Medical Sciences Commons^™

Computational Analysis Of Dna Methylation From Long-Read Sequencing, Yilei Fu, Winston Timp, Fritz J Sedlazeck

Faculty, Staff and Students Publications

DNA methylation is a critical epigenetic mechanism in numerous biological processes, including gene regulation, development, ageing and the onset of various diseases such as cancer. Studies of methylation are increasingly using single-molecule long-read sequencing technologies to simultaneously measure epigenetic states such as DNA methylation with genomic variation. These long-read data sets have spurred the continuous development of advanced computational methods to gain insights into the roles of methylation in regulating chromatin structure and gene regulation. In this Review, we discuss the computational methods for calling methylation signals, contrasting methylation between samples, analysing cell-type diversity and gaining additional genomic insights, and …

A Divergent Cyclic Nucleotide Binding Protein Promotes Plasmodium Ookinete Infection Of The Mosquito, Dominika Kwecka, Zhishuo Wang, Edvardas Eigminas, Lijia Liu, Jennifer C Regan, Choel Kim, Nisha Philip

Faculty, Staff and Students Publications

Colonisation of mosquitos by the malarial parasite is critically reliant on the invasive ookinete stage. Ookinete invasion of mosquito is coordinated by the apical complex, a specialised parasite structure containing components for secretion, attachment and penetration. While studies have investigated cytoskeletal and secretory elements, it is currently unknown if signalling modules are present or functional at the apical complex. Here we elucidate the role of a cryptic cyclic nucleotide-binding protein which we name CBP-O. PbCBP-O showed a marked localisation to the ookinete apex and disruption of the protein severely compromised ookinete invasion of mosquitos. Domain dissection analysis revealed that the …

Elephant Endotheliotropic Herpesvirus 2 Infection In 5 African Elephants (Loxodonta Africana) At Multiple North American Zoological Institutions, Taylor J Willis, Anne Burgdorf-Moisuk, Maren Connolly, Jan Raines, Cameron Ratliff, Zoltan S Gyimesi, Erica Lipanovich, Genevive A Dumonceaux, Kathryn L Perrin, Lauren L Howard, Matthew E Kinney, Kirk Suedmeyer, Erin Latimer, Tiffany L Kim, Jessica R Watts, Jie Tan, Paul Ling

Faculty, Staff and Students Publications

Objective: To acknowledge that elephant endotheliotropic herpesvirus (EEHV) is a well-recognized major threat to Asian elephants (Elephas maximus) and can cause acute and often fatal hemorrhagic disease (HD). Historically, EEHV-HD has been less frequently identified in African elephants (Loxodonta africana). This case series describes 5 recent cases of EEHV2 infection in African elephants within managed care at 5 North American institutions.

Animals: 5 African elephants (L africana).

Clinical presentation: The cases involved 4-, 7-, and 10-year-old males that died despite receiving aggressive medical therapy and 4- and 14-year-old females that survived. Clinical signs included lethargy, decreased appetite, lameness, changes in …

Evaluation Of A Novel Tc-24 Recombinant Antigen Elisa For Serologic Detection Of Trypanosoma Cruzi Infection In Dogs: A Pilot Study, Rojelio Mejia, Guilherme G Verocai, Ilana A Mosley, Ashley B Saunders, Bin Zhan, Lindsey Vongthavaravat, Rachel E Busselman, Sarah A Hamer

Faculty, Staff and Students Publications

Chagas disease, caused by the protozoan Trypanosoma cruzi, is a significant challenge for canine health, with limited diagnostic tools. This study assessed the performance of a novel Tc-24 recombinant antigen ELISA compared to three commercial diagnostic tests on 70 serum samples from kennel dogs in Texas. The Tc-24 ELISA demonstrated high sensitivity (87.5%) and specificity (91.2%) compared to Indirect Fluorescent Antibody (IFA) testing, with significant differences in Tc-24 optical density (OD) between positives and negatives (0.607 vs. 0.089, p < 0.001). When compared to Chagas Stat-Pak (SP), Tc-24 ELISA showed sensitivity and specificity values of 82.1% and 86.7%, respectively (p < 0.001). For Chagas Detect Plus (IB), the assay achieved a sensitivity of 80.0% and specificity of 93.1% (p < 0.001). Spearman correlation analysis revealed significant associations between Tc-24 OD and SP (r = 1.0, p = 0.0167), IB (r = 0.9, p = 0.0833) and IFA (r = 0.6273, p = 0.044). Elevated immunochromatographic values in commercial kits (SP or IB) correlated with Tc-24 OD (1.17 vs. 0.039, p < 0.001), achieving 100% sensitivity and 95.8% specificity based on positive results from commercial kits. These findings suggest that Tc-24 ELISA is a reliable and accurate serological tool for diagnosing T. cruzi infection in dogs, with the potential to enhance diagnostic capabilities in veterinary medicine.

