Medical Cell Biology Commons^™

Detecting Altered Hepatic Lipid Oxidation By Mri In An Animal Model Of Masld, Marc Mcleod, Mario C Chang, Anna Rushin, Mukundan Ragavan, Rohit Mahar, Gaurav Sharma, Arshee Badar, Anthony Giacalone, Max E Glanz, Vinay R Malut, Dalton Graham, Nishanth E Sunny, James A Bankson, Kenneth Cusi, Matthew E Merritt

Faculty, Staff and Student Publications

Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing annually and affects over a third of US adults. MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), characterized by severe hepatocyte injury, inflammation, and eventual advanced fibrosis or cirrhosis. MASH is predicted to become the primary cause of liver transplant by 2030. Although the etiology of MASLD/MASH is incompletely understood, dysregulated fatty acid oxidation is implicated in disease pathogenesis. Here, we develop a method for estimating hepatic β-oxidation from the metabolism of [D

Creb-Binding Protein/P300 Bromodomain Inhibition Reduces Neutrophil Accumulation And Activates Antitumor Immunity In Triple-Negative Breast Cancer, Xueying Yuan, Xiaoxin Hao, Hilda L Chan, Na Zhao, Diego A Pedroza, Fengshuo Liu, Kang Le, Alex J Smith, Sebastian J Calderon, Nadia Lieu, Michael J Soth, Philip Jones, Xiang Hf Zhang, Jeffrey M Rosen

Faculty, Staff and Students Publications

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB-binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing …

Targeting Ribosome Biogenesis Is A Novel Approach For The Management Of Pancreatic Cancer, Mudassier Ahmad, Haider Ahsan, Carlos Perez, Muhammad Bangash, Andrew Massey, Emmanuel Anning, Manish Tripathi, Dae Kim, Subhash C. Chauhan, Bilal Bin Hafeez

Research Colloquium

Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related deaths in the United States with limited therapeutic options available. Gemcitabine, a deoxycytidine nucleoside analog is currently considered the most effective therapy for PanCa. However, it shows only a marginal survival benefit of six months. Aberrant ribosome biogenesis occurs in most tumor types. We observed that PanCa cells are addicted to ribosome biogenesis, which supports their highly aggressive metastatic phenotypes. Thus, strategically targeting ribosome biogenesis process could be one of the ideal strategies for the prevention and treatment of PanCa. In this study, we elucidated the molecular mechanisms of POLR1A …

Role Of Poly(A)-Binding Protein Cytoplasmic 1, A Trna-Derived Rna Fragment-Bound Protein, In Respiratory Syncytial Virus Infection, Devin V Davis, Eun-Jin Choi, Deena Ismail, Miranda L Hernandez, Jong Min Choi, Ke Zhang, Kashish Khatkar, Sung Yun Jung, Wenzhe Wu, Xiaoyong Bao

Faculty, Staff and Students Publications

Respiratory Syncytial Virus (RSV) is a significant cause of lower respiratory tract infections (LRTI) across all demographics, with increasing mortality and morbidity among high-risk groups such as infants under two years old, the elderly, and immunocompromised individuals. Although newly approved vaccines and treatments have substantially reduced RSV hospitalizations, accessibility remains limited, and response to treatment varies. This underscores the importance of comprehensive studies on host-RSV interactions. tRNA-derived RNA fragments (tRFs) are recently discovered non-coding RNAs, notable for their regulatory roles in diseases, including viral infections. Our prior work demonstrated that RSV infection induces tRFs, primarily derived from the 5'-end of …

Final Outcomes From A Phase 2 Trial Of Posoleucel In Allogeneic Hematopoietic Cell Transplant Recipients, Sanjeet S Dadwal, Rajat Bansal, Michael W Schuster, Jean A Yared, Gary Douglas Myers, Michelle Matzko, Sama Adnan, David Mcneel, Julie Ma, Sarah A Gilmore, Spyridoula Vasileiou, Ann M Leen, Joshua A Hill, Jo-Anne H Young

