Digital Commons Network^™

Glycative Stress Disrupts The Mitochondrial-Lysosome Axis And Promotes Geroconversion In Aging Cardiomyocytes, Diana Bou-Teen, Simonas Valiuska, Elisabet Miro-Casas, Chiara Rubeo, Elena Bonzon-Kulichenko, Zuzana Nichtova, Celia Fernandez-Sanz, Javier Inserte, Antonio Rodriguez-Sinovas, Begoña Benito, Eduard Ródenas-Alesina, Jesús Vázquez, Ignacio Ferreira-González, Marisol Ruiz-Meana

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Aging is a major risk factor for heart failure, yet the molecular mechanisms linking cardiac aging to the inflammatory pathophysiology of heart failure remain elusive. Mitochondrial dysfunction and defective organelle quality control are emerging hallmarks of the aging heart, but their biochemical underpinnings are poorly defined. Using comprehensive glycomics, we found that cardiac mitochondria from physiologically aged mice (≥ 20 months) are the major intracellular reservoirs of advanced glycation end products (AGEs), derived primarily from the chemical attack of some α-oxoaldehydes on proteins. This was associated with mild mitochondrial dysfunction and structural remodeling. Lysosomes in aged hearts were enlarged, more …

Megakaryocyte And Platelet Thrombospondin-1 Regulates Matrix Remodeling By Stabilizing Basement Membrane Col6a1 In Lung Injury, Hernán F Peñaloza, Atish Gheware, Ananya Gupta, Donovan Watza, Anupam Kumari, Zeyu Xiong, Pooja Bhojraj, Jae-Sung Kim, Bo-Ram Jin, Kyunghee Choi, Matthew R Rosengart, Jaehyung Cho, Janet S Lee, Et Al.

2020-Current year OA Pubs

An early event after lung injury is extracellular matrix (ECM) remodeling and the formation of a provisional matrix. While megakaryocytes and platelets (Mgk/plt) play important roles in hemostasis, their impact on the matrix in lung injury is not fully understood. Using lung intravital microscopy, 3D large area scanning with multiphoton confocal hybrid imaging, and label-free quantitative proteomics, the matricellular protein thrombospondin-1 (TSP1) arising from Mgk/plt protects the lung from alveolar injury. Mgk/plt cell-specific Thbs1 knockout (cKO) mice show increased alveolar barrier disruption with exaggerated neutrophil-mediated injury. The cKO mice exhibit striking extracellular matrix re-organization with reduction in basement membrane matrix …

Mist: A Hierarchical Bayesian Framework For Detecting Differential Dna Methylation Dynamics In Single-Cell Data, Daoyu Duan, Wenjing Ma, Wen Tang, Hao Wu, Liangliang Zhang, Hao Feng

Faculty, Staff and Student Publications

Recent advancements in single-cell DNA methylation (scDNAm) sequencing technologies have enabled the profiling of epigenetic landscapes at unprecedented resolution, offering insights into cellular heterogeneity, differentiation and evolution. Trajectory inference, which orders cells along pseudotime, allows researchers to track genomics changes across continuous cell states and identify key loci exhibiting differential methylation. However, no methods currently exist to model methylation changes along pseudotime in scDNAm data. Here, we present a hierarchical Bayesian framework for scDNAm data analysis. Our method, named mist (methylation inference for single-cell along trajectory), models stage-specific biological variations, identifies genomic features with significant methylation changes along pseudotime, and …

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 …

Genetic Architecture Of The Murine Red Blood Cell Proteome Reveals Central Role Of Hemoglobin Beta Cysteine 93 In Maintaining Redox Balance., Gregory R Keele, Monika Dzieciatkowska, Ariel M Hay, Matthew Vincent, Callan O'Connor, Daniel Stephenson, Julie A Reisz, Travis Nemkov, Kirk C Hansen, Grier P Page, James C Zimring, Gary Churchill, Angelo D'Alessandro

