Digital Commons Network^™

Maldi Imaging Mass Spectrometry Visualizes The Distribution Of Antidepressant Duloxetine And Its Major Metabolites In Mouse Brain, Liver, Kidney, And Spleen Tissues, Saleh M Khalil, Xuan Qin, John M Hakenjos, Jian Wang, Zhaoyong Hu, Xinli Liu, Jin Wang, Mirjana Maletic-Savatic, Kevin R Mackenzie, Martin M Matzuk, Feng Li

Faculty, Staff and Student Publications

Imaging mass spectrometry (IMS) is a powerful tool for mapping the spatial distribution of unlabeled drugs and metabolites that may find application in assessing drug delivery, explaining drug efficacy, and identifying potential toxicity. This study focuses on determining the spatial distribution of the antidepressant duloxetine, which is widely prescribed despite common adverse effects (liver injury, constant headaches) whose mechanisms are not fully understood. We used high-resolution IMS with matrix-assisted laser desorption/ionization to examine the distribution of duloxetine and its major metabolites in four mouse organs where it may contribute to efficacy or toxicity: brain, liver, kidney, and spleen. In none …

The Ifitm5 Mutation In Osteogenesis Imperfecta Type V Is Associated With An Erk/Sox9-Dependent Osteoprogenitor Differentiation Defect, Ronit Marom, I-Wen Song, Emily C Busse, Megan E Washington, Ava S Berrier, Vittoria C Rossi, Laura Ortinau, Youngjae Jeong, Ming-Ming Jiang, Brian C Dawson, Mary Adeyeye, Carolina Leynes, Caressa D Lietman, Bridget M Stroup, Dominyka Batkovskyte, Mahim Jain, Yuqing Chen, Racel Cela, Alexis Castellon, Alyssa A Tran, Isabel Lorenzo, D Nicole Meyers, Shixia Huang, Alicia Turner, Vinitha Shenava, Maegen Wallace, Eric Orwoll, Dongsu Park, Catherine G Ambrose, Sandesh Cs Nagamani, Jason D Heaney, Brendan H Lee

Faculty, Staff and Students Publications

Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5). Here, we generated a conditional Rosa26-knockin mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with …

Cannabis Exposure During Pregnancy And Neural Mechanisms Of Parenting: Assessing Neural Responses To Infant Cues And Parenting Outcomes, Shannon Powers

Electronic Theses and Dissertations

As legalization of cannabis and cannabinoids spreads in the United States, access and use of cannabis during the prenatal period has increased. There is limited knowledge on the effects of prenatal cannabis use on the parental brain. One way to identify potential effects of cannabis on parenting is through studying parenting brain functions and behavior. Cannabis use disorder (CUD) has been shown to be associated with lower positive parenting and lower sensitivity to infants, but it is unclear by what mechanisms. The following two studies address this gap in knowledge by examining the association between cannabis use during the prenatal …

In-Silico Analysis Of Tmem2 As A Pancreatic Adenocarcinoma And Cancer-Associated Fibroblast Biomarker, And Functional Characterization Of Nsc777201, For Targeted Drug Development, Prateeti Srivastava, Vijesh Kumar Yadav, Tzu-Hao Chang, Emily Chia-Yu Su, Bashir Lawal, Alexander Th Wu, Hsu-Shan Huang

Faculty, Staff and Student Publications

Pancreatic adenocarcinoma (PAAD), known as one of the deadliest cancers, is characterized by a complex tumor microenvironment, primarily comprised of cancer-associated fibroblasts (CAFs) in the extracellular matrix. These CAFs significantly alter the matrix by interacting with hyaluronic acid (HA) and the enzyme hyaluronidase, which degrades HA - an essential process for cancer progression and spread. Despite the critical role of this interaction, the specific functions of CAFs and hyaluronidase in PAAD development are not fully understood. Our study investigates this interaction and assesses NSC777201, a new anti-cancer compound targeting hyaluronidase. This research utilized computational methods to analyze gene expression data …

