lee, Paul Corn, Christopher J Logothetis, Ana Aparicio, Nora Navone, Patricia Troncoso, Zhi Tan, Jianhua Zhang, Sue-Hwa Lin, Guocan Wang

Faculty, Staff and Students Publications

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal subtype of prostate cancer (PCa) that often emerges in response to androgen receptor pathway inhibitors (ARPIs), which are widely used in treating metastatic castration-resistant and hormone-sensitive prostate cancer. The incidence of NEPC is increasing, yet effective therapeutic strategies remain limited due to an incomplete understanding of its molecular drivers. Through transcriptomic analyses of human prostate tumor samples, we identified the histone lysine demethylase KDM4A as uniquely overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Functional validation demonstrated that KDM4A is a key regulator of NEPC progression and a …

Race And Patient-Physician Communication On Blood Pressure Management: Helping Improve Care, Samar A. Nasser, Ashley Pender, Ayan Ali, Kardie Tobb, Keith C. Ferdinand

Division of Cardiology Faculty Papers

PURPOSE OF REVIEW: To provide an overview of the relationship of race and ethnicity and patient-physician/clinician communication on blood pressure management.

RECENT FINDINGS: The suboptimal interactions experienced by patients from underrepresented racial and ethnic populations may be improved by enriching relationships among clinicians, population health scientists, policymakers, and community members/leaders. Current care communication and policies for managing hypertension appear to be insufficient. Implementing and disseminating effective strategies to efficiently improve the quality of hypertension care and recognize social determinants of health among minoritized populations is intertwined with enhanced communication.

SUMMARY: Approaches such as self-affirmation—encouraging patients to reflect on their strengths …

Beyond Neurons: Impact Of Cannabidiol On Glial Cells In Ischemic Stroke, Victória Linden De Rezende, Khiany Mathias, Cinara Ludvig Gonçalves, Rafael Mariano De Bitencourt, Tatiana Barichello, Fabricia Petronilho

Faculty, Staff and Student Publications

Ischemic stroke triggers a complex cascade of events involving inflammation, oxidative stress, and glial cell dysfunction, all of which contribute to neuronal damage and impaired recovery. Glial cells (e.g., astrocytes, microglia, and oligodendrocytes) play key roles in neuroinflammatory responses, making them attractive targets for therapeutic modulation. Cannabidiol, a non-psychoactive phytocannabinoid from Cannabis sativa, exhibits anti-inflammatory, antioxidant, and neuroprotective properties. Preclinical evidence indicates that cannabidiol attenuates glial reactivity, reduces pro-inflammatory signaling, mitigates oxidative stress, and preserves blood-brain and intestinal barrier integrity in stroke models. Moreover, cannabidiol modulates key molecular pathways (e.g., nuclear factor-κB, tumor necrosis factor, and calcium-related signaling), contributing to …

Structures Of Invertebrate Pezo-1 Isoforms With A Compact Architecture And A Dispensable Pore-Distal N-Terminal Blade, Briar Bell, Angela M Jaramillo-Granada, Daniel J Orlin, Wei-Hsiang Weng, Haosheng Wen, Marcos Sotomayor, Alexander T Chesler, Matthew L Baker, Julio F Cordero-Morales, Valeria Vásquez

Faculty, Staff and Student Publications

PIEZO channels are mechanosensitive ion channels conserved from plants to humans, yet structures exist for only a few mammalian orthologs. We define the structural and functional diversity of Caenorhabditis elegans PEZO-1, a single gene with extensive alternative splicing, by determining cryo-electron microscopy structures of three representative isoforms: G (full length), K (lacking the pore-distal N-terminal blade), and L (missing most of the blade). PEZO-1G displays mechanically evoked currents yet adopts a compact, semi-flattened conformation that significantly differs from the mammalian domes. The blades exhibit a three-step slope architecture stabilized by inter-blade latching among transmembrane helical units, yielding a circular, steering-wheel-like …

Structures Of Trpv1 Bound By Hyperthermia-Inducing Analgesics, Yu-Hao Gao, Yi-Zhe Huang, Zhao-Xing Li, Xiao-Ying Chen, Chang-Yan Shao, Han-Wen Li, Bin Liu, Fán Yang, Mei-Rong Chen, Mei-Ling Lu, Michael X Zhu, Fan Yang, Yi-Bei Xiao, Ye Yu

