Digital Commons Network^™

A Standardized Nomenclature For The Rods And Cones Of The Vertebrate Retina, Tom Baden, Takeshi Yoshimatsu, Joseph C. Corbo, Et Al.

2020-Current year OA Pubs

Vertebrate photoreceptors have been studied for well over a century, but a fixed nomenclature for referring to orthologous cell types across diverse species has been lacking. Instead, photoreceptors have been variably-and often confusingly-named according to morphology, presence/absence of 'rhodopsin', spectral sensitivity, chromophore usage, and/or the gene family of the opsin(s) they express. Here, we propose a unified nomenclature for vertebrate rods and cones that aligns with the naming systems of other retinal cell classes and that is based on the photoreceptor type's putative evolutionary history. This classification is informed by the functional, anatomical, developmental, and molecular identities of the neuron …

Elevated P16ink4a Expression Enhances Tau Phosphorylation In Neurons Differentiated From Human-Induced Pluripotent Stem Cells, Kristopher Holloway, Kashfia Neherin, Yingduo Song, Kazuhito Sato, Andrew Houston, Feng Chen, Li Ding, Hong Zhang

2020-Current year OA Pubs

Increased expression of the cyclin-dependent kinase inhibitor p16Ink4a (p16) is detected in neurons of human Alzheimer's disease (AD) brains and during normal aging. Importantly, selective eliminating p16-expressing cells in AD mouse models attenuates tau pathologies and improves cognition. But whether and how p16 contributes to AD pathogenesis remains unclear. To address this question, we tested whether induction of p16 expression in neurons exacerbates AD pathologies. We created a doxycycline-inducible system to trigger p16 up-regulation in human-induced pluripotent stem cells (iPSCs) and neurons differentiated from iPSCs. We demonstrated that up-regulated p16 expression in iPSCs reduces cell proliferation, down-regulates cell cycle genes, …

The Influence Of The American Association For Thoracic Surgery On Clinical Trial Development By Cardiothoracic Surgeons, Adishesh K Narahari, Taylor M Horgan, Anirudha S Chandrabhatla, Abhinav Kareddy, Ajami Gikandi, Marco A Zenati, David Harpole, David Jones, Leora T Yarboro, Bryan Burt, A Sasha Krupnick, J Hunter Mehaffey

Faculty, Staff and Students Publications

Objective: Clinical trials play a critical role in the rapidly evolving field of cardiothoracic surgery and the American Association for Thoracic Surgery Clinical Trials Methods Course has provided a biannual symposium led by preeminent surgeons with vast experience in planning, conducting, and analyzing surgical clinical trials. This study hypothesizes that participation in the course is associated with future success in clinical trial leadership.

Methods: A list of course attendees (2014-2022) was queried in ClinicalTrials.gov, a database of clinical trials funded by the US Department of Health and Human Services and the National Institutes of Health. The type of clinical trial …

Neurotransmitter Power Plays: The Synaptic Communication Nexus Shaping Brain Cancer, Jayanta Mondal, Jason T Huse

Faculty, Staff and Student Publications

Gliomas and brain metastases are notorious for their dismal prognosis and low survival rates, a challenge exacerbated by our incomplete grasp of the complex dynamics that govern brain cancers. Recently, a groundbreaking paradigm shift has emerged, highlighting the crucial role of synaptic communication between neurons and brain tumor cells in reshaping neuronal signaling to favor tumor growth. This review delves into the pivotal interplay of synaptic mechanisms, focusing on excitatory glutamatergic and inhibitory GABAergic pathways. Glutamatergic synapses utilize glutamate to propagate excitatory signals, while GABAergic synapses employ gamma-aminobutyric acid (GABA) to inhibit neuronal firing. Glutamatergic signaling can be broadly classified …

A Secretome Atlas Of Cardiac Fibroblasts From Healthy And Infarcted Mouse Hearts, Jasmin Bahr, Junedh M Amrute, Kory J Lavine, Et Al.