Faculty Research 2026

Red blood cells (RBCs) transport oxygen but accumulate oxidative damage over time, reducing function in vivo and during storage, critical for transfusions. To explore the genetics of RBC resilience, we profiled proteins, metabolites, and lipids from fresh and stored RBCs from 350 genetically diverse mice. Our analysis identified over 6,000 quantitative trait loci (QTLs). Compared to other tissues, the prevalence of trans genetic effects over cis ones reflects the absence of de novo protein synthesis in anucleated RBCs. QTL hotspots at Hbb, Hba, Mon1a, and (storage-specific) Steap3 linked ferroptosis to hemolysis. Proteasome QTLs clustered at multiple loci, underscoring the importance …

Genetic Architecture Of The Murine Red Blood Cell Proteome Reveals Central Role Of Hemoglobin Beta Cysteine 93 In Maintaining Redox Balance., Gregory R Keele, Monika Dzieciatkowska, Ariel M Hay, Matthew Vincent, Callan O'Connor, Daniel Stephenson, Julie A Reisz, Travis Nemkov, Kirk C Hansen, Grier P Page, James C Zimring, Gary Churchill, Angelo D'Alessandro

Faculty Research 2026

Red blood cells (RBCs) transport oxygen but accumulate oxidative damage over time, reducing function in vivo and during storage, critical for transfusions. To explore the genetics of RBC resilience, we profiled proteins, metabolites, and lipids from fresh and stored RBCs from 350 genetically diverse mice. Our analysis identified over 6,000 quantitative trait loci (QTLs). Compared to other tissues, the prevalence of trans genetic effects over cis ones reflects the absence of de novo protein synthesis in anucleated RBCs. QTL hotspots at Hbb, Hba, Mon1a, and (storage-specific) Steap3 linked ferroptosis to hemolysis. Proteasome QTLs clustered at multiple loci, underscoring the importance …

Molecular Insights Into The Regulation Of Gnptαβ By Lyset, Xi Yang, Balraj Doray, Danielle Henn, Varsha Venkatarangan, Benjamin C Jennings, Zhongzheng Dong, Jiaxuan Liang, Weichao Zhang, Bokai Zhang, Linchen Yu, Liang Chen, Stuart Kornfeld, Ming Li

2020-Current year OA Pubs

In vertebrates, newly synthesized lysosomal enzymes traffic to lysosomes through the mannose-6-phosphate (M6P) pathway. The Golgi membrane protein LYSET was recently discovered to regulate lysosome biogenesis by controlling the level of GlcNAc-1-phosphotransferase (GNPT). However, its working mechanism remained unclear. In this study, we demonstrate that LYSET is a two-transmembrane protein essential for GNPT stability, cleavage by Site-1 Protease (S1P), and enzymatic activity. We reconcile conflicting models by showing that LYSET enhances GNPT cleavage and prevents its mislocalization to lysosomes for degradation. We further establish that LYSET achieves this by interacting with GOLPH3 and retromer complexes to anchor the LYSET-GNPT complex …

Differential Contributions Of Clpx And Clpp To Pulmonary Virulence In Classical And Hypervirulent Klebsiella Pneumoniae, Nathan M Lin, Emily C Marino, Jordan M Schlotmann, David A Rosen

2020-Current year OA Pubs

No abstract provided.

Underexplored Maternal Microbiomes: Immune, Metabolic, And Microbial Pathways Shaping Pregnancy Outcomes, Rafael Tomoya Michita, Nicole Jimenez, Melissa M Herbst-Kralovetz, Indira U Mysorekar

Faculty, Staff and Students Publications

Maternal microbial ecosystems play critical roles in shaping reproductive physiology and pregnancy outcomes. During the pre-conception and prenatal periods, these communities modulate maternal physiology by regulating immune tolerance, nutrient metabolism, and susceptibility to pregnancy complications such as preterm birth, hypertensive disorders, and gestational diabetes. While the gut microbiota has been extensively studied, the roles of cervicovaginal, urinary, respiratory, oral, and upper reproductive tract microbiomes remain less clear. In this minireview, we synthesize current knowledge on these underexplored maternal microbiomes, with an emphasis on the cervicovaginal and urinary microbiota and their interactions with the placenta and fetus. We discuss cross-niche microbial …

Crossing The Finish Line Towards A Disease-Modifying Treatment For Angelman Syndrome, Matthew C Judson, Jason J Yi, Et Al.