A Consensus Guide To Preclinical Indirect Calorimetry Experiments, Alexander S Banks, David B Allison, Thierry Alquier, Ansarullah, Steven N Austad, Johan Auwerx, Julio E Ayala, Joseph A Baur, Stefania Carobbio, Gary A Churchill, Morten Dall, Rafael De Cabo, Jose Donato, Nathalia R V Dragano, Carol F Elias, Anthony W Ferrante, Brian N Finck, Jose E Galgani, Zachary Gerhart-Hines, Laurie J Goodyear, Justin L Grobe, Rana K Gupta, Kirk M Habegger, Sean M Hartig, Andrea L Hevener, Steven B Heymsfield, Corey D Holman, Martin Hrabě De Angelis, David E James, Lawrence Kazak, Jae Bum Kim, Martin Klingenspor, Xingxing Kong, Sander Kooijman, Louise Lantier, K C Kent Lloyd, James C Lo, Irfan J Lodhi, Paul S Maclean, Owen P Mcguinness, Gema Medina-Gómez, Raghavendra G Mirmira, Christopher D Morrison, Gregory J Morton, Timo D Müller, Yoshihiro Ogawa, David Pajuelo-Reguera, Matthew J Potthoff, Nathan Qi, Marc L Reitman, Patrick C N Rensen, Jan Rozman, Jennifer M Rutkowsky, Kei Sakamoto, Philipp E Scherer, Gary J Schwartz, Radislav Sedlacek, Mohammed Selloum, Saame Raza Shaikh, Shuai Chen, Gerald I Shulman, Vojtěch Škop, Alexander A Soukas, John R Speakman, Bruce M Spiegelman, Gregory R Steinberg, Katrin J Svensson, John P Thyfault, Tony Tiganis, Paul M Titchenell, Nigel Turner, Licio A Velloso, Antonio Vidal-Puig, Christopher S Ward, Ashley S Williams, Christian Wolfrum, Allison W Xu, Ying Xu, Juleen R Zierath, International Indirect Calorimetry Consensus Committee (Iiccc)

Children’s Nutrition Research Center Staff Publications

Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data …

The Potential Of 4-Methylumbelliferone To Be Repurposed For Treating Liver Fibrosis, Xi Chen, Huiqiao Li, Yanru Deng, Jieyi Meng, Shangang Zhao, Clavia Ruth Wooton-Kee, Xia Gao, Bingning Dong, Dongyin Guan, Chaodong Wu, Philipp E Scherer, Yi Zhu

Faculty, Staff and Students Publications

4-Methylumbelliferone (4-MU) is the active component of hymecromone, a choleretic and antispasmodic drug with an excellent safety profile. In rodent studies, high doses of 4-MU are also used to inhibit the production of hyaluronan (HA), a biomarker of liver fibrosis. Further, 4-MU shows excellent efficacy in inhibiting liver fibrosis of different etiologies in animal studies, eliciting interest in its repurposing for this condition. However, 4-MU's mechanism of action, and whether it inhibits liver fibrosis by impeding HA synthesis remains unclear. Using several transgenic mouse models with HA overproduction or degradation in different types of liver cells, we found that both …

Risk Of Second Primary Lung Cancer Among Cancer Survivors Stratified By The Site Of First Primary Cancer And The Lung Cancer Screening Eligibility Status, Sara Nofal, Edwin J Ostrin, Jianjun Zhang, Jia Wu, Paul Scheet, Mara B Antonoff, John V Heymach, Iakovos Toumazis

