Digital Commons Network^™

The Influence Of Obesity On Outcomes With Immune Checkpoint Blockade: Clinical Evidence And Potential Biological Mechanisms, Andrew W Hahn, Neha Venkatesh, Pavlos Msaouel, Jennifer L Mcquade

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) is a mainstay of treatment for advanced cancer, yet tumor response and host toxicity are heterogenous in those patients who receive ICB. There is growing interest in understanding how host factors interact with tumor intrinsic properties and the tumor microenvironment to influence the therapeutic index with ICB. Obesity, defined by body mass index, is a host factor associated with improved outcomes in select cancers when treated with ICB. While the biological mechanism for this obesity paradox is not fully understood, pre-clinical and translational studies suggest obesity may potentially impact tumor metabolism, inflammation, and angiogenesis. Herein, we …

Tgf-Β1 In Aplysia: Role In Long-Term Changes In The Excitability Of Sensory Neurons And Distribution Of Tβr-Ii-Like Immunoreactivity, Muhammad S Khan, Eun Kim, Quentin Le Hingrat, Adam Kleinman, Alessandro Ferrari, Jose C Sammartino, Elena Percivalle, Cuiling Xu, Shaohua Huang, Thomas W Kenniston, Irene Cassaniti, Fausto Baldanti, Ivona Pandrea, Andrea Gambotto, Cristian Apetrei

Faculty, Staff and Student Publications

The study provides important insights into the immunogenicity and efficacy of a tetravalent protein subunit vaccine candidate against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vaccine induced both humoral and cellular immune responses in nonhuman primates with controlled SIVagm infection and was able to generate Omicron variant-specific antibodies without specifically vaccinating with Omicron. These findings suggest that the tetravalent composition of the vaccine candidate could provide broad protection against multiple SARS-CoV-2 variants while minimizing the risk of immune escape and the emergence of new variants. Additionally, the use of rhesus macaques with controlled SIVsab infection may better represent vaccine …

Sdc1 And Itga2 As Novel Prognostic Biomarkers For Pdac Related To Ipmn, Chuan-Long Zhang, Qian Shen, Fu-Dong Liu, Fan Yang, Meng-Qi Gao, Xiao-Chen Jiang, Yi Li, Xi-Yuan Zhang, Ge-Er En, Xue Pan, Bo Pang

Faculty, Staff and Student Publications

The existing biomarkers are insufficient for predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary mucinous neoplasm (IPMN) is a precursor to PDAC; therefore, identifying biomarkers from differentially expressed genes (DEGs) of PDAC and IPMN is a new and reliable strategy for predicting the prognosis of PDAC. In this study, four datasets were downloaded from the Gene Expression Omnibus database and standardized using the R package 'limma.' A total of 51 IPMN and 81 PDAC samples were analyzed, and 341 DEGs in PDAC and IPMN were identified; DEGs were involved in the extracellular matrix and tumor microenvironment. An acceptable …

A Small-Molecule Inhibitor Of Topbp1 Exerts Anti-Myc Activity And Synergy With Parp Inhibitors, Fang-Tsyr Lin, Kang Liu, Lidija A Wilhelms Garan, Helena Folly-Kossi, Yongcheng Song, Shwu-Jiuan Lin, Weei-Chin Lin

Faculty, Staff and Students Publications

We have previously identified TopBP1 (topoisomerase IIβ-binding protein 1) as a promising target for cancer therapy, given its role in the convergence of Rb, PI(3)K/Akt, and p53 pathways. Based on this, we conducted a large-scale molecular docking screening to identify a small-molecule inhibitor that specifically targets the BRCT7/8 domains of TopBP1, which we have named 5D4. Our studies show that 5D4 inhibits TopBP1 interactions with E2F1, mutant p53, and Cancerous Inhibitor of Protein Phosphatase 2A. This leads to the activation of E2F1-mediated apoptosis and the inhibition of mutant p53 gain of function. In addition, 5D4 disrupts the interaction of TopBP1 …

