Digital Commons Network^™

Signaling By Intracellular Β2-Adrenergic Receptors Regulates Ampa Receptor Trafficking And Synaptic Plasticity, Boram Lee, Xiaomin Xing, Kyle E. Ireton, Bing Xu, Paul J. Gasser, Johannes W. Hell

Biomedical Sciences Faculty Research and Publications

Signaling by norepinephrine (NE) via adrenergic receptors (ARs) mediates attention, yet the underlying molecular mechanisms are largely unknown. AMPA receptors (AMPARs) form a complex with β2ARs, Gs, adenylyl cyclase, and protein kinase A (PKA) to augment AMPAR phosphorylation and, thereby, surface expression. We show that signaling by intracellular β2ARs is required for these effects and two different forms of long-term potentiation (LTP) that depend on β2AR signaling and phosphorylation of the AMPAR GluA1 subunit on S845. Inhibition of two NE transporters, the organic cation transporter 3 (OCT3) and the plasma membrane monoamine transporter (PMAT), impairs phosphorylation of the AMPAR GluA1 …

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 …

Ifit3 Activation Significantly Contributes To Hiv-1-Associated Neurodegenerative Disorder-Mediated Neuroinflammation, Ranjit Kumar Das, Nirakar Sahoo, Deepa Roy, Chun Xu, Jose Galarza, Maria Camila Mejia Garza, Hansapani Rodrigo, Asim K. Duttaroy, Upal Roy

Health & Biomedical Sciences Faculty Publications

Introduction: The advent of effective combination antiretroviral therapy (cART) has significantly improved HIV-1 treatment, saving millions of lives. However, HAND remains a concern, particularly among aging individuals with HIV-1. The mechanisms underlying HAND are not well understood.

Methods: This study investigated the role of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) and its upstream regulator, signal transducer, and activator of transcription 1 (STAT1), in HAND pathology. Using the SH-SY5Y neuroblastoma cell line and HIV-infected humanized mice, we examined the effects of the cART drugs, HIV Tat protein, and HIV-1 virus on STAT1 and IFIT3 expression.

Results: The results showed that …

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 …

Suppression Of Cardiac Allograft Vasculopathy By A Macrophage Efferocytosis Receptor, Sahil Shah, Aparnaa Ananthakrishnan, Matthew Deberge, Kristofor Glinton, Rebecca T L Jones, Mallory Filipp, Ivana Shen, Joey Lockhart, Connor W Lantz, Edward B Thorp

Faculty, Staff and Student Publications

Cardiac allograft vasculopathy remains a major cause of late morbidity following heart transplantation. While accumulating evidence implicates innate macrophages in the inflammatory progression of CAV, the underlying mechanisms remain incompletely understood. In murine models of CAV, we identified proteolytic cleavage of MERTK, a key anti-inflammatory receptor on macrophages, as a contributing factor to CAV progression. In a model of CAV, MERTK deficiency accelerated allograft rejection and increased intimal leukocyte infiltration. In contrast, mice expressing a genetically cleavage-resistant form of MERTK (MertkCR/CR) exhibited prolonged graft survival, reduced intimal thickening, diminished immune cell infiltration, and decreased circulating effector T cells. …

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 …

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 …

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 …

Progressive Respiratory Failure In A Term Neonate With Abca3 Surfactant Deficiency: Beyond The Common Causes Of Respiratory Distress, Andrew M Beverstock, Hillary C Lee, David S Moreno Mcneill, Morcos Hanna

Faculty, Staff and Students Publications

Background

Case

Astrocytes Expressing Mutant Hnrnpa1 Induce Non-Cell-Autonomous Motor Neuron Death, Qinxue Wu, Xionghao Liu, Tingting Zhang, Shiquan Cui, Bo Huang, Cao Huang, Qilin Cao, Xu-Gang Xia, Hongxia Zhou

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Pathogenic mutation of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is causative to amyotrophic lateral sclerosis (ALS). Neuron death resulting from pathogenic hnRNPA1 may not require its presence across all pertinent cells types, including neurons, glia, and muscles. Rather, the exclusive presence of pathogenic hnRNPA1 in a specific cell type, such as astrocytes, may suffice to substantially alter cellular functions. Consequently, this alteration initiates abnormal interaction within intricate neuron-glia networks, culminating in non-cell-autonomous motor neuron death. To investigate the pivotal role of non-cell-autonomous neuron death in hnRNPA1-associated ALS, we developed transgenic rats overexpressing mutant hnRNPA1 in specifically astrocytes. The confined overexpression of …

