Digital Commons Network^™

A Framework For Assessing The Trustworthiness Of Scientific Research Findings, Brian A Nosek, David B Allison, Kathleen Hall Jamieson, Marcia Mcnutt, A Beau Nielsen, Susan M Wolf

Children’s Nutrition Research Center Staff Publications

Vigorous debate has erupted over the trustworthiness of scientific research findings in a number of domains. The question "what makes research findings trustworthy?" elicits different answers depending on whether the emphasis is on research integrity and ethics, research methods, transparency, inclusion, assessment and peer review, or scholarly communication. Each provides partial insight. We offer a systems approach that focuses on whether the research is accountable, evaluable, well-formulated, has been evaluated, controls for bias, reduces error, and whether the claims are warranted by the evidence. We tie each of these components to measurable indicators of trustworthiness for evaluating the research itself, …

Molecular Determinant Of Low-Voltage Dependence Of Human Nav1.7 Inactivation Revealed By Efficacy-Based Nav1.7 Selective Inhibitor, Fang Zhao, Chuchu Xi, Jie Li, Kerui Ren, Qinglian Tang, Huaduan Liang, Shilong Yang, Michael X Zhu, Zhengyu Cao

Faculty, Staff and Student Publications

Nav1.7 is a voltage-gated sodium channel (VGSC) subtype predominantly expressed in sensory neurons, amplifying threshold currents. Here, we identify that Uvarigranol D (UGD) suppresses human (h) Nav1.7 with a much greater maximal inhibition than other VGSC subtypes, despite having similar apparent affinities. We demonstrate that Thr1398 determines the greater inhibitory efficacy of UGD, the leftward shift in voltage-dependence and faster inactivation kinetics of hNav1.7. UGD binds to the inactivated state, with Gln360, Ile394, Lys1395, Phe1737, and Tyr1744 being critically involved. Moreover, while UGD suppresses action potentials in both rat dorsal root ganglion neurons and human induced pluripotent stem cell-derived cardiomyocytes, …

Potential Mediators In The Relationship Between Racial Identity And Neuropsychological Performance In A Retired Nfl Cohort, Claire Stafford, Charles Golden, Ryan Bennett

Archives of Assessment Psychology

Historically, Black Americans have consistently performed more poorly than White Americans on various neuropsychological tests, with debates surrounding the causes of these differences ranging from genetic to societal factors. These differences have been documented across various cognitive domains, including memory, attention, executive function, and processing speed. Findings from previous research suggest that individuals with higher levels of education and stable marital relationships tend to exhibit better cognitive functioning, while certain football positions are linked to differences in cognitive abilities. However, the specific effects of these factors on neuropsychological performance require further investigation. The present archival study was derived from a …

Phytic Acid (Insp6) Activates Hdac3 Epigenetic Axis To Maintain Intestinal Barrier Function, Sujan Chatterjee, Katherine Huang, Kayci Huff-Hardy, Richard Rood, Anas Gremida, Martin Gregory, Chien-Huan Chen, Parakkal Deepak, Et Al.

2020-Current year OA Pubs

HDAC inhibition shows promise in cancer treatment but pan-HDAC inhibitors cause gastrointestinal issues in 48% of patients. Understanding HDAC activation mechanisms is crucial to treating diverse diseases beyond cancer. Our study reveals that inositol polyphosphate multikinase (IPMK) and inositol hexakisphosphate (InsP

Ubiquitination-Directed Cytosolic Dna Degradation Governs Cgas-Sting-Mediated Immune Response To Dna Damage, Lei Li, Qi Ye, Jinlu Ma, Zixi Wang, Tianjie Liu, Yuzeshi Lei, Mingming Lu, Jialu Kang, Haohan Xiang, Buyun Li, Shan Xu, Ke Wang, Yule Chen, Jiaqi Chen, Bohan Ma, Wenyue Huang, Mengjiao Cai, Nan Wu, Yanqiang Li, Jiale An, Chongming Jiang, Rui Ye, Jing Liu, Steven H Lin, Yang Gao, Jian Ma, Lei Li