2020-Current year OA Pubs

Cardiac fibroblasts (CF) are key players after myocardial infarction (MI), but their signaling is only incompletely understood. Here we report a first secretome atlas of CF in control (cCF) and post-MI mouse hearts (miCF), combining a rapid cell isolation technique with SILAC and click chemistry. In CF, numerous paracrine factors involved in immune homeostasis are identified. Comparing secretome, transcriptome (SLAMseq), and cellular proteome disclose protein turnover. In miCF at day 5 post-MI, significantly upregulated proteins include SLIT2, FN1, and CRLF1 in mouse and human samples. Comparing the miCF secretome at days 3 and 5 post-MI reveals the dynamic nature of …

Immune Cells And Arrhythmias, Joshua A Keefe, Jian Wang, Jiangping Song, Li Ni, Xander H T Wehrens

Faculty, Staff and Students Publications

Cardiac arrhythmias are a significant cause of morbidity and mortality worldwide. Emerging evidence has demonstrated that resident and infiltrating cardiac immune cells play direct, mechanistic roles in arrhythmia onset and progression. In this review, we provide a comprehensive summary and expert commentary on the role of each immune cell subtype in the pathogenesis of atrial and ventricular arrhythmias.

An Intranasally Administered Igm Protects Against Antigenically Distinct Subtypes Of Influenza A Viruses, Ashwin Kumar Ramesh, Jwala Priyadarsini Sivaccumar, Xiaohua Ye, Luona Yang, Hailong Guo, Chen-Ni Chin, Sha Ha, John W Shiver, William R Strohl, Yan Xu, Haijuan Du, Tongqing Zhou, Ningyan Zhang, Kai Xu, Xinli Liu, Tong-Ming Fu, Zhiqiang An

Faculty, Staff and Student Publications

Engineering broadly neutralizing monoclonal antibodies (mAbs) targeting the hemagglutinin (HA) of Influenza A virus (IAV) is a promising approach for intervention of seasonal flu. However, HA plasticity often leads to resistant strains that compromise mAb potency as bivalent IgGs. Here we hypothesize that multimerization of anti-IAV antibodies as IgMs can enhance coverage and neutralization potency. Here, we construct 18 IgM antibodies from known broadly neutralizing IgGs targeting different IAV HA epitopes and evaluate their breadth and potency of neutralization against distinct H1N1 and H3N2 IAVs. The IgM version of receptor binding site-specific IgG F045-092 shows increased breadth and antiviral potency …

Mapping The Developmental Profile Of Ventricular Zone-Derived Neurons In The Human Cerebellum, Anders W Erickson, Henry Tan, Liam D Hendrikse, Jake Millman, Zachary Thomson, Joseph Golser, Omar Khan, Guanyi He, Kathleen Bach, Arpit Suresh Mishra, Janja Kopic, Zeljka Krsnik, Ferechte Encha-Razavi, Giulia Petrilli, Fabien Guimiot, Evelina Silvestri, Kimberly A Aldinger, Michael D Taylor, Kathleen J Millen, Parthiv Haldipur

Faculty, Staff and Students Publications

The cerebellar ventricular zone (VZ) is the primary source of progenitors that generate cerebellar GABAergic neurons, including Purkinje cells (PCs) and interneurons (INs). This study provides detailed characterization of human cerebellar GABAergic neurogenesis using transcriptomic and histopathological analyses and reveals conserved and unique features compared to rodents. We show that the sequential progression of neurogenesis is conserved and occurs before 8 postconception weeks. Notably, PC differentiation occurs in the outer subventricular zone (SVZ), a region absent in the mouse cerebellum. Human PCs are generated during a compact two-week period before the onset of cerebral cortex histogenesis. A subset of human …

The Potential Of Brain Organoids In Addressing The Heterogeneity Of Synucleinopathies, Xiao-Jun Diao, Claudio Soto, Fei Wang, Yu Wang, Yun-Cheng Wu, Abhisek Mukherjee

