Medicine and Health Sciences Commons^™

Spase: Spatially Resolved Pathology Scores Using Optimal Transport On Spatial Transcriptomics Data, Mohammad Nuwaisir Rahman, Mohammed Abid Abrar, Vikram Rakesh Shaw, James F Martin, M Saifur Rahman, Md Abul Hassan Samee

Faculty, Staff and Students Publications

Pathological events often impact tissue regions in a spatial variable manner, making it challenging to identify therapeutic targets. Spatial transcriptomics (ST) is a powerful technology to map spatially variable molecular mechanisms, yet suitable analytical methods have been lacking. We introduce SPaSE (Spatially-resolved Pathology ScorE), an optimal transport-based algorithm to compare ST data from diseased and control tissues. SPaSE computes a “pathology score” for each spot in the diseased sample, quantifying the pathological impact at that spot. In post-MI (myocardial infarction) mouse hearts, these scores delineated zones that matched independent expert annotations. Modeling pathology scores from gene expression revealed signatures predictive …

Clinical Outcomes In Patients With Schizophrenia Treated With Long-Acting Injectable Vs Oral Antipsychotics: A Naturalistic Study, Francesca Bardi, Lorenzo Moccia, Georgios D Kotzalidis, Gianluca Boggio, Andrea Brugnami, Greta Sfratta, Delfina Janiri, Gabriele Sani, Alessio Simonetti

Faculty, Staff and Students Publications

Background/Objectives: Long-acting injectable antipsychotics (LAIs) represent a significant advancement in the treatment of schizophrenia (SCZ), particularly for improving adherence and long-term outcomes. This study aimed to assess the clinical outcomes of patients receiving atypical LAIs compared to those on various oral antipsychotics over a one-year follow-up in a naturalistic setting.

Methods: Sixty patients with SCZ were subdivided in two groups, those receiving LAIs (n = 25) and those receiving oral antipsychotics (n = 35). The groups were comparable for age, gender, educational attainment, employment status, marital status, smoking habits, and baseline SCZ severity, with no differences …

Development And Extensive Sequencing Of A Broadly-Consented Genome In A Bottle Matched Tumor-Normal Pair, Jennifer H Mcdaniel, Vaidehi Patel, Nathan D Olson, Hua-Jun He, Zhiyong He, Kenneth D Cole, Alexander A Gooden, Anthony Schmitt, Kristin Sikkink, Fritz J Sedlazeck, Harsha Doddapaneni, Shalini N Jhangiani, Donna M Muzny, Marie-Claude Gingras, Heer Mehta, Sairam Behera, Luis F Paulin, Alex R Hastie, Hung-Chun Yu, Victor Weigman, Alison Rojas, Katie Kennedy, Jamie Remington, Isai Salas-González, Mitch Sudkamp, Kelly Wiseman, Bryan R Lajoie, Shawn Levy, Miten Jain, Stuart Akeson, Giuseppe Narzisi, Zoe Steinsnyder, Catherine Reeves, Jennifer Shelton, Sarah B Kingan, Christine Lambert, Primo Baybayan, Aaron M Wenger, Ian J Mclaughlin, Aaron Adamson, Christopher Kingsley, Melanie Wescott, Young Kim, Benedict Paten, Jimin Park, Ivo Violich, Karen H Miga, Joshua Gardner, Brandy Mcnulty, Gail L Rosen, Rajiv Mccoy, Francesco Brundu, Erfan Sayyari, Konrad Scheffler, Sean Truong, Severine Catreux, Lesley Chapman Hannah, Doron Lipson, Hila Benjamin, Nika Iremadze, Ilya Soifer, Gat Krieger, Stephen Eacker, Mary Wood, Erin Cross, Greg Husar, Stephen Gross, Michael Vernich, Mikhail Kolmogorov, Tanveer Ahmad, Ayse G Keskus, Asher Bryant, Francoise Thibaud-Nissen, Jonathan Trow, Jacqueline Proszynski, Jeremy Wain Hirschberg, Krista Ryon, Christopher E Mason, Mital S Bhakta, J Zachary Sanborn, Elizabeth M Munding, Justin Wagner, Chunlin Xiao, Andrew S Liss, Justin M Zook

