Digital Commons Network^™

Senolytic-Resistant Senescent Cells Have A Distinct Sasp Profile And Functional Impact: The Path To Developing Senosensitizers, Utkarsh Tripathi, Masayoshi Suda, Vagisha Kulshreshtha, Bryan T Piatkowski, Allyson K Palmer, Nino Giorgadze, Christina Inman, Nathan Gasek, Ming Xu, Kurt O Johnson, Tamar Pirtskhalava, Selim Chaib, Larissa P G Langhi Prata, Yi Zhu, Renuka Kandhaya-Pillai, Stefan G Tullius, Saranya P Wyles, Rambabu Majji, Hari Krishna Yalamanchili, David B Allison, Tamar Tchkonia, James L Kirkland

Faculty, Staff and Students Publications

The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30%-70% of SCs, act by transiently disabling the senescent cell antiapoptotic pathways (SCAPs), which defend those SCs that are proapoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become "senolytic-resistant". Administering senolytics to obese mice selectively decreased the abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30%-70% of human senescent preadipocytes or human umbilical …

Mir-302 Regulates Pancreatic Progenitor Pool And Pancreatic Size, Ziyue Z Yang, Caroline G Snider, Ronald J Parchem

Faculty, Staff and Students Publications

Disruptions in pancreatic development can lead to health issues such as pancreatic agenesis and congenital diabetes mellitus. Understanding pancreatic organogenesis is critical for elucidating disease mechanisms and developing regenerative therapies. The pancreas consists of endocrine and exocrine cells, both of which are derived from multipotent progenitor cells (MPCs). MPC proliferation and differentiation are tightly controlled by multiple mechanisms, including post-transcriptional regulation by miRNAs. However, these regulatory factors are not fully understood. Here, we profiled miRNA expression in MPCs and identified that mir-302 was highly enriched during the earliest stages of pancreatic development. Loss of mir-302 resulted in reduced pancreatic size …

Cerebellar Deep Brain Stimulation Rescues Purkinje Cell Mitochondrial Density In A Genetic Mouse Model Of Cerebellar Ataxia, Lauren N Miterko-Myers, Lauren E Peacoe, Lita Duraine, Zhongyuan Zuo, Roy V Sillitoe

Faculty, Staff and Students Publications

Deep brain stimulation (DBS) improves motor function in a growing list of movement diseases including Parkinson's disease, dystonia, and tremor. There is evidence that DBS may also be effective in ataxia. It is not known why DBS is effective, but modulating cell activity and conferring neuroprotection are hypothesized to underlie its benefits. Understanding the effects of DBS on neurons is paramount to extending its clinical use in the treatment of various motor and non-motor diseases. Here, we stimulated the cerebellum of Car8 waddles (Car8wdl) mice, given the cerebellum's important role in ataxia pathophysiology. Using transmission electron microscopy, we tested the …

Multi-Omics To Study Chronic Respiratory Diseases And Viral Infections, Sobia Idrees, Hao Chen, Tayyaba Sadaf, Saima Firdous Rehman, Matt D Johansen, Keshav Raj Paudel, Gang Liu, Yuting Wang, Malte D Luecken, Elinor Hortle, Ashleigh S Philp, Kurtis F Budden, Matthew O'Rourke, Gerard E Kaiko, Sionne E M Lucas, Joanne L Dickinson, Peter C Allen, Joseph E Powell, Lai-Ying Zhang, Daniel C Chambers, Tamera Corte, Gaetano Caramori, Maor Sauler, Peter A Wark, Janine Gote-Schniering, Mareike Lehmann, Thomas M Conlon, Theodore S Kapellos, Ali Önder Yildirim, Rosa Faner, Shyamali C Dharmage, Craig E Wheelock, Maarten Van Den Berge, Martijn C Nawijn, Francesca Polverino, Gabrielle T Belz, Sanjay H Chotirmall, Leopoldo N Segal, Alen Faiz, Philip M Hansbro

Faculty, Staff and Students Publications

Integrating omics layers reveals complex biological systems, unveiling vital insights into chronic respiratory diseases and COVID-19. This holistic approach is crucial for developing more effective treatments and understanding intricate relationships. https://bit.ly/3VKFzJH

