Medical Specialties Commons^™

Hiding In Plain Sight: A Call To Prevent Cutaneous Leishmaniasis Transmission In The United States, Juan David Ramírez, Sarah M Gunter, Megan Coffee, Norman Beatty, Dawn M Wetzel

Faculty, Staff and Students Publications

Cutaneous leishmaniasis (CL), once considered a travel-associated tropical disease, is increasingly transmitted within the United States, particularly in southern regions. Despite mounting evidence of local transmission, public health recognition and preventive infrastructure remain limited. This Viewpoint highlights the urgent need to shift the U.S. CL response from questioning endemicity to preventing transmission. We review ecological, clinical, and surveillance data demonstrating the presence of competent vectors, animal reservoirs, and autochthonous human cases. Diagnostic delays, underreporting, and insufficient provider training contribute to missed prevention opportunities. Climate change and peri-urban rodent-human contact data further heighten future risk. A coordinated response is essential, including …

Natural Maternal Immunity Protects Neonates From Escherichia Coli Sepsis., Raymond E. Diep, Ujjwal Adhikari, Kubra Gokce Tezel, Giang Pham, Allison R. Burrell, Mary A. Staat, Nguyen Thi Khanh Nhu, Minh-Duy Phan, Kate M. Peters, Mark A. Schembri, Scott H. Saunders, David B. Haslam, John J. Erickson, Susana Chavez-Bueno, Sing Sing Way

Manuscripts, Articles, Book Chapters and Other Papers

Escherichia coli is a leading cause of neonatal sepsis, with infection occurring in approximately one in every 1,000 live births. However, with E. coli colonization beginning soon after birth and defects in neonatal host defence maturation, an alternative consideration is why infection does not occur even more frequently. Here we show that newborn babies with E. coli sepsis have selectively reduced vertically transferred natural antibodies that recognize E. coli, mechanistically explaining their susceptibility to infection. Complementary preclinical studies show that preconceptual intestinal colonization with probiotic E. coli Nissle 1917 (EcN) primes anti-E. coli immunoglobulin G (IgG) antibodies with broad cross-reactivity …

Neuropathological Hallmarks During The Chronic Phase Of Ischemic Stroke In Mice And Humans, Romeesa Khan, Gary Guzman, Trang Do, Patrick Devlin, John Ahn, Chunfeng Tan, Venugopal Reddy Venna, Sean P Marrelli, Haniyeh Koochak, Claudia M Di Gesù, Anthony Flores, Louise D Mccullough, Rodney M Ritzel

Faculty, Staff and Student Publications

Background: Advances in acute stroke care, including endovascular thrombectomy and improved neurocritical management, have increased survival after ischemic stroke. However, stroke remains a leading cause of long-term disability, with many survivors experiencing persistent neurological and cognitive impairments. The chronic neurological consequences of stroke, particularly its potential to accelerate brain aging, remain poorly understood.

Methods: We examined chronic neurobehavioral changes at 2 and 6 months after middle cerebral artery occlusion in male C57Bl/6 mice. Behavioral assessments included the open field test (OFT), novel object recognition test (NORT), fear conditioning (FC), nesting activity, and tail suspension testing. Transcriptomic profiling was performed using …

Dapk2 Regulates Pkm2 Phosphorylation At Threonine 45 To Facilitate Disturbed Flow-Induced Atherosclerosis, Shuai Guo, Long Xu, Yixin Chen, Yuan Zhao, Yuting Zhang, Runfa Yu, Kaixiang Cao, Litao Wang, Wenjia Ai, Jiang-Yun Luo, Lu Lu, Jun He, Yuan Zhou, Li Wang, Andrew H Baker, Yuqing Huo, Yiming Xu

Faculty, Staff and Students Publications

Background: Oscillatory shear stress (OSS), resulting from disturbed blood flow, is implicated in atherosclerotic plaque formation by incompletely understood mechanisms. This study aims to elucidate the involvement of death-associated protein kinase (DAPK) 2 in OSS-induced endothelial cell (EC) activation and atherosclerosis.