Faculty, Staff and Students Publications

The Genome in a Bottle Consortium (GIAB), hosted by the National Institute of Standards and Technology (NIST), is developing new matched tumor-normal samples, the first explicitly consented for public dissemination of genomic data and cell lines. Here, we describe a comprehensive genomic dataset from the first individual, HG008, including DNA from an adherent, epithelial-like pancreatic ductal adenocarcinoma (PDAC) tumor cell line and matched normal cells from duodenal and pancreatic tissues. Data for the tumor-normal matched samples comes from seventeen distinct state-of-the-art whole genome measurement technologies, including high depth short and long-read bulk whole genome sequencing (WGS), single cell WGS, Hi-C, …

Altered Patterning Of Neural Activity In A Neuropathology, Clarissa Hoffman, Jingheng Cheng, Rodrigo Morales, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Students Publications

The dynamics of neural circuits and their role in mediating cellular and organismal phenomena remain poorly understood, despite numerous efforts to dissect these processes through precise instantaneous measurements or longer-time averages and approximations. We use an alternative approach: we investigate these dynamics at the system's mesoscale by analyzing spike trains and waveforms. These extended activity patterns carry robust, tractable information, are highly responsive to physiological specifics, and enable detailed tracking of circuit behavior. In particular, this methodology allows for characterizing the functionality of tau-pathology-afflicted hippocampal circuits and identifying circuit-level abnormalities that are missed by through traditional analyses. In healthy mice, …

Parietal Cortex Is Recruited By Frontal And Cingulate Areas To Support Action Monitoring And Updating During Stopping, Jung Uk Kang, Layth Mattar, José Vergara, Victoria E Gobo, Hernan G Rey, Sarah R Heilbronner, Andrew J Watrous, Benjamin Y Hayden, Sameer A Sheth, Eleonora Bartoli

Faculty, Staff and Students Publications

Recent evidence indicates that the intraparietal sulcus (IPS) may play a causal role in action stopping, potentially representing a novel neuromodulation target for inhibitory control dysfunctions. Here, we leverage intracranial recordings in human subjects to establish the timing and directionality of information flow between IPS and prefrontal and cingulate regions during action stopping. Prior to successful inhibition, information flows primarily from the inferior frontal gyrus (IFG), a critical inhibitory control node, to IPS. In contrast, during stopping errors the communication between IPS and IFG is lacking, and IPS is engaged by posterior cingulate cortex, an area outside of the classical …

Neonatal Seizures: Advances In Diagnosis And Management, Elissa G Yozawitz, Ronit M Pressler, Eli M Mizrahi

Faculty, Staff and Students Publications

The International League Against Epilepsy (ILAE) created the ILAE Neonatal Task Force that classified neonatal seizures, defined neonatal epilepsy syndromes, and specified treatment guidelines. These frameworks, in addition to improved access to genetic testing and other recent advances, have revolutionized the diagnosis and management of neonatal seizures. PLAIN LANGUAGE SUMMARY: Neonatal seizures, occurring within the first 4 weeks of life, present unique challenges due to the immature neonatal brain. The International League Against Epilepsy (ILAE) Neonatal Task Force revolutionized diagnosis and management through classification, syndrome definition, and treatment guidelines. Despite advancements, challenges persist, including accurate diagnosis and limited evidence-based treatment …

Epha4 Signaling Dysregulation Links Abnormal Locomotion And The Development Of Idiopathic Scoliosis, Lianlei Wang, Xinyu Yang, Sen Zhao, Pengfei Zheng, Wen Wen, Kexin Xu, Xi Cheng, Qing Li, Anas M Khanshour, Yoshinao Koike, Junjun Liu, Xin Fan, Nao Otomo, Zefu Chen, Yaqi Li, Lulu Li, Haibo Xie, Panpan Zhu, Xiaoxin Li, Yuchen Niu, Shengru Wang, Sen Liu, Suomao Yuan, Chikashi Terao, Ziquan Li, Shaoke Chen, Xiuli Zhao, Pengfei Liu, Jennifer E Posey, Zhihong Wu, Guixing Qiu, Disco Study Group (Deciphering Disorders Involving Scoliosis & Comorbidities), Shiro Ikegawa, James R Lupski, Jonathan J Rios, Carol A Wise, Jianguo T Zhang, Chengtian Zhao, Nan Wu

Faculty, Staff and Students Publications

Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we first reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited …

Role Of Lipoprotein(A) In Atherosclerotic Cardiovascular Disease In South Asian Individuals, Darshan Patel, Marlys L Koschinsky, Anandita Agarwala, Pradeep Natarajan, Harpreet S Bhatia, Anurag Mehta, Jaideep Patel, Matthew Peters, Shreya Pandya, Usman Sagheer, Raman Puri, Salim S Virani, Dinesh K Kalra

Faculty, Staff and Students Publications

South Asian individuals (SA), representing approximately one quarter of the global population, experience a disproportionately high burden of cardiovascular disease. Some of this increased susceptibility is accounted for by traditional risk factors such as diabetes, hypertension, carbohydrate-rich diets, and rising rates of obesity and metabolic syndrome. However, other previously underappreciated risk factors may also play a crucial role. These include environmental pollution, genetic factors, and Lp(a) (lipoprotein(a)). Various epidemiological and genetic studies support the role of Lp(a) as a causal and independent risk factor for atherosclerotic cardiovascular disease. SA have a higher prevalence of elevated Lp(a) levels (25% have levels …

Gene Expression In Tumor And Adjacent Normal Tissues In Lung Adenocarcinoma Subtypes, Olga Y Gorlova, Ivan P Gorlov, R Taylor Ripley, Chao Cheng, Yafang Li, Bo Peng, Yanhong Liu, Hee-Jin Jang, Sung Wook Kang, Claire Lee, Priyanka Ranchod, Bryan M Burt, Hyun-Sung Lee, Christopher I Amos

Faculty, Staff and Students Publications

Background: Lung adenocarcinoma (LUAD) has several histologically distinct subtypes that differ by a number of clinical features including patient survival. Molecular mechanisms underlying histological and clinical differences between subtypes remain poorly understood.

Methods: We conducted a comparative analyses of gene expression in acinar, lepidic, papillary and solid subtypes, as well as mucinous adenocarcinoma. We used a novel, more efficient approach to identify subtype-specific genes. We compared the mean gene expression level separately for tumors and adjacent normal tissue with pure or a highly represented (≥ 75%) subtype of interest to the mean expression in tumors where the subtype of interest …

Exogenous Arginine Differentially Regulates Inflammatory Cytokine And Inducible Nitric Oxide Synthase Expression In Macrophages, Kelsey Stayer, Saliha Pathan, Aalekhya Biswas, Huiqiao Li, Yi Zhu, Fong Wilson Lam, Juan Marini, Sundararajah Thevananther

Faculty, Staff and Students Publications

Immune dysfunction and late mortality from multiorgan failure are hallmarks of severe sepsis. Arginine, a semi-essential amino acid important for protein synthesis, immune response, and circulatory regulation, is deficient in sepsis. However, arginine supplementation in sepsis remains controversial due to the potential to upregulate inducible nitric oxide synthase (iNOS)-mediated excessive nitric oxide (NO) generation in macrophages, leading to vasodilation and hemodynamic catastrophe. Citrulline supplementation has been considered an alternative to replenishing arginine via de novo synthesis, orchestrated by argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL). However, the functional relevance of the ASS1-ASL pathway in macrophages after endotoxin stimulation is …

Spatial Proximity Of Immune Cell Pairs To Cancer Cells In The Tumor Microenvironment As Biomarkers For Patient Stratification, Jian-Rong Li, Xingxin Pan, Yupei Lin, Yanding Zhao, Yanhong Liu, Yong Li, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

Background/objectives: The tumor microenvironment (TME) plays a critical role in cancer progression by shaping immune responses and influencing patient outcomes. We hypothesized that the relative proximity of specific immune cell pairs to cancer cells within the TME could help predict their pro- or anti-tumor functions and reflect clinically relevant immune dynamics.

