Digital Commons Network^™

Cdk8/Cdk19 Promotes Mitochondrial Fission Through Drp1 Phosphorylation And Can Phenotypically Suppress Pink1 Deficiency In Drosophila, Jenny Zhe Liao, Hyung-Lok Chung, Claire Shih, Kenneth Kin Lam Wong, Debdeep Dutta, Zelha Nil, Catherine Grace Burns, Oguz Kanca, Ye-Jin Park, Zhongyuan Zuo, Paul C Marcogliese, Katherine Sew, Hugo J Bellen, Esther M Verheyen

Faculty, Staff and Students Publications

Cdk8 in Drosophila is the orthologue of vertebrate CDK8 and CDK19. These proteins have been shown to modulate transcriptional control by RNA polymerase II. We found that neuronal loss of Cdk8 severely reduces fly lifespan and causes bang sensitivity. Remarkably, these defects can be rescued by expression of human CDK19, found in the cytoplasm of neurons, suggesting a non-nuclear function of CDK19/Cdk8. Here we show that Cdk8 plays a critical role in the cytoplasm, with its loss causing elongated mitochondria in both muscles and neurons. We find that endogenous GFP-tagged Cdk8 can be found in both the cytoplasm and nucleus. …

Fourteen-Day Vonoprazan-Based Bismuth Quadruple Therapy For H Pylori Eradication In An Area With High Clarithromycin And Levofloxacin Resistance: A Prospective Randomized Study (Vq-Hp Trial), Nuttapat Tungtrongchitr, Phubordee Bongkotvirawan, Sarita Ratana-Amornpin, Sith Siramolpiwat, Thanee Eiamsitrakoon, Pornpen Gamnarai, Arti Wongcha-Um, Yoshio Yamaoka, Kammal Kumar Pawa, Ratha-Korn Vilaichone

Faculty, Staff and Students Publications

Potassium-competitive acid blockers (P-CABs) provide potent acid inhibition, yet studies on P-CAB-based quadruple therapy for H. pylori eradication are limited. We theorized that integrating bismuth subsalicylate into a quadruple therapy regimen could enhance eradication rates. However, data on the efficacy of vonoprazan bismuth quadruple therapy are notably scarce. Therefore, the aim of this study was to evaluate the efficacy of vonoprazan-based bismuth quadruple therapy in areas with high clarithromycin and levofloxacin resistance. This was a prospective, single-center, randomized trial conducted to compare the efficacy of 7-day and 14-day vonoprazan-based bismuth quadruple therapy for H. pylori eradication between June 1, 2021, …

Ml241 Antagonizes Erk 1/2 Activation And Inhibits Rotavirus Proliferation, Jinlan Wang, Xiaoqing Hu, Jinyuan Wu, Xiaochen Lin, Rong Chen, Chenxing Lu, Xiaopeng Song, Qingmei Leng, Yan Li, Xiangjing Kuang, Jinmei Li, Lida Yao, Xianqiong Tang, Jun Ye, Guangming Zhang, Maosheng Sun, Yan Zhou, Hongjun Li

Faculty, Staff and Student Publications

Rotavirus (RV) is the main pathogen that causes severe diarrhea in infants and children under 5 years of age. No specific antiviral therapies or licensed anti-rotavirus drugs are available. It is crucial to develop effective and low-toxicity anti-rotavirus small-molecule drugs that act on novel host targets. In this study, a new anti-rotavirus compound was selected by ELISA, and cell activity was detected from 453 small-molecule compounds. The anti-RV effects and underlying mechanisms of the screened compounds were explored. In vitro experimental results showed that the small-molecule compound ML241 has a good effect on inhibiting rotavirus proliferation and has low cytotoxicity …

Tissue-Specific Atlas Of Trans-Models For Gene Regulation Elucidates Complex Regulation Patterns, Robert Dagostino, Assaf Gottlieb

Faculty, Staff and Student Publications

BACKGROUND: Deciphering gene regulation is essential for understanding the underlying mechanisms of healthy and disease states. While the regulatory networks formed by transcription factors (TFs) and their target genes has been mostly studied with relation to cis effects such as in TF binding sites, we focused on trans effects of TFs on the expression of their transcribed genes and their potential mechanisms.