Methods: Publicly available resources, including genome-wide microarray, RNA sequencing, and single-cell RNA sequencing, were utilized to identify key OSS-sensitive regulatory factors. Techniques such as mass spectrometry, immunoprecipitation, proximity ligation assay, and RNA sequencing were employed to identify pyruvate kinase M2 (PKM2) as the binding protein of DAPK2 and determine the specific site of PKM2 phosphorylation by DAPK2. To assess …

A Multidomain Peptide Hydrogel-Liposome Composite For Controlled Release Of A Cyclic Dinucleotide In Oral Cancer, Joseph W R Swain, Andrea H Molina, Gemalene M Sunga, Danielle Chew-Martinez, Neeraja Dharmaraj, Alejandra Cobos Perez, Arghadip Dey, Ephraim J Vázquez-Rosado, Simon Young, Jeffrey D Hartgerink

Faculty, Staff and Student Publications

While immunotherapy is a promising treatment strategy for cancer, the majority of head and neck squamous cell carcinoma (HNSCC) patients treated with single-agent immunotherapy do not respond. Therefore, researchers are investigating combination treatments with immunostimulatory molecules that can maximize anti-tumor responses. Cyclic dinucleotides (CDNs) are STING agonists that hold promise in combination approaches, but they require frequent intratumoral administration when used in both preclinical models of HNSCC and clinical trials. To reduce administration frequency, we have created a peptide hydrogel–liposome composite system, K2-Lip(CDN), for local and prolonged availability of CDN. We investigated the loading limits of cationic liposomes in both …

Evapecognition: An 18-Year Dataset Of Great Ape Cognition, Alejandro Sánchez-Amaro, Sonja J Ebel Van Wijk, Carin Molenaar, Akzira Abuova, Lizbeth Mujica-Manrique, Sarah M Leisterer-Peoples, Bret Beheim, Luke Maurits, Anna Albiach-Serrano, Matthias Allritz, Nazli Altınok, Federica Amici, Alice Mi Auersperg, Filippo Aureli, Elisa Bandini, Jochen Barth, Leïla Benziad, Bettina E Bläsing, Manuel Bohn, Marie Bourjade, Juliane Bräuer, Marie-Hélène Broihanne, Sarah F Brosnan, Nereida Bueno-Guerra, Thomas Bugnyar, David Buttelmann, Frances Buttelmann, Trix Cacchione, Malinda Carpenter, Fernando Colmenares, Catherine Crockford, Katherine A Cronin, África De Las Heras, Arianna De Marco, Sarah E Detroy, Valérie Dufour, Shona Duguid, Robin I M Dunbar, Johanna Eckert, Jan M Engelmann, Joel Fagot, Julia Fischer, Sofia Ingrid Fredrika Forss, Martina Funk, György Gergely, Julia R Greenberg, Johannes Großmann, Sebastian Grüneisen, Marta Halina, Daniel Hanus, Sarah R Heilbronner, Christophe Heintz, Robert Hepach, Esther Herrmann, Satoshi Hirata, Alenka Hribar, Gabriele Janzen, Juliane Kaminski, Patricia Kanngiesser, Fumihiro Kano, Katharina C Kirchhofer, Hagen Knofe, Kathrin S Kopp, Christopher Krupenye, Isabelle Barbara Laumer, Stephen C Levinson, Ulf Liszkowski, Héctor M Manrique, Gema Martin-Ordas, Emma Suvi Mcewen, Richard T Moore, Enric Munar, Marcos Nadal, Christian Nawroth, Suska Nolte, Marie Pelé, Patrizia Potì, Hannes Rakoczy, Julia Riedel, Amélie Romain, Federico Rossano, Yvan I Russell, Gloria Sabbatini, Marie Schäfer, Marina Scheumann, Martin Schmelz, Benjamin Schmid, Vanesa Schmitt, Carla Sebastián-Enesco, Amanda Madeleine Seed, Chikako Suda-King, Tibor Tauzin, Sebastian Tempelmann, Claudio Tennie, Valentina Truppa, Jana Uher, Amrisha Vaish, Edwin J C Van Leeuwen, Elisabetta M Visalberghi, Christoph J Völter, Victoria Vonau, Claudia A F Wascher, Roman M Wittig, Wouter Wolf, Michael Tomasello, Katja Liebal, Josep Call, Daniel B M Haun

Faculty, Staff and Students Publications

The study of great ape cognition offers insights into the evolutionary origins of human intelligence, but is hindered by small sample sizes and restricted access to data. To address this, we present the EVApeCognition Dataset, a publicly available resource comprising 262 experimental datasets from 150 scientific publications from the Wolfgang Köhler Primate Research Center (2004-2021) in Leipzig, Germany. Eighty-one apes participated in 150 studies, with a majority (N = 78) participating in more than one study. Publication of the dataset aims to make these unique datasets accessible for future meta-analyses and correlational analyses, helping us better understand how our great …

Versatile Smad2 And Smad3 Epitope-Tagged Mouse Models For Genomic Profiling Of Tgfβ Signaling: Uncovering Gdf9-Smad2/3 Targets, Zian Liao, Qian Zhang, Keisuke Shimada, Kaori Nozawa, Suni Tang, Masahito Ikawa, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