Methods: We analyzed imaging mass cytometry (IMC) data from lung adenocarcinoma (LUAD) and triple-negative breast cancer (TNBC) cohorts. For each immune cell pair, we calculated a relative distance (RD) score, which quantifies the spatial difference in proximity to cancer cells. We assessed the prognostic and predictive significance of these …

The Feasibility Of Passively Tracking Children’S Tv Viewing And Mobile Device Use In Naturalistic Settings, Teresia M O'Connor, Tatyana Garza, Uzair Alam, Anil Kumar Vadathya, Jennette P Moreno, Alicia Beltran, Samah Haidar, Nimah Haidar, Sheryl O Hughes, Debbe Thompson, Salma M A Musaad, Tom Baranowski, Jason A Mendoza, Joseph Young, Akane Sano, Ashok Veeraraghavan

Faculty, Staff and Students Publications

Research on children's technology and digital media (TDM) is hampered by a lack of robust approaches for assessing TDM use. This study assessed the feasibility of passively measuring children's TV screens and mobile devices (TDM) in a naturalistic setting. In the three-day feasibility study, FLASH-TV was set up on one to two TVs the child (5-12 year olds) typically used in the home (n=20). Children's mobile device use was assessed with either the Chronicle App or ScreenTime screenshots. Parents completed three TDM diaries. An exit interview with the parent explored their perceptions of the assessments and the child's TDM use …

Ovochymase 2 Is A Key Regulatory Factor Modulating Proteolytic Pathways And Sperm Maturation In The Mammalian Epididymis, Katarzyna Kent, Kaori Nozawa, Antrix Jain, Anna Malovannaya, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

Spermatozoa acquire fertilizing competence during epididymal transit through proteolytic, chaperone-mediated, and post-translational modifications. Ovochymase 2, an epididymis-specific trypsin-like serine protease, has emerged as a central regulator of this maturation process. Here, we integrate targeted gene disruption, comprehensive proteomic profiling, and affinity-based proteome enrichment to delineate how Ovochymase 2 influences sperm functionality. Deletion of Ovochymase 2 disrupts the proteome of epididymal sperm, resulting in diminished levels of core fertility-related factors-including a disintegrin and metalloprotease domain 3, β-defensins, and protease-inhibitor complexes-while inducing compensatory upregulation of alternate proteases and chaperones. Interaction assays confirm direct or indirect associations between Ovochymase 2 and sperm surface …

A Mouse Model Engineered To Spatiotemporally Control Cre Expression In Progesterone Receptor Positive Cells†, Elvis Quiroz, Ryan M Marquardt, Shu-Yun Li, Artiom Gruzdev, David Cunefare, Charan Ganta, San-Pin Wu, John P Lydon, Francesco J Demayo

Faculty, Staff and Students Publications

The Cre/loxP system is widely used for site-specific genetic manipulation in mice. The PgrCre mouse model, where Cre recombinase is driven by the progesterone receptor promoter, is commonly used for gene ablation in Pgr-positive uterine cells. However, the PgrCre is active in the neonatal uterus and does not allow temporal control. To enhance the functionality of the PgrCre mouse, we generated and characterized an inducible PgriCreERT2 mouse, in which iCreERT2 is inserted downstream of the endogenous Pgr promoter. PgriCreERT2 mice crossed with Rosa26-CAG-LSL-Sun1-sfGFP-myc reporter mice demonstrated tamoxifen-dependent recombination in uterine stromal fibroblasts and a subset of epithelial cells. Tamoxifen-induced ablation …

Impact Of Sanitation System Types On Residential And Environmental Presence Of Human Waste And Parasites In Alabama, Brandon Hunter, Catherine Coleman Flowers, Rojelio Mejia, Marc Arnold Deshusses

Faculty, Staff and Students Publications

Lowndes County is a predominantly Black rural county in Alabama, in the United States, which has a historical and current legacy of racial discrimination, creating inequitable infrastructure access and adverse health impacts. Over 80% rely on on-site sanitation infrastructure and most are failing. A community assessment of exposure to untreated sewage was conducted using samples from residential drinking water, surface swabs, and soil combined with environmental water and soil samples using culture-based and quantitative polymerase chain reaction (qPCR) methods. Testing varied slightly across samples, due to difficulty of access or availability. Of 43 households, 68% and 55% of houses had …