Faculty, Staff and Student Publications

Synucleinopathies are a group of diseases characterized by neuronal and glial accumulation of α-synuclein (aSyn) linked with different clinical presentations, including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), Dementia with Lewy Bodies (DLB) and Multiple system atrophy (MSA). Interestingly, the structure of the aSyn aggregates can vary across different synucleinopathies. Currently, it is unclear how the aSyn protein can aggregate into diverse structures and affect distinct cell types and various brain regions, leading to different clinical symptoms. Recent advances in induced pluripotent stem cells (iPSCs)-based brain organoids (BOs) technology provide an unprecedented opportunity to define the etiology of synucleinopathies …

Investigative Needle Core Biopsies Support Multimodal Deep-Data Generation In Glioblastoma, Kenny K H Yu, Sreyashi Basu, Gerard Baquer, Ryuhjin Ahn, Jennifer Gantchev, Sonali Jindal, Michael S Regan, Zaki Abou-Mrad, Michael C Prabhu, Marc J Williams, Alicia D D'Souza, Seth W Malinowski, Kelsey Hopland, Yuval Elhanati, Sylwia A Stopka, Alexei Stortchevoi, Charles Couturier, Zhong He, Jingjing Sun, Yulong Chen, Alexsandra B Espejo, Kin Hoe Chow, Smitha Yerrum, Pei-Lun Kao, Brittany Parker Kerrigan, Lisa Norberg, Douglas Nielsen, Vinay K Puduvalli, Jason Huse, Rameen Beroukhim, Betty Y S Kim, Sangeeta Goswami, Adrienne Boire, Sarah Frisken, Michael J Cima, Matthias Holdhoff, Calixto-Hope G Lucas, Chetan Bettegowda, Stuart S Levine, Tejus A Bale, Cameron Brennan, David A Reardon, Frederick F Lang, E Antonio Chiocca, Keith L Ligon, Forest M White, Padmanee Sharma, Viviane Tabar, Nathalie Y R Agar

Faculty, Staff and Student Publications

Glioblastoma (GBM) is an aggressive primary brain cancer with few effective therapies. Stereotactic needle biopsies are routinely used for diagnosis; however, the feasibility and utility of investigative biopsies to monitor treatment response remains ill-defined. Here, we demonstrate the depth of data generation possible from routine stereotactic needle core biopsies and perform highly resolved multi-omics analyses, including single-cell RNA sequencing, spatial transcriptomics, metabolomics, proteomics, phosphoproteomics, T-cell clonotype analysis, and MHC Class I immunopeptidomics on standard biopsy tissue obtained intra-operatively. We also examine biopsies taken from different locations and provide a framework for measuring spatial and genomic heterogeneity. Finally, we investigate the …

Intracellular And Extracellular Activities Of V-Domain Ig-Containing Suppressor Of T Cell Activation (Vista) Modulated By Immunosuppressive Factors Of Tumour Microenvironment, Maryam Abooali, Stephanie Schlichtner, Xi Lei, Nijas Aliu, Sabrina Ruggiero, Sonia Loges, Martin Ziegler, Franziska Hertel, Anna-Lena Volckmar, Albrecht Stenzinger, Petros Christopoulos, Michael Thomas, Elena Klenova, N Helge Meyer, Stergios Boussios, Nigel Heaton, Yoh Zen, Ane Zamalloa, Shilpa Chokshi, Luca Urbani, Sophie Richard, Kavitha Kirubendran, Rohanah Hussain, Giuliano Siligardi, Dietmar Cholewa, Steffen M Berger, Inna M Yasinska, Elizaveta Fasler-Kan, Vadim V Sumbayev

Peninsula Medical School

V-domain Ig-containing suppressor of T cell activation (VISTA) is a unique immune checkpoint protein, which was reported to display both receptor and ligand activities. However, the mechanisms of regulation of VISTA activity and functions by factors of tumour microenvironment (TME) remain unclear and understanding these processes is required in order to develop successful personalised cancer immunotherapeutic strategies and approaches. Here we report for the very first time that VISTA interacts with another immune checkpoint protein galectin-9 inside the cell most likely facilitating its interaction with TGF-β-activated kinase 1 (TAK1). This process is required for protection of lysosomes, which is crucial …