Surface Marker Identification To Capture Live Circulating Tumor Cells In Metastatic Triple-Negative Breast Cancer, Bree M Lege, Khushali J Patel, Brendan Panici, Ping Gong, Michael T Lewis, Matthew J Ellis, Chonghui Cheng

Faculty, Staff and Students Publications

Metastatic triple-negative breast cancer (TNBC) is highly aggressive and lacks targeted therapies. Circulating tumor cells (CTC) are invaluable for monitoring metastatic tumor progression and treatment response but are difficult to capture because of their rarity and heterogeneity. Surface-based staining for live CTCs is essential to preserve RNA quality in single cells, but current markers tend to perform poorly on more mesenchymal tumor cells such as TNBCs. To enhance live TNBC CTC detection, we developed a workflow for live CTC capture and single-cell RNA sequencing (scRNA-seq). Using a mouse model of metastatic TNBC, we identified four new CTC surface markers, AHNAK2, …

Unraveling Posttranslational Modification Complexity: Advances In Quantitative Histone Proteoform Mass Spectrometry, Karl F Poncha, Alyssa T Paparella, Nicolas L Young

Faculty, Staff and Students Publications

Histone proteins and their posttranslational modifications are central to chromatin structure and function. These modifications often occur in combinations, generating a diverse array of histone proteoforms that contribute to the dynamic regulation of chromatin architecture. Advancements in mass spectrometry-based proteomics, particularly top-down and middle-down approaches, have significantly enhanced our ability to characterize these proteoforms and elucidate PTM crosstalk. This review provides an analysis of the epigenetic machinery involved in the addition, recognition, and removal of histone PTMs, emphasizing the complexity introduced by histone variants and combinatorial PTM patterns. We examine the challenges and limitations of traditional antibody-based methods for PTM …

Noradrenergic Innervation Across Brain Regions Is Altered By Aging And By Disease Progression In A Mouse Model Of Alzheimer’S Disease Neuropathology, Nicole M Hernandez, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Norepinephrine plays critical roles in modulating arousal and attention, is highly dynamic in awake, behaving individuals, and has anti-inflammatory and neuroprotective actions. Notably, the locus coeruleus (LC), the primary source of norepinephrine in the central nervous system, is among the first brain regions to show pathological alterations in early stages of Alzheimer's disease (AD). LC neuronal loss and associated reductions in norepinephrine in the brain have therefore been postulated to play a key role in AD pathophysiology. LC neurons and their axons have been studied in several mouse models of AD-related neuropathology to investigate their contribution to brain dysfunction in …

Astrocytic Sox9 Overexpression In Alzheimer’S Disease Mouse Models Promotes Aβ Plaque Phagocytosis And Preserves Cognitive Function, Dong-Joo Choi, Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debosmita Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R Williamson, Teng-Wei Huang, Kaitlyn Sanchez, Joanna Jankowsky, Benjamin Deneen

Faculty, Staff and Students Publications

Astrocytes play essential roles in the brain, and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, knowledge of how astrocytes contribute to disease pathogenesis is incomplete; accordingly, harnessing their biology toward therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context-specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer's disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aβ) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aβ plaques by astrocytes …

Dynamic Progression Of Ectopic Lymphoid Structure Formation In Lacrimal Glands Of A Sjögren’S Disease Murine Model, Sara Abdelhamid, Alison V Ramirez, Emre Aksan, Elizaveta A Demianova, Cintia S De Paiva, Maria C Edman, J Andrew Mackay, Sarah F Hamm-Alvarez

Faculty, Staff and Students Publications

Background: Sjögren's Disease (SjD) is a chronic autoimmune condition characterized by lymphocytic infiltration of lacrimal glands (LG) and salivary glands (SG). In SG, these immune structures have properties of ectopic lymphoid structures (ELS) and appear to play a critical role in disease pathology. While the presence of ELS in patients' SG biopsies is linked to disease severity, their presence and composition in LG has not been well characterized.