Oral Dosing Of The Nucleoside Analog Obeldesivir Is Efficacious Against Rsv Infection In African Green Monkeys, Jared Pitts, J Lizbeth Reyes Zamora, Savrina Manhas, Thomas Aeschbacher, Josolyn Chan, Vincent Cutillas, Varsha Nair, Nicholas C Riola, Arya Vijjapurapu, Meghan S Vermillion, Stacey Eng, Christopher Richards, Dong Han, Jason K Perry, Subhra Chaudhuri, Szu-Wen Liu, Clarissa Martinez, Nadine Peinovich, Kai-Hui Sun, Arthur Cai, Ross Martin, Jasmine Moshiri, Charlotte Hedskog, Darius Babusis, Dustin S Siegel, Rao Kalla, Vasanthi Avadhanula, Pedro A Piedra, Kim Stobbelaar, Peter L Delputte, Caleb Marceau, Roberto Mateo, Evguenia Maiorova, Hongmei Mo, Raju Subramanian, Richard L Mackman, Tomas Cihlar, Simon P Fletcher, John P Bilello

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20–0.66 μM). Resistance selection studies with ODV and GS-441524 against RSV identify a single amino acid substitution, I777L, in the L polymerase with …

The Current And Future Burden Of Long Covid In The United States, Sarah M Bartsch, Kevin L Chin, Ulrich Strych, Danielle C John, Tej D Shah, Maria Elena Bottazzi, Kelly J O'Shea, Mckaylee Robertson, Colleen Weatherwax, Jessie Heneghan, Marie F Martinez, Allan Ciciriello, Sarah Kulkarni, Kavya Velmurugan, Alexis Dibbs, Sheryl A Scannell, Yanhan Shen, Denis Nash, Peter J Hotez, Bruce Y Lee

Faculty, Staff and Students Publications

Background: Long coronavirus disease (COVID), which affects an estimated 44.69-48.04 million people in the United States, is an ongoing public health concern that will persist as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread.

Methods: We developed a computational simulation model representing the clinical course, health effects, and associated costs of a person with long COVID.

Results: Simulations show that the average total cost of a long COVID case can range from $5084-$11 646 (assuming symptoms only last 1 year) with 92.5%-95.2% of these costs being productivity losses. Therefore, the current number of long COVID cases could cost …

Rapid High-Sensitivity Detection Of Antibodies To Trypanosoma Cruzi With A Recombinant Tc24 Antigen-Based Magneto-Immunoassay: A Pilot Study, Kavya L Singampalli, Bin Zhan, Rojelio Mejia, Peter B Lillehoj

Faculty, Staff and Students Publications

The diagnosis of chronic Chagas disease is challenging due to the wide genetic diversity of Trypanosoma cruzi, the causative agent of Chagas disease, and low levels of parasitemia, resulting in low sensitivity and accuracy with existing diagnostics. We report a magneto-immunoassay that employs dually labeled magnetic beads incorporating a recombinant Tc24 antigen, which is homologous across multiple discrete typing units of T cruzi. In this pilot study, 102 serum samples from 7 endemic countries were tested by this magneto-immunoassay, revealing its ability to distinguish Chagas-positive from Chagas-negative cases more accurately and faster than a standard Tc24-based immunoassay.

Global Diversity Of Soil-Transmitted Helminths Reveals Population-Biased Genetic Variation That Impacts Diagnostic Targets, Marina Papaiakovou, Andrea Waeschenbach, Olumide Ajibola, Sitara Sr Ajjampur, Roy M Anderson, Robin Bailey, Jade Benjamin-Chung, Maria Cambra-Pellejà, Nicolas R Caro, David Chaima, Rubén O Cimino, Piet Cools, Anélsio Cossa, Julia Dunn, Sean Galagan, Javier Gandasegui, Berta Grau-Pujol, Emma L Houlder, Moudachirou Ibikounlé, Timothy P Jenkins, Khumbo Kalua, Eyrun F Kjetland, Alejandro J Krolewiecki, Bruno Levecke, Adrian Jf Luty, Andrew S Macdonald, Inácio Mandomando, Malathi Manuel, Maria Martínez-Valladares, Rojelio Mejia, Zeleke Mekonnen, Augusto Messa, Harriet Mpairwe, Osvaldo Muchisse, Jose Muñoz, Pauline Mwinzi, Valdemiro Novela, Maurice R Odiere, Charfudin Sacoor, Judd L Walson, Steven A Williams, Stefan Witek-Mcmanus, D Timothy J Littlewood, Cinzia Cantacessi, Stephen R Doyle