Faculty, Staff and Student Publications

TRPV1, a member of the transient receptor potential vanilloid subfamily, mediates nociception and thermoregulation. TRPV1-targeting analgesics frequently induce hyperthermia, underscoring the need for structural insights to guide the development of safer compounds. Here, we determined the structures of rat TRPV1 bound to the clinical candidate analgesics AMG517, AMG9810, and SB366791. AMG517 and AMG9810 are deeply situated within the S3-S4 interface of the vanilloid pocket, where they interact with residues from the S3-S6 helices, as well as the S4-S5 linker. These interactions induce local deformations in the TRP-box and lower S6 helix, accompanied by a modest rotation of the S1-S4 bundle, …

Clinical Workflow Of Spine Stereotactic Radiotherapy And Radiosurgery: Insights From A Single-Institution Physics Perspective, Dennis Mackin, Gizem Cifter, Yana Zlateva, Jihong Wang, Yao Ding, Muhammad Shafiq Ul Hassan, Zhiheng Wang, Parmeswaran Diagaradjane, Fada Guan, Travis C Salzillo, Shane Krafft, Jing Li, Martin C Tom, Amol J Ghia, Tina Marie Briere

Faculty, Staff and Student Publications

Spine stereotactic radiotherapy and radiosurgery (SSRS) techniques, encompassing both fractionated stereotactic treatments and single-fraction radiosurgery, are widely used for the management of spinal metastases due to their ability to deliver highly conformal radiation while limiting dose to adjacent critical structures. Clinical outcomes following SSRS, including durable local control and acceptable toxicity, have been reported previously in multiple institutional series. In this manuscript, we describe the clinical workflow used to deliver SSRS at a high-volume academic center, with emphasis on the medical physics processes that support routine clinical practice. Key elements of the workflow include patient selection, treatment region-specific immobilization, CT …

Saga/Atac Complexes Sustain Aberrant Chromatin Regulation And Promote Tumorigenesis In Diffuse Midline Glioma, Rosemary U Richard, Caitlin Bagnetto, Rebecca L Murdaugh, Brittany R Eberl, Alan L Jiao, Adam F Kebede, Barry M Zee, Margaret M Harrington, Mariella G Filbin, Akdes Serin-Harmanci, Yang Shi, Jamie N Anastas

Faculty, Staff and Students Publications

Diffuse midline gliomas (DMG) are aggressive pediatric brain tumors characterized by chromatin and transcriptional dysregulation induced by H3K27M mutations. Strategies for overcoming epigenetic dysfunction to reduce DMG tumorigenesis remain limited. We identified multiple components of the SAGA and ATAC chromatin regulatory complexes as DMG genetic dependencies and found that genetic or pharmacological inhibition of the SAGA/ATAC-associated chromatin reader SGF29 reduces DMG proliferation. Small molecules targeting SAGA/ATAC-associated histone acetylation, ubiquitination, and methylation similarly suppressed DMG growth. Further chromatin profiling and RNAseq analyses reveal that SGF29 controls H3K9ac and H3K4me3 dynamics at both H3K27M-bound and H3K27M-independent target genes linked to proliferation, differentiation, …

Tead-Independent Mechanisms Of Yap Function In Cardiomyocyte Cell Cycle Reentry, Bing Xie, Jeffrey Steimle, Vaibhav Deshmukh, Lin Liu, Chang-Ru Tsai, Todd R Heallen, Wyatt Paltzer, Yuka Morikawa, Fansen Meng, Jun Wang, James F Martin

Faculty, Staff and Students Publications

Adult mammalian hearts exhibit limited regenerative capacity because of the restricted renewal of cardiomyocytes. Recent studies reveal that mammalian hearts exhibit transient regenerative potential within a short time frame after birth, suggesting a regulatory mechanism that prevents adult hearts from initiating a regenerative response to cardiac injury. Here, we discovered that an active form of YAP, named YAP6SA, which is not inhibited by the Hippo signaling pathway and does not interact with TEADs, induces cardiomyocyte cell cycle reentry. In addition, YAP6SA interacts with scaffold protein MPDZ to regulate Rho GTPases and promote cell cycle progression in cardiomyocytes (CMs). Importantly, YAP6SA …