Transforming growth factor β (TGFβ) signaling pathways are integral for a plethora of biological processes. SMAD2 and SMAD3 are the principal transcriptional effectors of TGFβ superfamily ligands, yet quantitative, genome-wide mapping of their DNA-associated complexes under physiological contexts has remained limited due to the lack of specific, robust models. Here, we generated two versatile epitope-tagged mouse models in which endogenous SMAD2 and SMAD3 proteins are globally tagged with hemagglutinin (HA) and podoplanin (PA) sequences, respectively, enabling high-fidelity profiling of SMAD2 and SMAD3 binding across tissues. To demonstrate the broad application of our models, we exemplified the usage of our lines …

Structural-Functional Analyses Of The Huntingtin/Hap40 Complex In Drosophila And Humans, Stephen M Farmer, Amanda Solbach, Shiyu Xu, Beatriz Rios, Xin Ye, Amy Gao, Daniela Covarrubias, Yue Yu, Lili Ye, Vicky Chuong, Erin Furr Stimming, Haiqing Zhao, Sheng Zhang

Faculty, Staff and Student Publications

Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal CAG expansion in the Huntingtin (HTT) gene. Given its simple genetic cause but complex pathogenic mechanisms, interest in targeting HTT for HD treatment is growing, necessitating a clear understanding of HTT regulation. HTT protein primarily exists in a core complex with HAP40, forming a highly ordered structure with two large globular domains connected by a bridge. We previously demonstrated that HAP40 is conserved in

The Impact Of Estrogen Replacement During Perimenopause On Lung Function And Airway Inflammation In The Vcd Mouse Model, William P Pederson, Laurie Michelle Ellerman, Riley D Hellinger, Joselyn Joanna Rojas Quintero, Francesca Polverino, John P Konhilas, Julie G Ledford

Faculty, Staff and Students Publications

Background:

Menopause associated asthma impacts a subset of women and is less responsive to current treatments. Mechanisms driving this late onset asthma are unknown. We recently developed a mouse model of menopause associated asthma using a combination of 4-Vinylcyclohexene Diepoxide (VCD) and House Dust Mite (HDM) exposures. The goal of this study was to determine how hormone replacement therapy during perimenopause impacts lung function and inflammation.

Methods:

The experimental groups included menopausal mice (VCD) with and without exposure to HDM (to model allergic airways disease) and menopausal mice with and without hormone replacement therapy (HRT; via estrogen pellet implantation). Lung …

Androgen Activity In The Male Embryonic Hindbrain Drives Lethal Pfa Ependymoma, Jiao Zhang, Winnie Ong, Alexandra Rasnitsyn, Ricardo Daniel Gonzalez, Rodrigo Lopez Gutierrez, Polina Balin, Amr Saadeldin, Xiaochong Wu, Maria C Vladoiu, Vicente Santa-Maria Lopez, Fernando Gonzalez-Salinas, Navneesh Yadav, Dinesh Mohanakrishnan, Kannan Boosi Narayana Rao, Raja Gopal Reddy Mooli, Hinda Najem, Sebastian Pacheco, Kaitlin Kharas, Cory Richman, David Przelicki, Evan Y Wang, Haipeng Su, Rachel Naomi Curry, Runze Yang, Michelle Masayo Kameda-Smith, Bryn Livingston, David Scott, Zaili Luo, Mingyang Xia, Namal Abeysundara, Anders W Erickson, Ncedile Mankahla, Lucas Zhongming Hu, Chu Pan, Raul Suarez, Ning Huang, Yihao Wu, Hao Wang, Tajana Douglas, Jonelle Pallota, Steven Hébert, Karen Ng, Krystin Mantione, Heather Whetstone, Hassaan Maan, Hussein Lakkis, Juyeun Lee, Sadeesh K Ramakrishnan, Yanxin Pei, Yujie Tang, Frank Y Lin, Guillermo Aldave, Marco Gallo, Robert M Friedlander, Faiyaz Notta, Laura K Donovan, Murali Chintagumpala, Bo Wang, Yun Li, Daniel D De Carvalho, Zhaolei Zhang, Ying Mao, Wei Hua, Charles Eberhart, Calixto-Hope G Lucas, Sriram Venneti, Poul H Sorensen, Alberto Delaidelli, Hao Li, Wenhao Zhou, Jason Kirk, Dean G Tang, Tao Jiang, Hailong Liu, Justin D Lathia, Hiromichi Suzuki, Jeremy N Rich, Lincoln D Stein, Nada Jabado, Vijay Ramaswamy, Q Richard Lu, Amy B Heimberger, Craig Daniels, Kulandaimanuvel Antony Michealraj, Claudia L Kleinman, Michael D Taylor