Faculty, Staff and Students Publications

Soil-transmitted helminths (STHs) are intestinal parasites that affect over a billion people worldwide. STH control relies on microscopy-based diagnostics to monitor parasite prevalence and enable post-treatment surveillance; however, molecular diagnostics are rapidly being developed due to increased sensitivity, particularly in low-STH-prevalence settings. The genetic diversity of helminths and its potential impact on molecular diagnostics remain unclear. Using low-coverage genome sequencing, we assess the genetics of STHs within worm, faecal, and purified egg samples from 27 countries, identifying differences in the genetic connectivity and diversity of STH-positive samples across regions and cryptic diversity between closely related human- and pig-infective species. We …

Braf V600e-Positive Mononuclear Cells In Blood At Diagnosis Portend Treatment Failure And Neurodegeneration In Pediatric Lch, Howard Lin, Akanksha Batajoo, Erin Peckham-Gregory, Daniel Zinn, Olive S Eckstein, Nader Kim El-Mallawany, Nitya Gulati, Zachary D Prudowsky, Brooks Scull, Jessica Velazquez, Harshal Abhyankar, Stephen J Simko, Daria Vakula, Ryan Fleischmann, Vivekanudeep Karri, M John Hicks, Kevin E Fisher, Choladda V Curry, Angshumoy Roy, Deborah Schiff, Kenneth M Heym, Michael E Scheurer, D Williams Parsons, Miriam Merad, Tsz-Kwong Man, Kenneth L Mcclain, Jennifer Picarsic, Carl E Allen

Faculty, Staff and Students Publications

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder driven by mitogen-activated protein kinase (MAPK) activation in hematopoietic cells. Historically, LCH has been staged according to involvement of "risk organs" (bone marrow, liver, and spleen), based on risk of death. With improvements in supportive care and efficacy of MAPK pathway inhibitors, patients with LCH now rarely die. However, most patients with LCH with multisystem disease are not cured with current front-line chemotherapy, and treatment failure is associated with long-term morbidity, including LCH-associated neurodegeneration (LCH-ND). In this study, we evaluated the impact of extent of LCH at presentation, tumor genotype, and …

Innovations In Tavr: The Latest In Device Technology, Omar Sheikh, Errol Moras, Lorraine Mascarenhas, Sahar Samimi, Waleed T Kayani, Syed Zaid

Faculty, Staff and Students Publications

Aortic stenosis is the most prevalent valvular disease globally. Transcatheter aortic valve replacement (TAVR) has become a well-established treatment for aortic stenosis, offering outcomes comparable to surgical aortic valve replacement (SAVR). Its use has expanded to include younger, lower-risk patients and those with more complex anatomies. Recent advancements in TAVR include the increased adoption of transfemoral access, prosthesis designs optimized for challenging anatomies, enhanced delivery systems with repositioning capabilities, and outer skirts to minimize paravalvular leaks. Despite these innovations, several challenges remain. This review highlights recent updates in transcatheter heart valve (THV) systems, leaflet modification devices, and the current limitations …

Genome Report: Whole-Genome Assembly Of The Relapsing Fever Tick Ornithodoros Turicata Dugès (Acari: Argasidae), Mackenzie Tietjen, Amanda R Stahlke, David Luecke, Perot Saelao, Sheina B Sim, Scott M Geib, Brian E Scheffler, Anna K Childers, Alexander R Kneubehl, Pete D Teel, Job E Lopez

Faculty, Staff and Students Publications

The soft tick family Argasidae contains vectors of medical and veterinary importance, but few molecular resources are available compared to hard ticks (Ixodidae). One example is Ornithodoros turicata, a recognized vector of Borrelia turicatae, causal agent of human relapsing fever, and a putative vector of African swine fever virus. To address the current lack of molecular resources for the Argasidae, we generated a chromosome-level genome assembly for O. turicata using PacBio sequencing in conjunction with an Illumina Hi-C library. The resulting reference genome has a total of 1.1 Gb in length and was assembled into 10 chromosomes and 368 unplaced …

Inferring Chromosome Segregation Error Stage And Crossover In Trisomic Disorders With Application To Down Syndrome, Zhenhua Li, Wenjian Yang, Gang Wu, Ti-Cheng Chang, Zhongshan Cheng, Meenakshi Devidas, Mary Shago, Andrew J Carroll, Nyla A Heerema, Julie M Gastier-Foster, Brent L Wood, Lauren Sanclemente, Elizabeth A Raetz, Stephen P Hunger, Mignon L Loh, Eleanor Feingold, Tracie C Rosser, Emily G Allen, Stephanie L Sherman, Karen R Rabin, Philip J Lupo, Jun J Yang