Faculty, Staff and Students Publications

Allogeneic hematopoietic cell transplantation (allo-HCT) recipients are susceptible to viral infections. We conducted a phase 2 trial evaluating the safety and rate of clinically significant infections (CSIs; viremia requiring treatment or end-organ disease) after infusion of posoleucel, a partially HLA-matched, allogeneic, off-the-shelf, multivirus-specific T-cell investigational product for preventing CSIs with adenovirus, BK virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, or JC virus. This open-label trial enrolled allo-HCT recipients at high risk based on receiving grafts from umbilical cord blood, haploidentical, mismatched, or matched unrelated donors; post-HCT lymphocytes of < 180/mm3; or use of T-cell depletion. Posoleucel dosing was initiated within 15 to 49 days of allo-HCT and subsequently every 14 days for up to 7 doses. The primary end point was the number of CSIs due to the 6 target viruses by week 14. Of the 26 patients enrolled, only 3 (12%) had a CSI by week 14, each with a single target virus. In vivo expansion of functional virus-specific T cells detected via interferon-γ enzyme-linked immunosorbent spot assay was associated with viral control. Persistence of posoleucel-derived T-cell clones for up to 14 weeks after the last infusion was confirmed by T-cell–receptor deep sequencing. Five patients (19%) had acute graft-versus-host disease grade 2 to 4. No patient experienced cytokine release syndrome. All 6 deaths were due to relapse or disease progression. allo-HCT recipients at high risk who received posoleucel had low rates of CSIs from 6 targeted viruses. Repeat posoleucel dosing was generally safe and well tolerated and associated with functional immune reconstitution.

The Scaffolding Function Of Lsd1 Controls Dna Methylation In Mouse Escs, Sandhya Malla, Kanchan Kumari, Carlos A García-Prieto, Jonatan Caroli, Anna Nordin, Trinh T T Phan, Devi Prasad Bhattarai, Carlos Martinez-Gamero, Eshagh Dorafshan, Stephanie Stransky, Damiana Álvarez-Errico, Paulina Avovome Saiki, Weiyi Lai, Cong Lyu, Ludvig Lizana, Jonathan D Gilthorpe, Hailin Wang, Simone Sidoli, Andre Mateus, Dung-Fang Lee, Claudio Cantù, Manel Esteller, Andrea Mattevi, Angel-Carlos Roman, Francesca Aguilo

Faculty, Staff and Student Publications

Lysine-specific histone demethylase 1 (LSD1), which demethylates mono- or di- methylated histone H3 on lysine 4 (H3K4me1/2), is essential for early embryogenesis and development. Here we show that LSD1 is dispensable for mouse embryonic stem cell (ESC) self-renewal but is required for mouse ESC growth and differentiation. Reintroduction of a catalytically-impaired LSD1 (LSD1MUT) recovers the proliferation capability of mouse ESCs, yet the enzymatic activity of LSD1 is essential to ensure proper differentiation. Indeed, increased H3K4me1 in Lsd1 knockout (KO) mouse ESCs does not lead to major changes in global gene expression programs related to stemness. However, ablation of LSD1 but …

Prognostic Impact Of Notch1 Intracellular Domain, P63, And C-Myc In Lacrimal Gland Adenoid Cystic Carcinoma, Jiawei Zhao, Michelle D Williams, Mike Hernandez, Grace Kuang, Hila Goldberg, Janet Fan, Jing Ning, Renata Ferrarotto, Bita Esmaeli

Faculty, Staff and Student Publications

PURPOSE: We assessed whether NICD1 expression, c-MYC expression, and P63 expression by immunohistochemistry (IHC) correlate with prognosis and high-risk clinicopathological features in lacrimal gland adenoid cystic carcinoma (ACC).

METHODS: Records of patients with lacrimal gland ACC who underwent surgery between 1998 to 2018 were reviewed. Clinicopathologic and treatment data were collected. Tumor tissues were subjected to light microscopy and IHC.