Methods: The properties and time course of apparent ELS development in LG from the male non-obese diabetes free (NOR) sub-strain of the Non-Obese Diabetic (NOD) mice was investigated at stages encompassing early …

Host- And Pathogen-Related Determinants Of Pulmonary Versus Extrapulmonary Tuberculosis, Begna Tulu, Thomas Theo Brehm, Reinout Van Crevel, Tobias Dallenga, Andrew R Dinardo, Keertan Dheda, Johanna Eggeling, Wendemagegn Enbiale, Matthias I Gröschel, Jialun Hao, Vinod Kumar, Arjan Van Laarhoven, Rolanda Londt, Gareth Prosser, Philippa Randall, Norbert Reiling, Jan Rybniker, Ulrich E Schaible, Erwin Schurr, Isabelle Suarez, Sebastian J Theobald, Robert J Wilkinson, Christoph Lange

Faculty, Staff and Students Publications

Tuberculosis (TB) primarily manifests as pulmonary TB (PTB), but extrapulmonary TB (EPTB) remains a major clinical challenge. Distinct diagnostic and therapeutic difficulties arise from differences in immune responses, pathogen behaviour and host susceptibility. However, the factors driving disease localisation are still incompletely understood. We conducted a comprehensive narrative review of studies examining differences between PTB and EPTB in terms of epidemiology, mycobacterial factors, genetic and epigenetic determinants, host immune responses, transcriptomic profiles, cytokine and chemokine patterns, and immunophenotypes. EPTB is more common among females, children, older adults and immunocompromised individuals with deficient granuloma formation. This review is intended to provide …

Eata Mediated Degradation Of Intestinal Mucus Is Species-Specific And Driven By Muc2 Structural Features, Sergio Trillo-Muyo, Brendan Dolan, Frida Svensson, Tim J Vickers, Liisa Arike, Maria-Jose García-Bonete, Jenny K Gustafsson, Mathias I Nielsen, Hans H Wandall, James M Fleckenstein, Gunnar C Hansson, Sjoerd Van Der Post

2020-Current year OA Pubs

Enterotoxigenic Escherichia coli (ETEC) infections are a leading cause of diarrheal illness, responsible for an estimated 100,000 deaths annually. ETEC pathogenesis is driven by various virulence factors, including toxins, adhesins, and noncanonical factors such as the protease EatA. The first line of host defense against intestinal pathogenic bacterial infections is the protective intestinal mucus layer. Here, we demonstrate the mechanism by which EatA degrades the core mucus component MUC2, thereby facilitating access to the epithelial cell surface and promoting infection. We identify the specific cleavage site region localized at the C-terminal of MUC2. EatA's protease activity depends on the interaction …

Molecular Detection Of Listeria Species From Diarrheic Human In Iraq, Sabah Adel Mahmood, Nagham Mohammed Al-Gburi

Muthanna Medical Journal

Background: Diarrhea is a serious global public health issue, especially in developing nations. The two categories most susceptible to infection are the elderly and children. L. monocytogenes is recognized as a causal agent of diarrhoea among the several bacterial pathogens linked to gastrointestinal illnesses. The current work was designed to investigate Listeria spp in diarrheal human stool samples in Baghdad City, Iraq.

Methods: One hundred stool samples from diarrheal patients were collected from private clinics in rural and urban areas. Listeria spp was identified by conventional culture methods using selective media, biochemical and CAMP tests, the Vitek 2compact system, and …

Chemotherapy-Induced Adipo-Lineage Cell Senescence Drives Bone Loss, Ganesh Kumar Raut, Taylor Malachowski, Anupama Melam, Renata Ramalho-Oliveira, Taylor Holt, Xianmin Luo, Zhangting Yao, Douglas V Faget, Qihao Ren, David G Denardo, Sheila A Stewart

2020-Current year OA Pubs

Chemotherapy-induced bone loss is a debilitating and common side effect of cancer treatment, though its underlying mechanisms remain poorly understood. Here, we show that, despite the systemic administration of chemotherapy, cellular senescence is restricted to bone marrow adipo-lineage cells specifically Cxcl12-abundant reticular (CAR) cells and bone marrow adipocytes (BMAds). Induction of senescence within these populations promotes RANK ligand (RANKL)-mediated osteoclastogenesis, leading to significant bone loss. Notably, we find that inhibition of the p38MAPK-MK2 pathway suppresses the senescence-associated secretory phenotype (SASP), including RANKL production abrogating bone loss. Furthermore, treatment with the senolytic combination dasatinib and quercetin (D + Q) selectively eliminates …