Reduced Sensitivity To Future Consequences Underlies Gambling Decision In Cerebellar Ataxia, Ruo-Yah Lai, Eli Levy, Christian J Amlang, Ihika Rampalli, Rory Mahabir, Ming-Kai Pan, Chi-Ying R Lin, Sheng-Han Kuo

Faculty, Staff and Students Publications

Introduction: Previous research has identified that people with cerebellar ataxia (CA) showed impaired reward-related decision-making in the Iowa Gambling Task (IGT). To investigate the mechanisms underlying this impairment, we examined CA participants' combination of performance in the IGT, which predominantly tests reward seeking, and the modified IGT (mIGT), which mainly assesses punishment avoidance.

Methods: Fifty participants with CA and one hundred controls completed the IGT and mIGT. Task performance in each of the five twenty-trial blocks was compared between groups and the learning rates were assessed with simple linear regressions. Each participant's IGT score and mIGT score were compared.

Results: …

Scanless Two-Photon Voltage Imaging, Ruth R Sims, Imane Bendifallah, Christiane Grimm, Aysha S Mohamed Lafirdeen, Soledad Domínguez, Chung Yuen Chan, Xiaoyu Lu, Benoît C Forget, François St-Pierre, Eirini Papagiakoumou, Valentina Emiliani

Faculty, Staff and Students Publications

Two-photon voltage imaging has long been heralded as a transformative approach capable of answering many long-standing questions in modern neuroscience. However, exploiting its full potential requires the development of novel imaging approaches well suited to the photophysical properties of genetically encoded voltage indicators. We demonstrate that parallel excitation approaches developed for scanless two-photon photostimulation enable high-SNR two-photon voltage imaging. We use whole-cell patch-clamp electrophysiology to perform a thorough characterization of scanless two-photon voltage imaging using three parallel illumination approaches and lasers with different repetition rates and wavelengths. We demonstrate voltage recordings of high-frequency spike trains and sub-threshold depolarizations from neurons …

Identification And Characterization Of Cannabichromene's Major Metabolite Following Incubation With Human Liver Microsomes, Alexandra M Ward, Touraj Shokati, Jost Klawitter, Jelena Klawitter, Vu Nguyen, Laura Kozell, Atheir I Abbas, David Jones, Uwe Christians

Faculty, Staff and Student Publications

Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the Cannabis sativa plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans. Therefore, the goal of this was study to identify the major CBC phase I-oxidized metabolite generated in vitro following incubation with human liver microsomes. The novel metabolite structure was identified as 2′-hydroxycannabicitran using gas chromatography–mass …

Chagas Disease In Immunocompromised Patients, Eva H Clark, Louisa A Messenger, Jeffrey D Whitman, Caryn Bern

Faculty, Staff and Students Publications

As Chagas disease remains prevalent in the Americas, it is important that healthcare professionals and researchers are aware of the screening, diagnosis, monitoring, and treatment recommendations for the populations of patients they care for and study. Management of Trypanosoma cruzi infection in immunocompromised hosts is challenging, particularly because, regardless of antitrypanosomal treatment status, immunocompromised patients with Chagas disease are at risk for T. cruzi reactivation, which can be lethal. Evidence-based practices to prevent and manage T. cruzi reactivation vary depending on the type of immunocompromise. Here, we review available data describing Chagas disease epidemiology, testing, and management practices for various …

Sars-Cov-2 Neurotropism: Understanding Effects At The Blood-Brain Barrier And Hematogenous Neuroinvasiveness, Taylor E. Martinez

USF Tampa Graduate Theses and Dissertations

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, has provisional counts of over 110 million documented cases and 1.218 million deaths (as of February 2024) in the United States since January 2020. SARS-CoV-2 is an airborne respiratory virus that primarily infects the lungs via the ACE2 receptor but has well-documented secondary target organs including the kidneys, the gastrointestinal tract, the heart, and the skin. SARS-CoV-2 also infects the brain, but the hematogenous route of viral entry to brain is still not fully characterized. Understanding how SARS-CoV-2 traverses the blood-brain barrier (BBB) as well as how it …