Faculty, Staff and Student Publications

Activation of cGAS-STING signaling in cancer cells requires cytosolic DNA produced by intrinsic or treatment-induced DNA damage. However, clinical efforts to exploit this pathway to improve immunotherapy have yielded limited success, highlighting gaps in understanding the link between DNA damage and immunotherapy. Here, we identify ubiquitination-directed cytosolic DNA degradation as a critical determinant for cGAS-STING activation following DNA damage. Mechanistically, the cytosolic DNA exonuclease TREX1 is degraded by the E3 ubiquitin ligase SPOP but is reversely stabilized by the deubiquitinase USP7. Cancer-associated SPOP mutations or USP7 overexpression elevate TREX1 levels, promoting cytosolic DNA degradation and impairing cGAS-STING-mediated immune activation. Notably, …

Multimodal Spatial-Omics Reveal Co-Evolution Of Alveolar Progenitors And Proinflammatory Niches In Progression Of Lung Precursor Lesions, Fuduan Peng, Ansam Sinjab, Yibo Dai, Warapen Treekitkarnmongkol, Sujuan Yang, Lorena I Gomez Bolanos, Tieling Zhou, Minyue Chen, Alejandra G Serrano, Avantika Krishna, Nastaran Karimi, Manvi Sharma, Akshay Basi, Guangsheng Pei, Jianlong Liao, Yunhe Liu, Jiping Feng, Zahraa Rahal, Yang Liu, Jiahui Jiang, Kai Yu, Tala Noun, Yuejiang Liu, Khaja Khan, Kyung Serk Cho, Jichao Chen, Luisa M Solis, Sarah Mazzilli, Steven Dubinett, Tina Cascone, Avrum E Spira, Stephen Swisher, Naoe Jimbo, Takuo Hayashi, Satsuki Kishikawa, Kazuya Takamochi, Tomoo Itoh, Takashi Yao, Kenji Suzuki, Neda Kalhor, Ignacio I Wistuba, Mingyao Li, Seyed Javad Moghaddam, Junya Fujimoto, Jared Burks, Jeffrey Myers, Kadir Akdemir, Linghua Wang, Humam Kadara

Faculty, Staff and Student Publications

The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are …

High-Throughput Multi-Organ Proteomics Workflow For Drug Efficacy And Toxicity Analysis, Yun Xiong, Lin Tan, Wai-Kin Chan, Dandan Zhu, Huimin Zhang, Eric S Yin, Sri Ramya Donepudi, Jibin Ding, Bo Wei, Bao Tran, Sara Martinez, Iqbal Mahmud, Faiza Hanif Waghu, Hamish I Stewart, Daniel J Hermanson, Rehan Akbani, John N Weinstein, Junjie Chen, Philip L Lorenzi

Faculty, Staff and Student Publications

Rapid and comprehensive analysis of complex proteomes across large sample sets is vital for unlocking the potential of systems biology. We present a high-throughput mass spectrometry (MS) proteomics method that integrates narrow-window data-independent acquisition (nDIA) with short-gradient micro-flow chromatography, enabling profiling of >240 samples per day. This optimized MS approach identifies 6,201 and 7,466 human proteins with 1- and 2-min gradients, respectively. As a practical application, we analyzed 507 samples composed of 13 different tissues from mice treated with the enzyme-drug L-asparaginase (ASNase) or its glutaminase-free Q59L mutant, generating a quantitative profile of 11,472 proteins following drug treatment. The MS …

Multimodal Spatial-Omics Reveal Co-Evolution Of Alveolar Progenitors And Proinflammatory Niches In Progression Of Lung Precursor Lesions, Fuduan Peng, Ansam Sinjab, Yibo Dai, Warapen Treekitkarnmongkol, Sujuan Yang, Lorena I Gomez Bolanos, Tieling Zhou, Minyue Chen, Alejandra G Serrano, Avantika Krishna, Nastaran Karimi, Manvi Sharma, Akshay Basi, Guangsheng Pei, Jianlong Liao, Yunhe Liu, Jiping Feng, Zahraa Rahal, Yang Liu, Jiahui Jiang, Kai Yu, Tala Noun, Yuejiang Liu, Khaja Khan, Kyung Serk Cho, Jichao Chen, Luisa M Solis, Sarah Mazzilli, Steven Dubinett, Tina Cascone, Avrum E Spira, Stephen Swisher, Naoe Jimbo, Takuo Hayashi, Satsuki Kishikawa, Kazuya Takamochi, Tomoo Itoh, Takashi Yao, Kenji Suzuki, Neda Kalhor, Ignacio I Wistuba, Mingyao Li, Seyed Javad Moghaddam, Junya Fujimoto, Jared Burks, Jeffrey Myers, Kadir Akdemir, Linghua Wang, Humam Kadara