RESULTS: Of 43 patients treated during the study period, 21 had archived tumor tissue available and were included. The median age at diagnosis was 47 years, and 13 patients (62%) were male. Thirteen patients (62%) had T2 disease, and none …

A Guideline On The Molecular Ecosystem Regulating Ferroptosis, Enyong Dai, Xin Chen, Andreas Linkermann, Xuejun Jiang, Rui Kang, Valerian E Kagan, Hülya Bayir, Wan Seok Yang, Ana J Garcia-Saez, Maria S Ioannou, Tobias Janowitz, Qitao Ran, Wei Gu, Boyi Gan, Dmitri V Krysko, Xiaofeng Zhu, Jiayi Wang, Stefan Krautwald, Shinya Toyokuni, Yangchun Xie, Florian R Greten, Qing Yi, Joel Schick, Jiao Liu, Dmitry I Gabrilovich, Jinbao Liu, Herbert J Zeh, Donna D Zhang, Minghua Yang, Juan Iovanna, Manfred Kopf, Timon E Adolph, Jen-Tsan Chi, Changfeng Li, Hidenori Ichijo, Michael Karin, Vijay G Sankaran, Weiping Zou, Lorenzo Galluzzi, Ashley I Bush, Binghui Li, Gerry Melino, Eric H Baehrecke, Michael T Lotze, Daniel J Klionsky, Brent R Stockwell, Guido Kroemer, Daolin Tang

Faculty, Staff and Student Publications

Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.

Targeting Nuclear Receptor Coactivator Src-1 Prevents Colorectal Cancer Immune Escape By Reducing Transcription And Protein Stability Of Pd-L1, Yilin Hong, Qiang Chen, Zinan Wang, Yong Zhang, Bei Li, Hanshi Guo, Chuanzhong Huang, Xu Kong, Pingli Mo, Nengming Xiao, Jianming Xu, Yunbin Ye, Chundong Yu

Faculty, Staff and Students Publications

Programmed death-ligand 1 (PD-L1) is overexpressed in multiple cancers and critical for their immune escape. It has previously shown that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability, yet its role in CRC immune escape is unclear. Here, we demonstrate that SRC-1 is positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibits PD-L1 expression in CRC cells and retards murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration of CD8

Altered Extracellular Matrix-Related Pathways Accelerate The Transition From Normal To Prefibroid Myometrium In Black Women, Maria Victoria Bariani, Sandra L Grimm, Cristian Coarfa, Digna R Velez Edwards, Qiwei Yang, Cheryl L Walker, Mohamed Ali, Ayman Al-Hendy

Faculty, Staff and Students Publications

Background: Black women experience a disproportionate impact of uterine fibroids compared to White women, including earlier diagnosis, higher frequency, and more severe symptoms. The etiology underlying this racial disparity remains elusive.

Objective: The aim of this study was to evaluate the molecular differences in normal myometrium (fibroid-free uteri) and at-risk myometrium (fibroid-containing uteri) tissues in Black and White women.

Study design: We conducted whole-genome RNA-seq on normal and at-risk myometrium tissues obtained from both self-identified Black and White women (not Hispanic or Latino) to determine global gene expression profiles and to conduct enriched pathway analyses (n=3 per group). We initially …

Disruption Of Fuz In Mouse Embryos Generates Hypoplastic Hindbrain Development And Reduced Cranial Nerve Ganglia, Carlo Donato Caiaffa, Yogeshwari S Ambekar, Manmohan Singh, Ying Linda Lin, Bogdan Wlodarczyk, Salavat R Aglyamov, Giuliano Scarcelli, Kirill V Larin, Richard H Finnell

Faculty, Staff and Students Publications

Background: The brain and spinal cord formation is initiated in the earliest stages of mammalian pregnancy in a highly organized process known as neurulation. Environmental or genetic interferences can impair neurulation, resulting in clinically significant birth defects known collectively as neural tube defects. The Fuz gene encodes a subunit of the CPLANE complex, a macromolecular planar polarity effector required for ciliogenesis. Ablation of Fuz in mouse embryos results in exencephaly and spina bifida, including dysmorphic craniofacial structures due to defective cilia formation and impaired Sonic Hedgehog signaling.