Dcpr: A Deep Learning Framework For Circadian Phase Reconstruction, Xiao Han, Xiaochen Cen, Zhijin Li, Xiaobo Zhou, Zhiwei Ji

Faculty, Staff and Student Publications

Background: The circadian clock is an evolutionarily conserved system that orchestrates 24-h physiological rhythms through transcriptional and translational feedback loops. Mounting evidence suggests a bidirectional relationship between circadian rhythm alteration and disease progression, positioning the circadian clock as a potential therapeutic target. Due to the scarcity of high-resolution temporal omics data, it remains very challenging to elucidate the underlying regulatory mechanisms of the circadian system. As a practical alternative, public untimed transcriptomic datasets offer the potential to infer gene expression oscillations retrospectively. However, existing computational approaches for circadian phase estimation often suffer from limited predictive accuracy, reducing their ability to …

The Concise Guide To Pharmacology 2025/26: Catalytic Receptors, Stephen P. H. Alexander, Doriano Fabbro, Chloe J. Peach, Alasdair J. Gibb, Eamonn Kelly, Alistair A. Mathie, Emma L. Veale, Jane F. Armstrong, Elena Faccenda, Simon D. Harding, Christopher Southan, Jamie A. Davies, Annie Beuve, Peter Brouckaert, Clare Bryant, John C. Burnett, Richard W. Farndale, Andreas Friebe, John Garthwaite, Adrian J. Hobbs, Gavin E. Jarvis, Laura Kilpatrick, Doris Koesling, Michaela Kuhn, Birgit Leitinger, David Macewan, Tom P. Monie, Lincoln R. Potter, Michael Russwurm, Harald H. H. W. Schmidt, Johannes-Peter Stasch, Scott A. Waldman

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

The Concise Guide to Pharmacology 2025/26 marks the seventh edition in this series of biennial publications in the British Journal of Pharmacology. Presented in landscape format, the guide provides a comparative overview of the pharmacology of drug target families. The concise nature of the Concise Guide refers to the style of presentation, being clear, accessible, and well-structured, rather than the scope of the content, which spans approximately 500 pages. The Concise Guide summarises the key pharmacological properties of around 1900 human drug targets, and nearly 7000 interactions, involving around 4400 ligands. While the content is a substantially condensed version of …

Sex Differences In Bile Acid Homeostasis And Excretion Underlie The Disparity In Liver Cancer Incidence Between Males And Females, Megan E Patton, Sherwin Kelekar, Lauren J Taylor, Angela E Dean, Qianying Zuo, Rhishikesh N Thakare, Sung Hwan Lee, Emily C Gentry, Morgan Panitchpakdi, Pieter Dorrestein, Yazen Alnouti, Zeynep Madak-Erdogan, Ju-Seog Lee, Milton J Finegold, Sayeepriyadarshini Anakk

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC), the common liver cancer, exhibits higher incidence in males. Here, we report that mice lacking bile acid (BA) regulators, Farnesoid X Receptor (FXR also termed NR1H4) and Small Heterodimer Partner (SHP also termed NR0B2), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and NR1H4 and NR0B2 double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. To assess translational relevance, we examined if transcriptomic signatures obtained from this murine HCC model correlate …

Batf2 Is A Glutamine-Responsive Tumour Suppressor Required For Type-I Interferon-Dependent Anti-Tumour Immunity, Wang Gong, Hülya F Taner, Yuesong Wu, Yumin He, Xingwu Zhou, Zaiye Li, Xin Hu, Charisse Ursin, Kala Chand Debnath, Kohei Okuyama, Qiang Hu, Christopher R Donnelly, Felipe Nör, Chamila D Perera, Emily Bellile, Arash Yunesi, Zhiqian Zhai, Mei Zhao, Wanqing Cheng, Zackary R Fitzsimonds, Luke Broses, Jiaqian Li, Shadmehr Demehri, Deepak Nagrath, Gregory T Wolf, Andrew G Sikora, Yanbao Yu, Haitao Wen, Lei Wei, Steven B Chinn, Jeffrey N Myers, Shizuo Akira, Yuying Xie, James J Moon, Yu Leo Lei