Faculty, Staff and Student Publications

Personal history of cancer is an independent risk factor for developing lung cancer. However, it is not considered in the current US lung cancer screening (LCS) guidelines. In this study, we assessed the risk of developing lung cancer among cancer survivors across 24 different sites of first primary cancer stratified by their LCS eligibility status. Using data from the Patient History Database at the University of Texas MD Anderson Cancer Center, we calculated and compared the cumulative incidence of second primary lung cancer, the overall and the LCS eligibility status-specific, stratified by the site of first primary cancer among cancer …

Wuse-Oil Compound 03 Mitigates Radiation-Induced Oral Mucositis By Modulating Oral Microbiota To Mediate Tlr4/Nf-Κb Pathway And Inhibit M1 Macrophage Polarization, Liqun Jia, Rong Huang, Chen Chen, Feng Teng, Tian Gu, Huafeng Liu, Li Ma, Ye Feng, Jingyi Long, Zihan Jin, Dong Li, Dongmei Chen, Yanni Lou

Faculty, Staff and Student Publications

Background: Radiation-induced oral mucositis (RIOM) is a prevalent condition among patients with head and neck cancer undergoing radiotherapy. It is characterized by a high incidence and severe symptoms that significantly compromise patients' quality of life. Currently, there exists no consensus regarding an effective treatment modality. Wuse-oil Compound 03 (WC03), a Traditional Chinese Herbal Medicine, demonstrates potential in managing RIOM.

Purpose: This study aims to investigate the efficacy of WC03 in treating RIOM through the modulation of oral microbiota and associated biological pathways.

Study design: Mechanism study experimental design.

Methods: A rat model of RIOM was established via radiation exposure. WC03 …

In Situ Programming Of The Tumor Microenvironment To Alleviate Immunosuppression For Pancreatic Cancer Immunotherapy, Man Sun, Huan Zhang, Yarui Ma, Simiao Wang, Jiayi Chen, Yaxin Cui, Yun Zhang, Siyuan Hu, Dan Zhou, Pengchen Zhang, Yahui Liu, Betty Y S Kim, Wen Jiang, Xiaobing Wang, Zhaogang Yang

Faculty, Staff and Student Publications

Recent studies have highlighted the pivotal role of the cGAS‐STING pathway in cancer immunotherapy. However, clinical trials with cGAS‐STING pathway agonists have faced setbacks thanks to their short biological half‐life, lack of tumor specificity, and potential to promote tumor immune evasion. To address these challenges, a novel exosome‐based drug delivery platform, termed cmExoaCD11b is developed, designed to precisely target and reprogram the tumor microenvironment (TME) in situ for pancreatic cancer immunotherapy. cmExoaCD11b is engineered to encapsulate high copy numbers of IL‐12 mRNA and 2′3’‐cGAMP (cGAMP) and is functionalized with CD11b antibodies for targeted delivery to macrophages. Notably, cmExoaCD11b facilitated the …

Polydrug Abuse: Choice Between Drugs As A Function Of Concurrent Nonindependent Ratio Sizes, Richard A Meisch, Thomas H Gomez, Scott D Lane

Faculty, Staff and Student Publications

Polydrug abuse is the persistent self-administration of more than one reinforcing drug. The present study provided rhesus monkeys concurrent access to two drugs: 8% alcohol and solutions of either cocaine or methadone. The liquids were available under concurrent nonindependent fixed-ratio (FR) schedules across increasing and then decreasing ratio sizes. These schedules generate high rates of changeover responses and yield a dependent variable of responses per delivery that is not rigidly tied to the ratio-schedule value. The programmed schedule size was equal for both liquids and increased in the sequence 8, 16, 32, and so on until responding decreased, whereupon the …

Rna-Binding Proteins Mediate The Maturation Of Chromatin Topology During Differentiation, Bondita Dehingia, Małgorzata Milewska-Puchała, Marcin Janowski, Mahmoud-Reza Rafiee, Misbah Abbas, Aleksandra Piotrowska, Jan Senge, Piotr Blaut, Dietrich Walsh, Jacqueline Severino, Debadeep Chaudhury, Sajjad Iqbal, Rogelio Montiel-Manriquez, Sylwia Jankowska, Peyman Zare, Wolfgang Huber, Jianliang Xu, Rafael Casellas, Timo Zimmermann, Paweł Dłotko, Jeroen Krijgsveld, Aleksandra Pękowska