Results: We demonstrate that knocking Fuz out during embryonic mouse development results in …

Meti: Deep Profiling Of Tumor Ecosystems By Integrating Cell Morphology And Spatial Transcriptomics, Jiahui Jiang, Yunhe Liu, Jiangjiang Qin, Jianfeng Chen, Jingjing Wu, Melissa P Pizzi, Rossana Lazcano, Kohei Yamashita, Zhiyuan Xu, Guangsheng Pei, Kyung Serk Cho, Yanshuo Chu, Ansam Sinjab, Fuduan Peng, Xinmiao Yan, Guangchun Han, Ruiping Wang, Enyu Dai, Yibo Dai, Bogdan A Czerniak, Andrew Futreal, Anirban Maitra, Alexander Lazar, Humam Kadara, Amir A Jazaeri, Xiangdong Cheng, Jaffer Ajani, Jianjun Gao, Jian Hu, Linghua Wang

Faculty, Staff and Student Publications

Recent advances in spatial transcriptomics (ST) techniques provide valuable insights into cellular interactions within the tumor microenvironment (TME). However, most analytical tools lack consideration of histological features and rely on matched single-cell RNA sequencing data, limiting their effectiveness in TME studies. To address this, we introduce the Morphology-Enhanced Spatial Transcriptome Analysis Integrator (METI), an end-to-end framework that maps cancer cells and TME components, stratifies cell types and states, and analyzes cell co-localization. By integrating spatial transcriptomics, cell morphology, and curated gene signatures, METI enhances our understanding of the molecular landscape and cellular interactions within the tissue. We evaluate the performance …

Regulatory Complexity Of Cellular Differentiation In Candida Albicans Revealed Through Systematic Screening Of Protein Kinase Mutants, Michael C Lorenz

Faculty, Staff and Student Publications

A recent study in mBio reports the construction and preliminary screening of a library containing mutants of 99 of the 119 predicted protein kinases in Candida albicans (the majority of the remaining 20 are probably essential) (J. Kramara, M.-J. Kim, T. L. Ollinger, L. C. Ristow, et al., mBio e01249-24, 2024, https://doi.org/10.1128/mbio.01249-24). Using a quantitative competition assay in 10 conditions that represent nutritional, osmotic, cell wall, and pH stresses that are considered to model various aspects of the host environment allowed them to phenotypically cluster kinases, which highlight both the integration and specialization of signaling pathways, suggesting novel functions …

Persistence Of Daptomycin-Resistant And Vancomycin-Resistant Enterococci In Hospitalized Patients With Underlying Malignancies: A 7-Year Follow-Up Study, Lynn El Haddad, Georgios Angelidakis, Yuting Zhai, Layale Yaghi, Cesar A Arias, Samuel A Shelburne, Kwangcheol Casey Jeong, Roy F Chemaly

Faculty, Staff and Student Publications

Vancomycin-resistant enterococci (VRE) commonly colonize the gut of individuals with hematologic malignancies or undergoing hematopoietic cell transplant (HCT) and may cause bacteremia. In 2012, we identified VRE isolates from patients and patients' rooms and showed transmission networks of highly genetically related daptomycin-resistant (DR)-VRE strains. This is a follow-up study performing whole-genome sequencing (WGS) and phylogenetic analyses on 82 clinical VRE strains isolated from stools and blood cultures of patients with leukemia and HCT between 2015 and 2019. Here, we observed transmission of highly genetically related strains between rooms on the same or on different floors, including a DR-VRE strain identified …

Development Of A Novel Amplifiable System To Quantify Hydrogen Peroxide In Living Cells, Lingfei Wang, Hanfeng Lin, Bin Yang, Xiqian Jiang, Jianwei Chen, Sandipan Roy Chowdhury, Ninghui Cheng, Paul A Nakata, David M Lonard, Meng C Wang, Jin Wang

Faculty, Staff and Students Publications

Although many redox signaling molecules are present at low concentrations, typically ranging from micromolar to sub-micromolar levels, they often play essential roles in a wide range of biological pathways and disease mechanisms. However, accurately measuring low abundant analytes has been a significant challenge due to the lack of sensitivity and quantitative capability of existing measurement methods. In this study, we introduced a novel chemically induced amplifiable system for quantifying low-abundance redox signaling molecules in living cells. We utilized H2O2 as a proof-of-concept analyte and developed a probe that quantifies cellular peroxide levels by combining the NanoBiT system with androgen receptor …

Fine-Tuning Ampk In Physiology And Disease Using Point-Mutant Mouse Models, Naghmana Ashraf, Jeanine L Van Nostrand