Faculty, Staff and Student Publications

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING. The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for …

Exploring Cellular Heterogeneity: Single-Cell And Spatial Transcriptomics Of Alzheimer's Disease Brains And Ipsc-Derived Microglia, Anjali Garg, Sheeny Vo, Iara D De Souza, Ayslan Castro Brant, Logan Brase, Ekaterina Aladyeva, Ricardo D 'O Albanus, Aasritha Nallapu, Hongjun Fu, Oscar Harari

2020-Current year OA Pubs

BACKGROUND: Microglia, the brain’s resident immune cells, play a pivotal role in Alzheimer’s disease (AD) pathogenesis. These cells exhibit diverse transcriptional states in response to neuroinflammatory stimuli, and characterizing these states is essential for understanding AD mechanisms. METHODS: We integrated single-cell and spatial transcriptomic datasets from multiple cohorts and brain regions, encompassing both experimental models and human tissues. Findings were validated through immunostaining of human brain samples. RESULTS: Our comprehensive atlas revealed pronounced heterogeneity among microglial states, with disease-associated microglia (DAM) significantly enriched in AD brains compared to controls. Spatial transcriptomics and immunohistochemistry demonstrated that DAM predominantly localize to external …

A Spatiotemporal Model Of Cxcl10 As A Master Regulator Of Immune Evasion And Metastasis In Osteosarcoma, Benjamin B Gyau, Tsz-Kwong Man

Faculty, Staff and Students Publications

The C-X-C motif chemokine ligand 10 (CXCL10) is implicated in the progression of osteosarcoma (OS), the most aggressive pediatric bone malignancy. However, its role often presents a profound clinical paradox: although high circulating levels are strongly linked to poor prognosis, its canonical function is to recruit anti-tumor immune cells. This review unravels these contrasting roles by proposing a novel spatiotemporal model. We argue that in the early stages, immune-evading OS cells initiate the formation of a pre-metastatic niche (PMN) in the lungs, creating a localized inflammatory environment that becomes the primary source of elevated circulating CXCL10. As the disease progresses, …

Distinct Populations Of Lung Capillary Endothelial Cells And Their Functional Significance, Joel James, Dan Yi, Zhiyu Dai, Et Al.

2020-Current year OA Pubs

The role of the lung's microcirculation and capillary endothelial cells in normal physiology and the pathobiology of pulmonary diseases is obviously vital. The recent discovery of molecularly distinct aerocytes and general capillary (gCaps) endothelial cells by single-cell transcriptomics (scRNAseq) advanced the field in understanding microcirculatory milieu and cellular communications. However, increasing evidence from different groups indicated the possibility of a more heterogeneous nature of lung capillaries. Therefore, we investigated enriched lung endothelial cells by scRNAseq and identified five novel populations of gCaps with distinct molecular signatures and roles. Our analysis suggests that two major populations of gCaps that express Scn7a(Na

Phospholipid Scramblase 1 (Plscr1) Regulates Interferon-Lambda Receptor 1 (Ifn-Λr1) And Ifn-Λ Signaling In Influenza A Virus (Iav) Infection, Alina Xiaoyu Yang, Lisa Ramos-Rodriguez, Parand Sorkhdini, Dongqin Yang, Carmelissa Norbrun, Sonoor Majid, Sanghyun Lee, Yong Zhang, Michael Holtzman, David F Boyd, Yang Zhou

2020-Current year OA Pubs

Phospholipid scramblase 1 (PLSCR1) is an interferon-stimulated gene (ISG) that has several known anti-influenza functions. However, the mechanisms in relation to its expression compartment and enzymatic activity have not been completely explored. Moreover, only limited animal models have been studied to delineate its role at the tissue level in influenza infections. Our results showed that influenza A virus (IAV)-infected