RESULTS: We provide a comprehensive tissue-specific atlas, spanning 49 tissues of TF variations affecting gene expression through computational models considering two potential mechanisms, including combinatorial regulation by the expression of the TFs, and by genetic variants within the …

Eye Infection Risks From Pseudomonas Aeruginosa Via Hand Soap And Eye Drops, Anna Gitter, Kristina D Mena, Karla S Mendez, Fuqing Wu, Charles P Gerba

Faculty, Staff and Student Publications

Eye infections from bacterial contamination of bulk-refillable liquid soap dispensers and artificial tear eye drops continue to occur, resulting in adverse health outcomes that include impaired vision or eye enucleation. Pseudomonas aeruginosa (P. aeruginosa), a common cause of eye infections, can grow in eye drop containers and refillable soap dispensers to high numbers. To assess the risk of eye infection, a quantitative microbial risk assessment for P. aeruginosa was conducted to predict the probability of an eye infection for two potential exposure scenarios: (i) individuals using bacteria-contaminated eye drops and (ii) contact lens wearers washing their hands with …

Surface-Functionalized Magnetic Silica-Malachite Tricomposite (Fe–M–Si Tricomposite): A Promising Adsorbent For The Removal Of Cypermethrin, Shaoyu Kong, Min Ouyang, Yi An, Wei Cao, Xiaobo Chen

Faculty, Staff and Student Publications

Surface charges of catalysts have important influences on the thermodynamics and kinetics of electrochemical reactions. Herein, we develop a modified version of the grand-canonical potential kinetics (GCP-K) method based on density functional theory (DFT) calculations to explore the effect of surface charges on reaction thermodynamics and kinetics. Using the hydrogen evolution reaction (HER) on the Pt(111) surface as an example, we show how to track the change of surface charge in a reaction and how to analyze its influence on the kinetics. Grand-canonical calculations demonstrate that the optimum hydrogen adsorption energy on Pt under the standard hydrogen electrode condition (SHE) …

Brafv600e-Mutant Metastatic Nsclc: Disease Overview And Treatment Landscape, David Planchard, Rachel E Sanborn, Marcelo V Negrao, Aria Vaishnavi, Egbert F Smit

Faculty, Staff and Student Publications

In this review, we cover the current understanding of BRAF mutations and associated clinical characteristics in patients with metastatic NSCLC, approved and emerging treatment options, BRAF sequencing approaches, and unmet needs. The BRAFV600E mutation confers constitutive activity of the MAPK pathway, leading to enhanced growth, proliferation, and survival of tumor cells. Testing for BRAF mutations enables patients to be treated with therapies that directly target BRAFV600E and the MAPK pathway, but BRAF testing lags behind other oncogene testing in metastatic NSCLC. Additional therapies targeting BRAFV600E mutations provide options for patients with metastatic NSCLC. Emerging therapies and combinations under investigation could …

Emerging Variants Develop Total Escape From Potent Monoclonal Antibodies Induced By Ba4/5 Infection, Chang Liu, Raksha Das, Aiste Dijokaite-Guraliuc, Daming Zhou, Alexander J Mentzer, Piyada Supasa, Muneeswaran Selvaraj, Helen M E Duyvesteyn, Thomas G Ritter, Nigel Temperton, Paul Klenerman, Susanna J Dunachie, Neil G Paterson, Mark A Williams, David R Hall, Elizabeth E Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I Stuart, Gavin R Screaton

Faculty, Staff and Student Publications

The rapid evolution of SARS-CoV-2 is driven in part by a need to evade the antibody response in the face of high levels of immunity. Here, we isolate spike (S) binding monoclonal antibodies (mAbs) from vaccinees who suffered vaccine break-through infections with Omicron sub lineages BA.4 or BA.5. Twenty eight potent antibodies are isolated and characterised functionally, and in some cases structurally. Since the emergence of BA.4/5, SARS-CoV-2 has continued to accrue mutations in the S protein, to understand this we characterize neutralization of a large panel of variants and demonstrate a steady attrition of neutralization by the panel of …

Revolutionizing Diabetic Foot Ulcer Care: The Senotherapeutic Approach, Guiqin Zhang, Priyadarshani Nadeeshika Samarawickrama, Li Gui, Yuan Ma, Mei Cao, Hong Zhu, Wei Li, Honglin Yang, Kecheng Li, Yang Yang, Enfang Zhu, Wen Li, Yonghan He