Faculty, Staff and Students Publications

AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that monitors the cellular energy status to adapt it to the fluctuating nutritional and environmental conditions in an organism. AMPK plays an integral part in a wide array of physiological processes, such as cell growth, autophagy and mitochondrial function, and is implicated in diverse diseases, including cancer, metabolic disorders, cardiovascular diseases and neurodegenerative diseases. AMPK orchestrates many different physiological outcomes by phosphorylating a broad range of downstream substrates. However, the importance of AMPK-mediated regulation of these substrates in vivo remains an ongoing area of investigation to better understand its precise …

Pbi-05204, A Supercritical Co2 Extract Of Nerium Oleander, Suppresses Glioblastoma Stem Cells By Inhibiting Grp78 And Inducing Programmed Necroptotic Cell, Sharmistha Chakraborty, Daoyan Wei, Megan Tran, Frederick F Lang, Robert A Newman, Peiying Yang

Faculty, Staff and Student Publications

Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression …

Herpes Vegetans In A Patient With Acquired Immunodeficiency Syndrome (Aids) In The Setting Of Immune Reconstitution Inflammatory Syndrome, Angelique Ruml, Ibeth Caceres, Anna Catinis, Theodore Rosen

Faculty, Staff and Students Publications

Herpes simplex virus (HSV) infections classically present as a vesicular eruption on an erythematous base; however, viral infections may present much differently in the setting of immune deficiency. Herpes vegetans is an atypical presentation of HSV that occurs in immunocompromised patients, typically those with human immunodeficiency virus infection and acquired immunodeficiency syndrome (AIDS). Herpes vegetans is characterized by hyperkeratotic, exophytic, and, sometimes, ulcerated nodules, often with a chronic and persistent course. Herein, we present an interesting example of biopsy-confirmed anogenital herpes vegetans in a 61-year-old male with AIDS in the setting of immune reconstitution inflammatory syndrome, an association that is …

Mechanisms Of Neurodevelopmental Toxicity Of Topiramate, John W Steele, Vaishnav Krishnan, Richard H Finnell

Faculty, Staff and Students Publications

Prescriptions for antiseizure medications (ASMs) have been rapidly growing over the last several decades due, in part, to an expanding list of clinical indications for which they are now prescribed. This trend has raised concern for potential adverse neurodevelopmental outcomes in ASM-exposed pregnancies. Recent large scale population studies have suggested that the use of topiramate (TOPAMAX, Janssen-Cilag), when prescribed for seizure control, migraines, and/or weight management, is associated with an increased risk for autism spectrum disorder (ASD), intellectual disability, and attention-deficit/hyperactivity disorder (ADHD) in exposed offspring. Here, we critically review epidemiologic evidence demonstrating the neurobehavioral teratogenicity of topiramate and speculate …

Interpreting Ppv And Npv Of Diagnostic Tests With Uncertain Prevalence, Yakov Ben-Haim, Clifford C Dacso

Faculty, Staff and Students Publications

OBJECTIVE: Medical decision-making is often uncertain. The positive predictive value (PPV) and negative predictive value (NPV) are conditional probabilities characterizing diagnostic tests and assessing diagnostic interventions in clinical medicine and epidemiology. The PPV is the probability that a patient has a specified disease, given a positive test result for that disease. The NPV is the probability that a patient does not have the disease, given a negative test result for that disease. Both values depend on disease incidence or prevalence, which may be highly uncertain for unfamiliar diseases, epidemics, etc. Probability distributions for this uncertainty are usually unavailable. We develop …

Differential Effect Of An Evolving Amyloid And Tau Pathology On Brain Phospholipids And Bioactive Lipid Mediators In Rat Models Of Alzheimer-Like Pathology, Sonia Do Carmo, Marie Audrey I. Kautzmann, Surjyadipta Bhattacharjee, Bokkyoo Jun, Carolyn Steinberg, Joshua T. Emmerson, Janice C. Malcolm, Quentin Bonomo, Nicolas G. Bazan, A. Claudio Cuello

School of Graduate Studies Faculty Publications

Background: Brain inflammation contributes significantly to the pathophysiology of Alzheimer’s disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved. Methods: In this study, we examined the cortical levels of DHA- and AA-derived bioactive …