Faculty, Staff and Students Publications

Errors in chromosome segregation during gametogenesis, such as nondisjunction (NDJ) errors, have severe consequences in human reproduction, and a better understanding of their etiology is of fundamental interest in genetics. Mapping NDJ errors to meiotic/mitotic stages typically requires proband-parent comparison, limiting its applicability. Herein, we develop Mis-segregation Error Identification through Hidden Markov Models (MeiHMM), a method for inferring NDJ error stage and crossover events based on only genomic data of trisomic probands. Guided by triallelic genotype/haplotype configurations, MeiHMM discerns the allelic origin at each locus, which informs NDJ error during gamete formation, without identifying the parental origin of the trisomy. …

Clinically Important Endpoints In Individuals With Leukodystrophy: A Multisite Study, Emma R Kotes, Sarah Woidill, Russell D'Aiello, Amina Khan, Jacob Mccann, Mark Ramos, Francesco Gavazzi, Stephanie Keller, Keith Van Haren, Ali Fatemi, Florian Eichler, Joshua Bonkowsky, Jamie Fraser, Lisa Emrick, Omar Sherbini, Ashley Hackett, Jeilo Gauna, Dandre Amos, Jordan Goodman, Amena Smith Fine, Amanda Nagy, Seungil Lee, Nicole Page, Johanna Schmidt, Amy Pizzino, Kayla Muirhead, Mariko Bennett, Amy Waldman, Justine Shults, Laura Adang, Robert Grundmeier, Adeline Vanderver

Faculty, Staff and Students Publications

Importance: Leukodystrophies are a diverse group of rare disorders that disrupt central myelination. These disorders present with a broad spectrum of neurologic severity and are associated with a range of potential secondary complications, such as scoliosis and failure of independent feeding.

Objective: we explore real-world data of leukodystrophy complications to inform future evidence-based care guidelines across these rare diseases.

Design: In a cross-sectional observational study, we use a leukodystrophy-specific research consortium and the availability of electronic health records (EHR) to capture a cross-section of real-world data.

Setting: Subjects were identified using EHR data from five hospital systems with established expertise …

Distinct Systemic Impacts Of Aβ42 And Tau Revealed By Whole-Organism Snrna-Seq, Ye-Jin Park, Tzu-Chiao Lu, Tyler Jackson, Lindsey D Goodman, Lindsey Ran, Jiaye Chen, Chung-Yi Liang, Erin Harrison, Christina Ko, Xi Chen, Baiping Wang, Ao-Lin Hsu, Elizabeth Ochoa, Kevin F Bieniek, Shinya Yamamoto, Yi Zhu, Hui Zheng, Yanyan Qi, Hugo J Bellen, Hongjie Li

Faculty, Staff and Students Publications

Both neuronal and peripheral tissues become disrupted in Alzheimer's disease (AD). However, a comprehensive understanding of how AD impacts different tissues across the whole organism is lacking. Using Drosophila, we generated an AD Fly Cell Atlas (AD-FCA) based on whole-organism single-nucleus transcriptomes of 219 cell types from flies expressing AD-associated proteins, either human amyloid-β 42 peptide (Aβ42) or Tau, in neurons. We found that Aβ42 primarily affects the nervous system, including sensory neurons, while Tau induces accelerated aging in peripheral tissues. We identified a neuronal cluster enriched in Aβ42 flies, which has high lactate dehydrogenase (LDH) expression. This LDH-high cluster …

Single-Cell Profiling Of Bone Metastasis Ecosystems From Multiple Cancer Types Reveals Convergent And Divergent Mechanisms Of Bone Colonization, Fengshuo Liu, Yunfeng Ding, Zhan Xu, Xiaoxin Hao, Tianhong Pan, George Miles, Siyue Wang, Yi-Hsuan Wu, Jun Liu, Igor L Bado, Weijie Zhang, Ling Wu, Yang Gao, Liqun Yu, David G Edwards, Hilda L Chan, Sergio Aguirre, Michael Warren Dieffenbach, Elina Chen, Yichao Shen, Dane Hoffman, Luis Becerra Dominguez, Charlotte Helena Rivas, Xiang Chen, Hai Wang, Zbigniew Gugala, Robert L Satcher, Xiang H-F Zhang