Faculty, Staff and Student Publications

The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are …

Consensus Paper: Models Of Cerebellar Functions, Shinji Kakei, Andreea C Bostan, Timothy J Ebner, Mohammad Amin Fakharian, Hiroaki Gomi, Xavier Guell, Marie Hemelt, Huu Hoang, Court Hull, Masato Inoue, Takahiro Ishikawa, Masashi Kameda, Mitsuo Kawato, Shigeru Kitazawa, Mario Manto, Javier F Medina, Hiroshi Mitoma, Keiko Ohmae, Shogo Ohmae, Ken-Ichi Okada, Laurentiu S Popa, Jeremy D Schmahmann, Reza Shadmehr, Peter L Strick, Hirokazu Tanaka, Masaki Tanaka, Tadashi Yamazaki

Faculty, Staff and Students Publications

For a long time, from the nineteenth century to most of the twentieth century, the cerebellum was thought to be an organ that regulates movement. Towards the end of the twentieth century, the brain functions associated with the cerebellum began to extend beyond motor control. Now, there is a consensus that the cerebellum is involved not only in motor functions but also in the most basic autonomic functions and the most complex cognitive and emotional functions, with a focus on predictions and internal models. A new functional model of the cerebellum is needed to explain all layers of brain functions …

Ex Vivo Microfluidic Model Identifies A Role For Shear Stress During Ovarian Tumor Cell Attachment To Peritoneal Mesothelial Cells, Vasilios A Morikis, Breanna Baker, Jillian A Martin, Angela Schab, Alessandra Dimauro, Gregory D Longmore, Whitney R Grither

2020-Current year OA Pubs

Ascites, or a pathologic accumulation of intra-abdominal fluid, is a key feature of intraperitoneally disseminating cancers, such as ovarian cancer. This pathological fluid buildup can influence the adhesive abilities of ovarian cancer cells, as they spread throughout the abdominal cavity to form metastatic implants on organs lined with a specialized monolayer of mesothelial cells. Robust methods for assessing the impact of fluid shear stress on this cell-cell interaction are lacking. Here, we develop and characterize a novel microfluidic device that allows for the determination of the attachment of ovarian tumor cells to mesothelial cells under the influence of fluid flow. …

Myokine Sirpα Exacerbates Kidney Disease In Diabetes, Jiao Wu, Elisa Russo, Daniela Verzola, Qingtian Li, Helena Zhang, Bhuvaneswari Krishnan, David Sheikh-Hamad, Zhaoyong Hu, William E Mitch, Sandhya S Thomas

Faculty, Staff and Students Publications

Mechanisms responsible for skeletal muscle kidney crosstalk have not been defined. We have determined that a circulating mediator, signal regulatory protein α (SIRPα), impairs intracellular insulin-mediated functions. To elucidate the effect of myokine SIRPα on diabetic kidney disease (DKD), flox mice and muscle-specific (m-specific) SIRPα-KO mice were subjected to an obesity-induced model of diabetes, high-fat diet (HFD; 60%) or insulin-deficient hyperglycemia model, streptozotocin (STZ), and were subsequently exposed to anti-SIRPα monoclonal antibodies. In the obesity-induced diabetic mice, serum SIRPα increased. Genetic deletion of muscle SIRPα protected against obesity and improved intracellular insulin signaling in muscle and adipose tissue, with reduced …

Ex Vivo Microfluidic Model Identifies A Role For Shear Stress During Ovarian Tumor Cell Attachment To Peritoneal Mesothelial Cells, Vasilios A Morikis, Breanna Baker, Jillian A Martin, Angela Schab, Alessandra Dimauro, Gregory D Longmore, Whitney R Grither

2020-Current year OA Pubs

Ascites, or a pathologic accumulation of intra-abdominal fluid, is a key feature of intraperitoneally disseminating cancers, such as ovarian cancer. This pathological fluid buildup can influence the adhesive abilities of ovarian cancer cells, as they spread throughout the abdominal cavity to form metastatic implants on organs lined with a specialized monolayer of mesothelial cells. Robust methods for assessing the impact of fluid shear stress on this cell-cell interaction are lacking. Here, we develop and characterize a novel microfluidic device that allows for the determination of the attachment of ovarian tumor cells to mesothelial cells under the influence of fluid flow. …

Discovery And Characterization Of A Novel Pseudomonas Phage Of A New Genus, Paul Nicholls, Justin R Clark, Anthony Maresso

Faculty, Staff and Students Publications

Background: Bacteriophages exhibit great diversity and are classically divided into lytic and temperate lifestyles. Commonly, bioinformatics is used to predict the temperate lifestyle. As the nosocomial pathogen Pseudomonas aeruginosa is common in freshwater, this biome represents an ideal location for the discovery of Pseudomonas phages.