Toll-Like Receptor 4 And Cd11b Expressed On Microglia Coordinate Eradication Of Candida Albicans Cerebral Mycosis, Yifan Wu, Shuqi Du, Lynn H Bimler, Kelsey E Mauk, Léa Lortal, Nessim Kichik, James S Griffiths, Radim Osicka, Lizhen Song, Katherine Polsky, Lydia Kasper, Peter Sebo, Jill Weatherhead, J Morgan Knight, Farrah Kheradmand, Hui Zheng, Jonathan P Richardson, Bernhard Hube, Julian R Naglik, David B Corry

Faculty, Staff and Students Publications

The fungal pathogen Candida albicans is linked to chronic brain diseases such as Alzheimer's disease (AD), but the molecular basis of brain anti-Candida immunity remains unknown. We show that C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted aspartic proteinases (Saps) and candidalysin. Saps disrupt tight junction proteins of the blood-brain barrier (BBB) to permit fungal brain invasion. Saps also hydrolyze amyloid precursor protein (APP) into amyloid β (Aβ)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while candidalysin engages the integrin CD11b (Mac-1) on microglia. …

Constitutive Interleukin-7 Cytokine Signaling Enhances The Persistence Of Epstein-Barr Virus-Specific T-Cells, Sandhya Sharma, Tim Sauer, Bilal A Omer, Thomas Shum, Lisa A Rollins, Cliona M Rooney

Faculty, Staff and Students Publications

The efficacy of therapeutic T-cells is limited by a lack of positive signals and excess inhibitory signaling in tumor microenvironments. We previously showed that a constitutively active IL7 receptor (C7R) enhanced the persistence, expansion, and anti-tumor activity of T-cells expressing chimeric antigen receptors (CARs), and C7R-modified GD2.CAR T-cells are currently undergoing clinical trials. To determine if the C7R could also enhance the activity of T-cells recognizing tumors via their native T-cell receptors (TCRs), we evaluated its effects in Epstein–Barr virus (EBV)-specific T-cells (EBVSTs) that have produced clinical benefits in patients with EBV-associated malignancies. EBVSTs were generated by stimulation of peripheral …

Diaph1-Mfn2 Interaction Regulates Mitochondria-Sr/Er Contact And Modulates Ischemic/Hypoxic Stress, Gautham Yepuri, Lisa M Ramirez, Gregory G Theophall, Sergei V Reverdatto, Nosirudeen Quadri, Syed Nurul Hasan, Lei Bu, Devi Thiagarajan, Robin Wilson, Raquel López Díez, Paul F Gugger, Kaamashri Mangar, Navneet Narula, Stuart D Katz, Boyan Zhou, Huilin Li, Aleksandr B Stotland, Roberta A Gottlieb, Ann Marie Schmidt, Alexander Shekhtman, Ravichandran Ramasamy

Faculty, Staff and Student Publications

Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. …

Recent Advances In The Synthesis And Antioxidant Activity Of Low Molecular Mass Organoselenium Molecules, João M Anghinoni, Paloma T Birmann, Marcia J Da Rocha, Caroline S Gomes, Michael J Davies, César A Brüning, Lucielli Savegnago, Eder J Lenardão

Faculty, Staff and Student Publications

Selenium is an essential trace element in living organisms, and is present in selenoenzymes with antioxidant activity, like glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). The search for small selenium-containing molecules that mimic selenoenzymes is a strong field of research in organic and medicinal chemistry. In this review, we review the synthesis and bioassays of new and known organoselenium compounds with antioxidant activity, covering the last five years. A detailed description of the synthetic procedures and the performed in vitro and in vivo bioassays is presented, highlighting the most active compounds in each series.