The Impact Of Epac2-Associated Junction Plakoglobin On Respiratory Syncytial Virus Infection, Chaitra A Takle, Eun-Jin Choi, Eun Seok Choi, Devang Deepak, Kashish Khatkar, Jong Min Choi, Ke Zhang, Sung Yun Jung, Tian Wang, Wenzhe Wu, Xiaoyong Bao

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants, young children, and immunocompromised individuals. Currently, FDA-approved monoclonal antibody therapies are limited to infants and young children with severe RSV disease. As a result, there is an urgent need for comprehensive studies of RSV pathogenesis to support the development of new therapeutic strategies. Exchange proteins directly activated by cAMP (EPAC) have recently emerged as key regulators in various viral infections. Our previous work identified EPAC isoform 2 (EPAC2) as a critical factor in RSV replication and host innate immune responses. However, …

Building A Pre-Surgical Multiparametric-Mri-Based Morphologic, Qualitative, Semiquantitative, First And High-Order Radiomic Predictive Treatment Response Model For Undifferentiated Pleomorphic Sarcoma To Replace Recist, Raul F Valenzuela, Elvis Duran-Sierra, Mathew Antony, Behrang Amini, Sam Lo, Keila E Torres, Robert S Benjamin, Jingfei Ma, Ken-Pin Hwang, R Jason Stafford, Dejka Araujo, Andrew J Bishop, Ravin Ratan, Wei-Lien Wang, Jossue Espinoza, Pia V Valenzuela, Chengyue Wu, John E Madewell, William A Murphy, Colleen M Costelloe

Faculty, Staff and Student Publications

Background: Undifferentiated pleomorphic sarcoma (UPS) is the largest subgroup of soft-tissue sarcomas. It demonstrates post-therapeutic hemosiderin deposition, granulation tissue formation, fibrosis, and calcification. Our research aims to establish the multiparametric MRI (mp-MRI) value for predicting UPS treatment response.

Methods: An IRB-approved retrospective study included 33 extremity UPS patients with pre-operative mp-MRI, including diffusion-weighted imaging (DWI), contrast-enhanced susceptibility-weighted imaging (CE-SWI), and perfusion-weighted imaging with dynamic contrast-enhancement (PWI/DCE), and surgical resection between February 2021 and May 2023. Lesions were visually classified on CE-SWI into one of 6 morphology patterns. On PWI/DCE, lesions were classified into one of 6 patterns, and time-intensity curves …

Structural Insights Into The Function, Dysfunction And Modulation Of Kv3 Channels, Manuel Covarrubias, Qiansheng Liang, Linh Nguyen-Phuong, Kyle J. Kennedy, Tyler D. Alexander, Ms, Andrew Sam

Department of Neuroscience Faculty Papers

The third subfamily of voltage-gated K⁺ (Kv) channels includes four members, Kv3.1, Kv3.2, Kv3.3 and Kv3.4. Fast gating and activation at relatively depolarized membrane potentials allows Kv3 channels to be major drivers of fast action potential repolarization in the nervous system. Consequently, they help determine the fast-spiking phenotype of inhibitory interneurons and regulate fast synaptic transmission at glutamatergic synapses and the neuromuscular junction. Recent studies from our group and a team of collaborators have used cryo-EM to demonstrate the surprising gating role of the Kv3.1 cytoplasmic T1 domain, the structural basis of a developmental epileptic encephalopathy caused by the …

Acute Brcaness Induction And Ar Pathway Blockage Through Cdk12/7/9 Degradation Enhances Parp Inhibitor Sensitivity In Prostate Cancer, Fu Gui, Baishan Jiang, Jie Jiang, Zhixiang He, Takuya Tsujino, Tomoaki Takai, Seiji Arai, Celine Pana, Jens Köllermann, Gary Andrew Bradshaw, Robyn Eisert, Marian Kalocsay, Anne Fassl, Steven P Balk, Adam S Kibel, Li Jia