Faculty, Staff and Student Publications

Topologically associating domains (TADs) and chromatin architectural loops impact promoter-enhancer interactions, with CCCTC-binding factor (CTCF) defining TAD borders and loop anchors. TAD boundaries and loops progressively strengthen upon embryonic stem (ES) cell differentiation, underscoring the importance of chromatin topology in ontogeny. However, the mechanisms driving this process remain unclear. Here we show a widespread increase in CTCF-RNA-binding protein (RBP) interactions upon ES to neural stem (NS) cell differentiation. While dispensable in ES cells, RBPs reinforce CTCF-anchored chromatin topology in NS cells. We identify Pantr1, a non-coding RNA, as a key facilitator of CTCF-RBP interactions, promoting chromatin maturation. Using acute CTCF …

Mechanisms Underlying Treatment-Resistant Depression: Exploring Sex-Based Biological Differences, Francisco E R Da Silva, Atakan Yucel, Antonio P M Menezes, Ana C Ruiz, Marcela C Carbajal Tamez, Tatiana Barichello, Giselli Scaini, Joao Quevedo

Faculty, Staff and Student Publications

Treatment-resistant depression (TRD) represents a severe and complex subtype of major depressive disorder (MDD), affecting approximately 30% of patients who fail to respond adequately to multiple standard antidepressant therapies. While the pathophysiology of TRD remains incompletely understood, emerging evidence suggests that sex-based biological differences might influence its onset, progression, and treatment response. Women are disproportionately affected by depression and are more likely to experience residual symptoms and treatment resistance, potentially due to hormonal fluctuations, immune system differences, and variations in brain circuitry and neuroplasticity. This narrative explores the current literature on the mechanisms underlying TRD, with a particular emphasis on …

Mechanisms Underlying Treatment-Resistant Depression: Exploring Sex-Based Biological Differences, Francisco E R Da Silva, Atakan Yucel, Antonio P M Menezes, Ana C Ruiz, Marcela C Carbajal Tamez, Tatiana Barichello, Giselli Scaini, Joao Quevedo

Faculty, Staff and Student Publications

Treatment-resistant depression (TRD) represents a severe and complex subtype of major depressive disorder (MDD), affecting approximately 30% of patients who fail to respond adequately to multiple standard antidepressant therapies. While the pathophysiology of TRD remains incompletely understood, emerging evidence suggests that sex-based biological differences might influence its onset, progression, and treatment response. Women are disproportionately affected by depression and are more likely to experience residual symptoms and treatment resistance, potentially due to hormonal fluctuations, immune system differences, and variations in brain circuitry and neuroplasticity. This narrative explores the current literature on the mechanisms underlying TRD, with a particular emphasis on …

The Antifungal Mechanism Of Entv-Derived Peptides Is Associated With A Reduction In Extracellular Vesicle Release, Giuseppe Buda De Cesare, Melissa R Cruz, Shane A Cristy, Luis A Vega, Robert Zarnowski, Antonino Zito, Shantanu Guha, David R Andes, Danielle A Garsin, Michael C Lorenz

Faculty, Staff and Student Publications

Candida albicans, an opportunistic fungal pathogen, causes systemic and superficial infections, especially in immunocompromised patients. Treatment of fungal infections is complicated by limited antifungal options and the development of drug resistance. Previous work from our group demonstrated the efficacy of the anti-virulence peptide EntV and shorter variants against C. albicans infection in various animal models, including mouse models of oropharyngeal candidiasis and disseminated infection and a rat venous catheter model. However, the mechanism of action, which abrogates fungal virulence without fungicidal or fungistatic activity, has remained unknown. We used a combination of cell biological, biochemical, genomic, and genetic approaches to …

Adaptive Filters At The First Olfactory Synapse, Elizabeth H Moss, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

The olfactory system is able to filter odor representations based on attention and learning. Two PLoS Biology studies reveal how short axon cells in the olfactory bulb integrate cholinergic input from the basal forebrain to dynamically regulate olfactory input.