Faculty, Staff and Students Publications

Posterior fossa type A (PFA) ependymoma is an unusual infantile brain tumour with few known somatic mutations, thought to be driven by epigenetic mechanisms1. PFA ependymoma has a markedly higher incidence and worse prognosis in male children than in female children2. The mechanisms that underlie these sex differences are at present unknown. Here we show that the cellular hierarchy of PFA ependymoma is less differentiated in male individuals than it is in female individuals. In the normal developing mouse hindbrain, male gliogenic progenitors are less differentiated than matched female sibling controls. To further parse the effects …

Rexinoid Net-3ib Promotes Resident Macrophage Gene Expression And Mitigates Desiccation-Induced Ocular Surface Disease, Jehan Alam, Yangluowa Qu, Jianming Shao, Ebru Yaman, Karen Zheng, Hiroki Kakuta, Stephen C Pflugfelder

Faculty, Staff and Students Publications

Purpose: To evaluate the effects of rexinoid NEt-3IB on desiccating stress-induced dry eye, as well as monocyte/macrophage gene expression and cellular trajectory.

Methods: Eyes were topically treated with rexinoid NEt-3IB (5 µM) or vehicle three times a day for 5 days of desiccating stress-induced dry eye. Single-cell RNA sequencing (RNA-seq) profiled gene expression in conjunctival immune cells. RNA-seq was also used to evaluate gene expression in lipopolysaccharide (LPS)-stimulated, dexamethasone-treated (Dex, 1 µM), or NEt-3IB-treated (1-1000 nM) cultured monocytes. Cellular state trajectory and latent time were inferred with scVelo, and latent-time-associated genes were identified using Monocle 3. Permeability to Oregon Green-labeled …

Weaning Drives Microbiome-Mediated Epigenetic Regulation To Shape Immune Memory In Mice, Li Yang, Robert C Peery, Shirui Zhou, Xiaomin Chen, Leah M Farmer, Fabiola Gutierrez, Stephanie Fowler, Lanjing Zhang, Julia M Salamat, Karen Riggins, Jiejun Shi, Lanlan Shen

Children’s Nutrition Research Center Staff Publications

During weaning, the transition to solid food diversifies the gut microbiome, triggering a programmed immune response critical for long-lasting mucosal immunity. Previous work showed that the gut microbiome mediates epigenetic development in intestinal stem cells (ISCs) during suckling, but what happens during weaning is unclear. Here, genome-wide profiling revealed that weaning-driven microbiome changes shape the DNA methylome and transcriptome of murine ISCs in an IFNγ-dependent manner. Specifically, we observe demethylation of enhancer elements essential for MHC class II genes, which results in a transcriptional memory that persists through differentiation into adulthood. IFNγ blockade, or low-dose penicillin to target Gram-positive bacteria, …

Dominant Clones Leverage Developmental Epigenomic States To Drive Ependymoma, Alisha S Kardian, Hua Sun, Siri Ippagunta, Nicholas Laboe, Srinidhi Varadharajan, Kwanha Yu, Hsiao-Chi Chen, Erik Emanus, Tuyu Zheng, Riley M Deneen, Jon P Connelly, Yong-Dong Wang, Jiangshan Zhan, Hengxi Liu, Kimberley Lowe, Taylor Bugbee, Rakesh Pathak, Amanda Bland, Sanya Mehta, Sophie Cochiolo, Amir Arabzade, Blake Holcomb, Kaitlin M Budd, Gabriele Kembuan, Tristen Wright, Emma Caesar, Maxwell Park, Amelia Hancock, David Gee, Joel Murdoch, Yi Xiao, Samuel K Mcbrayer, Thomas E Merchant, Jun Qi, Adam D Durbin, Lindsay A Schwarz, Li Wang, Andrew M Donson, Nicholas K Foreman, Sameer Agnihotri, Alfonso Lavado, Suzanne J Baker, David W Ellison, Hyun Kyoung Lee, Shondra M Pruett-Miller, Kelsey C Bertrand, Benjamin Deneen, Stephen C Mack

Faculty, Staff and Students Publications

ZFTA–RELA is the most recurrent genetic alteration seen in paediatric supratentorial ependymoma (EPN) and is sufficient to initiate tumours in mice1. Despite its oncogenic potential, ZFTA–RELA (ZR) is observed nearly exclusively in childhood EPN, with tumours located distinctly in the supratentorial brain of the central nervous system1. We proposed that specific chromatin modules accessible during brain development would render distinct cell lineage programs at direct risk of transformation by ZR. To test this hypothesis, we performed combined single-nucleus assay for transposase-accessible chromatin and RNA (snMultiome) sequencing of the developing mouse forebrain compared with ZR-driven mouse …