Rest-Dependent Downregulation Of Von Hippel-Lindau Tumor Suppressor Promotes Autophagy In Shh-Medulloblastoma, Ashutosh Singh, Donghang Cheng, Jyothishmathi Swaminathan, Yanwen Yang, Yan Zheng, Nancy Gordon, Vidya Gopalakrishnan

Faculty, Staff and Student Publications

The RE1 silencing transcription factor (REST) is a driver of sonic hedgehog (SHH) medulloblastoma genesis. Our previous studies showed that REST enhances cell proliferation, metastasis and vascular growth and blocks neuronal differentiation to drive progression of SHH medulloblastoma tumors. Here, we demonstrate that REST promotes autophagy, a pathway that is found to be significantly enriched in human medulloblastoma tumors relative to normal cerebella. In SHH medulloblastoma tumor xenografts, REST elevation is strongly correlated with increased expression of the hypoxia-inducible factor 1-alpha (HIF1α)-a positive regulator of autophagy, and with reduced expression of the von Hippel-Lindau (VHL) tumor suppressor protein - a …

Central Thromboxane A2, Prostaglandin F2Α, Prostaglandin E, And Prostaglandin D Contribute To The Cardiovascular Effects Elicited By Nesfatin-1, Gökçen Güvenç Bayram, Murat Yalçin

Turkish Journal of Medical Sciences

Background/aim: Our recent study revealed that the expression of lipoxygenase (LOX) and cyclooxygenase (COX) enzymes in the hypothalamus is activated by nesfatin-1, leading to the liberation of leukotrienes and prostaglandins (PG), respectively. Moreover, our prior report explained that intracerebroventricular (ICV) nesfatin-1 treatment triggers cardiovascular responses mediated by central LOX and COX enzymes. Building upon our prior reports, the present investigation sought to clarify the role of cardiovascularly active central COX products, such as thromboxane (TX) A2, PGF2α, PGE, and PGD, in orchestrating nesfatin-1-evoked reactions in mean arterial pressure (MAP) and heart rate (HR).Materials and methods: The Sprague Dawley rats, which …

Sting Activation Increases The Efficiency Of Temozolomide In Pten Harbouring Glioblastoma Cells, Zafer Yildirim, Eda Doğan, Hale Güler Kara, Buket Kosova, Vi̇ldan Bozok

Turkish Journal of Medical Sciences

Background/aim: Glioblastoma is one of the most aggressive tumours, resistant to all applied therapy regiments and prone to relapse. Median survival rates are therefore only expressed as months. STING agonists are immunomodulatory molecules that activate type I interferon expression, making them potentially useful in regulating the tumour microenvironment. Since PTEN serves as a critical phosphatase in activating interferon-regulating transcription factors and is frequently mutated in glioblastoma cells, this study aimed to investigate STING activation in glioblastoma cell lines, examining whether they harbour the PTEN protein or not.°Materials and methods: T98G and U118MG glioblastoma cell lines were treated with the 2ʹ3ʹ-c-di-AM(PS)2(Rp,Rp) …

Small Rna Signatures Of Acute Ischemic Stroke In L1cam Positive Extracellular Vesicles, Bharti Manwani, Nivetha Brathaban, Abiya Baqai, Yashee Munshi, Hilda W Ahnstedt, Mengqi Zhang, Kajsa Arkelius, Ted Llera, Edilberto Amorim, Fanny M Elahi, Neel S Singhal