Materials and methods: We characterized a genetically distinct species of Pseudomonas phage using next-generation sequencing and conventional microbiological methods. We characterized its lifestyle by purifying infected colonies and identifying persistent phage production.

Results: Genetics revealed a phage of a novel genus. Characterization showed a narrow host range and bioinformatics suggested a lytic lifestyle. Experimental data …

Microrna Expression In Putative Cancer Stem Cells Isolated From Canine Mammary Gland Tumour Cells With Differing Sensitivity To Doxorubicin, Kabiru Sahabi, Gayathri Thevi Selvarajah, Mohd Mokrish Md Ajat, Rasedee Abdullah, Cheah Y. Kqueen

The Thai Journal of Veterinary Medicine

Cancer stem cells (CSCs) are capable of initiating tumour development and causing recurrence after treatment. The objective of this study was to determine the miRNAs, downstream target mRNAs, and signalling pathways in CSCs isolated from doxorubicin-sensitive and doxorubicin-resistant canine mammary adenocarcinoma cell lines. MicroRNA expression was profiled using Agilent SurePrint^® microarrays. MicroRNA data were analyzed using Agilent GeneSpring^® software, and TargetScan and WikiPathways were used to identify genes and pathways targeted by the differentially expressed miRNAs. Six miRNAs were differentially expressed in CSCs isolated from doxorubicinsensitive cells, while fourteen miRNAs were differentially expressed in CSCs isolated from doxorubicin-resistant …

Preliminary Development Of Visual And Real-Time Loop-Mediated Isothermal Amplification Assays For Megalocytivirus Detection In Betta Fish (Betta Splendens), Kitikarn Sakuna, Supaporn Noochu, Kittichon U-Taynapun, Nion Chirapongsathonkul, Saransiri Nuanmanee

The Thai Journal of Veterinary Medicine

This study developed rapid detection of Megalocytivirus using visual and real-time loop-mediated isothermal amplification (LAMP) assays. The primer was designed with the major capsid protein gene of Megalocytivirus, including red sea bream iridovirus (RSIV), infectious spleen and kidney necrosis virus (ISKNV), and turbot reddish body iridovirus (TRBIV). The visual and real-time LAMP assays were evaluated using DNA extracted from symptomatic betta fish that tested negative for Megalocytivirus by the broad-range PCR assay, as well as a chemically synthesized Megalocytivirus DNA template. Visual LAMP was found sensitive enough to detect up to 10 pg per reaction of the target DNA …

Schwannomatosis Tumor Modeling: Progress And Prospects For Translational Research, Mackenzie S Madison, Huazhen Xu, Yarelis Gonzalez-Vargas, Marybeth G Yonk, Charee M Thompson, Hurley Haney, Danielle Babbitt, Yuhong Du, Angela C Hirbe, Nicholas M Boulis, Ren-Yuan Bai, Kecheng Lei

2020-Current year OA Pubs

BACKGROUND: Schwannomatosis (SWN) is a rare genetic condition characterized by the development of benign schwannomas along peripheral and spinal nerves, and this tumor development often results in chronic peripheral pain and significant neurological deficits. Despite surgical resection being the current standard of care for SWN-related pain, scientists are searching for accurate preclinical models that can be used for drug efficacy testing, but existing models often fail to fully recapitulate the complex genotypic diversity and tumor-nerve interface pathology seen in patients. MAIN TEXT: This review first summarizes the genotypic and phenotypic characteristics of SWN subtypes resulting from key mutations in NF2, …

Therapeutic Reprogramming Of Tumour-Associated Macrophages In Pancreatic Cancer Using A Cytotoxic Ccr2-Targeted Nanotheranostic, Vikas Kumar Somani, Xiaohui Zhang, Timothy Hung-Po Chen, Ashenafi Bulle, Sapana Bansod, Lin Li, Yutong Geng, Liang-I Kang, Gyu Seong Heo, Hannah Luehmann, Yuena Zhang, Muhammad A Saeed, Kory J Lavine, David G Denardo, Russell K Pachynski, Yongjian Liu, Kian-Huat Lim