Folliculin Deletion In The Mouse Kidney Results In Cystogenesis Of The Loops Of Henle Via Aberrant Tfeb Activation, Ola Shalaby, Tomoko Ohmori, Koichiro Miike, Shunsuke Tanigawa, Luh Ade Wilan Krisna, Alessia Calcagnì, Andrea Ballabio, Yoshiaki Kubota, Laura S Schmidt, W Marston Linehan, Takaaki Ito, Masaya Baba, Ryuichi Nishinakamura

Duncan NRI Faculty and Staff Publications

The mammalian kidney contains numerous nephrons connected to the collecting ducts, and each nephron consists of a glomerulus, a proximal tubule, the loop of Henle (LoH), and a distal tubule. Folliculin (FLCN) is a causative gene for Birt-Hogg-Dubé syndrome, which is characterized by a variety of manifestations, including renal cysts and cancer. Although deletion of Flcn in the mouse collecting duct and distal nephron leads to cyst formation, its precise role in the entire nephron remains unclear. Herein, nephron-specific Flcn knockout mice exhibited cystogenesis along the entire nephron segments, most prominent in the LoH, preceded by an irregularly shaped lumen …

Coenzyme Q Headgroup Intermediates Can Ameliorate A Mitochondrial Encephalopathy, Guangbin Shi, Claire Miller, Sota Kuno, Alejandro G Rey Hipolito, Salsabiel El Nagar, Giulietta M Riboldi, Megan Korn, Wyatt C Tran, Zixuan Wang, Lia Ficaro, Tao Lin, Quentin Spillier, Begoña Gamallo-Lana, Drew R Jones, Matija Snuderl, Soomin C Song, Adam C Mar, Alexandra L Joyner, Roy V Sillitoe, Robert S Banh, Michael E Pacold

Duncan NRI Faculty and Staff Publications

Decreased brain levels of coenzyme Q10 (CoQ10), an endogenously synthesized lipophilic antioxidant1,2, underpin encephalopathy in primary CoQ10 deficiencies3,4 and are associated with common neurodegenerative diseases and the ageing process5,6. CoQ10 supplementation does not increase CoQ10 pools in the brain or in other tissues. The recent discovery of the mammalian CoQ10 headgroup synthesis pathway, in which 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) makes 4-hydroxymandelate (4-HMA) to synthesize the CoQ10 headgroup precursor 4-hydroxybenzoate (4-HB)7, offers an opportunity to pharmacologically restore CoQ10 synthesis and mechanistically treat CoQ10 deficiencies. To test whether 4-HMA …

Deciphering Transcriptomic Changes In Chemobrain: A Comprehensive Review, Tusar Kanta Acharya, Yuan Pan, Peter M Grace, Cobi J Heijnen, Rajasekaran Mahalingam

Faculty, Staff and Student Publications

Chemotherapy-induced cognitive impairments (CICI), colloquially known as "chemobrain," represents a profound and debilitating side effect experienced by a significant number of cancer survivors, impacting their memory, multitasking, and quality of life. This review critically evaluates the molecular mechanisms underlying CICI, with a particular focus on the insights gained from transcriptomic analyses. As cancer incidence rises globally, understanding the complex interplay between chemotherapy agents and their cognitive repercussions becomes increasingly vital. Key mechanisms implicated in CICI include blood-brain barrier disruption, neuroinflammation, and oxidative stress as a result of various chemotherapy treatments, such as doxorubicin, cisplatin, and paclitaxel. We delve into advanced …

Ras-Membrane Interaction And Oligomerization: There Is More Than Meets The Eye, Abraham C Sianoya, Vijay K Bhardwaj, Alemayehu A Gorfe

Faculty, Staff and Student Publications

Membrane association is fundamental to Rat sarcoma (RAS) function, driving both its physiologic signaling and oncogenic transformation. This review consolidates recent advances in the study of RAS-membrane interactions, emphasizing the molecular mechanisms underlying its membrane engagement and oligomerization. We first discuss the roles of RAS lipid modification and conformational diversity of its intrinsically disordered C-terminus in these processes, and we then examine the debate surrounding RAS dimerization and its potential role in the formation of higher-order oligomers. By integrating emerging insights into these issues, we offer our own perspectives on the driving forces of RAS oligomerization and propose potential new …