Faculty, Staff and Student Publications

Current treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) pathway. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR pathway inhibitors (APPIs) remains ongoing challenges. Here, we present BSJ-5-63, a proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, offering a multipronged approach to CRPC therapy. BSJ-5-63 degrades CDK12, diminishing BRCA1 and BRCA2 expression and inducing a sustained "BRCAness" state. This sensitizes cancer cells to PARP inhibitors (PARPis) regardless of their homologous recombination repair (HRR) status. Furthermore, CDK7 and CDK9 degradation attenuates AR signaling, enhancing its therapeutic efficacy. Preclinical studies, including …

The P130cas-Crk/Crkl Axis: A Therapeutic Target For Invasive Cancers Unveiled By Collaboration Among P130cas, Crk, And Crkl., Pegah Farhadi, Taeju Park

Manuscripts, Articles, Book Chapters and Other Papers

Numerous studies have documented the involvement of p130Cas (Crk-associated substrate) in a wide range of cellular processes across different types of cells. These processes encompass cell transformation, the connection between the extracellular matrix and the actin cytoskeleton, cell migration and invasion, and cardiovascular development. Moreover, p130Cas has been associated with the regulation of various physiological processes, including mammary, bone, brain, muscle, and liver homeostasis. The diverse functions of p130Cas can be attributed to its possession of multiple protein-protein interaction domains, which sets it apart as a unique class of adaptor protein. It is well established that p130Cas interacts critically with …

Difference In Clinical Presentation And Surgical Outcomes In Pediatric And Adult Patients With Chiari Malformation Type 1: A Single Center Retrospective Study, Erik Öhlén, Victor Gabriel El-Hajj, Victor E. Staartjes, Pascal Jabbour, Erik Edström, Adrian Elmi-Terander

Department of Neurosurgery Faculty Papers

INTRODUCTION: Chiari malformation type 1 (CM1) is a common congenital disorder affecting both children and adults. Although pediatric and adult CM1 patients share many characteristics, the differences between the groups are not fully described.

METHOD: A comparative analysis was made of two previously defined cohorts of adult and pediatric non-syndromic CM1, surgically treated at the study center. Clinical outcomes were assessed using the Chicago Chiari outcome scale (CCOS) and radiological outcomes were measured as change in cerebellar tonsil and syringomyelia status.

RESULTS: A total of 209 patients (73 pediatric, 136 adults) were included, with median ages of 11 and 33 …

Idh Status Dictates Ohsv Mediated Metabolic Reprogramming Affecting Anti-Tumor Immunity, Upasana Sahu, Matthew P Mullarkey, Sara A Murphy, Joshua C Anderson, Vasanta Putluri, Abu Hena Mostafa Kamal, Jun Hyoung Park, Tae Jin Lee, Alexander L Ling, Benny A Kaipparettu, Ashok Sharma, Nagireddy Putluri, Pamela L Wenzel, Christopher D Willey, E Antonio Chiocca, James M Markert, Balveen Kaur

Faculty, Staff and Student Publications

Identification of isocitrate dehydrogenase (IDH) mutations has uncovered the crucial role of metabolism in gliomagenesis. Oncolytic herpes virus (oHSV) initiates direct tumor debulking by tumor lysis and activates anti-tumor immunity, however, little is known about the role of glioma metabolism in determining oHSV efficacy. Here we identify that oHSV rewires central carbon metabolism increasing glucose utilization towards oxidative phosphorylation and shuttling glutamine towards reductive carboxylation in IDH wildtype glioma. The switch in metabolism results in increased lipid synthesis and cellular ROS. PKC induces ACSL4 in oHSV treated cells leading to lipid peroxidation and ferroptosis. Ferroptosis is critical to launch an …

Impact Of Antidiabetic Medication Type On A New Episode Of Depression: A Retrospective Cohort Study In Texas, Usa, Lin-Na Chou, Mukaila A Raji, Holly M Holmes, Yong-Fang Kuo

Faculty, Staff and Student Publications

Objectives: To examine the associations between antidiabetic medication type and a new episode of depression using 100% Texas Medicare database during 2009 and 2018.

Design: A retrospective cohort study.

Setting: A population-based study using the Texas Medicare data.