2020-Current year OA Pubs

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits a profoundly immunosuppressive tumour microenvironment (TME) dominated by inflammatory monocytes (IMs) and tumour-associated macrophages (TAMs), which restrict adaptive immunity and drive resistance to immune checkpoint blockade (ICB). Recruitment of CCR2⁺ IMs by tumour-derived CCL2 is a central mechanism underlying TAM accumulation. Conventional gemcitabine (GEM) and small-molecule CCR2 inhibitors provide limited benefit due to poor intratumoural delivery, transient target engagement, and compensatory myeloid recruitment. METHODS: We engineered a CCR2-targeted nanotheranostic by conjugating a CCR2-binding peptide (ECL1i) and GEM onto ultrasmall copper nanoclusters (CuNCs-ECL1i-GEM; C-E-G). Therapeutic efficacy and immune remodelling were evaluated using orthotopic subcutaneous and …

Early Prediction And Diagnosis Of Peripheral Neuropathy In Type 2 Diabetes Using Biochemical Parameters, Eman Naim Taher, Narjis Hadi Al – Saadi

Al-Ameed Journal for Medical Research and Health Sciences

Background: Type II diabetes mellitus is commonly related to diabetic peripheral neuropathy (DPNP), which manifests as a gradual progression of damage to the peripheral nerves after excluding other causes. As initial alterations may lie hidden, focus has moved to easy crude markers. Neuron-specific Enolase (NSE) was chosen since it increases early after axonal injury, Whereas, Nerve Growth Factor (NGF) reflects neurotrophic activity. Material and Methods: A case control study was done on 45 cases of DPNP after diagnosing through a nerve conduction study (NCS), 48 diabetics without neuropathy DWNP and 45 healthy individuals. Ages ranged from 35 to 60. …

Genome And Transcriptome-Wide Analyses Identify Multiple Candidate Genes And A Significant Polygenic Contribution In Bicuspid Aortic Valve, Sébastien Thériault, Jacob A Holdcraft, Dinara Sharipova, Adèle Faucherre, Radoslaw M Debiec, Gina M Peloso, Baravan Al-Kassou, Sary Aranki, Elena Ashikhmina Swan, Andrea Ballotta, Michele Bellino, Hanna M Björck, Anne Sophie Boureau, Peter S Braund, François Corriveau, François Dagenais, Lasse Folkersen, Amalia Forte, Michael D Francke, Alessandro Frigiola, Svetlana Gorbatov, Dongchuan Guo, Karam M Habchi, Mahyar Heydarpour, Eric M Isselbacher, Chris Jopling, Fabien Laporte, Solena Le Scouarnec, Zhonglin Li, Peter Lichtner, Carlo Maj, Hasanga D Manikpurage, Christopher P Nelson, Thy B Nguyen, Russell A Norris, Chin Siang Ong, Philippe Pibarot, Tanmoy Roychowdhury, Berardo Sarubbi, Floriane Simonet, Thoralf Sundt, Ida Surakka, Idit Tessler, Cristen J Willer, Susanne Wittmann, Bo Yang, Igor Berezovets, Stefanie A Doppler, Martina Dreßen, Katharina Knoll, Thomas Puehler, Heribert Schunkert, Jean-François Avierinos, Malenka M Bissell, Aidan P Bolger, Yohan Bossé, Eduardo Bossone, María Brion, Rodolfo Citro, Carlo De Vincentiis, G Michael Deeb, Alessandro Della Corte, Christian Dina, Ronen Durst, Stephan Ensminger, Per Eriksson, Arturo Evangelista, Anders Franco-Cereceda, Dan Gilon, Betti Giusti, Simon L Hetherington, Gordon S Huggins, Markus Krane, Thierry Le Tourneau, Giuseppe Limongelli, Patrick Mathieu, David Messika-Zeitoun, Hector I Michelena, Dianna Milewicz, Jochen D Muehlschlegel, David R Murdock, Georg Nickenig, Stefano Nistri, Markus M Nöthen, Francesca Pluchinotta, Siddharth K Prakash, Nilesh J Samani, Jean-Jacques Schott, Tom R Webb, Stéphane Zaffran, Salim Abdelilah-Seyfried, Kim Eagle, Johannes Schumacher, Teresa Trenkwalder, Simon Body

Faculty, Staff and Student Publications

Background: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV.