Enolase Inhibitors As Early Lead Therapeutics Against Trypanosoma Brucei, Colm P Roster, Danielle Lavigne, Jillian E Milanes, Emily Knight, Heidi D Anderson, Sabrina Pizarro, Elijah M Harding, Meredith T Morris, Victoria C Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C Rees, Brian Dominy, Daniel C Whitehead, Md Nasir Uddin, Steven W Millward, James C Morris

Faculty, Staff and Student Publications

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO (TbENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) …

The Lin28b/Wnt5a Axis Drives Pancreas Cancer Through Crosstalk Between Cancer Associated Fibroblasts And Tumor Epithelium, Zhaoqi Shu, Minghe Fan, Bo Tu, Zhiheng Tang, Haojie Wang, Haimeng Li, Hengchao Li, Meng Yuan, Jingru Bai, Sihan Huo, Lina Wang, Wei-Guo Zhu, Wei Wang, Xiaoyun Liu, Shaokun Shu, Ying Zhao

Faculty, Staff and Student Publications

Bidirectional signal transduction between tumor epithelial cells and tumor microenvironment (TME) is important for tumor development. Here we show that Lin28b/let-7 pathway is indispensable for modulating the expression of Wnt5a in tumor epithelium, which could be secreted and then up-regulates Lin28b in cancer-associated fibroblasts (CAFs). Moreover, we demonstrate that Lin28b in CAFs promoted growth of PDAC by inducing cytokine PCSK9's production. Using an orthotopic mouse model of PDAC, we find that depletion of Lin28b in CAFs reduced tumor weight, highlighting the importance of Lin28b in PDAC stroma. Thus, our study shows that the Lin28b-Wnt5a axis plays a critical role in …

Wastewater Sequencing Reveals Community And Variant Dynamics Of The Collective Human Virome, Michael Tisza, Sara Javornik Cregeen, Vasanthi Avadhanula, Ping Zhang, Tulin Ayvaz, Karen Feliz, Kristi L Hoffman, Justin R Clark, Austen Terwilliger, Matthew C Ross, Juwan Cormier, Hannah Moreno, Li Wang, Katelyn Payne, David Henke, Catherine Troisi, Fuqing Wu, Janelle Rios, Jennifer Deegan, Blake Hansen, John Balliew, Anna Gitter, Kehe Zhang, Runze Li, Cici X Bauer, Kristina D Mena, Pedro A Piedra, Joseph F Petrosino, Eric Boerwinkle, Anthony W Maresso

Faculty, Staff and Student Publications

Wastewater is a discarded human by-product, but its analysis may help us understand the health of populations. Epidemiologists first analyzed wastewater to track outbreaks of poliovirus decades ago, but so-called wastewater-based epidemiology was reinvigorated to monitor SARS-CoV-2 levels while bypassing the difficulties and pit falls of individual testing. Current approaches overlook the activity of most human viruses and preclude a deeper understanding of human virome community dynamics. Here, we conduct a comprehensive sequencing-based analysis of 363 longitudinal wastewater samples from ten distinct sites in two major cities. Critical to detection is the use of a viral probe capture set targeting …

Neuroprotective Agents With Therapeutic Potential For Covid-19, César A Zaa, Clara Espitia, Karen L Reyes-Barrera, Zhiqiang An, Marco A Velasco-Velázquez

Faculty, Staff and Student Publications

COVID-19 patients can exhibit a wide range of clinical manifestations affecting various organs and systems. Neurological symptoms have been reported in COVID-19 patients, both during the acute phase of the illness and in cases of long-term COVID. Moderate symptoms include ageusia, anosmia, altered mental status, and cognitive impairment, and in more severe cases can manifest as ischemic cerebrovascular disease and encephalitis. In this narrative review, we delve into the reported neurological symptoms associated with COVID-19, as well as the underlying mechanisms contributing to them. These mechanisms include direct damage to neurons, inflammation, oxidative stress, and protein misfolding. We further investigate …

Irf1 Regulates Self-Renewal And Stress Responsiveness To Support Hematopoietic Stem Cell Maintenance, Alexandra J S Rundberg Nilsson, Hongxu Xian, Shabnam Shalapour, Jörg Cammenga, Michael Karin