Faculty, Staff and Student Publications

L1CAM-positive extracellular vesicles (L1EV) are an emerging biomarker that may better reflect ongoing neuronal damage than other blood-based biomarkers. The physiological roles and regulation of L1EVs and their small RNA cargoes following stroke is unknown. We sought to characterize L1EV small RNAs following stroke and assess L1EV RNA signatures for diagnosing stroke using weighted gene co-expression network analysis and random forest (RF) machine learning algorithms. Interestingly, small RNA sequencing of plasma L1EVs from patients with stroke and control patients (n = 28) identified micro(mi)RNAs known to be enriched in the brain. Weighted gene co-expression network analysis (WGCNA) revealed small RNA …

Structural Analysis Of The Female Reptile Reproductive System By Micro-Computed Tomography And Optical Coherence Tomography†, Bonnie K Kircher, Michaela A Mccown, Deirdre M Scully, Richard R Behringer, Irina V Larina

Faculty, Staff and Student Publications

Volumetric data provide unprecedented structural insight to the reproductive tract and add vital anatomical context to the relationships between organs. The morphology of the female reproductive tract in non-avian reptiles varies between species, corresponding to a broad range of reproductive modes and providing valuable insight to comparative investigations of reproductive anatomy. However, reproductive studies in reptilian models, such as the brown anole studied here, have historically relied on histological methods to understand the anatomy. While these methods are highly effective for characterizing the cell types present in each organ, histological methods lose the 3D relationships between images and leave the …

Machine Learning In Time-Lapse Imaging To Differentiate Embryos From Young Vs Old Mice†, Liubin Yang, Carolina Leynes, Ashley Pawelka, Isabel Lorenzo, Andrew Chou, Brendan Lee, Jason D Heaney

Faculty, Staff and Students Publications

Time-lapse microscopy for embryos is a non-invasive technology used to characterize early embryo development. This study employs time-lapse microscopy and machine learning to elucidate changes in embryonic growth kinetics with maternal aging. We analyzed morphokinetic parameters of embryos from young and aged C57BL6/NJ mice via continuous imaging. Our findings show that aged embryos accelerated through cleavage stages (from 5-cells) to morula compared to younger counterparts, with no significant differences observed in later stages of blastulation. Unsupervised machine learning identified two distinct clusters comprising of embryos from aged or young donors. Moreover, in supervised learning, the extreme gradient boosting algorithm successfully …

An Inducible Genetic Tool To Track And Manipulate Specific Microglial States Reveals Their Plasticity And Roles In Remyelination, Kia M Barclay, Nora Abduljawad, Zuolin Cheng, Min Woo Kim, Lu Zhou, Jin Yang, Justin Rustenhoven, Jose A Mazzitelli, Leon C D Smyth, Dvita Kapadia, Simone Brioschi, Wandy Beatty, Jinchao Hou, Naresha Saligrama, Marco Colonna, Guoqiang Yu, Jonathan Kipnis, Qingyun Li

The Brown Foundation: Institute of Molecular Medicine

Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative region-associated microglia (PAM) in developing white matter and disease-associated microglia (DAM) prevalent in various neurodegenerative conditions. PAM and DAM share a similar core gene signature. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreERT2, that targets PAM and DAM in the brain parenchyma. Utilizing this tool, we profiled labeled cells during development and in several …

Slow Proliferation Of Bap1-Deficient Uveal Melanoma Cells Is Associated With Reduced S6 Signaling And Resistance To Nutrient Stress, Vivian Chua, Melisa Lopez-Anton, Mizue Terai, Ryota Tanaka, Usman Baqai, Timothy J Purwin, Jelan I Haj, Francis J Waltrich, Isabella Trachtenberg, Kristine Luo, Rohith Tudi, Angela Jeon, Anna Han, Inna Chervoneva, Michael A Davies, Julio A Aguirre-Ghiso, Takami Sato, Andrew E Aplin

Faculty, Staff and Student Publications

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and …

Role Of Ethanolamine Utilization And Bacterial Microcompartment Formation In Listeria Monocytogenes Intracellular Infection, Ayan Chatterjee, Karan Gautam Kaval, Danielle A Garsin