Adams Contribute To Triple Negative Breast Cancer Via Mtorc1 Pathway: Targeting Adam-Mtor Axis Improves Efficacy, Shuying Liu, Huiqin Chen, Mihai Gagea, Lorenzo Federico, Fan Zhang, Javier Gomez, Kim-Anh Do, William F Symmans, Gabriel N Hortobagyi, Gordon B Mills, Ana M Gonzalez-Angulo, Debasish Tripathy

Faculty, Staff and Student Publications

Breast cancer is the most frequently diagnosed cancer globally and the second leading cause of cancer-related deaths in American women. Triple-negative breast cancer (TNBC) lacks estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Thus, fewer targeting therapies are available for this most aggressive subtype. The A Disintegrin and Metalloproteinase (ADAM) family plays a vital role in cancer pathophysiology. Previous studies focused on single ADAM members. However, none of these have entered into the clinical arena as diagnostics or therapeutics for breast cancer. In this study, we demonstrate the upregulation of a panel of ADAM members in TNBC, …

Nf1-Depleted Er+ Breast Cancers Are Differentially Sensitive To Cdk4/6 Inhibitors, Ze-Yi Zheng, Anran Chen, Eric J Jaehnig, Meenakshi Anurag, Jonathan T Lei, Long Feng, Chenwei Wang, Diana Fandino, Purba Singh, Hilda Kennedy, Ghazal Yadav, Craig T Vollert, Jill Tsai, Xi Chen, Yi Li, Bora Lim, Alastair Thompson, Shunqiang Li, Charles E Foulds, Bing Zhang, Matthew J Ellis, Eric C Chang

Faculty, Staff and Students Publications

Neurofibromin/NF1 is a RAS (rat sarcoma virus) GTPase activating protein and estrogen receptor (ER) transcriptional corepressor. NF1low status, identified by copy number loss or low mRNA/protein expression is associated with endocrine therapy resistance in approximately 20% of ER+/HER2− (human epidermal growth factor receptor 2) early-stage breast cancers. The identification of targeted treatments for NF1low ER+/HER2− breast cancer is therefore a priority. In this study proteogenomic analysis of ER+/HER2− breast cancer demonstrated that NF1low tumors exhibited elevated cyclin-dependent kinase 4/6 (CDK4/6) activity. In cell lines, NF1-deletion had a dual effect on CDK4 activity. First, by promoting ER recruitment to CCND1 …

Heterozygous Variants In Plcg1 Affect Hearing, Vision, Cardiac, And Immune Function, Mengqi Ma, Yiming Zheng, Mingxi Deng, Shenzhao Lu, Xueyang Pan, Xi Luo, Michelle Etoundi, David Li-Kroeger, Kim C Worley, Lindsay C Burrage, Lauren S Blieden, Aimee Allworth, Wei-Liang Chen, Giuseppe Merla, Barbara Mandriani, Catherine E Otten, Pierre Blanc, Jill A Rosenfeld, Debdeep Dutta, Shinya Yamamoto, Michael F Wangler, Ian A Glass, Jingheng Chen, Elizabeth Blue, Paolo Prontera, Jeremie Rosain, Sandrine Marlin, Seema R Lalani, Hugo J Bellen, Undiagnosed Diseases Network

Duncan NRI Faculty and Staff Publications

Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG), important signaling molecules involved in many cellular processes including Ca²⁺ release from the endoplasmic reticulum (ER). PLCG1 encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations of PLCG1 are observed in multiple cancers, but only one germline variant has been reported. Here, we describe seven individuals with heterozygous missense variants in PLCG1 [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] who present with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). To model these …

A Protective Role Of Src-1 Against Aging Associated Cognitive Decline, Hesong Liu, Yongjie Yang, Jonathan C Bean, Yang He, Hailan Liu, Rambabu Majji, Chen Liang, Nan Zhang, Meng Yu, Longlong Tu, Qingzhuo Liu, Yue Deng, Kristine M Conde, Na Yin, Mengjie Wang, Yongxiang Li, Junying Han, Sanika Vattakuzhiyil Jossy, Megan Elyse Burt, Hari Krishna Yalamanchili, Chunmei Wang

Duncan NRI Faculty and Staff Publications

Introduction: Research indicates a strong correlation between obesity and the risk of dementia, both are linked to steroid receptor coactivator-1 (SRC-1), a transcriptional coactivator.