The Interaction Of Endorepellin And Neurexin Triggers Neuroepithelial Autophagy And Maintains Neural Tube Development, Lei Lu, Meizhu Bai, Yufang Zheng, Xiukun Wang, Zhongzhong Chen, Rui Peng, Richard H Finnell, Tongjin Zhao, Chengtao Li, Bo Wu, Yunping Lei, Jinsong Li, Hongyan Wang

Faculty, Staff and Students Publications

Heparan sulfate proteoglycan 2 (HSPG2) gene encodes the matrix protein Perlecan, and genetic inactivation of this gene creates mice that are embryonic lethal with severe neural tube defects (NTDs). We discovered rare genetic variants of HSPG2 in 10% cases compared to only 4% in controls among a cohort of 369 NTDs. Endorepellin, a peptide cleaved from the domain V of Perlecan, is known to promote angiogenesis and autophagy in endothelial cells. The roles of enderepellin in neurodevelopment remain unclear so far. Our study revealed that endorepellin can migrate to the neuroepithelial cells and then be recognized and bind with the …

N-Myc And Stat Interactor Is An Endometriosis Suppressor, Yuri Park, Xiaoming Guan, Sang Jun Han

Faculty, Staff and Students Publications

In patients with endometriosis, refluxed endometrial fragments evade host immunosurveillance, developing into endometriotic lesions. However, the mechanisms underlying this evasion have not been fully elucidated. N-Myc and STAT Interactor (NMI) have been identified as key players in host immunosurveillance, including interferon (IFN)-induced cell death signaling pathways. NMI levels are markedly reduced in the stromal cells of human endometriotic lesions due to modulation by the Estrogen Receptor beta/Histone Deacetylase 8 axis. Knocking down NMI in immortalized human endometrial stromal cells (IHESCs) led to elevated RNA levels of genes involved in cell-to-cell adhesion and extracellular matrix signaling following IFNA treatment. Furthermore, NMI …

Adult Zymosan Re-Exposure Exacerbates The Molecular Alterations In The Brainstem Rostral Ventromedial Medulla Of Rats With Early Life Zymosan-Induced Cystitis, Bhavana Talluri, Sankar Addya, Maia Terashvili, Bidyut K. Medda, Anjishnu Banerjee, Reza Shaker, Jyoti N. Sengupta, Banani Banerjee

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

Recent evidence suggests that the descending modulatory pathways from the brainstem rostral ventromedial medulla (RVM) are important for bladder inflammatory pain. This study aimed to identify the long-term molecular changes in RVM neurons due to early life cystitis during neuronal development and the effect of reexposure later in adulthood. RVM tissues from two treatment protocols were used: (1) neonatal zymosan exposures with acute adult rechallenge (RC) and (2) only neonatal zymosan exposures (NRC). RNAseq analysis showed upregulation of several genes associated with synaptic plasticity (Grin1, Grip2, Notch1, Arc, and Scn2b) in the cystitis groups compared to controls in both protocols. …

Hyaluronan Mediates Cold-Induced Adipose Tissue Beiging, Xi Chen, Yifan Wang, Huiqiao Li, Yanru Deng, Charlise Giang, Anying Song, Yu'e Liu, Qiong A Wang, Yi Zhu

Faculty, Staff and Students Publications

Adipose tissue beiging refers to the process by which beige adipocytes emerge in classical white adipose tissue depots. Beige adipocytes dissipate chemical energy and secrete adipokines, such as classical brown adipocytes, to improve systemic metabolism, which is beneficial for people with obesity and metabolic diseases. Cold exposure and β3-adrenergic receptor (AR) agonist treatment are two commonly used stimuli for increasing beige adipocytes in mice; however, their underlying biological processes are different. Transcriptional analysis of inguinal white adipose tissue (iWAT) has revealed that changes in extracellular matrix (ECM) pathway genes are specific to cold exposure. Hyaluronic acid (HA), a non-sulfated linear …

Refining The Optimal Caf Cluster Marker For Predicting Tme-Dependent Survival Expectancy And Treatment Benefits In Nsclc Patients, Kai Li, Rui Wang, Guo-Wei Liu, Zi-Yang Peng, Ji-Chang Wang, Guo-Dong Xiao, Shou-Ching Tang, Ning Du, Jia Zhang, Jing Zhang, Hong Ren, Xin Sun, Yi-Ping Yang, Da-Peng Liu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we …