Faculty, Staff and Student Publications

Ethanolamine (EA) affects the colonization and pathogenicity of certain human bacterial pathogens in the gastrointestinal tract. However, EA can also affect the intracellular survival and replication of host cell invasive bacteria such as Listeria monocytogenes (LMO) and Salmonella enterica serovar Typhimurium (S. Typhimurium). The EA utilization (eut) genes can be categorized as regulatory, enzymatic, or structural, and previous work in LMO showed that loss of genes encoding functions for the enzymatic breakdown of EA inhibited LMO intracellular replication. In this work, we sought to further characterize the role of EA utilization during LMO infection of host …

Frontotemporal Dementia-Like Disease Progression Elicited By Seeded Aggregation And Spread Of Fus, Sonia Vazquez-Sanchez, Britt Tilkin, Fatima Gasset-Rosa, Sitao Zhang, Diana Piol, Melissa Mcalonis-Downes, Jonathan Artates, Noe Govea-Perez, Yana Verresen, Lin Guo, Don Cleveland, James Shorter, Sandrine Da Cruz

Department of Biochemistry and Molecular Biology Faculty Papers

RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation …

Rigor And Reproducibility In Human Brain Organoid Research: Where We Are And Where We Need To Go, Soraya O Sandoval, Gerarda Cappuccio, Karina Kruth, Sivan Osenberg, Saleh M Khalil, Natasha M Méndez-Albelo, Krishnan Padmanabhan, Daifeng Wang, Mark J Niciu, Anita Bhattacharyya, Jason L Stein, André M M Sousa, Elisa A Waxman, Elizabeth D Buttermore, Dosh Whye, Carissa L Sirois, Cross-Iddrc Human Stem Cell Consortium, Aislinn Williams, Mirjana Maletic-Savatic, Xinyu Zhao

Faculty, Staff and Students Publications

Human brain organoid models have emerged as a promising tool for studying human brain development and function. These models preserve human genetics and recapitulate some aspects of human brain development, while facilitating manipulation in an in vitro setting. Despite their potential to transform biology and medicine, concerns persist about their fidelity. To fully harness their potential, it is imperative to establish reliable analytic methods, ensuring rigor and reproducibility. Here, we review current analytical platforms used to characterize human forebrain cortical organoids, highlight challenges, and propose recommendations for future studies to achieve greater precision and uniformity across laboratories.

Intouch Week Of June 10, 2024, New York Medical College

InTouch

• Kenneth Theobalds To Be Honored at NYMC’s Annual Golf Tournament
• NYMC Opens New Online Store
• Dylan Kwart, Ph.D., M.Sc., Presents at the Neighborhood Science Seminar Series
• NYMC Welcomes D.P.T. Class of 2027 at New Student Orientation
• Construction on the MEC Roadway
• Metropolitan Hospital Center Research Day Highlights NYMC Residents Work
• Socioeconomic Disparities Exist in Treatment of Teen Femoral Fractures
• Student Spotlight: SOM Student Harry Fruchtman Sheds Lights on New Cancer Treatments with Publications in Nature

Protein Nanoparticles As Vaccine Platforms For Human And Zoonotic Viruses, Kush Kumar Pandey, Bikash R. Sahoo, Asit K. Pattnaik

Nebraska Center for Virology: Faculty Publications

Vaccines are one of the most effective medical interventions, playing a pivotal role in treating infectious diseases. Although traditional vaccines comprise killed, inactivated, or liveattenuated pathogens that have resulted in protective immune responses, the negative consequences of their administration have been well appreciated. Modern vaccines have evolved to contain purified antigenic subunits, epitopes, or antigen-encoding mRNAs, rendering them relatively safe. However, reduced humoral and cellular responses pose major challenges to these subunit vaccines. Protein nanoparticle (PNP)-based vaccines have garnered substantial interest in recent years for their ability to present a repetitive array of antigens for improving immunogenicity and enhancing protective …