Interventions: 11 common antihyperglycaemic medication types, alone and in combinations: metformin-only, five non-metformin-containing regimens (dipeptidyl peptidase-4 inhibitor (DPP4i) only, sulfonylureas (SU) only, thiazolidinediones (TZD) only, SU/DPP4i and SU/TZD) and five metformin-containing combination treatments (metformin/DPP4i, metformin/SU, metformin/TZD, metformin/SU/DPP4i and metformin/SU/TZD).

Participants: This study included 59 057 type 2 diabetes (T2D) patients from a cohort of Texas Medicare beneficiaries who were aged ≥66 years, …

Inhibition Of Soluble Epoxide Hydrolase Confers Neuroprotection And Restores Microglial Homeostasis In A Tauopathy Mouse Model, Shuo Wang, Chuangye Qi, Chetan Rajpurohit, Baijayanti Ghosh, Wen Xiong, Baiping Wang, Yanyan Qi, Sung Hee Hwang, Bruce D Hammock, Hongjie Li, Li Gan, Hui Zheng

Center on Aging Staff Publications

Background: The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer's disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood.

Methods: Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the …

Hand1, Partially Mediated Through Ape-Specific Ltr Binding, Is Essential For Human Extra-Embryonic Mesenchyme Derivation From Ipscs., Zukai Liu, Yuliana Tan, William F Flynn, Lili Sun, Ponthip Pratumkaew, Juliana Alcoforado Diniz, Nélio A J Oliveira, Justin A Mcdonough, William C Skarnes, Paul Robson

Faculty Research 2025

The specification of extra-embryonic mesenchyme (ExMC) is a prime example of developmental divergence between mouse and human. Derived from definitive mesoderm during mouse gastrulation, the human ExMC first appears at peri-implantation prior to gastrulation and therefore its human cellular origin, still unknown, must differ. In a human pluripotent stem cell model, we report that ExMC shares progenitor cells with trophoblast, suggesting a trophectoderm origin. This ability to form ExMC appears to extend to human trophoblast stem cell lines. We define HAND1 as an essential regulator of ExMC specification, with null cells remaining in the trophoblast lineage. Bound by HAND1, ape-specific, …

Tobacco Smoking Functional Networks: A Whole-Brain Connectome Analysis In 24 539 Individuals, Yezhi Pan, Chuan Bi, Zhenyao Ye, Hwiyoung Lee, Jiaao Yu, Luba Yammine, Tianzhou Ma, Peter Kochunov, L Elliot Hong, Shuo Chen

Faculty, Staff and Student Publications

Introduction: Nicotine addiction, a multifaceted neuropsychiatric disorder, profoundly impacts brain functions through interactions with neural pathways. Despite its significance, the impact of tobacco smoking on the whole-brain functional connectome remains largely unexplored.

Aims and methods: We conducted a whole-brain analysis on 24 539 adults aged 40 and above from the United Kingdom Biobank cohort. Subjects were categorized into individuals who use nicotine and those who do not use nicotine based on current and chronic tobacco smoking information. Functional connectivity was assessed using resting-state functional magnetic resonance imaging. We employed a network analysis method to assess the systematic effects of tobacco …

The Havcr1-Centric Host Factor Network Drives Zika Virus Vertical Transmission, Wenzhe Yu, Jun Tao, Hongmin Cao, Wanshan Zheng, Beiang Zhang, Yue Zhang, Peiqun Xu, Yiwei Zhang, Xuan Liu, Yinan Wang, Han Cai, Gang Liu, Fan Liu, Haibin Wang, Haiyan Zhao, Indira U Mysorekar, Xiaoqian Hu, Bin Cao

Center on Aging Staff Publications

Zika virus (ZIKV) vertical transmission results in devastating congenital malformations and pregnancy complications; however, the specific receptor and host factors facilitating ZIKV maternal-fetal transmission remain elusive. Here, we employ a genome-wide CRISPR screening and identify multiple placenta-intrinsic factors modulating ZIKV infection. Our study unveils that hepatitis A virus cellular receptor 1 (HAVCR1) serves as a primary receptor governing ZIKV entry in placental trophoblasts. The GATA3-HAVCR1 axis regulates heterogeneous cell tropism in the placenta. Notably, placenta-specific Havcr1 deletion in mice significantly impairs ZIKV transplacental transmission and associated adverse pregnancy outcomes. Mechanistically, the immunoglobulin variable-like domain of HAVCR1 binds to ZIKV via …