Faculty, Staff and Student Publications

Diabetic foot ulcers (DFUs) are a prevalent and profoundly debilitating complication that afflicts individuals with diabetes mellitus (DM). These ulcers are associated with substantial morbidity, recurrence rates, disability, and mortality, imposing substantial economic, psychological, and medical burdens. Timely detection and intervention can mitigate the morbidity and disparities linked to DFU. Nevertheless, current therapeutic approaches for DFU continue to grapple with multifaceted limitations. A growing body of evidence emphasizes the crucial role of cellular senescence in the pathogenesis of chronic wounds. Interventions that try to delay cellular senescence, eliminate senescent cells (SnCs), or suppress the senescence-associated secretory phenotype (SASP) have shown …

Self-Assembled Sting-Activating Coordination Nanoparticles For Cancer Immunotherapy And Vaccine Applications, Xiaoqi Sun, Xuehui Huang, Kyung Soo Park, Xingwu Zhou, Andrew A Kennedy, Carla D Pretto, Qi Wu, Ziye Wan, Yao Xu, Wang Gong, Jonathan Z Sexton, Andrew W Tai, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

The cGAS-STING pathway plays a crucial role in innate immune activation against cancer and infections, and STING agonists based on cyclic dinucleotides (CDN) have garnered attention for their potential use in cancer immunotherapy and vaccines. However, the limited drug-like properties of CDN necessitate an efficient delivery system to the immune system. To address these challenges, we developed an immunostimulatory delivery system for STING agonists. Here, we have examined aqueous coordination interactions between CDN and metal ions and report that CDN mixed with Zn2+ and Mn2+ formed distinctive crystal structures. Further pharmaceutical engineering led to the development of a functional coordination …

Microbiome And Cancer Immunotherapies, Haoyan Chen, Laurence Zitvogel, Zhi Peng, Xiaochen Yin, Florencia Mcallister

Faculty, Staff and Student Publications

Here, we present 3 different perspectives on how the microbiome has impacted cancer patients, treatment, and clinical studies. We hear about the challenges of implementing microbiome analyses into the clinics, the impact these analyses might have on patients' care, and treatment in the future, specifically for gastric cancer treatment. These are a few of the many voices that are highlighting the role of the microbiome in cancer development, treatment, and clinical outcomes.

Jennifer A Wargo, Nadim J Ajami, And Carrie R Daniel-Macdougall, Jennifer A Wargo, Nadim J Ajami, Carrie R Daniel-Macdougall

Faculty, Staff and Student Publications

Dr. Jennifer A. Wargo, Dr. Nadim J. Ajami, and Dr. Carrie R. Daniel-MacDougall describe their academic and clinical work on the role of the microbiome to determine response to immunotherapies and discuss current challenges and potential needs to integrate their findings into clinical practice.

Multilocus Pathogenic Variants Contribute To Intrafamilial Clinical Heterogeneity: A Retrospective Study Of Sibling Pairs With Neurodevelopmental Disorders, Tugce Bozkurt-Yozgatli, Davut Pehlivan, Richard A Gibbs, Ugur Sezerman, Jennifer E Posey, James R Lupski, Zeynep Coban-Akdemir

Faculty, Staff and Students Publications

BACKGROUND: Multilocus pathogenic variants (MPVs) are genetic changes that affect multiple gene loci or regions of the genome, collectively leading to multiple molecular diagnoses. MPVs may also contribute to intrafamilial phenotypic variability between affected individuals within a nuclear family. In this study, we aim to gain further insights into the influence of MPVs on a disease manifestation in individual research subjects and explore the complexities of the human genome within a familial context.

METHODS: We conducted a systematic reanalysis of exome sequencing data and runs of homozygosity (ROH) regions of 47 sibling pairs previously diagnosed with various neurodevelopmental disorders (NDD). …

Genetic Testing For Supravalvar Aortic Stenosis: What To Do When It Is Not Williams Syndrome, Sara B Stephens, Tyler Novy, Gabrielle N Spurzem, Benjamin Jacob, Taylor Beecroft, Emily Soludczyk, Beth A Kozel, Justin Weigand, Shaine A Morris

Faculty, Staff and Students Publications

Background: We aimed to describe the frequency and yield of genetic testing in supravalvar aortic stenosis (SVAS) following negative evaluation for Williams-Beuren syndrome (WS).