Cdk2 Inhibitor Blu-222 Synergizes With Cdk4/6 Inhibitors In Drug Resistant Breast Cancers Through P21/P27 Induction, Linjie Luo, Yan Wang, Tuyen Bui, Xiaoting Jiang, Mei-Kuang Chen, Xiayu Rao, Sepideh Mohammadhosseinpour, Mi Li, Serena Kim, Rachel Y Kim, Saba Kamaliasl, Carmen W Ulizio, Spyros Tsavachidis, Juliana Navarro-Yepes, Nicole M Kettner, Hannah Wingate, Funda Meric-Bernstam, Kelly K Hunt, Jing Wang, Kerrie Faia, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard first-line treatment for hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer, but resistance inevitably develops. In triple-negative breast cancer (TNBC), the efficacy of CDK4/6i remains uncertain. Our study shows that the selective CDK2 inhibitor BLU-222, while effective alone, enhances synergistic activity when combined with CDK4/6i in resistant HR+/HER2- and TNBC models, leading to increased apoptosis and cell cycle arrest. In vivo, combining BLU-222 with palbociclib or ribociclib produced significant antitumor activity across eight resistant models, driving durable tumor regression and prolonged survival. Mechanistically, BLU-222, alone or with palbociclib, upregulated …

Cdk2 Inhibitor Blu-222 Synergizes With Cdk4/6 Inhibitors In Drug Resistant Breast Cancers Through P21/P27 Induction, Linjie Luo, Yan Wang, Tuyen Bui, Xiaoting Jiang, Mei-Kuang Chen, Xiayu Rao, Sepideh Mohammadhosseinpour, Mi Li, Serena Kim, Rachel Y Kim, Saba Kamaliasl, Carmen W Ulizio, Spyros Tsavachidis, Juliana Navarro-Yepes, Nicole M Kettner, Hannah Wingate, Funda Meric-Bernstam, Kelly K Hunt, Jing Wang, Kerrie Faia, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard first-line treatment for hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer, but resistance inevitably develops. In triple-negative breast cancer (TNBC), the efficacy of CDK4/6i remains uncertain. Our study shows that the selective CDK2 inhibitor BLU-222, while effective alone, enhances synergistic activity when combined with CDK4/6i in resistant HR+/HER2- and TNBC models, leading to increased apoptosis and cell cycle arrest. In vivo, combining BLU-222 with palbociclib or ribociclib produced significant antitumor activity across eight resistant models, driving durable tumor regression and prolonged survival. Mechanistically, BLU-222, alone or with palbociclib, upregulated …

Low Intensity Vibration With Zoledronate Reduces Musculoskeletal Weakness And Adiposity In Estrogen Deprived Female Mice, Gabriel M Pagnotti, Trupti Trivedi, Laura E Wright, Sutha K John, Sreemala Murthy, Ryan R Pattyn, Monte S Willis, Yun She, Sukanya Suresh, Aji F Touray, William R Thompson, Clinton T Rubin, Khalid S Mohammad, Theresa A Guise

Faculty, Staff and Student Publications

Aromatase inhibitors are widely used in the treatment of hormone-sensitive breast cancer, but their suppression of estrogen production accelerates bone loss, increases fracture risk, and negatively impacts muscle and fat metabolism. Here, we demonstrate that daily low intensity vibration, serving as a non-drug mimetic for exercise, protects musculoskeletal health in skeletally immature, female mice under complete estrogen deprivation. Subsequent improvements in vertebral bone density are paralleled by greater and leaner skeletal muscle mass and function alongside reduced fat accretion and circulating metabolites. In mature, estrogen deprived mice, vibration enhances weekly bisphosphonate treatment, improving bone density, cortical thickness, and mechanical resistance …

Microfluidic Capillary Transit Velocity As A Functional Measure For Sickle Cell Disease And In Vitro-Derived Red Blood Cells, Solomon Oshabaheebwa, Yuxuan Du, Christopher L. Wirth, Zoe Sekyonda, Zoe Sekyonda, Bryan L. Benson, Payam Fadaei, Yusang B. Ley, Michael A. Suster, Pedram Mohseni, Umut A. Gurkan

Faculty Scholarship

Emerging therapies in sickle cell disease (SCD) aim to restore healthy red blood cell (RBC) function, but they often yield heterogeneous cellular responses. There are no proven techniques to evaluate restored rheological functionality and heterogeneity in these RBCs. We present a biomimetic microcapillary network, high-speed imaging, and computational algorithms to analyze RBC capillary velocity profiles of the entire sample population at single-cell resolution. Using peripheral RBCs from SCD patients and healthy donors, we showed that RBC capillary transit velocity correlated with cell shape, hydrodynamic adaptability, and elongation index. Healthy RBCs exhibited a velocity distribution skewed toward higher values, whereas RBCs …

What Needs To Be Standardized For Reliable, Reproducible, And Robust Tractography?, Jon Haitz Legarreta, Simona Schiavi, Wei Tang, Garrett Banks, Matthew Cieslak, Kurt Schilling, Alberto De Luca, Jacques-Donald Tournier, John Kruper, Francois Rheault, Stamatios N Sotiropoulos, Franco Pestilli, Jelle Veraart, Joseph Yuan-Mou Yang, Maxime Descoteaux, Sarah Heilbronner, Ariel Rokem