Membrane Vectorial Lipidomic Features Of Coral Host Cells’ Plasma Membrane And Lipid Profiles Of Their Endosymbionts Cladocopium, Tatyana V Sikorskaya, Ekaterina V Ermolenko, Taliya T Ginanova, Andrey V Boroda, Kseniya V Efimova, Mikhail Bogdanov

Faculty, Staff and Student Publications

The symbiotic relationships between coral animal host and autotrophic dinoflagellates are based on the mutual exchange and tight control of nutritional inputs supporting successful growth. The corals Sinularia heterospiculata and Acropora aspera were cultivated using a flow-through circulation system supplying seawater during cold and warm seasons of the year, then sorted into host cells and symbionts and subjected to phylogenetic, morphological, and advanced lipid analyses. Here we show, that the lipidomes of the dinoflagellates Cladocopium C1/C3 and acroporide-specific Cladocopium hosted by the corals, are determined by lipidomic features of different thermosensitivity and unique betaine- and phospholipid molecular species. Phosphatidylserines and …

Systemic Interindividual Dna Methylation Variants In Cattle Share Major Hallmarks With Those In Humans, Wen-Jou Chang, Maria S Baker, Eleonora Laritsky, Chathura J Gunasekara, Uditha Maduranga, Justine C Galliou, Joseph W Mcfadden, Jessica R Waltemyer, Bruce Berggren-Thomas, Brianna N Tate, Hanxue Zhang, Benjamin D Rosen, Curtis P Van Tassell, George E Liu, Cristian Coarfa, Yi Athena Ren, Robert A Waterland

Faculty, Staff and Students Publications

BACKGROUND: We recently identified ~ 10,000 correlated regions of systemic interindividual epigenetic variation (CoRSIVs) in the human genome. These methylation variants are amenable to population studies, as DNA methylation measurements in blood provide information on epigenetic regulation throughout the body. Moreover, establishment of DNA methylation at human CoRSIVs is labile to periconceptional influences such as nutrition. Here, we analyze publicly available whole-genome bisulfite sequencing data on multiple tissues of each of two Holstein cows to determine whether CoRSIVs exist in cattle.

RESULTS: Focusing on genomic blocks with ≥ 5 CpGs and a systemic interindividual variation index of at least 20, …

Transcriptomic Analysis Reveals The Anti-Cancer Effect Of Gestational Mesenchymal Stem Cell Secretome, Salvatore Vaiasicca, Gianmarco Melone, David W James, Marcos Quintela, Jing Xiao, Seydou Yao, Richard H Finnell, Robert S Conlan, Lewis W Francis, Bruna Corradetti

Faculty, Staff and Students Publications

The environment created during embryogenesis contributes to reducing aberrations that drive structural malformations and tumorigenesis. In this study, we investigate the anti-cancer effect of mesenchymal stem cells (MSCs) derived from 2 different gestational tissues, the amniotic fluid (AF) and the chorionic villi (CV), with emphasis on their secretome. Transcriptomic analysis was performed on patient-derived AF- and CV-MSCs collected during prenatal diagnosis and identified both mRNAs and lncRNAs, involved in tissue homeostasis and inhibiting biological processes associated with the etiology of aggressive cancers while regulating immune pathways shown to be important in chronic disorders. Secretome enrichment analysis also identified soluble moieties …

Full-Length Αiibβ3 Cryo-Em Structure Reveals Intact Integrin Initiate-Activation Intrinsic Architecture, Tong Huo, Hongjiang Wu, Zeinab Moussa, Mehmet Sen, Valerie Dalton, Zhao Wang

Faculty, Staff and Students Publications

Integrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation and a proven drug-target for antithrombotic therapies. Here we resolve the cryoEM structures of the full-length αIIbβ3, which covers three distinct states along the activation pathway. Firstly, we obtain the αIIbβ3 structure at 3Å resolution in the inactive state, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the ligand-binding domain tucked in a specific angle proximity to the TM region. After the addition of a Mn2+ agonist, we resolve two coexisting structures representing two new states between inactive and active state. Our structures show …