Faculty, Staff and Student Publications

Hematopoietic stem cells (HSCs) are tightly controlled to maintain a balance between blood cell production and self-renewal. While inflammation-related signaling is a critical regulator of HSC activity, the underlying mechanisms and the precise functions of specific factors under steady-state and stress conditions remain incompletely understood. We investigated the role of interferon regulatory factor 1 (IRF1), a transcription factor that is affected by multiple inflammatory stimuli, in HSC regulation. Our findings demonstrate that the loss of IRF1 from mouse HSCs significantly impairs self-renewal, increases stress-induced proliferation, and confers resistance to apoptosis. In addition, given the frequent abnormal expression of IRF1 in …

Rna-Based Translation Activators For Targeted Gene Upregulation, Yang Cao, Huachun Liu, Shannon S Lu, Krysten A Jones, Anitha P Govind, Okunola Jeyifous, Christine Q Simmons, Negar Tabatabaei, William N Green, Jimmy L Holder, Soroush Tahmasebi, Alfred L George, Bryan C Dickinson

Duncan NRI Faculty and Staff Publications

Technologies capable of programmable translation activation offer strategies to develop therapeutics for diseases caused by insufficient gene expression. Here, we present "translation-activating RNAs" (taRNAs), a bifunctional RNA-based molecular technology that binds to a specific mRNA of interest and directly upregulates its translation. taRNAs are constructed from a variety of viral or mammalian RNA internal ribosome entry sites (IRESs) and upregulate translation for a suite of target mRNAs. We minimize the taRNA scaffold to 94 nucleotides, identify two translation initiation factor proteins responsible for taRNA activity, and validate the technology by amplifying SYNGAP1 expression, a haploinsufficiency disease target, in patient-derived cells. …

Decoding Meningioma Heterogeneity And Neoplastic Cell-Macrophage Interaction Through Single-Cell Transcriptome Profiling Across Pathological Grades, Hailang Fan, Lairong Song, Jian Fan, Junpeng Ma, Xiaojie Li, Junting Zhang, Jian Hu, Zhen Wu, Dake Zhang, Liang Wang

Faculty, Staff and Student Publications

Background: Analyzing meningioma of distinct pathological types at the single-cell level can provide new and valuable insights into the specific biological mechanisms of each cellular subpopulation, as well as their vital interplay within the tumor microenvironment.

Methods: We recruited patients diagnosed with four distinct types of meningioma and performed single-cell RNA sequencing on their tumor samples, concurrently analyzing a publicly available dataset for comparison. Next, we separated the cells into discrete clusters and identified their unique identities. Using pseudotime analysis, we demonstrated cellular differentiation and dynamics. To investigate biological function, we employed weighted gene co-expression network analysis, gene regulatory network, …

Localized Cardiac Small Molecule Trajectories And Persistent Chemical Sequelae In Experimental Chagas Disease, Zongyuan Liu, Rebecca Ulrich Vonbargen, April L Kendricks, Kate Wheeler, Ana Carolina Leão, Krithivasan Sankaranarayanan, Danya A Dean, Shelley S Kane, Ekram Hossain, Jeroen Pollet, Maria Elena Bottazzi, Peter J Hotez, Kathryn M Jones, Laura-Isobel Mccall

Faculty, Staff and Students Publications

Post-infectious conditions present major health burdens but remain poorly understood. In Chagas disease (CD), caused by Trypanosoma cruzi parasites, antiparasitic agents that successfully clear T. cruzi do not always improve clinical outcomes. In this study, we reveal differential small molecule trajectories between cardiac regions during chronic T. cruzi infection, matching with characteristic CD apical aneurysm sites. Incomplete, region-specific, cardiac small molecule restoration is observed in animals treated with the antiparasitic benznidazole. In contrast, superior restoration of the cardiac small molecule profile is observed for a combination treatment of reduced-dose benznidazole plus an immunotherapy, even with less parasite burden reduction. Overall, …

Methyl-Branched Liposomes As A Depot For Sustained Drug Delivery, Yang Li, Rachelle Shao, Claire A Ostertag-Hill, Matthew Torre, Ran Yan, Daniel S Kohane