Methods: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified …

Tracking Focal Adhesion Turnover: A Novel Reporter For Fa-Phagy Flux, Kuizhi Qu, Mengjun Dai, Ying Jiang, Sophie Liu, John P Hagan, Louise D Mccullough, Zhen Xu, Yan-Ning Rui

Faculty, Staff and Student Publications

Focal adhesions (FAs) are critical multi-protein complexes regulating cell adhesion, migration, and survival, and their dysregulation contributes to cancer metastasis and vascular diseases. Despite extensive research on FA formation, little is known about FA turnover, particularly its regulation by autophagy. This study introduces a novel tandem fluorescence reporter capable of tracking the entire FA-phagy flux, from autophagosome formation to lysosomal degradation. The reporter, based on a red–green fluorescence system with a lysosome-specific cleavage site, integrates seamlessly into endogenous focal adhesion complexes, demonstrating sensitivity and specificity to autophagy stimuli. Validated in multiple cell lines, the tool revealed dynamic FA-phagy responses to …

Extracellular Matrix Mediates Circulating Tumor Cell Clustering In Triple-Negative Breast Cancer Metastasis, Georg Om Bobkov, Khushali J Patel, Bree M Lege, Rong Zheng, Gad Shaulsky, Matthew J Ellis, Chonghui Cheng

Faculty, Staff and Students Publications

Metastatic tumor cell dissemination is the leading cause of cancer-related deaths. Clustered circulating tumor cells (CTCs) possess higher metastatic potential than single CTCs. Epithelial adherens junction (AJ) proteins typically mediate stable cell-cell interactions; however, these proteins are frequently lost in highly aggressive triple-negative breast cancers (TNBCs), raising the question of how CTCs from such tumors cluster. Here we show that the extracellular matrix (ECM) component hyaluronan (HA) mediates AJ-independent CTC clustering in TNBCs. HA is necessary and sufficient to drive clustering of tumor cells expressing its receptor CD44. Mechanistically, HA initiates contact between neighboring cells through actin-based membrane protrusions. As …

The Setd2 L1609p Mutation Found In Leukemia Disrupts Methyltransferase Activity And Reduces Histone H3k36 Trimethylation, Christina Michail, Jérémy Berthelet, Ariel E Mechaly, Linh-Chi Bui, Haopeng Yang, Duo Cai, Amira Al Mahi, Aowei Xie, Valeria Bisio, Valentina Sirri, Jean-Marie Dupret, Fabien Guidez, Ximing Xu, Nicolas Joly, Leslie Regad, Mireille Viguier, Frédérique Deshayes, Nicolas Dulphy, Michael R Green, Ahmed Haouz, Fernando Rodrigues Lima

Faculty, Staff and Student Publications

SETD2 is the primary methyltransferase responsible for generating H3K36me3, an epigenetic mark that is essential for transcriptional regulation and chromatin integrity. SETD2 mutations are frequently observed in various cancers and tend to cluster within its catalytic SET domain. Despite the clinical relevance of SETD2 missense mutations in cancer, their biochemical and structural consequences remain insufficiently characterized. Here, we present the enzymatic and structural characterization of the SETD2 L1609P mutant enzyme identified in leukemia. The L1609 residue is located in the SET domain within a conserved hydrophobic pocket that is involved in substrate H3K36 recognition. Interestingly, site-directed mutagenesis of residues within …

Endothelial Oncogenic Kras Mutation Drives The Dynamics Of Microglia And Macrophages In Brain Arteriovenous Malformation, Hyejin Park, Jung-Eun Park, Bridger H Freeman, Bosco Seong Kyu Yang, Shun-Ming Ting, Alexander K Suh, Jude Pj Savarraj, Shuning Huang, Jakob Körbelin, Huimahn Alex Choi, Sean P Marrelli, Jaroslaw Aronowski, Peng Roc Chen, Eunhee Kim, Eun S Park

