Digital Commons Network^™

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 …

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 …

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 …

Simian Immunodeficiency Virus-Infected Rhesus Macaques With Aids Co-Develop Cardiovascular Pathology And Encephalitis, Kevin S. White, Joshua A. Walker, John Wang, Patrick Autissier, Andrew D. Miller, Nadia N. Abuelezan, Rachel Burrack, Qingsheng Li, Woong-Ki Kim, Kenneth C. Williams

Nebraska Center for Virology: Faculty Publications

Despite effective antiretroviral therapy, HIV co-morbidities remain where central nervous system (CNS) neurocognitive disorders and cardiovascular disease (CVD)-pathology that are linked with myeloid activation are most prevalent. Comorbidities such as neurocogntive dysfunction and cardiovascular disease (CVD) remain prevalent among people living with HIV. We sought to investigate if cardiac pathology (inflammation, fibrosis, cardiomyocyte damage) and CNS pathology (encephalitis) develop together during simian immunodeficiency virus (SIV) infection and if their co-development is linked with monocyte/ macrophage activation. We used a cohort of SIV-infected rhesus macaques with rapid AIDS and demonstrated that SIV encephalitis (SIVE) and CVD pathology occur together more frequently …

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 …

Impacting T-Cell Fitness In Multiple Myeloma: Potential Roles For Selinexor And Xpo1 Inhibitors, Adam Binder, Christopher Walker, Tomer Mark, Muhamed Baljevic

Department of Medical Oncology Faculty Papers

Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate …

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. …

A Phase I Trial Of Sirolimus With "7&3" Induction Chemotherapy In Patients With Newly Diagnosed Acute Myeloid Leukemia, Neil Palmisiano, Grace Jeschke, Lindsay Wilde, Onder Alpdogan, Matthew Carabasi, Joanne Filicko-O'Hara, Dolores Grosso, Thomas Klumpp, Ubaldo Martinez, John L Wagner, Martin Carroll, Alexander Perl, Margaret Kasner

Department of Medicine Faculty Papers

Chemotherapy remains a primary treatment for younger AML patients, though many relapse. Data from our group have shown that highly phosphorylated S6 in blasts may predict response to sirolimus given with chemotherapy. We report the results of a phase I study of this combination in newly diagnosed AML and the pharmacodynamic analysis of pS6 before and after treatment. Subjects received sirolimus (12 mg on day 1, 4 mg daily, days 2-10), then idarubicin and cytarabine (days 4-10). Response was assessed at hematologic recovery or by day 42 using a modified IWG criteria. Fifty-five patients received sirolimus. Toxicity was similar to …

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 …

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, …

Environmental Detection Of Parasites In The Marginalized Paiute Reservations Compared To A Nearby Area, Shannon Mckim, Kristen Kopystynsky, Nathaniel Wolf, Fahim A Akbar, Maria Elena Bottazzi, Peter J Hotez, Rojelio Mejia

Faculty, Staff and Students Publications

The amounts of parasite DNA in soil samples from different playgrounds and other public areas can help identify areas of possible microbe transmission as well as giving indications of possible occurrence of parasite infection in nearby communities. We collected 207 soil samples from parks located on Paiute indigenous tribal areas in southwest Utah and from higher income city of St. George, Utah, and tested them for the presence of 11 parasites that can cause human disease. Molecular tests revealed elevated odds ratio of detecting the helminth Trichuris trichiura 3.072 (1.114 to 8.065) and any protozoa (not including Acanthamoeba ) 3.036 …

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 …

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 …

Activation Of Coagulation And Proinflammatory Pathways In Thrombosis With Thrombocytopenia Syndrome And Following Covid-19 Vaccination, Malika Aid, Kathryn E. Stephenson, Ai-Ris Y. Collier, Joseph P. Nkolola, James V. Michael, Steven E. Mckenzie, Dan H. Barouch

Cardeza Foundation for Hematologic Research

Thrombosis with thrombocytopenia syndrome (TTS) is a rare but potentially severe adverse event following immunization with adenovirus vector-based COVID-19 vaccines such as Ad26.COV2.S (Janssen) and ChAdOx1 (AstraZeneca). However, no case of TTS has been reported in over 1.5 million individuals who received a second immunization with Ad26.COV2.S in the United States. Here we utilize transcriptomic and proteomic profiling to compare individuals who receive two doses of Ad26.COV2.S with those vaccinated with BNT162b2 or mRNA-1273. Initial Ad26.COV2.S vaccination induces transient activation of platelet and coagulation and innate immune pathways that resolve by day 7; by contrast, patients with TTS show robust …

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 …

Research Progress On The Regulation And Mechanism Of Borneol On The Blood-Brain Barrier In Pathological States: A Narrative Review Focused On Ischemic Stroke And Cerebral Glioma, Xinghua Tan, Ke Zhang, Wenyin Shi, Zhihu Tang

Department of Radiation Oncology Faculty Papers

Background and Objective: The blood-brain barrier (BBB) serves as a dynamic, selective shield, safeguarding the central nervous system (CNS) by separating the brain from circulating blood, preserving its microenvironment, and ensuring stability. However, in the presence of brain pathology, drug delivery across the BBB and blood-tumor barrier (BTB) becomes challenging, hindering effective treatments. Borneol exhibits promise in bidirectionally modulating the BBB under pathological conditions, suggesting at potential clinical applications for related diseases. Our primary goal in this review is to investigate borneol’s potential clinical utility in bidirectionally regulating the BBB under pathological conditions.

Methods: The PubMed database, CNKI (China National …

Penyembuhan Luka: Aspek Seluler Dan Biomolekuler, Yefta Moenadjat

Department of Surgery Teaching Materials and Monographs

Mengulas aspek seluler dan molekuler penyembuhan luka di setiap fase, dimulai dari hemostasis, inflamasi dan resolusi inflamasi, proliferasi, dan maturasi. Pada bagian terakhir dulas pula gangguan proses penyembuhan luka (luka kronik, non–healing wound) yang kerap dijumpai di klinik.

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 …

Lower Versus Higher Oxygen Targets For Out-Of-Hospital Cardiac Arrest: A Systematic Review And Meta-Analysis, Xin Cheng, Yu Zhang, Haidong Deng, Yuning Feng, Weelic Chong, Yang Hai, Pengfei Hao, Jialing He, Tiangui Li, Liyuan Peng, Peng Wang, Yangchun Xiao, Fang Fang

Student Papers, Posters & Projects

BACKGROUND: Supplemental oxygen is commonly administered to patients after out-of-hospital cardiac arrest. However, the findings from studies on oxygen targeting for out-of-hospital cardiac arrest are inconclusive. Thus, we conducted a systematic review and meta-analysis to evaluate the impact of lower oxygen target compared with higher oxygen target on patients after out-of-hospital cardiac arrest.

METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, from inception to February 6, 2023, for randomized controlled trials comparing lower and higher oxygen target in adults (aged ≥ 18 years) after out-of-hospital cardiac arrest. We screened studies and extracted data independently. The primary …

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 …