Driving Pressure Decoded: Precision Strategies In Adult Respiratory Distress Syndrome Management, Muhammad Adrish, Sai Doppalapudi, Dmitry Lvovsky

Faculty, Staff and Students Publications

Mechanical ventilation (MV) is an important strategy for improving the survival of patients with respiratory failure. However, MV is associated with aggravation of lung injury, with ventilator-induced lung injury (VILI) becoming a major concern. Thus, ventilation protection strategies have been developed to minimize complications from MV, with the goal of relieving excessive breathing workload, improving gas exchange, and minimizing VILI. By opting for lower tidal volumes, clinicians seek to strike a balance between providing adequate ventilation to support gas exchange and preventing overdistension of the alveoli, which can contribute to lung injury. Additionally, other factors play a role in optimizing …

Novel Human Recombinant N-Acetylgalactosamine-6-Sulfate Sulfatase Produced In A Glyco-Engineered Escherichia Coli Strain, Luisa N. Pimentel-Vera, Alexander Rodríguez-López, Angela J. Espejo-Mojica, Aura María Ramírez, Carolina Cardona, Luis H. Reyes, Shunji Tomatsu, Thapakorn Jaroentomeechai, Matthew P. Delisa, Oscar F. Sánchez, Carlos J. Alméciga-Díaz

Department of Pediatrics Faculty Papers

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), resulting in the accumulation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). Previously, it was reported the production of an active human recombinant GALNS (rGALNS) in E. coli BL21(DE3). However, this recombinant enzyme was not taken up by HEK293 cells or MPS IVA skin fibroblasts. Here, we leveraged a glyco-engineered E. coli strain to produce a recombinant human GALNS bearing the eukaryotic trimannosyl core N-glycan, Man3GlcNAc2 (rGALNSoptGly). The N-glycosylated GALNS was produced at 100 …

The Brainstem As A Conserved System For Consciousness: Integrating Phylogeny, Neurology, And Psychology, Shadia Kawkabani, Kevin P. Kaut

Journal of Neuropsychology and Behavioral Processes

Historically, scientists and physicians have taken a corticocentric view of consciousness, emphasizing the need for a cortex in producing the conscious experience. The preserved consciousness observed in hydranencephalic children and decorticated rats suggests that some form of consciousness may be produced by a subcortical network. The brainstem, a phylogenetically conserved brain system, could serve as the major integrative network to produce this form of consciousness—referred to as ‘affective consciousness’, the evolutionary antecedent to the reflective consciousness allowing humans to reflect on experiences. The functional integration of the brainstem with the amygdala, motor network, and other subcortical structures provides the architecture …

Distinct Expression Patterns Of Hedgehog Signaling Components In Mouse Gustatory System During Postnatal Tongue Development And Adult Homeostasis, Archana Kumari, Nicole E Franks, Libo Li, Gabrielle Audu, Sarah Liskowicz, John D Johnson, Charlotte M Mistretta, Benjamin L Allen

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The Hedgehog (HH) pathway regulates embryonic development of anterior tongue taste fungiform papilla (FP) and the posterior circumvallate (CVP) and foliate (FOP) taste papillae. HH signaling also mediates taste organ maintenance and regeneration in adults. However, there are knowledge gaps in HH pathway component expression during postnatal taste organ differentiation and maturation. Importantly, the HH transcriptional effectors GLI1, GLI2 and GLI3 have not been investigated in early postnatal stages; the HH receptors PTCH1, GAS1, CDON and HHIP, required to either drive HH pathway activation or antagonism, also remain unexplored. Using lacZ reporter mouse models, we mapped expression of the HH …

Vertebral Hu Value And The Pectoral Muscle Index Based On Chest Ct Can Be Used To Opportunistically Screen For Osteoporosis, Xiong-Yi Wang, Sheng Pan, Wei-Feng Liu, Yi-Ke Wang, Si-Min Yun, You-Jia Xu