Methods and results: This retrospective cohort study included patients with SVAS at our institution who had a negative evaluation for WS from May 1991 to September 2021. SVAS was defined as (1) peak supravalvar velocity of ≥2 meters/second, (2) sinotubular junction or ascending aortic Z score < -2.0, or (3) sinotubular junction Z score < -1.5 with family history of SVAS. Patients with complex congenital heart disease, aortic valve disease as the primary condition, or only postoperative SVAS were excluded. Genetic testing and diagnoses were reported. Of 162 patients who were WS negative meeting inclusion criteria, 61 had genetic testing results available (38%). Chromosomal microarray had been performed in 44 of 61 and was nondiagnostic for non-WS causes of SVAS. Sequencing of 1 or more genes was performed in 47 of 61. Of these, 39 of 47 underwent ELN sequencing, 20 of 39 (51%) of whom had a diagnostic variant. Other diagnoses made by gene sequencing were Noonan syndrome (3 PTPN11, 1 RIT1), Alagille …

Multi-Omics Analysis Reveals Immune Features Associated With Immunotherapy Benefit In Patients With Squamous Cell Lung Cancer From Phase Iii Lung-Map S1400i Trial, Edwin Roger Parra, Jiexin Zhang, Dzifa Yawa Duose, Edgar Gonzalez-Kozlova, Mary W Redman, Hong Chen, Ganiraju C Manyam, Gayatri Kumar, Jianhua Zhang, Xingzhi Song, Rossana Lazcano, Mario L Marques-Piubelli, Caddie Laberiano-Fernandez, Frank Rojas, Baili Zhang, Len Taing, Aashna Jhaveri, Jacob Geisberg, Jennifer Altreuter, Franziska Michor, James Provencher, Joyce Yu, Ethan Cerami, Radim Moravec, Kasthuri Kannan, Rajyalakshmi Luthra, Gheath Alatrash, Hsin-Hui Huang, Hui Xie, Manishkumar Patel, Kai Nie, Jocelyn Harris, Kimberly Argueta, James Lindsay, Roshni Biswas, Stephen Van Nostrand, Seunghee Kim-Schulze, Jhanelle E Gray, Roy S Herbst, Ignacio I Wistuba, Scott Gettinger, Karen Kelly, Lyudmila Bazhenova, Sacha Gnjatic, J Jack Lee, Jianjun Zhang, Cara Haymaker

Faculty, Staff and Student Publications

PURPOSE: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need.

EXPERIMENTAL DESIGN: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non-small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink.

RESULTS: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse …

Longitudinal Regression Of Covariance Matrix Outcomes, Yi Zhao, Brian S Caffo, Xi Luo

Faculty, Staff and Student Publications

In this study, a longitudinal regression model for covariance matrix outcomes is introduced. The proposal considers a multilevel generalized linear model for regressing covariance matrices on (time-varying) predictors. This model simultaneously identifies covariate-associated components from covariance matrices, estimates regression coefficients, and captures the within-subject variation in the covariance matrices. Optimal estimators are proposed for both low-dimensional and high-dimensional cases by maximizing the (approximated) hierarchical-likelihood function. These estimators are proved to be asymptotically consistent, where the proposed covariance matrix estimator is the most efficient under the low-dimensional case and achieves the uniformly minimum quadratic loss among all linear combinations of the …

Icariin Accelerates Bone Regeneration By Inducing Osteogenesis-Angiogenesis Coupling In Rats With Type 1 Diabetes Mellitus, Sheng Zheng, Guan-Yu Hu, Jun-Hua Li, Jia Zheng, Yi-Kai Li

Faculty, Staff and Student Publications

BACKGROUND: Icariin (ICA), a natural flavonoid compound monomer, has multiple pharmacological activities. However, its effect on bone defect in the context of type 1 diabetes mellitus (T1DM) has not yet been examined.

AIM: to explore the role and potential mechanism of ICA on bone defect in the context of T1DM.