2020-Current year OA Pubs

Recent progress in the development of genetic therapies promises that impactful treatments for single-gene neurodevelopmental disorders are imminent. But can derailed neurodevelopmental processes be mended after broken genes are replaced or otherwise restored? The results of ongoing clinical trials for Angelman syndrome will soon yield answers to this pressing question, yet the trials face significant obstacles. Here we identify insights needed to aid the quest for a disease-modifying Angelman syndrome therapy, which could serve as a roadmap for the expeditious development of genetic therapies for other single-gene neurodevelopmental disorders.

Translation Of Expanded Cgg Repeats In Lrp12 Associated Oculopharyngodistal Myopathy, Chengcheng Li, Jil A Daw, Sara K Pittman, Connor J Maltby, Hidetoshi Sakurai, Peter K Todd, Conrad C Weihl

2020-Current year OA Pubs

Oculopharyngodistal myopathy (OPDM) is characterized by ptosis, ophthalmoparesis, dysphagia, and distal weakness. Myopathological features include rimmed vacuoles and intranuclear inclusions. OPDM is associated with a pathogenic CGG repeat expansions in the 5'UTR of LRP12, NOTCH2NLC, GIPC1, RILPL1 and ABCD3. Translation of the repeat in the glycine reading frame has been demonstrated for expansions in FMR1, NOTCH2NLC and GIPC1. To assess for a similar phenomenon with LRP12, we expressed normal or expanded CGG repeats in the context of the 5'UTR of LRP12, upstream of a green fluorescent protein (GFP) in the three repeat reading frames. Repeat dependent translation occurs exclusively in …

A New Chromosome-Level Genome Assembly For Western Painted Turtle Chrysemys Picta Bellii, A Model For Extreme Physiological Adaptations, Junhao Chen, John R Bermingham Jr, Patrick Minx, Milinn Kremitzky, Zhenguo Lin, Daniel E Warren

2020-Current year OA Pubs

The western painted turtle, Chrysemys picta bellii, has the greatest tolerance to anoxia of any tetrapod studied to date. These turtles reside in the northern United States and southern Canada, and survive months of anoxia while submerged in ice-locked ponds and bogs. Reference genomes provide an important resource for elucidating the molecular bases for such unique physiological traits. The initial reference genome for this species, published in 2013, is highly fragmented, thereby limiting downstream analyses and biological interpretation. We created a new and improved assembly by combining PacBio HiFi, 10 × Genomics Chromium, Hi-C sequence data and Bionano optical mapping …

Prevention Of Transgene Silencing During Human Pluripotent Stem Cell Differentiation., Takeshi Uenaka, Alan Napole, Aninda Dibya Saha, Duo Sun, Angelina Singavarapu, Elizabeth Calzada, Jiahui Chen, Lena Erlebach, Amanda Mcquade, Daniel M Ramos, Alessandra Rigamonti, Lisa Salazar, Avi J Samelson, Kamilla Sedov, Natalie J Welsh, Katleen Wild, Qianxin Wu, Ernest Arenas, Andrew R Bassett, Martin Kampmann, Deborah Kronenberg-Versteeg, Florian T Merkle, Birgitt Schüle, Leslie M Thompson, William C Skarnes, Michael E Ward, Marius Wernig

Faculty Research 2026

Transgenes are often silenced upon differentiation of pluripotent stem cells using conventional expression systems. Here, we developed the TK4 PiggyBac vector to conduct a comparative analysis to evaluate the impact of various promoters, transcriptional regulatory elements, insulators, and genomic integration sites on transgene silencing during neuronal differentiation. Our findings reveal that specific combinations of CAG and Ubc promoters with the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) can prevent transgene silencing during differentiation, whereas chromatin insulators have less impact on sustained expression. Three novel safe harbor loci, distant from known genes, as well as the citrate lyase beta-like (CLYBL) locus, …

Brd4-Mediated Er Membrane Contact Creates Functionally Distinct Mitochondrial Subtypes, Brandon Chen, Rachel M Guerra, David J Pagliarini, Et Al.