Faculty, Staff and Student Publications

BACKGROUND: Existing studies have shown that computed tomography (CT) attenuation and skeletal muscle tissue are strongly associated with osteoporosis; however, few studies have examined whether vertebral HU values and the pectoral muscle index (PMI) measured at the level of the 4th thoracic vertebra (T4) are strongly associated with bone mineral density (BMD). In this study, we demonstrate that vertebral HU values and the PMI based on chest CT can be used to opportunistically screen for osteoporosis and reduce fracture risk through prompt treatment.

METHODS: We retrospectively evaluated 1000 patients who underwent chest CT and DXA scans from August 2020-2022. The …

Defining The Kras- And Erk-Dependent Transcriptome In Kras-Mutant Cancers, Jeffrey A Klomp, Jennifer E Klomp, Clint A Stalnecker, Kirsten L Bryant, A Cole Edwards, Kristina Drizyte-Miller, Priya S Hibshman, J Nathaniel Diehl, Ye S Lee, Alexis J Morales, Khalilah E Taylor, Sen Peng, Nhan L Tran, Laura E Herring, Alex W Prevatte, Natalie K Barker, Laura D Hover, Jill Hallin, Alexey Sorokin, Preeti Marie Kanikarla, Saikat Chowdhury, Oluwadara Coker, Hey Min Lee, Craig M Goodwin, Prson Gautam, Peter Olson, James G Christensen, John P Shen, Scott Kopetz, Lee M Graves, Kian-Huat Lim, Andrea Wang-Gillam, Krister Wennerberg, Adrienne D Cox, Channing J Der

Faculty, Staff and Student Publications

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and ERK-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges significantly from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome and other components of the cell cycle machinery as …

Cost-Effectiveness And Threshold Analysis Of Deep Brain Stimulation Vs Treatment-As-Usual For Treatment-Resistant Depression, Katherine E Kabotyanski, Ricardo A Najera, Garrett P Banks, Himanshu Sharma, Nicole R Provenza, Benjamin Y Hayden, Sanjay J Mathew, Sameer A Sheth

Faculty, Staff and Students Publications

Treatment-resistant depression (TRD) affects approximately 2.8 million people in the U.S. with estimated annual healthcare costs of $43.8 billion. Deep brain stimulation (DBS) is currently an investigational intervention for TRD. We used a decision-analytic model to compare cost-effectiveness of DBS to treatment-as-usual (TAU) for TRD. Because this therapy is not FDA approved or in common use, our goal was to establish an effectiveness threshold that trials would need to demonstrate for this therapy to be cost-effective. Remission and complication rates were determined from review of relevant studies. We used published utility scores to reflect quality of life after treatment. Medicare …

Metabolic Regulator Errγ Governs Gastric Stem Cell Differentiation Into Acid-Secreting Parietal Cells, Mahliyah Adkins-Threats, Sumimasa Arimura, Yang-Zhe Huang, Margarita Divenko, Sarah To, Heather Mao, Yongji Zeng, Jenie Y Hwang, Joseph R Burclaff, Shilpa Jain, Jason C Mills

Faculty, Staff and Students Publications

Parietal cells (PCs) produce gastric acid to kill pathogens and aid digestion. Dysregulated PC census is common in disease, yet how PCs differentiate is unclear. Here, we identify the PC progenitors arising from isthmal stem cells, using mouse models and human gastric cells, and show they preferentially express cell-metabolism regulator and orphan nuclear receptor Estrogen-related receptor gamma (Esrrg, encoding ERRγ). Esrrg expression facilitated the tracking of stepwise molecular, cellular, and ultrastructural stages of PC differentiation. Esrrg^P2ACreERT2 lineage tracing revealed Esrrg expression commits progenitors to differentiate into mature PCs. scRNA-seq indicated the earliest Esrrg+ PC progenitors preferentially …