Platelets Cause Microvascular Occlusion And Delayed Neurological Deficits After Subarachnoid Hemorrhage In Mice., Ari Dienel, Sung-Ha Hong, Kiara Torres, Kanako Matsumura, Jose Guzman, Peeyush Thankamani Pandit, Bibek Samal, Harveen Kaur, Samitha Nemirajaiah, Angelica Bernal, H Alex Choi, Louise D Mccullough, Spiros L Blackburn, Jaroslaw Aronowski, Devin W Mcbride

Faculty, Staff and Student Publications

After subarachnoid hemorrhage (SAH), some patients develop delayed neurological deficits (DND). Microthrombi are considered a contributing factor to DND, but clinical trials of antiplatelets had mixed results. Existing research suggests that platelets play a role in the etiology of DND, but no comprehensive study has tested causality between platelets and DND after SAH. Here we hypothesize that after SAH, platelet activation promotes microthrombi formation, occlusion of the brain microvasculature and contributes to DND, and that inhibiting platelet aggregation is a therapeutic strategy. Mice experiencing SAH were administered various interventions. The animals were subjected to stimulation of platelets, platelet depletion, or …

Multiparametric Mri To Predict Response To Irreversible Electroporation Plus Anti-Pd-1 Immunotherapy In Pancreatic Ductal Adenocarcinoma, Qizhen Cao, Mark D Pagel, Charles V Kingsley, Jingfei Ma, James P Long, Xiaoxia Wen, Seth T Gammon, Jorge Delacerda, Sanaz Javadi, Chun Li

Faculty, Staff and Student Publications

Purpose: To investigate contrast-enhanced T1-weighted MRI and diffusion-weighted magnetic resonance imaging (DWI) for early prediction of tumor response to combined irreversible electroporation (IRE) and anti-PD-1 immunotherapy.

Methods: Murine pancreatic ductal adenocarcinoma (PDAC) cells KRAS* were inoculated into the pancreas of C57BL/6 mice. IRE was performed when tumors became palpable. After IRE, mice received six intraperitoneal injections of anti-PD-1 over 2 weeks. T2-weighted MRI, T1-weighted MRI with macromolecular contrast agent poly(L-glutamic acid)-conjugated gadolinium (PG-Gd), and DWI were performed before and after IRE. Survival was analyzed using Kaplan-Meier curves. Mice surviving at least 100 days without recurrence after IRE were considered complete …

Neutrophil-Microglia Interaction Drives Motor Dysfunction In A Neuromyelitis Optica Model Induced By Subarachnoid Aqp4-Igg, Fangfang Qi, Vanda A Lennon, Shunyi Zhao, Yong Guo, Husheng Ding, Caiyun Liu, Whitney M Bartley, Tingjun Chen, Claudia F Lucchinetti, Long-Jun Wu

Faculty, Staff and Student Publications

Neutrophils and neutrophil extracellular traps (NETs) contribute to early neuromyelitis optica (NMO) histopathology initiated by IgG targeting astrocytic aquaporin-4 (AQP4) water channels. Yet, the mechanisms underlying neutrophil recruitment and their pathogenic roles in disease progression remain unclear. To investigate molecular-cellular events preceding classical complement cascade activation in a mouse NMO model, we continuously infused, via spinal subarachnoid route, a non-complement-activating mouse monoclonal AQP4-IgG. Parenchymal infiltration of netting neutrophils containing C5a ensued with microglial activation and motor impairment but no blood-brain barrier leakage. Motor impairment and neuronal dysfunction both reversed when AQP4-IgG infusion stopped. Two-photon microscopy and electron microscopy-based reconstructions revealed …

Gompertz Growth With A Shared Carrying Capacity Optimally Simulates Primary And Metastatic Tumor Growth Dynamics, Pirmin Schlicke, Preethi Korangath, Xiaoxi Pan, Caner Ercan, Kathleen Gabrielson, Lyndsey Werhane, Yinyin Yuan, Sébastien Benzekry, Robert Ivkov, Heiko Enderling

Faculty, Staff and Student Publications

Background: Cancer is a systemic disease with most deaths attributed to metastatic burden. Primary and metastatic tumors, albeit at different anatomic locations, are interconnected through multiple biological processes. Pre-clinical and clinical observations of growth acceleration of metastases after surgery, or abscopal effects outside the radiation field are widely reported, yet reliably triggering favorable and avoiding unfavorable systemic responses remains an unmet clinical need. Understanding local and systemic tumor interaction dynamics will help guide future treatments.