Duncan NRI Faculty and Staff Publications

Inadequate drug loading and control of payload leakage limit the duration of the effect of liposomal drug carriers and may cause toxicity. Here, we report a liposome system as a depot for sustained drug delivery whose design is inspired by the low permeability of Archaeal membranes to protons and solutes. Incorporating methyl-branched phospholipids into lipid bilayers decreased payload diffusion across liposomal membranes, thereby enhancing the drug load capacity by 10-16% and reducing the release of small molecules in the first 24 h by 40-48%. The in vivo impact of this approach was demonstrated by injection at the sciatic nerve. Methyl-branched …

Identification Of Chronic Wasting Disease Prions In Decaying Tongue Tissues From Exhumed White-Tailed Deer, Paulina Soto, Francisca Bravo-Risi, Rebeca Benavente, Stuart Lichtenberg, Mitch Lockwood, J Hunter Reed, Rodrigo Morales

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) prions cause fatal neuropathies in farmed and free-ranging cervids. The deposition of prions in natural and humanmade environmental components has been implicated as a major mechanism mediating CWD spread in wild and captive populations. Prions can be deposited in the environment through excreta, tissues, and carcasses from pre-clinical and clinical animals. Furthermore, burial of CWD-positive animals may reduce but not completely mitigate prion spread from carcasses into the surrounding environment. Here, we analyzed exhumed, decaying deer carcasses for the presence of CWD prions. By analyzing tongue tissues through the protein misfolding cyclic amplification (PMCA) technique, we …

Uracil-Dna Glycosylase Of Murine Gammaherpesvirus 68 Binds Cognate Viral Replication Factors Independently Of Its Catalytic Residues, Kyle R Smith, Somnath Paul, Qiwen Dong, Orchi Anannya, Darby G Oldenburg, J Craig Forrest, Kevin M Mcbride, Laurie T Krug

Faculty, Staff and Student Publications

Herpesviruses are large double-stranded DNA viruses that encode core replication proteins and accessory factors involved in nucleotide metabolism and DNA repair. Mammalian uracil-DNA glycosylases (UNG) excise deleterious uracil residues from their genomic DNA. Each herpesvirus UNG studied to date has demonstrated conservation of the enzymatic function to excise uracil residues from DNA. We previously reported that a murine gammaherpesvirus (MHV68) with a stop codon in ORF46 (ORF46.stop) that encodes for vUNG was defective in lytic replication and latency in vivo. However, a mutant virus that expressed a catalytically inactive vUNG (ORF46.CM) had no replication defect unless coupled with additional …

Catalase Produced By Candida Albicans Protects Streptococcus Mutans From H2o2 Stress-One More Piece In The Cross-Kingdom Synergism Puzzle, Callahan Katrak, Bruna A Garcia, Louise M Dornelas-Figueira, Mary Nguyen, Robert B Williams, Michael C Lorenz, Jacqueline Abranches

Faculty, Staff and Student Publications

Co-infection with Streptococcus mutans and Candida albicans is associated with dental caries, and their co-cultivation results in enhanced biofilm matrix production that contributes to increased virulence and caries risk. Moreover, the catalase-negative S. mutans demonstrates increased oxidative stress tolerance when co-cultivated in biofilms with C. albicans, a catalase-producing yeast. Here, we sought to obtain mechanistic insights into the increased H2O2 tolerance of S. mutans when co-cultivated with clinical isolates of Candida glabrata, Candida tropicalis, and C. albicans. Additionally, the C. albicans SC5314 laboratory strain, its catalase mutant (SC5314Δcat1), and S. mutans UA159 and its glucosyltransferase B/C …

Causal Models And Causal Modelling In Obesity: Foundations, Methods And Evidence, Roger S Zoh, Xiaoxin Yu, Philip Dawid, George Davey Smith, Stephen J French, David B Allison