METHODS: The effects of ICA on osteogenesis and angiogenesis were evaluated by alkaline phosphatase staining, alizarin red S staining, quantitative real-time polymerase chain reaction, Western blot, and immunofluorescence. Angiogenesis-related assays were conducted to investigate the relationship between osteogenesis and angiogenesis. A bone defect model was established in T1DM rats. The …

Vhl Governs M6a Modification And Pik3r3 Mrna Stability In Clear Cell Renal Cell Carcinomas, Hyemin Lee, Li Zhuang, Boyi Gan

Faculty, Staff and Student Publications

N6-Methyladenosine (m6A), a prevalent posttranscriptional modification, plays an important role in cancer progression. Clear cell renal cell carcinoma (ccRCC) is chiefly associated with the loss of the von Hippel-Lindau (VHL) gene, encoding a component of the E3 ubiquitin ligase complex. In this issue of the JCI, Zhang and colleagues unveiled a function of VHL beyond its canonical role as an E3 ubiquitin ligase in regulating hypoxia-inducible factors (HIFs). It also governed m6A modification by orchestrating the assembly of m6A writer proteins METTL3 and METTL14, thereby stabilizing PIK3R3 mRNA. Mechanistically, PIK3R3 contributed to p85 ubiquitination, which restrained PI3K/AKT signaling and consequently …

Vitamin A Status Modulates Epithelial Mesenchymal Transition In The Lung: The Role Of Furin, M Teresa Cabezuelo, Luis Torres, Elena Ortiz-Zapater, Gerardo López-Rodas, M Pilar Marín, Joaquín Timoneda, Juan R Viña, Rosa Zaragozá, Teresa Barber

Faculty, Staff and Student Publications

Vitamin A deficiency (VAD) induced TGF-β hyperactivation and reduced expression of cell adhesion proteins in the lung, suggesting that the disruption of retinoic acid (RA) signaling leads to epithelial-mesenchymal transition (EMT). To elucidate the role of lung vitamin A status in EMT, several EMT markers and the expression of the proprotein convertase furin, which activates TGF-β, were analyzed in two experimental models. Our in vivo model included control rats, VAD rats, and both control rats and VAD rats, treated with RA. For the in vitro studies, human bronchoalveolar epithelial cells treated with RA were used. Our data show that EMT …

Identifying Covariate-Related Subnetworks For Whole-Brain Connectome Analysis, Shuo Chen, Yuan Zhang, Qiong Wu, Chuan Bi, Peter Kochunov, L Elliot Hong

Faculty, Staff and Student Publications

Whole-brain connectome data characterize the connections among distributed neural populations as a set of edges in a large network, and neuroscience research aims to systematically investigate associations between brain connectome and clinical or experimental conditions as covariates. A covariate is often related to a number of edges connecting multiple brain areas in an organized structure. However, in practice, neither the covariate-related edges nor the structure is known. Therefore, the understanding of underlying neural mechanisms relies on statistical methods that are capable of simultaneously identifying covariate-related connections and recognizing their network topological structures. The task can be challenging because of false-positive …

Hammerhead-Type Fxr Agonists Induce An Enhancer Rna Fincor That Ameliorates Nonalcoholic Steatohepatitis In Mice, Jinjing Chen, Ruoyu Wang, Feng Xiong, Hao Sun, Byron Kemper, Wenbo Li, Jongsook Kemper

Faculty, Staff and Student Publications

The nuclear receptor, farnesoid X receptor (FXR/NR1H4), is increasingly recognized as a promising drug target for metabolic diseases, including nonalcoholic steatohepatitis (NASH). Protein-coding genes regulated by FXR are well known, but whether FXR also acts through regulation of long non-coding RNAs (lncRNAs), which vastly outnumber protein-coding genes, remains unknown. Utilizing RNA-seq and global run-on sequencing (GRO-seq) analyses in mouse liver, we found that FXR activation affects the expression of many RNA transcripts from chromatin regions bearing enhancer features. Among these we discovered a previously unannotated liver-enriched enhancer-derived lncRNA (eRNA), termed FXR-induced non-coding RNA (

Risk Assessment And Sources Apportionment Of Toxic Metals In Two Commonly Consumed Fishes From A Subtropical Estuarine Wetland System, Md Moudud Ahmed, As-Ad Ujjaman Nur, Salma Sultana, Yeasmin N Jolly, Bilal Ahamad Paray, Takaomi Arai, Jimmy Yu, Mohammad Belal Hossain

Faculty, Staff and Student Publications

The widespread occurrence of heavy metals in aquatic environments, resulting in their bioaccumulation within aquatic organisms like fish, presents potential hazards to human health. This study investigates the concentrations of five toxic heavy metals (Pb, Hg, Zn, Cu, and Cr) and their potential health implications in two economically important fish species (Otolithoides pama and Labeo bata) from a subtropical estuarine wetland system (Feni estuary, Bangladesh). Muscle and gill samples from 36 individual fish were analyzed using energy dispersive X-ray fluorescence (EDXRF). The results revealed that the average quantities of heavy metals in both fishes' muscle followed the declining …