Prolonged Exposure To Food Odors Suppresses Feeding Via An Olfactory Bulb-To-Hypothalamus Circuit, Yao Liu, Hailan Liu, Huey-Xian Kelly Wong, Niccole Auld, Kristine M Conde, Yongxiang Li, Meng Yu, Yue Deng, Qingzhuo Liu, Xing Fang, Mengjie Wang, Yuhan Shi, Olivia Z Ginnard, Yuxue Yang, Longlong Tu, Hesong Liu, Jonathan C Bean, Junying Han, Megan E Burt, Sanika V Jossy, Yongjie Yang, Chunmei Wang, Qingchun Tong, Benjamin R Arenkiel, Hongjie Li, Yong Xu, Yang He

The Brown Foundation: Institute of Molecular Medicine

Olfactory perception of food odors is a key determinant of eating behavior, including triggering appetite, facilitating food seeking and influencing food choice. While transient food-related olfactory cues stimulate appetite and provoke cravings in states of hunger, emerging evidence implies that prolonged and sustained exposure to food-derived odor (FO) suppresses feeding. However, the mechanisms by which olfaction induces hypophagia remain elusive. In this study, we show that prolonged FO exposure significantly suppresses food intake in male mice. We identified a subset of neurons in the ventral subiculum (vSub) that are specifically activated by FO. We further discovered that these FO-activated neurons …

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 …

A Multimodal Approach To Assess A Liposomal Carrier’S Biodistribution, Stability, And Clearance, Cayla A Wood, Claire E Jones, Ananthakrishnan Soundaram Jeevarathinam, Riley Watson, Sangheon Han, Jennifer Meyer, Konstantin V Sokolov, Richard R Bouchard

Faculty, Staff and Student Publications

Liposomal carriers, used for site-specific drug delivery, are being investigated for diagnostic approaches by replacing the therapeutic with an imaging contrast agent, exploring potential for selective treatment planning. There remains a critical need to improve in vivo assessment of biodistribution, stability, and clearance kinetics of liposomal carriers. This pilot study presents a multimodal approach in which liposome-encapsulated J-aggregated indocyanine green (ICG) dye (Lipo-JICG) is imaged with high spatial resolution using both in vivo photoacoustic (PA) imaging, to assess the absorbance characteristics of JICG and monomeric ICG, and ex vivo cryofluorescence tomography (CFT), to measure ICG fluorescence. An in vitro assay …

Prolonging Lung Cancer Response To Egfr Inhibition By Targeting The Selective Advantage Of Resistant Cells, Lisa Brunet, David Alexandre, Jiyoung Lee, Maria Del Mar Blanquer-Rosselló, David Bracquemond, Alexis Guernet, Houssein Chhouri, Mathilde Goupil, Zoulika Kherrouche, Arnaud Arabo, Maicol Mancini, Dorthe Cartier, Shen Yao, David Godefroy, Julie Dehedin, Jian-Rong Li, Céline Duparc, Philippe Jamme, Audrey Vinchent, Caroline Bérard, David Tulasne, Sabrina Arena, Alberto Bardelli, Chao Cheng, Byoung Chul Cho, Olivier Wurtz, Cédric Coulouarn, Antonio Maraver, Stuart A Aaronson, Alexis B Cortot, Youssef Anouar, Luca Grumolato

Faculty, Staff and Students Publications

Non-small cell lung cancers (NSCLCs) treated with tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) almost invariably relapse in the long term, due to the emergence of subpopulations of resistant cells. Through a DNA barcoding approach, we show that the clinically approved drug sorafenib specifically abolishes the selective advantage of EGFR-TKI-resistant cells, while preserving the response of EGFR-TKI-sensitive cells. Sorafenib is active against multiple mechanisms of resistance/tolerance to EGFR-TKIs and its effects depend on early inhibition of MAPK-interacting kinase (MKNK) activity and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and later down-regulation of MCL1 and …

Effectiveness Of Glucagon-Like Peptide 1 Receptor Agonists In The Treatment Of Heart Failure, Lisa Kristen Schloemann

SIU Journal of Medical Science Scholarly Works

ABSTRACT

Purpose: The purpose of this article is to review the use of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in heart failure (HF) treatment considering the HF phenotype and comorbidities, including type 2 diabetes mellitus (DM) and obesity.

Method: A PubMed and Google Scholar literature search was conducted with search terms, HF and GLP-1 RA. Seven pertinent articles were retrieved and served as the basis for this clinical review.