Methods: We analyze the data of multiple in vivo tumor models. We formalize the systemic interplay of tumors as mathematical differential equation and calibrate parameters …

Breast Cancer-Derived Extracellular Vesicle Mir-425-5p (Mir-425) Promotes Brain Metastasis Via Activating Astrocytes Through The Novel Mir-425-Znf24-Ccl8 Signaling Axis, Grace L Wong, Munazza S Khan, Sara Manore, Shivani Bindal, Ravi Singh, Hui-Wen Lo

Faculty, Staff and Student Publications

Mechanisms underlying breast cancer brain metastasis (BCBM) are still not well understood. Here, we identified that BCBM patient serum contained extracellular vesicles (EVs) with high levels of microRNAs (miRNAs)-107 and -425. Levels of miR-107 and miR-425 were elevated in brain metastases, and the elevation was associated with poor patient prognoses. Ectopic expression of miR-107 and miR-425 promoted mammospheres; however, the inhibition of miR-425, but not miR-107, suppressed breast cancer mammosphere formation. We further observed that EVs from miR-425-overexpressing breast cancer cells strongly activated astrocytes whereas their inhibitors abrogated the effect. Conditioned media from miR-425-activated astrocytes promoted mammospheres. To elucidate how …

Gene-Agnostic Therapeutic Strategies For Inherited Retinal Diseases: Neuroprotection And Immunomodulation, Lucas W. Rowe, S. Patricia Becerra, Robert E. Maclaren, Robert L. Avery, Charles C. Wykoff, Allen C. Ho, Carl D. Regillo, Dean Eliott, Andrew Osborne, Katie M. Binley, Thomas A. Ciulla

Wills Eye Hospital Papers

Background/Objectives: Inherited retinal diseases (IRDs) represent a genetically heterogeneous group of disorders caused by mutations in over 280 genes with more than 3100 identified variants. While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical. This review examines gene-agnostic therapeutic approaches utilizing neuroprotection and immunomodulation that target common pathophysiological mechanisms shared across multiple IRD genotypes. Methods: We reviewed the literature on neuroprotective and immunomodulatory gene therapy strategies for IRDs, focusing on neurotrophic factors and complement system modulation. Results: Neuroprotective approaches delivering neurotrophic factors—including pigment …

Mouse White Matter Matters: Cortical Origins And Spatial Organization Of Mouse White Matter Tracts, Sofia D Gordeev, Melissa Franch, Sarah R Heilbronner

Faculty, Staff and Students Publications

White matter—the fundamental structure underlying network connectivity—lies at the heart of the brain’s computational power. White matter is organized into fiber tracts, or bundles, in both human and nonhuman primate brains. These bundles consist of long-range axonal projections with a set of shared origin and termination points and exhibit a predictable organization. However, the organization of white matter in the mouse brain remains relatively unknown. This knowledge gap is surprising given the central role of mice in neuroscience, with mouse brains serving as the dominant model for transgenics, in vivo calcium imaging, and circuit manipulation. To address this gap, we …

Immunotherapy Of Tsa-1.C4 Or In Combination With Bnz Confers Protection Against Trypanosoma Cruzi Infection With A Distinct Cytokine Response, Landy Magaly Pech-Pisté, Victor Dzul-Huchim, Christian Florian Teh-Poot, Fabian Gusovsky, Kathryn Jones, Peter Hotez, Liliana Estefanía Villanueva-Lizama, Maria Elena Bottazzi, Jaime Ortega-Lopez, Julio Vladimir Cruz-Chan

Faculty, Staff and Students Publications

Chagas disease is a poverty-related neglected tropical disease caused by the protozoan Trypanosoma cruzi affecting approximately 6.3 million people, predominantly in the Americas. Approximately 30% of T. cruzi infections progress to chronic cardiomyopathy and 10% of these cases end in death from cardiac failure. The first-line drug Benznidazole (BNZ) require a prolonged treatment regimen and can be highly toxic. Here, we evaluate a therapeutic vaccine in T. cruzi-infected mice, based on the recombinant Trypomastigote Surface Antigen 1 (TSA-1.C4) protein and the emulsified adjuvant E6020, and in combination with a suboptimal dose of BNZ. We observed a reduced burden parasite in …

Fibrinogen-Bmal1 Signaling As A Therapeutic Target To Limit Aortic Dissection By Preserving Vsmc Contractility, Xiaohan Zhong, Dongjie Li, Yuanfei Zhao, Lu Dai, Jinzhang Li, Zhiqi Ji, Bojing Zuo, Hongshan Liu, Haixia Huang, Wei Wang, Haiyang Li, Yuyong Liu, Ming Gong, Xin-Liang Ma, Wenjian Jiang, Meili Wang, Hongjia Zhang

Department of Emergency Medicine Faculty Papers

Aortic dissection (AD) is a life-threatening vascular disease with a high mortality rate. Surgery is essential in the acute phase but carries significant risks, whereas elective surgery during the chronic phase yields better outcomes. However, no pharmacological therapy has been proven effective in slowing AD progression. In our recent pilot clinical study, an association between higher plasma fibrinogen levels and improved clinical outcomes was observed in AD patients, suggesting a potential protective role of fibrinogen. However, direct evidence supporting this hypothesis is lacking. In this study, a population-based analysis of nonsurgically managed patients with acute AD revealed a distinct association: …