Micu2 Controls Mitochondrial Calcium Signaling And Migration In Neurons During Development, Elena Berezhnaya, Benjamín Cartes-Saavedra, Raghavendra Singh, Macarena Rodríguez-Prados, Orly Reiner, Fowzan S Alkuraya, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Neurological disorders are linked to mitochondrial dysfunction and calcium overload. Mitochondrial calcium uptake is mediated by the mitochondrial calcium uniporter (mtCU), regulated by MICU1, which can be either homodimerized or heterodimerized with MICU2 or MICU3. Though MICU2 is scarce in the adult brain, MICU2 loss in patients leads to a neurodevelopmental disorder. We hypothesized that MICU2 is required for developmental calcium signaling and neuronal migration. MICU2 is present in the developing mouse brain but disappears by maturation, contrasting with other mtCU subunits that increase. MICU2 loss in mice does not affect cytoplasmic calcium but augments the mitochondrial matrix calcium rise …

Ribosomal Protein Control Of Hematopoietic Stem Cell Transformation Through Regulation Of Metabolism, Bryan Harris, Stephen Sykes, Et Al.

2020-Current year OA Pubs

We report here that expression of the ribosomal protein RPL22 is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), and reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from altered metabolism, including increased fatty acid oxidation (FAO) and a striking induction of the stemness factor Lin28b in the resulting leukemia. Lin28b promotes a substantial increase in lipid …

Sox11 Modulates Bcr Signaling Through The Pax5/Cd19 Axis For Therapeutic Targeting In Btk-Resistant Mantle Cell Lymphoma, Rudra Prasad Dutta, Heng-Huan Lee, Violetta V Leshchenko, Ravi Prakash Shukla, Fangfang Yan, Yang Liu, H Ümit Kaniskan, Xing Qiu, Jian Jin, Lapo Alinari, Michael Wang, Samir Parekh

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma. Despite multiple approved Bruton tyrosine kinase inhibitors (BTKis), resistance to BTKi continues to pose a major clinical challenge. The transcription factor sex determining region Y-box 11 (SOX11) is expressed in most patients with MCL and is associated with poor outcomes. We have previously demonstrated SOX11-dependent B-cell receptor (BCR) signaling in transgenic models of MCL. Here, we report that SOX11 drives BCR signaling via the transcriptional activation of the PAX5/CD19 axis. The translational potential of these results is significant as single-cell RNA sequencing data show that SOX11 is overexpressed …

Coordinated Changes In Stromal And Hematopoietic Cells That Define The Perinatal To Juvenile Transition In The Mouse Thymus, Anusha Vasudev, Colin R Moore, Aparna Calindi, Seung Woo Kang, Bryan R Helm, Jayashree Srinivasan, Siddhartha Shah, Erin Baker, Ruiting Zong, Nandini Singarapu, Scott Casey, Andrew N Macintyre, Ken S Lau, Laura P Hale, Qi Liu, Nancy R Manley, Lauren I R Ehrlich, Ellen R Richie

Faculty, Staff and Student Publications

Perinatal T cells have distinctive phenotypes and functions that may be due in part to age-associated features of stromal cells in the perinatal thymus. We identify age-associated changes in mouse thymic epithelial cells, mesenchyme, endothelium, and hematopoietic antigen-presenting cells from birth to one month of age using single-cell transcriptional profiling, flow cytometry, and imaging. Coordinated cellular and molecular changes occur at 7-14 days of age, designated "transitional ages," as thymus growth switches to homeostasis. E2F target gene expression declines, and the expression of type I interferon response genes increases across diverse cell types at transitional ages. Alterations in thymic stromal …

Eif3d And Eif3e Mediate Selective Translational Control Of Hypoxia That Can Be Inhibited By Small Molecules, Stephen C Purdy, Kate Matlin, Christopher Alderman, Amber Baldwin, Natasha Shrivastava, Goksu Sarioglu, Somnath Dutta, Kristofor J Webb, Arthur Wolin, Dillon P Boulton, Annika Gustafson, Jyoti Kapali, John D Landua, Michael T Lewis, M Cecilia Caino, James C Costello, William Old, Xiang Wang, Rui Zhao, Heide L Ford, Neelanjan Mukherjee