Results: The efficacy of GLP-1 RA therapy in patients with heart failure with reduced ejection fractions (HFrEF) is unclear, with one study showing increased adverse cardiac events including tachyarrhythmias, and …

Prefrontal Cortex Astrocytes Modulate Distinct Neuronal Populations To Control Anxiety-Like Behavior, Eunyoung Kim, Hairuo Du, Yanqi Tan, Brandon L Brown, Yaowen Chang, Blanca Díaz-Castro, Jonathan V Sweedler, Xinzhu Yu

Faculty, Staff and Student Publications

Accumulating evidence has supported diverse regulatory functions of astrocytes in different neural circuits as well as various aspects of complex behaviors. However, little is known about how astrocytes regulate different neuronal subpopulations that are linked to specific behavioral aspects within a single brain region. Here, we show that astrocytes in the medial prefrontal cortex (mPFC) encode anxiogenic environmental cues in freely behaving mice. Silencing mPFC astrocyte Ca

Circzfr/Ythdf3 Axis Drives Lymph Node Metastasis In Cervical Cancer Via Fasn Translation, Mingyi Zhou, Yan Gao, Yong Zhang, Lian He, Bo Gao, Yue Zhang, Francois X Claret, George A Calin, Danbo Wang

Faculty, Staff and Student Publications

Background: Lymph node metastasis is a key driver of poor outcomes in cervical cancer. However, the molecular mechanisms of circular RNAs (circRNAs) driving cervical cancer lymph node metastasis remain unclear.

Methods: We identified circZFR, fatty acid synthase (FASN) and YTH N6-methyladenosine RNA binding protein F3 (YTHDF3) protein expression in the cervical cancer patients with long and short disease-free survival (DFS). Functional experiments were performed to investigate the function of circZFR, FASN and YTHDF3 on cell migration and invasion. MeRIP-qPCR, RNA pulldown, RNA Immunoprecipitation (RIP), and Co-Immunoprecipitation (Co-IP) assays were executed to investigate the mechanism of circZFR regulating FASN protein expression. …

Current Mechanobiological Pathways And Therapies Driving Spinal Health, Rahul Kumar, Kyle Sporn, Harlene Kaur, Akshay Khanna, Phani Paladugu, Nasif Zaman, Alireza Tavakkoli

SKMC Student Presentations and Publications

Spinal health depends on the dynamic interplay between mechanical forces, biochemical signaling, and cellular behavior. This review explores how key molecular pathways, including integrin, yeas-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), Piezo, and Wingless/Integrated (Wnt) with β-catenin, actively shape the structural and functional integrity of spinal tissues. These signaling mechanisms respond to physical cues and interact with inflammatory mediators such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), driving changes that lead to disc degeneration, vertebral fractures, spinal cord injury, and ligament failure. New research is emerging that shows scaffold designs that can …

Targeted Proteomic Analysis Identifies Acvrl1 As A Marker Of Cerebral Edema In Aneurysmal Subarachnoid Hemorrhage, Bosco Seong Kyu Yang, Lena O'Keefe, Sarah Hinds, Hua Chen, Athziry Paz, Jude Savarraj, Han-Gil Jeong, Moon-Ku Han, Aaron Gusdon, Xuefang Sophie Ren, Spiros Blackburn, Huimahn Alex Choi

Faculty, Staff and Student Publications

Cerebral edema (CE) is a major component of early brain injury from aneurysmal subarachnoid hemorrhage (SAH). Despite the utility of blood-based protein markers, biomarkers targeting cerebral edema have yet to be developed. We performed a targeted proteomic search analyzing 141 proteins in plasma samples taken from 80 adult patients within 48 hours after aneurysmal rupture to identify plasma biomarkers of cerebral edema. The protein expression profiles were analyzed for associations with a higher level of the subarachnoid hemorrhage early brain edema score measured in admission computed tomography scans. Five differentially expressed proteins-brorin, ectodysplasin A2 receptor, layilin, scavenger receptor class A …

Bcg Vaccine-Induced Innate And Adaptive Pulmonary Immunity Correlating With Protective Efficacy Against Mycobacterium Tuberculosis In The Lungs, Mayank Khanna, Alistair J. Ramsay

School of Graduate Studies Faculty Publications

Background/Objectives: Effective prophylaxis for Mycobacterium tuberculosis (Mtb) requires greater understanding of immune correlates of protection. With renewed interest in BCG as an Mtb vaccine, particularly via the intravenous (IV) route, our objective was to characterize both innate and adaptive immune correlates of vaccine-induced pulmonary immunity as potential biomarkers for protective efficacy in a murine model of Mtb infection. Methods: Mice were given BCG via different routes and some boosted with recombinant virus constructs encoding Mtb Ag85B. Responding innate lymphoid cell (ILC) populations, T cells and B cells were analyzed by fluorescence activated cell sorting (FACS) for surface markers and by …