Children’s Nutrition Research Center Staff Publications

Discussing causes in science, if we are to do so in a way that is sensible, begins at the root. All too often, we jump to discussing specific postulated causes but do not first consider what we mean by, for example, causes of obesity or how we discern whether something is a cause. In this paper, we address what we mean by a cause, discuss what might and might not constitute a reasonable causal model in the abstract, speculate about what the causal structure of obesity might be like overall and the types of things we should be looking …

Dual Targeted Extracellular Vesicles Regulate Oncogenic Genes In Advanced Pancreatic Cancer, Chi-Ling Chiang, Yifan Ma, Ya-Chin Hou, Junjie Pan, Sin-Yu Chen, Ming-Hsien Chien, Zhi-Xuan Zhang, Wei-Hsiang Hsu, Xinyu Wang, Jingjing Zhang, Hong Li, Lili Sun, Shannon Fallen, Inyoul Lee, Xing-Yu Chen, Yeh-Shiu Chu, Chi Zhang, Tai-Shan Cheng, Wen Jiang, Betty Y S Kim, Eduardo Reategui, Robert Lee, Yuan Yuan, Hsiao-Chun Liu, Kai Wang, Michael Hsiao, Chi-Ying F Huang, Yan-Shen Shan, Andrew S Lee, L James Lee

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted …

Age-Associated Spinal Stenosis In The Turquoise Killifish, Su-Hyeon Cho, Seongsin Lee, Jae-Il Park, Yoon La Yang, Song-Rae Kim, Juhee Ahn, Hoibin Jeong, Hye-Yeon Jung, Nayoung Gwak, Kil-Nam Kim, Yumi Kim

Faculty, Staff and Student Publications

Aging triggers spinal degeneration, including common spinal stenosis, which causes back and leg pain in older individuals, significantly impacting their quality of life. Here, we explored aging traits in turquoise killifish spines, potentially offering a model for age-linked spinal stenosis in humans. Aged turquoise killifish exhibited body shape deformation and increased vertebral collapse, which was further accelerated by spawning. High-resolution CT scans revealed suppressed cortical bone thickness and hemal arch area in vertebrae due to spawning, and osteophyte formation was observed in both aged and breeding fish populations. Scale mineralization mirrored these changes, increasing with age but being suppressed by …

Early Resveratrol Treatment Mitigates Joint Degeneration And Dampens Pain In A Mouse Model Of Pseudoachondroplasia (Psach), Jacqueline T Hecht, Alka C Veerisetty, Debabrata Patra, Mohammad G Hossain, Frankie Chiu, Claire Mobed, Francis H Gannon, Karen L Posey

Faculty, Staff and Student Publications

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 …

Early Resveratrol Treatment Mitigates Joint Degeneration And Dampens Pain In A Mouse Model Of Pseudoachondroplasia (Psach), Jacqueline T Hecht, Alka C Veerisetty, Debabrata Patra, Mohammad G Hossain, Frankie Chiu, Claire Mobed, Francis H Gannon, Karen L Posey

Faculty, Staff and Student Publications

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 …

Adaptive Design Of Mrna-Loaded Extracellular Vesicles For Targeted Immunotherapy Of Cancer, Shiyan Dong, Xuan Liu, Ye Bi, Yifan Wang, Abin Antony, Daeyong Lee, Kristin Huntoon, Seongdong Jeong, Yifan Ma, Xuefeng Li, Weiye Deng, Benjamin R Schrank, Adam J Grippin, Jonghoon Ha, Minjeong Kang, Mengyu Chang, Yarong Zhao, Rongze Sun, Xiangshi Sun, Jie Yang, Jiayi Chen, Sarah K Tang, L James Lee, Andrew S Lee, Lirong Teng, Shengnian Wang, Lesheng Teng, Betty Y S Kim, Zhaogang Yang, Wen Jiang