Faculty, Staff and Student Publications

Mutation of KRAS in endothelial cells (KRAS-EC) leads to intracerebral hemorrhage (ICH) in brain arteriovenous malformations (bAVM), resulting in severe disabilities or even death. However, it is unclear what causes this hemorrhagic conversion of bAVM. Here, using a locally established, clinically-relevant sporadic bAVM mouse model, created by overexpressing mutant KRAS (KRASG12V) in the brain EC, we demonstrate that KRAS-EC act as trigger for microglia (MG) activation and infiltration of macrophages (Mϕ). Using three-dimensional immunostaining approach with cleared human and mouse bAVM tissues, we demonstrate an abundance of MG/Mϕ around the bAVM nidus. The presence of MG/Mϕ are correlated to the …

Bi-Allelic Variants In Neuronal Adhesion Molecule Astrotactin 1 Gene Astn1 Cause Diverse Neurodevelopmental Disorders, Jesse M Levine, Daniel G Calame, Riccardo Sangermano, Haowei Du, Ahmed Saad, Jasmin Lisfeld, Tatjana Bierhals, Jonas Denecke, Eyyup Uctepe, Merve Yoldas Celik, Ahmet Yesilyurt, Hilal Yildiz Er, Elif Yilmaz Gulec, Aziza Mushiba, Naif Almontashiri, Pawel Gawlinski, Wojciech Wiszniewski, Ender Karaca, Lama Alabdi, Davut Pehlivan, Dana Marafi, Maha S Zaki, Fowzan S Alkuraya, Joseph G Gleeson, Shalini N Jhangiani, Richard A Gibbs, Jennifer E Posey, Kinga M Bujakowska, James R Lupski

Faculty, Staff and Students Publications

ASTN1 encodes astrotactin 1, a neuronal-glial ligand in the developing brain that promotes neuronal migration along radial glia in brain structures with laminar organization, such as the cerebral cortex, hippocampus, and cerebellum. In mouse models, disruption of Astn1 results in neuronal migration deficits, a mild reduction in cerebellar volume, and balance and coordination deficits. In humans, bi-allelic ASTN1 variants have been identified in nine individuals with neurodevelopmental disorders (NDDs) with or without brain malformations. ASTN1 additionally interacts with astrotactin 2 (ASTN2) to implement neuronal migration; ASTN2 deletions associate with NDDs with reduced penetrance. Here, we describe eighteen individuals with NDDs …

Sclerostin Deficiency Sensitizes White Adipocytes To Thermogenic Signals That Induce Beiging In Mice, Gillian M Choquette, Soohyun P Kim, Kevin J Wilkinson, Belen C Avelar, Sushrut Pathy, Zhu Li, Jasmine Wu, Susan Aja, Daniel L J Thorek, Michael J Wolfgang, Ryan C Riddle

2020-Current year OA Pubs

Maintenance of bone mass is coordinated with adipose tissue function through the secretion of hormones and endocrine factors that act on the opposing tissue. Sclerostin, a small glycoprotein produced by osteocytes embedded within the bone matrix, potently suppresses bone formation by antagonizing Wnt/β-catenin signaling while stimulating adipose tissue accumulation via the same mechanism of action. Since sclerostin-deficient mice develop pockets of multilocular adipocytes in subcutaneous adipose, we investigate the influence of sclerostin on thermogenic and β3-adrenergic stimuli-induced white adipose tissue beiging. Here, we report that Sost gene expression in bone and serum sclerostin levels are induced by β3-adrenergic agonists via …

Targeting Tau In Alzheimer's Disease: Rationale, Approach And Challenges, Aram Aslanyan, Martha S Foiani, Tatiana A Giovannucci, Eric Mcdade, Karen E Duff, Catherine J Mummery, Michael Schöll, Kristin R Wildsmith, Ross W Paterson

2020-Current year OA Pubs

Alzheimer’s Disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia characterised by the accumulation of beta amyloid (Aβ) plaques and neurofibrillary tangles (NFT). Several monoclonal antibodies against amyloid in early AD have shown the utility of reducing brain amyloid in large phase 3 studies, resulting in modest clinical benefit. To further slow, or even halt disease progression, targeting additional pathobiological pathways is likely to be necessary. In this review, we aim to appraise the scientific rationale for targeting tau in AD. The burden of tau pathology is correlated with disease severity and its role in …

Multiparent Recombinant Inbred Lines Crossed To A Tester Provide Novel Insights Into Sources Of Cis And Trans Regulation Of Gene Expression, Fabio Marroni, Alison M Morse, Adalena V Nanni, Nadja Nolte, Patricka Williams-Simon, Luis G León-Novelo, Rita M Graze, Paul Schmidt, Elizabeth King, Lauren M Mcintyre