Methods: We used RNA sequencing analysis (RNA-Seq) to investigate the transcriptome of SRC-1-KO mice, and identified S100 calcium-binding protein A6 (S100A6), an AD associated gene, as one target of SRC-1. We tested cognitive behaviors in SRC-1-KO mice and mice with a humanized SRC-1 mutation (SRC-1L1376P), and performed promoter luciferase assays on S100A6.

Results: Loss of SRC-1 caused alterations in gene signatures that are commonly associated with neurodegenerative diseases, including AD, and diminished the neural plasticity of …

The Role Of Recruited Adipose Stromal Cells And Their Fibroblastic Differentiation In Cancer, Lingyi Cai, Mikhail G Kolonin, Dimitris Anastassiou

Faculty, Staff and Student Publications

Adipose stromal cells (ASCs) are perivascular mesenchymal progenitors of adipose tissue. In cancer patients, ASCs can mobilize and migrate to the tumor, where they subsequently play an important role in cancer progression. This biological process involves the conversion of recruited ASCs into cancer-associated fibroblasts (CAFs). ASC-derived CAFs influence the tumor microenvironment through extracellular matrix remodeling, vascularization, and immunomodulation. These and other processes mediated by secreted paracrine factors also affect gene expression in carcinoma cells to promote the epithelial-mesenchymal transition (EMT), metabolic adaptation, survival, and invasiveness of cancer cells. ASC-derived CAFs can enhance tumor aggressiveness, accounting in part for the link …

Dissection Of Surface Area-Dependent Lipolysis At A Single Organelle Level, Chengxin Ma, Yan Liang, Xinmeng Che, Yuqi Li, Jin Wu, Li Xu, Hongyuan Yang, Tong-Jin Zhao, Feng-Jung Chen, Peng Li

Faculty, Staff and Student Publications

Lipid droplets are dynamic organelles whose size and number signify their role in energy. However, owing to cellular heterogeneity and technological limitations, the relationship between the lipolytic ability and lipid droplet morphology is unclear. Here, we developed a live-cell imaging assay using geometric analysis to quantify cellular lipolysis at a single organelle level, designated imaging lipolysis. Using imaging lipolysis and super-resolution imaging, we found that lipolysis is controlled by both lipase-accessible lipid droplet surface area and lipase activity. Moreover, lipid droplet fusion regulatory proteins CLSTN3β/CIDEs promote lipolysis by increasing the total lipid droplet surface area-to-volume ratio in biophysical regulation. We …

Pfkfb3 Activates Cad To Enhance De Novo Pyrimidine Synthesis For Cell Growth, Qingen Da, Yongfeng Cai, Qian Ma, Qiuhua Yang, Yapeng Cao, Yaqi Zhou, Dingwei Zhao, Zhiping Liu, Jiean Xu, Junming Quan, Liang Zhang, Rui Wang, Xuejun Jiang, Xiao Liu, Kunfu Ouyang, Zhen Han, Jikui Liu, Tao Wang, Chunxiang Zhang, Neal L Weintraub, David J R Fulton, Jun Zhao, Mei Hong, Zigang Li, Yuqing Huo

Faculty, Staff and Students Publications

Aerobic glycolysis, termed the Warburg effect, is one of the aberrant metabolic pathways in highly proliferating cells. Glycolysis provides glycolytic metabolites to support the generation of biomass, such as nucleotides, amino acids, and lipids. Research on the direct interactions between glycolysis and other metabolic pathways is an emerging field that has garnered significant interest. Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) activates glycolysis by synthesizing fructose-2,6-bisphosphate (F2,6BP), which allosterically activates the rate-limiting enzyme 6-phosphofructo-1-kinase (PFK-1). In this study, we found that PFKFB3 directly interacts with and regulates the phosphorylation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), the enzyme catalyzing the first three …