2020-Current year OA Pubs

Inter-organellar communication is critical for cellular metabolism. One of the most abundant inter-organellar interactions occurs at the endoplasmic reticulum and mitochondria contact sites (ERMCSs). However, an understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism is limited by a lack of tools that permit temporal induction and reversal. Through screening approaches, we identified fedratinib, an FDA-approved drug that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology, induces a distinct ER-mitochondria envelopment structure, and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondrial electron transport chain …

Bi-Allelic Variants In Nrdc Cause A Neurodevelopmental Disorder Characterized By Neonatal Lethality, Microcephaly, And Brain Abnormalities, Davut Pehlivan, Abigail Sandoval, Reza Maroofian, François Lecoquierre, Aisha M Al Shamsi, Gyu S Lee, Osman Yesilbas, Preston Taylor, Matthew B Mcdougal, Vahid Bahrambeigi, Omid Aryani, Juan Felipe Ramirez, Khalid Hama Salih, Chadi Al Alam, Heba Morsy, Haytham Hussien, Tarek Omar, Ibrahim M Abdelrazek, Anne Claire Brehin, Dana Marafi, Tugba Kalayci, Jubran Abu Rahma, Jawabreh Kassem Talbeya, Husein Dabbah, Eric Verspyck, Toktam Moosavian, Jawid M Fatih, Tadahiro Mitani, Gulsen Akay, Daniel G Calame, Anne-Marie Guerrot, Wendy K Chung, Henry Houlden, James R Lupski, Adel Shalata, Wan Hee Yoon

Faculty, Staff and Students Publications

Nardilysin (NRDC) plays a role in multiple cellular functions in diverse cellular compartments, including ectodomain shedding in the plasma membrane, as well as chaperoning a key Krebs cycle enzyme in mitochondria. We had previously reported limited clinical information from two individuals with homozygous frameshift variants in NRDC. With inclusion of previously published individuals, here we report 14 individuals (10 females, four males) from nine unrelated families carrying homozygous NRDC pathogenic variants. Common clinical features include severe to profound developmental delay/intellectual disability (12/12), microcephaly (13/13), prematurity (5/13), lethality in the first 3 years of life (9/14), seizures (7/11), joint contractures (4/8), …

An Acetylation-Dependent Switch Underlies Host Disease Tolerance During Streptococcal Infection, Sumit Kumar Paudel, Sowmya Gannavaram, Michael G Caparon, Wei Xu

2020-Current year OA Pubs

Building on our finding that Streptococcus pyogenes pyruvate dehydrogenase (PDH) suppresses host disease tolerance (DT) via short-chain fatty acid (SCFA)-mediated modulation of host acetyl-CoA and IL-10 levels, we characterize the global transcriptomic and epigenetic mechanisms underlying this immunometabolic manipulation. Combining new histological and ultrastructural analyses with an in-depth re-analysis of single-cell and bulk RNA-seq datasets to more comprehensively characterize the DT response, we show that PDH deficiency is associated with broad immunologic rewiring, characterized by intracellular bacterial containment within phagocytes, expansion of pro-resolving myeloid cells, and altered cell-cell communication. Metabolic analysis of ΔPdh-infected tissues revealed a shift away from acetyl-CoA …

Modulating Alternative Splicing Of Mecp2 Is A Potential Therapeutic Strategy For Rett Syndrome, Harini P Tirumala, Li Wang, Yan Li, Sameer S Bajikar, Ashley G Anderson, Wei Wang, Alexander J Trostle, Mahla Zahabiyon, Aleksandar Bajic, Jean J Kim, Hu Chen, Zhandong Liu, Huda Y Zoghbi

Faculty, Staff and Students Publications

Rett syndrome (RTT) is a neurological disorder caused by loss-of-function mutations in methyl CpG binding protein 2 (MECP2), a transcriptional regulator essential for maintenance of normal neuronal function. The current FDA-approved treatment for RTT, Trofinetide, mildly alleviates some symptoms. In contrast, re-introducing MeCP2 or increasing its amount through transgenesis in mouse RTT models improves most neurological phenotypes and enhances survival. Here, we devised a therapeutic strategy to moderately increase MeCP2 protein by modulating the alternative splicing of MECP2 to switch the less efficiently translated e2 to the more efficiently translated e1 isoform. We deleted Mecp2 exon 2 (unique …