Faculty, Staff and Students Publications

Bone is a common site for metastasis of solid cancers. The diversity of histological and molecular characteristics of bone metastases (BMs) remains poorly studied. Here, we performed single-cell RNA sequencing on 42 BMs from eight cancer types, identifying three distinct ecosystem archetypes, each characterized by an enrichment of specific immune cells: macrophages/osteoclasts, regulatory/exhausted T cells, or monocytes. We validated these archetypes by immunostaining on tissue sections and bioinformatic analysis of bulk RNA sequencing/microarray data from 158 BMs across more than 10 cancer types. Interestingly, we found only a modest correlation between the BM archetypes and the tissues of origin; BMs …

Psilocybin Treatment Extends Cellular Lifespan And Improves Survival Of Aged Mice, Kosuke Kato, Jennifer M Kleinhenz, Yoon-Joo Shin, Cristian Coarfa, Ali J Zarrabi, Louise Hecker

Faculty, Staff and Students Publications

Psilocybin, the naturally occurring psychedelic compound produced by hallucinogenic mushrooms, has received attention due to considerable clinical evidence for its therapeutic potential to treat various psychiatric and neurodegenerative indications. However, the underlying molecular mechanisms remain enigmatic, and few studies have explored its systemic impacts. We provide the first experimental evidence that psilocin (the active metabolite of psilocybin) treatment extends cellular lifespan and psilocybin treatment promotes increased longevity in aged mice, suggesting that psilocybin may be a potent geroprotective agent.

The Benefits Of Exercise Training In Combination With Weight Loss Therapies, Bryan C Jiang, Dennis T Villareal

Faculty, Staff and Students Publications

The primary treatment for obesity involves calorie restriction (CR) to promote dietary weight loss achieved through interventions including behavioral modification, bariatric surgery, and antiobesity medications. In adults with obesity, CR-induced weight loss enhances physical function and improves quality of life, while also reducing the burden of various obesity-related chronic conditions, including hypertension, diabetes, obstructive sleep apnea, and atherosclerotic heart disease. However, it is also associated with a decline in lean mass and bone mineral density, which increases the risk of sarcopenia and osteoporosis. When performed alongside CR, progressive resistance training (RT) attenuates this loss of lean mass and bone mass, …

The Co-Occurrence Of Autism Spectrum Disorder And Aarskog-Scott Syndrome In An Accomplished Young Man, Raisa S Romanova, Oksana I Talantseva, Katerina V Lind, Victoria A Manasevich, Julia E Kuznetsova, Elena L Grigorenko

Faculty, Staff and Students Publications

Objectives/Background: Aarskog-Scott syndrome (AAS), also known as faciogenital dysplasia, is a rare X-linked genetic disorder primarily characterized by its diverse physical manifestations. Previous evidence suggests a potential association between AAS and neurodevelopmental disorders, including autism spectrum disorder (ASD).

Methods: This case study presents a male adolescent with ASD and a novel genetic variant in FGD1 underlying AAS. We conducted comprehensive clinical, genetic, and behavioral assessments to characterize the neurodevelopmental presentation. Moreover, we examined the existing literature on AAS and comorbid neurodevelopmental disorders.

Results: The patient demonstrated features consistent with both AAS and ASD, presenting with characteristic physical features of AAS …

Infantile Pyknocytosis Revisited: Possible Familial Trend In A Study Of 9 Patients, Aileen Y Hu, Amy M Coffey, Jyotinder N Punia, Andrea N Marcogliese, Choladda V Curry, M Tarek Elghetany

Faculty, Staff and Students Publications

Context.—: Infantile pyknocytosis (IP) is an uncommon cause of transient neonatal hemolytic anemia and hyperbilirubinemia occurring in approximately 10% of cases of unexplained neonatal hemolytic anemia.

Objective.—: To study cases of IP with focus on long-term follow-up, perinatal events, and family history.

Design.—: Cases were prospectively identified during review of peripheral blood smears for neonatal hyperbilirubinemia during an 11-year period. Clinical and laboratory parameters, follow-up data, and family history were recorded.

Results.—: Nine cases of IP were identified from the morphologic recognition of pyknocytes and clinical and laboratory evidence of hemolysis, and included 6 males and 3 females. Age at …