First-Principles Study Of Electronic Properties Of Substitutionally Doped Monolayer Snp3, Junfeng Jin, Fang Lv, Wei Cao, Ziyu Wang

Faculty, Staff and Student Publications

Isovalent doping offers a method to enhance the thermoelectric properties of semiconductors, yet its influence on the phonon structure and propagation is often overlooked. Here, we take CdX (X=Te, Se) compounds as an example to study the role of isovalent doping in thermoelectrics by first-principles calculations in combination with the Boltzmann transport theory. The electronic and phononic properties of Cd8Se8, Cd8Se7Te, Cd8Te8, and Cd8Te7Se are compared. The results suggest that isovalent doping with CdX significantly improves the thermoelectric performance. Due to the similar properties of Se and Te atoms, the electronic properties remain unaffected. Moreover, doping enhances anharmonic phonon scattering, …

Afamitresgene Autoleucel For Advanced Synovial Sarcoma And Myxoid Round Cell Liposarcoma (Spearhead-1): An International, Open-Label, Phase 2 Trial, Sandra P D'Angelo, Dejka M Araujo, Albiruni R Abdul Razak, Mark Agulnik, Steven Attia, Jean-Yves Blay, Irene Carrasco Garcia, John A Charlson, Edwin Choy, George D Demetri, Mihaela Druta, Edouard Forcade, Kristen N Ganjoo, John Glod, Vicki L Keedy, Axel Le Cesne, David A Liebner, Victor Moreno, Seth M Pollack, Scott M Schuetze, Gary K Schwartz, Sandra J Strauss, William D Tap, Fiona Thistlethwaite, Claudia Maria Valverde Morales, Michael J Wagner, Breelyn A Wilky, Cheryl Mcalpine, Laura Hudson, Jean-Marc Navenot, Tianjiao Wang, Jane Bai, Stavros Rafail, Ruoxi Wang, Amy Sun, Lilliam Fernandes, Erin Van Winkle, Erica Elefant, Colin Lunt, Elliot Norry, Dennis Williams, Swethajit Biswas, Brian A Van Tine

Faculty, Staff and Student Publications

Background: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.

Methods: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid …

Genome-Wide Screening Identifies Trim33 As An Essential Regulator Of Dendritic Cell Differentiation, Ioanna Tiniakou, Pei-Feng Hsu, Lorena S Lopez-Zepeda, Görkem Garipler, Eduardo Esteva, Nicholas M Adams, Geunhyo Jang, Chetna Soni, Colleen M Lau, Fan Liu, Alireza Khodadadi-Jamayran, Tori C Rodrick, Drew Jones, Aristotelis Tsirigos, Uwe Ohler, Mark T Bedford, Stephen D Nimer, Vesa Kaartinen, Esteban O Mazzoni, Boris Reizis

Faculty, Staff and Student Publications

The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected Flt3L-driven DC differentiation using CRISPR-Cas9-based screening. Genome-wide screening identified multiple regulators of DC differentiation including subunits of TSC and GATOR1 complexes, which restricted progenitor growth but enabled DC differentiation by inhibiting mTOR signaling. An orthogonal screen identified the transcriptional repressor Trim33 (TIF-1γ) as a regulator of DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes …

In Silico And In Vitro Study Of Isoquercitrin Against Kidney Cancer And Inflammation By Triggering Potential Gene Targets, Safia Iqbal, Md Rezaul Karim, Shahnawaz Mohammad, Jong Chan Ahn, Anjali Kariyarath Valappil, Ramya Mathiyalagan, Deok-Chun Yang, Dae-Hyo Jung, Hyocheol Bae, Dong Uk Yang

Faculty, Staff and Student Publications

Kidney cancer has emerged as a major medical problem in recent times. Multiple compounds are used to treat kidney cancer by triggering cancer-causing gene targets. For instance, isoquercitrin (quercetin-3-O-β-d-glucopyranoside) is frequently present in fruits, vegetables, medicinal herbs, and foods and drinks made from plants. Our previous study predicted using protein-protein interaction (PPI) and molecular docking analysis that the isoquercitrin compound can control kidney cancer and inflammation by triggering potential gene targets of IGF1R, PIK3CA, IL6, and PTGS2. So, the present study is about further in silico and in vitro validation. We performed molecular dynamic (MD) simulation, gene ontology (GO), Kyoto …