A Neural Circuit Framework For Economic Choice: From Building Blocks Of Valuation To Compositionality In Multitasking, Aldo Battista, Camillo Padoa-Schioppa, Xiao-Jing Wang

2020-Current year OA Pubs

Value-guided decisions are a cornerstone of cognition, yet the underlying circuit-level mechanisms remain elusive. We used reinforcement learning to train recurrent neural network models endowed with Dale's law on a battery of economic choice tasks, which revealed a two-stage computational framework. First, value estimation occurs at the input level, where learned weights store subjective preferences and approximate the non-linear multiplication of reward magnitude and probability to yield expected values. This feedforward mechanism enables generalization to novel choice options. Second, option values are compared within the recurrent network, where specific connectivity patterns mediate robust winner-take-all decisions, with both excitatory and inhibitory …

Ifn Signaling Is Associated With Radiotherapy Response In Malignant Peripheral Nerve Sheath Tumors., Iowis Zhu, Julian Chien, Gabriel E Rech, Kanish Mirchia, Sixuan Pan, Kaeli Miller, Joanna Pak, Rosanna Wustrack, Varun Monga, Steve E Braunstein, Mark D Adams, Line Jacques, Melike Pekmezci, S John Liu, Harish N Vasudevan

Faculty Research 2026

Patients with malignant peripheral nerve sheath tumors (MPNSTs) have poor outcomes despite multimodal treatment with surgery, radiation, and systemic therapy. The responses to radiotherapy (RT) are mixed, and the biologic mechanisms underlying this heterogeneity in the radiation response of MPNSTs are not understood. Here, we combined bulk and single-cell transcriptomics, genome-wide CRISPR interference screens, and multiplatform molecular analysis across MPNST cells, mouse allograft models, and patients' samples to understand the mediators of the radiation response. Our data revealed that MPNSTs, but not benign plexiform neurofibromas, induced a type I IFN signature that functionally mediated the radiation response. Moreover, irradiation of …

Ifn Signaling Is Associated With Radiotherapy Response In Malignant Peripheral Nerve Sheath Tumors., Iowis Zhu, Julian Chien, Gabriel E Rech, Kanish Mirchia, Sixuan Pan, Kaeli Miller, Joanna Pak, Rosanna Wustrack, Varun Monga, Steve E Braunstein, Mark D Adams, Line Jacques, Melike Pekmezci, S John Liu, Harish N Vasudevan

Faculty Research 2026

Patients with malignant peripheral nerve sheath tumors (MPNSTs) have poor outcomes despite multimodal treatment with surgery, radiation, and systemic therapy. The responses to radiotherapy (RT) are mixed, and the biologic mechanisms underlying this heterogeneity in the radiation response of MPNSTs are not understood. Here, we combined bulk and single-cell transcriptomics, genome-wide CRISPR interference screens, and multiplatform molecular analysis across MPNST cells, mouse allograft models, and patients' samples to understand the mediators of the radiation response. Our data revealed that MPNSTs, but not benign plexiform neurofibromas, induced a type I IFN signature that functionally mediated the radiation response. Moreover, irradiation of …

Jax Animal Behavior System (Jabs), A Genetics-Informed, End-To-End Advanced Behavioral Phenotyping Platform For The Laboratory Mouse., Anshul Choudhary, Brian Q Geuther, Thomas J. Sproule, Glen L Beane, Vivek Kohar, Jarek Trapszo, Vivek Kumar

Faculty Research 2026

Automated detection of complex animal behavior remains a challenge in neuroscience. Developments in computer vision have greatly advanced automated behavior detection and allow high-throughput preclinical and mechanistic studies. An integrated hardware and software solution is necessary to facilitate the adoption of these advances in the field of behavioral neurogenetics, particularly for non-computational laboratories. We have published a series of papers using an open field arena to annotate complex behaviors such as grooming, posture, and gait as well as higher-level constructs such as biological age and pain. Here, we present our integrated rodent phenotyping platform, JAX Animal Behavior System (JABS), to …