Silvestrol Inhibits Nasopharyngeal Carcinoma Cells And Synergizes With Cx‑5461: Insights From A Proteomics Study, Maelinda Daker, Munirah Ahmad, Alan Khoo, Lu Ping Tan, Siok-Fong Chin, Siaw San Hwang, Paul Neilsen

Department of Medical Oncology Faculty Papers

Nasopharyngeal carcinoma (NPC) is a cancer arising from the epithelial cells of the nasopharynx, which is rare in Western countries but extremely prevalent in Borneo and the Southern China region. Present-day hurdles in NPC treatment that lead to poor quality of life and poor survival include distant metastasis and resistance to chemoradiotherapy. Silvestrol and its 5'''-epimer, episilvestrol, are compounds isolated from the plant Aglaia stellatopilosa, which is endemic to Borneo. Silvestrol, a protein synthesis inhibitor, preferentially inhibits the translation of cancer-associated mRNAs. CX-5461 is an inhibitor of RNA polymerase I that catalyzes rRNA synthesis. The present study sought to …

Lipid-Laden Microglia: Characterization And Roles In Diseases, Jiani Xing, Takese Mckenzie, Jian Hu

Faculty, Staff and Student Publications

Microglia are resident phagocytes of the central nervous system that play an essential role in brain development and homeostasis. When the intracellular lipid content exceeds the metabolic capacity of microglia, lipid droplets accumulate, giving rise to a distinct population termed lipid-laden microglia (LLMs). LLMs have been implicated in various neuroinflammatory and neurodegenerative diseases, functioning as both regulators/indicators of inflammation and potential therapeutic targets. This review summarizes the current research on LLMs, focusing on disease-specific regulators and functions, protective roles, interactions with neighboring cells, and advances in diagnostic and analytical tools. We also discuss the blurred distinction between LLMs and macrophages, …

Therapeutic Targeting Of Syndecan-1 Axis Overcomes Acquired Resistance To Kras-Targeted Therapy In Gastrointestinal Cancers, Madelaine S Theardy, Mitsunobu Takeda, Alexey Sorokin, Shuaitong Chen, Zecheng Yang, Xiaofei Wang, Preeti Kanikarla, Oluwadara Coker, Phuoc Nguyen, Yongkun Wei, Jun Yao, Liang Yan, Yanqing Jin, Yiming Cai, Masakatsu Paku, Ziheng Chen, Kara Z Li, Francesca Citron, Hideo Tomihara, Sisi Gao, Angela K Deem, Jun Zhao, Huamin Wang, Samir Hanash, Ronald A Depinho, Anirban Maitra, Giulio F Draetta, Haoqiang Ying, Scott Kopetz, Wantong Yao

Faculty, Staff and Student Publications

The therapeutic benefit of recently developed mutant KRAS (KRAS∗) inhibitors remains limited by the rapid onset of resistance. Here, we aim to delineate mechanisms underlying acquired resistance and identify actionable targets for overcoming this clinical challenge. Previously, we identified syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by KRAS∗. By leveraging both pancreatic and colorectal cancer models, we show that surface SDC1 expression initially diminishes upon KRAS∗ inhibition but recovers in tumor cells that bypass KRAS∗ dependency. Mechanistically, we reveal that YAP1 activation drives the recovery of SDC1 surface localization to enhance macropinocytosis-mediated …

Causes Of Symptoms And Symptom Persistence In Long Covid And Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Anthony L Komaroff, Robert Dantzer

Faculty, Staff and Student Publications

Debilitating symptoms for many years can follow acute COVID-19 ("long COVID"), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and various post-acute infection syndromes (PAISs). Together, long COVID and ME/CFS affect 60-400 million individuals, globally. Many similar underlying biological abnormalities have been identified in both conditions including autoantibodies against neural targets, endothelial dysfunction, acquired mitochondrial dysfunction, and a pro-inflammatory gut microbiome. Each of these abnormalities may directly cause some of the symptoms. In addition, the symptoms also may be caused by ancient, evolutionarily conserved symptomatic and metabolic responses to vital threats-sickness behavior and torpor-responses mediated by specific, recently discovered neural circuits. These neural …

Trpc4 Regulates Limbic Behavior And Neuronal Development By Stabilizing Dendrite Branches Through Actomyosin-Driven Integrin Activation, Jaepyo Jeon, Travis I Moore, Insuk So, Marc Freichel, Veit Flockerzi, Lutz Birnbaumer, Michael X Zhu