Faculty, Staff and Students Publications

Tractography is a key component of efforts to map brain connectivity. As a rapidly evolving field of neuroscience, current tractography methods are diverse, often varying across research laboratories and different software pipelines. Therefore, it suffers from a lack of standardization, leading to inconsistencies in results, which can limit reproducibility and affect the robustness needed for research and clinical applications of these methods. Variability in data acquisition procedures, inconsistencies in spatial referencing schemes and implementations, and anatomical heterogeneity-at the individual level, across the lifespan, and across species-hinder comparative analyses. Additionally, the lack of consensus on best practices complicates the development of …

Simulated Complex Cells Contribute To Object Recognition Through Representational Untangling, Mitchell B Slapik, Harel Z Shouval

Faculty, Staff and Student Publications

The visual system performs a remarkable feat: it takes complex retinal activation patterns and decodes them for object recognition. This operation, termed "representational untangling," organizes neural representations by clustering similar objects together while separating different categories of objects. While representational untangling is usually associated with higher-order visual areas like the inferior temporal cortex, it remains unclear how the early visual system contributes to this process-whether through highly selective neurons or high-dimensional population codes. This article investigates how a computational model of early vision contributes to representational untangling. Using a computational visual hierarchy and two different data sets consisting of numerals …

B Lymphocytes Impede Tregs To Erode Islet Tolerance In Type 1 Diabetes, Christopher S Wilson, Blair T Stocks, Alexander C Falk, Daniel J Moore

Faculty, Staff and Students Publications

B lymphocytes are thought to drive β-cell destruction in type 1 diabetes (T1D) by activating anti-islet T cells. However, the observation that autoreactive T-cell activation and disease progression can occur without B cells challenges this view. Still, preclinical and clinical studies have shown that B-cell depletion alleviates β-cell destruction, suggesting a critical role for B cells in T1D. Our findings propose an alternative function for B cells, impairing regulatory T cells (Tregs) that would otherwise protect islets. In the NOD islet transplant model, we show that B-cell absence enables transplant tolerance, allowing Tregs to become responsive to immune therapy and …

The Evolution Of Public Health Statistical Modeling Approaches And How To Advance Their Incorporation Into Modern Arboviral Surveillance, Maggie Mccarter, Stella C W Self, Alex Ewing, Mufaro Kanyangarara, Sarah M Gunter, Melissa S Nolan

Faculty, Staff and Students Publications

Statistical modeling of infectious disease transmission patterns has been in existence since the mid-1700s, evolving in their utility as the scientific and technological revolutions progressed. Despite the expansion of emerging mathematical and statistical methodologies over the past 250 yr, their usage has largely remained restricted to academic settings. This forum article will discuss the evolution of disease modeling techniques, the most common types of models in use today, and recommendations on how key archetypes can be incorporated into future public health practice. With the recent global impetus to predict and forecast novel pathogens, this article raises the question: Why are …

A Review Of 3d-Printed Medical Devices For Cancer Radiation Therapy., Radiah Pinckney, Santosh Kumar Parupelli, Peter Sandwall, Sha Chang, Salil Desai

Oncology Articles

This review explores the transformative role of three-dimensional (3D) printing in radiation therapy for cancer treatment, emphasizing its potential to deliver patient-specific, cost-effective, and sustainable medical devices. The integration of 3D printing enables rapid fabrication of customized boluses, compensators, immobilization devices, and GRID collimators tailored to individual anatomical and clinical requirements. Comparative analysis reveals that additive manufacturing surpasses conventional machining in design flexibility, lead time reduction, and material efficiency, while offering significant cost savings and recyclability benefits. Case studies demonstrate that 3D-printed GRID collimators achieve comparable dosimetric performance to traditional devices, with peak-to-valley dose ratios optimized for spatially fractionated radiation …

Radionuclide-Stimulated Dynamic Therapy Induces Complementary Immunogenic Necroptosis And Apoptosis Cancer Cell Death Pathways, Christopher Egbulefu, Kvar Black, Xinming Su, Partha Karmakar, Lemoyne Habimana-Griffin, Gail Sudlow, Julie Prior, Ezugo Onejeme, Alex Zheleznyak, Baogang Xu, Yalin Xu, Alison Esser, Matthew Mixdorf, Evan Moss, Brad Manion, Cody Hongsermeier, Nisha Gamadia, Nicole Blasi, Luke Stallings, Chidube Alagbaoso, Nathan Reed, Matthew M Gubin, Chieh-Yu Lin, Robert Schreiber, Katherine Weilbaecher, Samuel Achilefu