Targeting Cardiomyocyte-Derived Extracellular Vesicle Mir-574-5p Protects Against Cognitive Impairment Induced By Ischemia-Reperfusion, Erya Chen, Xiaoyu Zhu, Haiqing Chang, Qi Li, Zhenkun Zhao, Changteng Zhang, Yu Cao, Yajing Wang, Xinliang Ma, Tao Zhu, Shu Zhang, Lu Gan, Jin Liu, Chan Chen

Department of Emergency Medicine Faculty Papers

BACKGROUND:  Acute myocardial ischemia/reperfusion (MI/R) increases risk for cognitive decline, yet the underlying mechanisms mediating heart-brain communication remain poorly understood. Small extracellular vesicles (sEVs) have emerged as novel long-range signaling mediators and may play a critical role.

METHODS: MI/R was induced by transient ligation of the left anterior descending artery. Cognitive performance was assessed using multiple behavioral tests. sEVs derived from cardiomyocytes were labeled to track their distribution and cellular uptake in the brain. Heart and brain tissues were analyzed for microRNAs (miRNAs) expression using bioinformatics, qPCR, and RNAScope. The role of specific miRNAs was investigated through genetic inhibition of …

Polθ Activity Modulates Sensitivity To Standard Therapies In Dnmt3a-Deficient Leukemia, Bac Viet Le, Umeshkumar Vekariya, Monika M. Toma, Margaret Nieborowska-Skorska, Marie-Christine Caron, Malgorzata Gozdecka, Zayd Haydar, Martin Walsh, Jayashri Ghosh, Elaine Vaughan-Williams, Paulina Podszywalow-Bartnicka, Anna-Mariya Kukuyan, Sylwia Ziolkowska, Jessica Atkins, Emir Hadzijusufovic, Gurushankar Chandramouly, Reza Nejati, Katarzyna Piwocka, Richard T. Pomerantz, George S. Vassiliou, Brian J.P. Huntly, Peter Valent, Mariusz Wasik, Alfonso Bellacosa, Jean-Yves Masson, Gaorav P. Gupta, Grant A. Challen, Tomasz Skorski

Department of Biochemistry and Molecular Biology Faculty Papers

Myeloid malignancies carrying somatic DNMT3A mutations (DNMT3Amut) are refractory to standard therapy. DNMT3Amut leukemia cells accumulate toxic DNA double-strand breaks (DSBs) and stalled replication forks, rendering them dependent on DNA damage response (DDR). We report here that DNA polymerase theta (Polθ), a key element in DSB repair by end-joining (Polθ-mediated end-joining [TMEJ]) and in fork restarting, promotes survival and proliferation of DNMT3Amut leukemia cells. Polθ is overexpressed in DNMT3Amut leukemia cells due to abrogation of PARP1 PARylation-dependent UBE2O E3 ligase-mediated ubiquitination and proteasomal degradation of Polθ. In addition, PARP1-mediated recruitment of the SMARCAD1-MSH2/MSH3 repressive complex to DSBs is diminished in …

Pkmζ-Kibra Interactions, Molecular Turnover, And Memory, Changchi Hsieh, David A Cano, Panayiotis Tsokas, James E Cottrell, André Antonio Fenton, Harel Shouval, Todd Charlton Sacktor

Faculty, Staff and Student Publications

How can the molecules that strengthen synaptic connections maintain memory in the face of molecular turnover? Our previous work showed that persistent interaction between the postsynaptic scaffolding protein, KIBRA, and the autonomously active PKC isoform, PKMζ, is crucial for maintaining synaptic long-term potentiation (LTP) and memory lasting at least a month. This duration is longer than the lifespans of individual KIBRA and PKMζ molecules. Biophysical modeling of the interaction suggests oligomers of KIBRA-PKMζ dimers, but not individual dimers or monomers, can overcome molecular turnover by continuously incorporating newly synthesized KIBRA and PKMζ, replacing those that have degraded. Here we used …

Mechanometabolism Instructs Hematopoietic Stem Cell Specification, Paulina D Horton, Alina Syed, Michelle Winkler, Abishek B Vaidya, Michael Rariden, Neha Arora, Yong Zhou, Michihiro Kobayashi, Momoko Yoshimoto, Hyun Jung Lee, Hyun-Eui Kim, John P Hagan, Catherine Denicourt, Travis I Moore, Pamela L Wenzel