Faculty, Staff and Student Publications

The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock …

The Effect Of Heat-Moisture Treatment Changed The Binding Of Starch, Protein And Lipid In Rice Flour To Affect Its Hierarchical Structure And Physicochemical Properties, Seung Hee Yoo, Mi Jin Jue, Yu-Hee Kim, Sooyoung Cho, Won-Joong Kim, Kye-Min Kim, Jong In Han, Heeseung Lee

Faculty, Staff and Student Publications

Dexmedetomidine prevents postoperative cognitive dysfunction by inhibiting high-mobility group box 1 (HMGB1), which acts as an inflammatory marker. This study investigated the HMGB1 levels and the cognitive function using a Mini-Cog© score in elderly patients undergoing orthopedic surgery with dexmedetomidine infusion. In total, 128 patients aged ≥ 65 years were analyzed. The patients received saline in the control group and dexmedetomidine in the dexmedetomidine group until the end of surgery. Blood sampling and the Mini-Cog© test were performed before the surgery and on postoperative days 1 and 3. The primary outcomes were the effect of dexmedetomidine on the HMGB1 levels …

Braf D594a Mutation Defines A Unique Biological And Immuno-Modulatory Subgroup Associated With Functional Cd8+ T Cell Infiltration In Colorectal Cancer, Wenjing Li, Chenyi Zhao, Wenhui Li, Yang Gong, Kaili Ma, Yujie Lu, Xiaowei Liu, Lianjun Zhang, Feng Guo

Faculty, Staff and Student Publications

BACKGROUND: BRAF non-V600 mutation occupies a relatively small but critical subset in colorectal cancer (CRC). However, little is known about the biological functions and impacts of BRAF class III mutation in CRC. Here, we aim to explore how D594A mutation impacts on biological behaviors and immune related signatures in murine CRC cells.

METHODS: BRAF V600E (class I), G469V (class II) and D594A (class III) mutant cell lines were established based on MC38 cells. The biological behaviors of cells were evaluated in respect of cell growth, cell proliferation, cell apoptosis, cell migration and invasion by the methods of colony-forming assay, CCK-8 …

Biomechanical Origins Of Proprioceptor Feature Selectivity And Topographic Maps In The Drosophila Leg, Akira Mamiya, Anne Sustar, Igor Siwanowicz, Yanyan Qi, Tzu-Chiao Lu, Pralaksha Gurung, Chenghao Chen, Jasper S Phelps, Aaron T Kuan, Alexandra Pacureanu, Wei-Chung Allen Lee, Hongjie Li, Natasha Mhatre, John C Tuthill

Faculty, Staff and Students Publications

Our ability to sense and move our bodies relies on proprioceptors, sensory neurons that detect mechanical forces within the body. Different subtypes of proprioceptors detect different kinematic features, such as joint position, movement, and vibration, but the mechanisms that underlie proprioceptor feature selectivity remain poorly understood. Using single-nucleus RNA sequencing (RNA-seq), we found that proprioceptor subtypes in the Drosophila leg lack differential expression of mechanosensitive ion channels. However, anatomical reconstruction of the proprioceptors and connected tendons revealed major biomechanical differences between subtypes. We built a model of the proprioceptors and tendons that identified a biomechanical mechanism for joint angle selectivity …

Reprogramming Of Cis-Regulatory Networks During Skeletal Muscle Atrophy In Male Mice, Hongchun Lin, Hui Peng, Yuxiang Sun, Meijun Si, Jiao Wu, Yanlin Wang, Sandhya S Thomas, Zheng Sun, Zhaoyong Hu

Faculty, Staff and Students Publications

A comprehensive atlas of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of cellular structure maintenance, metabolism, and responses to the environment. Here we show, using matched single-nucleus chromatin accessibility and RNA-sequencing from juvenile male C57BL6 mice, an atlas of accessible chromatin regions in both normal and denervated skeletal muscles. We identified cell-type-specific cis-regulatory networks, highlighting the dynamic regulatory circuits mediating transitions between myonuclear types. Through comparison of normal and perturbed muscle, we delineated the reprogramming of cis-regulatory networks in response to denervation, described the interplay of promoters/enhancers and target genes. We further unveil a …