Samd9 Senses Cytosolic Double-Stranded Nucleic Acids In Epithelial And Mesenchymal Cells To Induce Antiviral Immunity, Gaopeng Hou, Wandy Beatty, Juhee Son, Yinxing Zhu, Qingyu Sheng, Wanyi Huang, Dian Li, Constin Liu, Chen Shen, L David Sibley, Siyuan Ding, Et Al.

2020-Current year OA Pubs

Sensing of cytosolic, double-stranded (ds) DNA or dsRNA molecules derived from microbial or endogenous sources triggers cell-intrinsic innate immunity, but sensors recognizing both cytosolic dsDNA and dsRNA are sparsely reported. Here we find that full-length human SAMD9 protein directly binds to synthetic or viral dsDNA or dsRNA. Overexpression of SAMD9 from various vertebrate species leads to robust production of interferons and pro-inflammatory cytokines. By contrast, loss of endogenous SAMD9 impairs the interferon responses to cytosolic dsDNA and dsRNA stimulation in multiple cell types and enhances the infectivity of pathogenic dsDNA and dsRNA viruses. Mice lacking Samd9l, the human SAMD9 homolog, …

Disuse-Driven Plasticity In The Human Thalamus And Putamen, Roselyne J Chauvin, Dillan J Newbold, Ashley N Nielsen, Ryland L Miller, Samuel R Krimmel, Athanasia Metoki, Anxu Wang, Andrew N Van, David F Montez, Scott Marek, Vahdeta Suljic, Noah J Baden, Nadeshka Ramirez-Perez, Kristen M Scheidter, Julia S Monk, Forrest I Whiting, Babatunde Adeyemo, Jarod L Roland, Abraham Z Snyder, Benjamin P Kay, Marcus E Raichle, Timothy O Laumann, Evan M Gordon, Nico U F Dosenbach

2020-Current year OA Pubs

Subcortical plasticity has mainly been studied using invasive electrophysiology in animals. Here, we leverage precision functional mapping (PFM) to study motor plasticity in the human subcortex during 2 weeks of upper-extremity immobilization with daily resting-state and motor task fMRI. We found previously that, in the cortex, limb disuse drastically impacts disused primary motor cortex functional connectivity (FC) and is associated with spontaneous fMRI pulses. It remains unknown whether disuse-driven plasticity pulses and FC changes are cortex specific or whether they could also affect movement-critical nodes in the thalamus and striatum. Tailored analysis methods now show spontaneous disuse pulses and FC …

Tips For Quality Publishing; Lessons From The Neuroscience Editorial Team, Francesca Cirulli, Rachael Dangarembezi, Victor De Lafuente, Anthony J Hannan, Amanda C Kentner, Tatsuya Mima, Laurel Morris, Sarah J Spencer, Long-Jun Wu, Chen Zhang

The Brown Foundation: Institute of Molecular Medicine

In pursuit of excellence in scholarly publishing, the Neuroscience editorial team shares valuable insights that are essential for authors, reviewers, and the broader scientific community. Firstly, we emphasize that impactful research is built on rigorous study design and execution. Beyond fundamental methodological safeguards such as randomization and blinded analysis, we highlight the importance of thoughtfully selecting study models, with deliberate attention to biological variables like sex and gender, as well as appropriate nomenclature. Secondly, as technological innovations reshape research landscapes, we advocate for combining methodological rigor with suitable analytical tools to ensure robust data collection and transparent reporting. Thirdly, for …

Structural Basis For Polθ-Helicase Dna Binding And Microhomology-Mediated End-Joining, Fumiaki Ito, Ziyuan Li, Leonid Minakhin, Htet A. Khant, Richard T. Pomerantz, Xiaojiang S. Chen