Faculty, Staff and Student Publications

Mechanical force generated by blood flow stimulates emergence of the first hematopoietic stem cells (HSCs) that populate the blood system. Force drives the transition of HSC precursors from an endothelial to hematopoietic identity, yet the molecular regulation of this fate switch remains poorly understood. We report that shear stress triggers adaptation in mitochondrial composition, ultrastructure, and function, which are essential for hematopoietic fate and engraftment potential. Shear stress remodels mitochondria in hemogenic endothelium by promoting mitochondrial gene transcription and protein synthesis. Laminar flow selectively initiates translation of 5' terminal polypyrimidine (5'TOP) motif-containing transcripts, which commonly encode ribosome and translation machinery. …

Ectopic B Lymphocyte Follicles Exacerbate Ischemic Brain Damage Via Mif-Cd74/Cxcr4 And Interferon Signaling, Sheng Yang, Hang Zhang, Lu-Lu Xu, Luo-Qi Zhou, Yun-Hui Chu, Lian Chen, Xiao-Wei Pang, Lu-Yang Zhang, Li-Fang Zhu, Ming-Hao Dong, Ke Shang, Jun Xiao, Long-Jun Wu, Wei Wang, Dai-Shi Tian, Chuan Qin

Faculty, Staff and Student Publications

Neuroinflammation, encompassing both innate and adaptive immune responses, plays a crucial role in ischemic stroke. Although B lymphocytes are central to adaptive immunity, their contributions to ischemic stroke remain poorly understood. Here, we demonstrated that B lymphocytes accumulate in ischemic lesions, forming germinal center-like structures at the later stage after stroke, which mainly depended on in situ proliferation. This accumulation correlated with worsened neuroinflammation and ischemic injury, whereas B cell depletion reduced chronic brain damage during stroke. Mechanistically, microglia recruited B cells into ischemic lesions through MIF-CD74/CXCR4 signaling during the early phase of stroke, while IFN-related pathways in B cells …

Activin A Secretion By Muscle-Repairing Macrophages Induces Heterotopic Ossification In Mice, Wenqiang Yin, Kazuo Okamoto, Asuka Terashima, Warunee Pluemsakunthai, Takehito Ono, Taku Ito-Kureha, Shizuo Akira, Yoshinobu Hashizume, Roland Baron, Satoshi Ueha, Kouji Matsushima, Martin M Matzuk, Yuji Mishina, Hiroshi Takayanagi

Faculty, Staff and Students Publications

The immune system is not only essential for host defense, but it is also involved in tissue maintenance and disease pathogenesis. Macrophages play a key role in tissue repair, fibrosis, and tumorigenesis, but the mechanisms underlying their multifunctionality have not been fully explored. Here, we identified Mrep (Ly6ChiCX3CR1loPDPN+CD9+) as a crucial subset of macrophages for muscle regeneration after muscle injury. Muscle regeneration required Mrep-derived activin A, which was produced via the TLR4/TIR domain-containing adapter-inducing interferon-β/TANK-binding kinase 1/interferon regulatory factor 3/7 signaling pathway in response to muscle injury. Mrep exerted pathological effects by secreting activin A in a model of genetically …

Poly(Adp-Ribose) Glycohydrolase Enforces P21 Degradation Via Deparylation To Promote Gastric Cancer Progression, Yangchan Hu, Qimei Bao, Yixing Huang, Yan Wang, Xin Zhao, Junjun Nan, Yuxin Meng, Mingcong Deng, Yuancong Li, Zirui Zhuang, Hanyi He, Dan Zu, Yuke Zhong, Chunkai Zhang, Bing Wang, Ran Li, Yanhua He, Qihan Wang, Min Liu, John A Tainer, Yin Shi, Xiangdong Cheng, Ji Jing, Zu Ye

Faculty, Staff and Student Publications

Dysregulation of cell cycle checkpoints is a cancer hallmark, with ubiquitination-controlled protein stability playing a pivotal role. Although p21, a key cyclin-dependent kinase inhibitor, is tightly regulated by ubiquitin-mediated degradation, the key upstream modulators of its ubiquitination remain incompletely defined. Here, we identify poly(ADP-ribose) glycohydrolase (PARG) as a regulator of p21 stability in gastric cancer (GC) cells. We show that PARG expression is markedly upregulated in GC tissues and correlates with poor patient prognosis. Functional assays revealed that genetic depletion of PARG triggers G2/M phase arrest and impairs GC cell proliferation. Mechanistically, we demonstrate that PARG loss enhances p21 PARylation, …

Selective Deletion Of Fgfr1 In Agrp Neurons Impairs Energy Homeostasis Under High-Fat Diet In Mice, Daniel Shookster, Shea O'Connell, Patel Darshan, Taylor Landry, Wyatt Bunner, Zhiying Jiang, Qingchun Tong, Hu Huang

Faculty, Staff and Student Publications

Background: The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined.

Methods: To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models.

Results: Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 …