Faculty, Staff and Student Publications

To understand the relative importance of cis and trans effects on regulation, we crossed multi-parent recombinant-inbred lines (RILs) to a common tester and measured allele-specific gene expression in the offspring. Testing the difference of allelic imbalance between two RIL × Tester crosses is a test of cis or trans, depending on the RIL alleles compared. The study design also enables to separation of two sources of trans variation, genetic and environmental, detected via interactions with cis effects. We demonstrate the effectiveness of this approach in a long-read RNA-seq experiment in female abdominal tissue at two time points in Drosophila melanogaster. …

Ubiquitination Of Oncogenic Mutant P53 Via Attenuation Of Ribosome Biogenesis Machinery Effectively Inhibits Pancreatic Tumor Growth, Mudassier Ahmad, Sahir Sultan Alvi, Haider Ahsan, Carlos Perez, Andrew Massey, Vivek K Kashyap, Neeraj Chauhan, Emmanuel Anning, Manish K Tripathi, Dae J Kim, Nirakar Sahoo, Tamer Oraby, Murali M Yallapu, Mohammad Moshahid Khan, Manu M Sebastian, Subhash C Chauhan, Bilal B Hafeez

Faculty, Staff and Student Publications

Dysregulated ribosome biogenesis and p53 mutations are known to play oncogenic roles in various cancers, including pancreatic cancer. In this study, we demonstrated the therapeutic potential of BMH-21, a pharmacologic inhibitor of RNA polymerase I, against pancreatic cancer by uncovering a novel molecular mechanism involving RPA194-mediated ubiquitination of mutant p53 without affecting the ubiquitination of wild-type p53. Our key findings are that (i) BMH-21 selectively induces apoptosis and cell growth inhibition of pancreatic cancer cells with no effect on normal human pancreatic ductal epithelial cells; (ii) BMH-21 degrades RPA194; (iii) BMH-21 inhibits recruitment of both RPA194 and RPA135 on rDNA …

Tumor Radiosensitization With Gold Nanoparticles: Evolving Strategies To Improve Tumoral Gold Uptake And Catalyze Future Clinical Translation, Prapannajeet Biswal, Geraldine V Vijay, Gabrielle Krouse, Phuoc Minh Quan Mai, Bhoomika Muruvekere Lakshmisha, Sanaz Keshavarz Shahbaz, Mahdieh Yousefi Taba, Aria Sabbagh, Lydia Wt Cheung, Yuri Mackeyev, Khadijeh Koushki, Sunil Krishnan

Faculty, Staff and Student Publications

Radiation therapy is integral to the treatment regimens of over 50% of cancer patients. However, it is not biologically targeted to just the tumor, leading to adverse effects in peritumoral normal tissue. Selective uptake of gold nanoparticles (AuNPs) by tumors realizes tumor-specific radiosensitization via increased secondary electron release from high atomic number gold atoms. Here, we review AuNP-mediated radiosensitization and outline strategies to optimize tumor-targeted AuNP delivery. Modifying the physicochemical characteristics of AuNPs, including size, shape, charge, and surface chemistry, can increase their ability to evade the reticuloendothelial system (RES) and penetrate the dense tumor stromal architecture, thereby promoting tumor …

Repurposing Of The Macrolide Antibiotic Clarithromycin For The Prevention Of Lung Cancer, Shanshan Deng, Tabish Hussain, Thais F Bartelli, Manu M Sebastian, Melody Zarghooni, Walter V Velasco, Brandon Somerville, Linda Phan, Michelle I Savage, Yurong Song, John L Clifford, Humam Kadara, Florencia Mcallister, Powel H Brown, Seyed Javad Moghaddam, C Marcelo Aldaz

Faculty, Staff and Student Publications

Drug repurposing is the process of reusing existing pharmaceuticals for novel clinical purposes, which offers advantages such as streamlined clinical trial access and reduced drug development costs. Clarithromycin (CAM), a member of the macrolide antibiotics family, is a promising candidate for repurposing in cancer therapy due to its known preclinical and clinical immunomodulatory and anticancer properties. In the current study, we investigated whether CAM could be repurposed as a preventive treatment for KRAS-mutant lung cancer, a subtype of lung adenocarcinoma that is strongly associated with heavy smoking. CCSPCre; LSL-KrasG12D mice at an early stage of tumor development were treated with …