Multiplex Imaging Mass Cytometry Reveals Prognostic Immunosuppressive Subpopulations And Macrophage-Driven Metastasis In Osteosarcoma, Benjamin B Gyau, Junyan Wang, Weiguo Wu, Brooks Scull, Angela M Major, Weidong Jin, Justin M M Cates, John Hicks, Tsz-Kwong Man

Faculty, Staff and Students Publications

Osteosarcoma is a type of bone cancer that mostly affects kids and teens. The biggest danger is when the cancer spreads to the lungs, and current treatments do not work well for those cases. Immunotherapy, which helps the body’s immune system fight cancer, has worked for other cancers but is limited for osteosarcoma because we do not fully understand the environment around the tumor. Our research looked at various cells around the tumor to study why patients have worse outcomes. We found that certain cells, called M2 macrophages (M2) and myeloid-derived suppressor cells (MDSC), which weaken the immune system, are …

High-Speed Voltage Imaging Of Action Potentials In Molecular Layer Interneurons Reveals Sensory-Driven Synchrony That Augments Movement, Spencer T Brown, Meghana R Holla, Michelle A Land, Shuyuan Yang, Alex J Mcdonald, François St-Pierre, Indira M Raman

Faculty, Staff and Students Publications

Testing whether the synchrony of action potential firing is a cerebellar coding mechanism requires simultaneous recording, with high temporal fidelity, from populations of identified neurons. Here, we used targeted one-photon voltage imaging at 2–4 kHz to record action potentials from groups of ~10–300 molecular layer interneurons (MLIs) expressing a positively tuned, genetically encoded voltage indicator, FORCE1f or pAce. In awake resting mice, crus I MLIs fired brief (~1-ms) spikes at 20–60 spikes/s. Sensory stimuli of air puffs to the whiskers evoked short-latency (< 10 ms) increases in spiking probability. In most trials, >50% of MLIs fired synchronously with 4-ms temporal precision. The magnitude of puff-evoked whisks correlated tightly with …

Cathartocytosis: Jettisoning Of Cellular Material During Reprogramming Of Differentiated Cells, Jeffrey W Brown, Xiaobo Lin, Gabriel Anthony Nicolazzi, Xuemei Liu, Thanh Nguyen, Megan D Radyk, Joseph Burclaff, Jason C Mills

Faculty, Staff and Students Publications

Injury causes differentiated cells to undergo massive reprogramming to become proliferative and repair tissue via paligenosis. Gastric chief cells use paligenosis to reprogram into progenitor-like spasmolytic-polypeptide-expressing metaplasia (SPEM) cells. Stage 1 of paligenosis is the downscaling of mature cell architecture via a process involving lysosomes. Here, we notice that sulfated glycoproteins are not only digested during paligenosis but also excreted into the gland. Various genetic and pharmacological approaches show that endoplasmic reticulum membranes and secretory granule cargo are also excreted and that the process proceeds in parallel with but is mechanistically independent of autophagy. Three-dimensional light and electron microscopy demonstrated …

Targeting Sting To Disrupt Macrophage-Mediated Adhesion In Encapsulating Peritoneal Sclerosis, Juan Sun, Yuxiang Sun, Dandan Guo, Huolin Ye, Qiang Huang, Hu Zhou, Canming Li, Mei Liao, Yujia You, Hongli Shang, Pan Zhou, Dongxuan Wu, Janusz Witowski, Zhaoyong Hu, Hui Peng

Faculty, Staff and Students Publications

Encapsulating peritoneal sclerosis (EPS) is a life-threatening fibrotic condition characterized by severe abdominal adhesions, chronic inflammation, and significant morbidity. The lack of effective treatments for EPS stems from a limited understanding of its underlying mechanisms. In this study, we developed a modified mouse model of PD-induced EPS and investigated the role of the STING signaling pathway in disease progression. Our findings reveal that STING activation in peritoneal mesothelial cells significantly increases the secretion of the macrophage chemokine CCL2, leading to enhanced macrophage infiltration and the formation of pathological adhesions. Notably, pharmacological inhibition of STING using the inhibitor H151 effectively reduced …