Faculty, Staff and Student Publications

Radionuclide-stimulated dynamic therapy (RaST) utilizes Cerenkov-radiating radiopharmaceuticals to activate light-sensitive drugs and materials, generating reactive oxygen species (ROS) that inhibit cancer progression. However, the underlying cell death mechanisms are not fully understood. Using ROS-regenerative nanophotosensitizers coated with a tumor-targeting transferrin-titanocene complex and radiolabeled 2-fluorodeoxyglucose, we found that RaST induced apoptosis and necroptosis, characterized by the activation of RIPK-1, RIPK-3, nuclear factor kappa B, and mixed lineage kinase domain-like pseudokinase, leading to membrane permeabilization, cytokine release, and the expression of immunogenic damage-associated molecular patterns. In immune-deficient breast tumor-bearing mice with adequate stroma and growth factors, RaST did not prevent tumor growth …

Comprehensive Metabolic Profiling Across Five Lifespan Stages In Murine Hippocampus And Cortex Reveals Sex-Related Variation In Age-Related Cognitive Decline, Xi Long, Wuping Liu, Changhan Chen, Qi Guo, Yidan Wang, Fang Yu, Yujin Zhang, Rodney E Kellems, Yang Xia

Faculty, Staff and Student Publications

This study employs Barnes maze behavioral assessments, untargeted liquid chromatography-mass spectrometry metabolomics, and 13C6-glucose isotopic tracing to systematically investigate cognitive function and metabolic profiles in hippocampal and cortical tissues of male and female mice across five distinct age-ranges. Behavioral analyses reveal significant cognitive decline in both sexes by 16-months-of-age, with females exhibiting more severe impairment by 23-months, demonstrating a sex-related variation. 13C6-glucose tracing analyses reveals that glucose is rapidly and preferentially metabolized toward the Tricarboxylic acid cycle over glycolysis and the pentose phosphate pathway (PPP), with metabolism rates increasing from juvenility to meet developmental demands and maintaining homeostasis into pre-elderly. …

Glutamatergic Projection Neurons In The Basal Forebrain Underlie Learned Olfactory Associational Valence Assignments, Pey-Shyuan Chin, Zhuokun Ding, Mikhail Kochukov, Snigdha Srivastava, Elizabeth H Moss, Qingchun Tong, Benjamin R Arenkiel

Faculty, Staff and Student Publications

Sensory perception is shaped by experience, giving stimuli behavioral significance. Basal forebrain (BF) cholinergic neurons in mice, which are crucial for arousal and motivation, also regulate sensory processing. Within BF nuclei, glutamatergic (vGlut2BF) neurons receive cholinergic input and modulate behaviors, but their roles in encoding sensory significance remain unclear. Using in vivo calcium imaging, we found that vGlut2BF neurons initially poorly encoded odor identity. However, their response to conditioned odors increased following associative learning, and their population activity more distinctly encoded paired stimuli, reflecting emergent value representation. Furthermore, pairing stimulation or inhibition of vGlut2BF neurons with specific odors altered odor …

Role Of The Etv5/P38 Signaling Axis In Aggressive Thyroid Cancer Cells, Jerry H Houl, Rozita Bagheri-Yarmand, Muthusamy Kunnimalaiyaan, Paola Miranda Mendez, Joseph L Kidd, Ali Dadbin, Andrea Ruiz-Jurado, Parag A Parekh, Ying C Henderson, Nikhil S Chari, Aatish Thennavan, Reid T Powell, Clifford C Stephan, Xiao Zhao, Anastasios Maniakas, Roza Nurieva, Naifa L Busaidy, Maria E Cabanillas, Ramona Dadu, Mark Zafereo, Jennifer R Wang, Stephen Y Lai, Marie-Claude Hofmann

Faculty, Staff and Student Publications

Patients with poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) face a much poorer prognosis than those with differentiated thyroid cancers. Around 25% of PDTCs and 35% of ATCs carry the BRAFV600E mutation, which constitutively activates the MAPK pathway, a key driver of cell growth. Although combining BRAF and MEK inhibitors can shrink tumors, resistance often develops. The exact cause of this resistance remains unclear. We previously found that in PDTC and ATC cells, the BRAFV600E mutation is strongly linked to the expression of ETV5, a transcription factor downstream of the MAPK pathway. In the current study, we …