Jax Animal Behavior System (Jabs), A Genetics-Informed, End-To-End Advanced Behavioral Phenotyping Platform For The Laboratory Mouse., Anshul Choudhary, Brian Q Geuther, Thomas J. Sproule, Glen L Beane, Vivek Kohar, Jarek Trapszo, Vivek Kumar

Faculty Research 2026

Automated detection of complex animal behavior remains a challenge in neuroscience. Developments in computer vision have greatly advanced automated behavior detection and allow high-throughput preclinical and mechanistic studies. An integrated hardware and software solution is necessary to facilitate the adoption of these advances in the field of behavioral neurogenetics, particularly for non-computational laboratories. We have published a series of papers using an open field arena to annotate complex behaviors such as grooming, posture, and gait as well as higher-level constructs such as biological age and pain. Here, we present our integrated rodent phenotyping platform, JAX Animal Behavior System (JABS), to …

The Relationship Between Apparent Potentiation And The Magnitude Of The Control Response, Joe Henry Steinbach, Gustav Akk

2020-Current year OA Pubs

The effect of a potentiating drug on ion channel function is typically evaluated by comparing current responses to the control agonist in the presence and absence of the potentiator. Differences in ratios of responses are then taken as proof of distinct potentiation properties when comparing modulation by different compounds. In these experiments, the concentration of the agonist is typically kept low to generate a small fractional control response. The precise relative magnitude of the control response is, however, not standardized among labs and can range from a concentration producing a response equal to just 2% of maximal (EC2) to over …

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 …

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, …

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. …

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 …

Meta-Analysis Of Genetic Mapping Studies In Mice Reveals Candidate Epilepsy Modifier Genes That Are Outside The Current Drug Development Landscape., Giovanna L Durante, Anna L. Tyler, Rod C Scott, Amanda E Hernan, J Matthew Mahoney

Faculty Research 2026

OBJECTIVE: Despite decades of development in anti-seizure medications, ~30% of individuals remain refractory to all treatments, and none of the existing therapies are disease modifying. Identifying targets outside the current preclinical paradigm is critically important. This study aimed to characterize the landscape of current epilepsy treatments at the level of gene interaction networks and identify novel genetic modifiers of epilepsy as potential novel therapeutic targets.

METHODS: We performed a functional network analysis to score genes based on their interactions with known epilepsy genes, and we integrated these functional scores with population genetics data and drug tractability information. In parallel, we …

Meta-Analysis Of Genetic Mapping Studies In Mice Reveals Candidate Epilepsy Modifier Genes That Are Outside The Current Drug Development Landscape., Giovanna L Durante, Anna L. Tyler, Rod C Scott, Amanda E Hernan, J Matthew Mahoney

Faculty Research 2026

OBJECTIVE: Despite decades of development in anti-seizure medications, ~30% of individuals remain refractory to all treatments, and none of the existing therapies are disease modifying. Identifying targets outside the current preclinical paradigm is critically important. This study aimed to characterize the landscape of current epilepsy treatments at the level of gene interaction networks and identify novel genetic modifiers of epilepsy as potential novel therapeutic targets.

METHODS: We performed a functional network analysis to score genes based on their interactions with known epilepsy genes, and we integrated these functional scores with population genetics data and drug tractability information. In parallel, we …

Cholecalciferol (Vitamin D3) Is An Agonist Of The Alzheimer's Disease-Associated Immune Receptor Trem2, Hunter B Dean, Ryan A Tuckey, Rory A Greer, Jessica A Greven, Shan-Zhong Yang, Daniel S Elston, Gunnar N Eastep, Yuwei Song, Thomas J Brett, Yuhua Song, Erik D Roberson

2020-Current year OA Pubs

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is one of the strongest genetic risk factors for late-onset Alzheimer's disease (AD). Several TREM2 ligands are known, including charged lipids and AD-associated proteins like apolipoprotein E and amyloid-β, but the full range of endogenous ligands for TREM2 remains unknown. Here we combined virtual screening of the Human Metabolome Database with molecular dynamics simulations, binding free energy estimation, and biolayer interferometry to identify novel TREM2 ligands and map their binding sites. Cholecalciferol, the unmodified parent form of vitamin D3, emerged as a top candidate. Structural modeling indicated that cholecalciferol binds TREM2 at …