Faculty, Staff and Students Publications

Exposure to hypoxia is linked to increased cellular plasticity and enhanced metastasis, effects that are primarily attributed to the transcriptional activation of large gene programs downstream of hypoxia-inducible factors (HIFs). However, translational effects in hypoxia, which likely precede transcriptional effects, have remained largely unexplored. Using ribosome profiling, we uncovered a selective translational response in acute hypoxia that is eukaryotic initiation factor (eIF)3d/eIF3e dependent and controls downstream hypoxic responses, including HIF1α accumulation and cellular invasion. We further demonstrated that eIF3e copy number and eIF3e and eIF3d expression signatures are associated with worsened outcomes for patients with breast cancer. Finally, we identified …

Current Controversies On Adequate Circulating Vitamin D Levels In Ckd, Adriana S Dusso, Daniela J Porta, Carlos Bernal-Mizrachi

2020-Current year OA Pubs

Management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) has evolved dramatically over the past five decades, driven by discoveries that have fundamentally reshaped our understanding of the vitamin D endocrine system and its role in disease progression. This review synthesizes the key pathophysiological insights and clinical evidence underlying three critical paradigm shifts. The first shift moved beyond simple calcitriol replacement with the development of selective vitamin D receptor activators (VDRAs) designed to minimize hypercalcemia while maximizing PTH suppression. Crucially, these analogs revealed unexpected survival benefits, suggesting protective VDR actions extending beyond mineral metabolism. The second shift recognized the …

Discovery Of Small Molecules And A Druggable Groove That Regulate Dna Binding And Release Of The Ap-1 Transcription Factor Δfosb, Sean Mcneme, Yun Young Yim, Ashwani Kumar, Yi Li, Brandon Hughes, Corey Peyton St Romain, Galina Aglyamova, Jianping Chen, Nghi D Nguyen, Shanghua Fan, Gabriel S Stephens, Wen-Ning Zhao, Samantha Kruzshak, Molly Estill, Corrine Brener, Solange Tofani, Anil Kumar, Earnest P Chen, Nadeen Takatka, Alfred J Robison, Haiying Chen, Reid T Powell, Stephen J Haggarty, Clifford Stephan, Eric J Nestler, Jeannie Chin, Mischa Machius, Jia Zhou, Gabby Rudenko

Faculty, Staff and Students Publications

ΔFOSB, a member of the AP-1 family of transcription factors, mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP-1 transcription factors are notoriously difficult to modulate pharmacologically due to the absence of well-defined binding pockets. Here, we identify a novel site on ΔFOSB, located outside the DNA-binding cleft, that accommodates small molecules. We show that sulfonic acid-containing compounds bind to this site via an induced-fit mechanism, reorienting side chains critical for DNA binding, and that they may hinder the ΔFOSB bZIP α-helix from binding to the major groove of DNA. In vivo, direct …

A Protein Complex In The Extreme Distal Tip Of Vertebrate Motile Cilia Controls Their Organization, Length, And Function, Juyeon Hong, Jiehong Pan, Amjad Horani, Steven L Brody, Et Al.

2020-Current year OA Pubs

The beating of cilia on multi-ciliated cells (MCCs) is essential for normal development and homeostasis in animals. But while the structure and function of basal bodies and axonemes have received significant attention recently, the distal tips of MCC cilia remain relatively poorly defined. Here, we characterize the molecular organization of the distal tip of vertebrate MCC cilia, characterizing two distinct domains occupied by distinct protein constituents. Using frog, mouse, and human MCCs, we find that two largely uncharacterized proteins, Ccdc78 and Ccdc33, occupy a previously undefined region at the extreme distal tip, and these are required for the normal organization …

Development Of A Procedure For Prion Surveillance In The Laboratory Setting, Damian Gorski, Isaac Schauer, Kane Spicker, Ananya Tupaki-Sreepurna, Fei Wang, Claudio Soto, Sandra Pritzkow

Faculty, Staff and Student Publications

Infectious prions readily adhere to common surfaces, retain infectivity, and are highly resistant to conventional decontamination, posing significant biosafety challenges in the medical and research environments. Recent occupational exposures underscore the urgency of improving safety measures. Here, we describe an approach combining foam-swab surface sampling and protein misfolding cyclic amplification to enhance prion surveillance. Our results demonstrate the ability to detect prions most relevant to human health directly from contaminated surfaces, even at 100 million-fold dilutions of the brain. We applied our method to assess the completeness of prion decontamination and show that high prion quantities can resist even approved …