Capn2 Correlates With Insulin Resistance States In Pcos As Evidenced By Multi-Dataset Analysis, Xi Luo, Yunhua Dong, Haishan Zheng, Xiaoting Zhou, Lujuan Rong, Xiaoping Liu, Yun Bai, Yunxiu Li, Ze Wu

Faculty, Staff and Student Publications

OBJECTIVE: IR emerges as a feature in the pathophysiology of PCOS, precipitating ovulatory anomalies and endometrial dysfunctions that contribute to the infertility challenges characteristic of this condition. Despite its clinical significance, a consensus on the precise mechanisms by which IR exacerbates PCOS is still lacking. This study aims to harness bioinformatics tools to unearth key IR-associated genes in PCOS patients, providing a platform for future therapeutic research and potential intervention strategies.

METHODS: We retrieved 4 datasets detailing PCOS from the GEO, and sourced IRGs from the MSigDB. We applied WGCNA to identify gene modules linked to insulin resistance, utilizing IR …

Serum Neuroactive Metabolites Of The Tryptophan Pathway In Patients With Acute Phase Of Affective Disorders, Yanli Li, Leilei Wang, Junchao Huang, Ping Zhang, Yanfang Zhou, Jinghui Tong, Wenjin Chen, Mengzhuang Gou, Baopeng Tian, Wei Li, Xingguang Luo, Li Tian, L Elliot Hong, Chiang-Shan R Li, Yunlong Tan

Faculty, Staff and Student Publications

BACKGROUND: Many studies showed disrupted tryptophan metabolism in patients with affective disorders. The aims of this study were to explore the differences in the metabolites of tryptophan pathway (TP) and the relationships between TP metabolites and clinical symptoms, therapeutic effect in patients with bipolar disorder with acute manic episode (BD-M), depressive episode (BD-D) and major depressive disorder (MDD).

METHODS: Patients with BD-M (n=52) and BD-D (n=39), MDD (n=48) and healthy controls (HCs, n=49) were enrolled. The serum neuroactive metabolites levels of the TP were measured by liquid chromatography-tandem mass spectrometry. Hamilton Depression Scale-17 item (HAMD-17) and Young Mania Rating Scale …

Combined Deletion Of Men1, Atrx And Pten Triggers Development Of High-Grade Pancreatic Neuroendocrine Tumors In Mice, Mary Esmeralda Fuentes, Xiaoyin Lu, Natasha M Flores, Simone Hausmann, Pawel K Mazur

Faculty, Staff and Student Publications

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of tumors that exhibit an unpredictable and broad spectrum of clinical presentations and biological aggressiveness. Surgical resection is still the only curative therapeutic option for localized PanNET, but the majority of patients are diagnosed at an advanced and metastatic stage with limited therapeutic options. Key factors limiting the development of new therapeutics are the extensive heterogeneity of PanNETs and the lack of appropriate clinically relevant models. In that context, genomic sequencing of human PanNETs revealed recurrent mutations and structural alterations in several tumor suppressors. Here, we demonstrated that combined loss of MEN1, …

Influence Of Rna Circularity On Target Rna-Directed Microrna Degradation, Federico Fuchs Wightman, Jerónimo Lukin, Sebastián A Giusti, Michael Soutschek, Laureano Bragado, Berta Pozzi, María L Pierelli, Paula González, Juan P Fededa, Gerhard Schratt, Rina Fujiwara, Jeremy E Wilusz, Damián Refojo, Manuel De La Mata

Faculty, Staff and Students Publications

A subset of circular RNAs (circRNAs) and linear RNAs have been proposed to 'sponge' or block microRNA activity. Additionally, certain RNAs induce microRNA destruction through the process of Target RNA-Directed MicroRNA Degradation (TDMD), but whether both linear and circular transcripts are equivalent in driving TDMD is unknown. Here, we studied whether circular/linear topology of endogenous and artificial RNA targets affects TDMD. Consistent with previous knowledge that Cdr1as (ciRS-7) circular RNA protects miR-7 from Cyrano-mediated TDMD, we demonstrate that depletion of Cdr1as reduces miR-7 abundance. In contrast, overexpression of an artificial linear version of Cdr1as drives miR-7 degradation. Using plasmids that …