Faculty, Staff and Student Publications

Transient Receptor Potential Canonical 4 (TRPC4) channels have been implicated in multiple neurological functions, including anxiety and sociability. TRPC4 variants were also found in patients with autism. However, the contributions of TRPC4 to neurodevelopment remain undefined. Here, we show that neurobehavioral deficits appear early in young TRPC4 knockout (Trpc4^−/−) mice immediately after weaning, manifesting as alterations in multiple, limbic-related behaviors, such as nesting, marble burying, burrowing, self-grooming, and social interactions. Hippocampal neurons of Trpc4−/− mice exhibit reduced dendritic arborization both in vivo and in vitro. Mechanistically, we found that TRPC4 expression in dendrites surged at the …

Anti-Tumor Activity Of Camptothecin Analog Conjugate Of An Rspo4-Based Peptibody Targeting Lgr4/5/6 In Preclinical Models Of Colorectal Cancer, Yukimatsu Toh, Ling Wu, Jianghua Tu, Zhengdong Liang, Adela M Aldana, Jake J Wen, Li Li, Sheng Pan, Julie H Rowe, Martha E Hensel, Carolyn L Hodo, Rick A Finch, Kendra S Carmon, Qingyun J Liu

The Brown Foundation: Institute of Molecular Medicine

Background: Antibody-drug conjugates (ADCs) are a significant advancement in targeted cancer therapy, but none are approved for colorectal cancer (CRC). LGR4/5/6, highly expressed in most CRCs, are promising targets. While LGR5-targeting ADCs show strong anti-tumor effects, their efficacy is limited by LGR5 loss in some CRC cells. RSPO4, a natural ligand for LGR4/5/6, binds all three receptors with high affinity. This research develops RSPO4-based peptibody drug-conjugates (PDCs) to simultaneously target LGR4/5/6, offering a novel therapeutic approach for CRC.

Methods: LGR4/5/6 expression in CRCs was analysed using RNA-seq datasets and Western blot. Peptibody binding affinities were measured, conjugated to camptothecin analog, …

Mechano-Signal Transduction Pathways Of The Diaphragmatic Muscle And Role Of Cytoskeleton, Junaith S Mohamed, Patricia S Pardo, Aladin M Boriek

Faculty, Staff and Students Publications

Mechanotransduction, also referred to as mechano-signal transduction, is a biophysical process wherein cells perceive and respond to mechanical stimuli by converting them into biochemical signals that initiate specific cellular responses. This mechanism is fundamental to the development and growth, and proper functioning of mechanically active tissues, such as the diaphragm-a respiratory muscle vital for breathing in mammals. In vivo, the diaphragm is subjected to transdiaphragmatic pressure, and therefore, its muscle fibers are subjected to mechanical forces not only in the direction of the muscle fibers but also in the direction transverse to the fibers. Previous research conducted in our laboratory …

Management Of Critically Ill Patients Following Earthquake Disasters, Esat Kivanç Kaya, Burçi̇n Halaçli, Mehmet Yildirim, Arzu Topeli̇

Turkish Journal of Medical Sciences

The devastating earthquakes that struck southeastern Turkiye on February 6, 2023, emphasized the profound societal and healthcare challenges posed by natural disasters. These events highlighted the essential need for healthcare professionals to be well-prepared and equipped with the expertise to manage such crises effectively. Earthquake-induced trauma presents a wide array of medical and surgical complications, frequently requiring urgent hospitalization and specialized management for critically ill patients. However, the limited availability of comprehensive data and evidence-based guidelines complicates optimal care delivery in these scenarios. This review outlines current recommendations for the multidisciplinary management of critically ill patients with earthquake-related trauma. It …

Mirna-Target Gene Network Analysis In Siblings With Cystic Fibrosis And Phenotypic Variability, Ayberk Mustafaoğlu, Senem Noyan, Yeli̇z Z. Akkaya Ulum, Bala Gür Dedeoğlu, Nagehan Emi̇rali̇oğlu, Uğur Özçeli̇k, Ebru Yalçin, Deni̇z Doğru, Nural Ki̇per, Di̇dem Dayangaç Erden

Turkish Journal of Medical Sciences

Background/aim: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF is characterized by respiratory tract infections, pancreatic insufficiency, meconium ileus, intestinal obstruction, and male infertility. A genotype to phenotype correlation is difficult to establish because of the heterogeneity of disease severity. Even patients with the same CFTR mutation can have varying clinical severities. In recent years, studies have explored the role of microRNA (miRNA) expression in the regulation of respiratory diseases. However, no research has been conducted to date on miRNAs in siblings with the same CFTR mutation. …