Department of Biochemistry and Molecular Biology Faculty Papers

DNA double-strand breaks (DSBs) present a critical threat to genomic integrity, often precipitating genomic instability and oncogenesis. Repair of DSBs predominantly occurs through homologous recombination (HR) and non-homologous end joining (NHEJ). In HR-deficient cells, DNA polymerase theta (Polθ) becomes critical for DSB repair via microhomology-mediated end joining (MMEJ), also termed theta-mediated end joining (TMEJ). Thus, Polθ is synthetically lethal with BRCA1/2 and other HR factors, underscoring its potential as a therapeutic target in HR-deficient cancers. However, the molecular mechanisms governing Polθ-mediated MMEJ remain poorly understood. Here we present a series of cryo-electron microscopy structures of the Polθ helicase domain (Polθ-hel) …

Amyotrophic Lateral Sclerosis And Frontotemporal Dementia Mutation Reduces Endothelial Tdp-43 And Causes Blood-Brain Barrier Defects., Ashok Cheemala, Amy L Kimble, Emily N Burrage, Stephen B Helming, Jordan D Tyburski, Nathan K Leclair, Omar M Omar, Aamir Zuberi, Melissa Murphy, Evan R Jellison, Bo Reese, Xiangyou Hu, Cathleen Lutz, Riqiang Yan, Patrick A Murphy

Faculty Research 2025

Mutations in the TARDBP gene encoding TDP-43 protein are linked to loss of function in neurons and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We recently identified reduced nuclear TDP-43 in capillary endothelial cells (ECs) of donors with ALS-FTD. Because blood-brain barrier (BBB) permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD–associated mutation in TDP-43 (Tardbp^G348C) and that this leads to cell-autonomous loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain …

Rnase1-Driven Alk-Activation Is An Oncogenic Driver And Therapeutic Target In Non-Small Cell Lung Cancer, Zhengyu Zha, Chunxiao Liu, Meisi Yan, Cong Chen, Cheng Yu, Yaohui Chen, Chenhao Zhou, Lu Li, Yi-Chuan Li, Hiro Yamaguchi, Leiguang Ye, Tong Liu, Ying-Nai Wang, Heng-Huan Lee, Wen-Hao Yang, Li-Chuan Chan, Baozhen Ke, Jennifer L Hsu, Lieming Ding, Dong Ji, Peng Pan, Yiran Meng, Yue Pu, Lunxu Liu, Mien-Chie Hung

Faculty, Staff and Student Publications

Targeted therapy has achieved significant success in the treatment of non-small cell lung cancer (NSCLC), particularly in patients harboring common oncogenic driver mutations such as EGFR, KRAS, and ALK rearrangement. However, ~35-50% of NSCLC patients without tyrosine kinase mutation or rearrangement (non-mutated) cannot benefit from these targeted treatments, highlighting the urgent need for novel therapeutic strategies for this patient population. In this study, we report a non-canonical role of human secretory ribonuclease 1 (RNase1), which binds to and activates wild-type ALK in lung cancer cells, thereby triggering its downstream signaling pathway. RNase1-driven ALK-activation (RDAA) cells exhibit enhanced cell proliferation, migration, …

Molecular Mechanism Establishing The Off Pathway In Vision, Florentina Soto, Chin-I Lin, Andrew Jo, Ssu-Yu Chou, Ellen G Harding, Philip A Ruzycki, Gail K Seabold, Ronald S Petralia, Daniel Kerschensteiner

2020-Current year OA Pubs

Parallel ON and OFF (positive- and negative-contrast) pathways fundamental to vision arise at the complex synapse of cone photoreceptors. Cone pedicles form spatially segregated functionally opposite connections with ON and OFF bipolar cells. Here, we discover that mammalian cones express LRFN2, a cell-adhesion molecule, which localizes to the pedicle base. LRFN2 stabilizes basal contacts between cone pedicles and OFF bipolar cell dendrites to guide pathway-specific partner choices, encompassing multiple cell types. In addition, LRFN2 trans-synaptically organizes glutamate receptor clusters, determining the contrast preferences of the OFF pathway. ON and OFF pathways converge in the inner retina to regulate bipolar cell …