Digital Commons Network^™

The Dark Kinase Stk32a Regulates Hair Cell Planar Polarity Opposite Of Emx2 In The Developing Mouse Inner Ear., Shihai Jia, Evan M Ratzan, Ellison J Goodrich, Raisa Abrar, Luke Heiland, Basile Tarchini, Michael R Deans

Faculty Research 2023

The vestibular maculae of the inner ear contain sensory receptor hair cells that detect linear acceleration and contribute to equilibrioception to coordinate posture and ambulatory movements. These hair cells are divided between two groups, separated by a line of polarity reversal (LPR), with oppositely oriented planar-polarized stereociliary bundles that detect motion in opposite directions. The transcription factor EMX2 is known to establish this planar polarized organization in mouse by regulating the distribution of the transmembrane receptor GPR156 at hair cell boundaries in one group of cells. However, the genes regulated by EMX2 in this context were previously not known. Using …

Species Differences In Platelet Protease-Activated Receptors, Stephanie A Renna, Steven E. Mckenzie, James V. Michael

Cardeza Foundation for Hematologic Research

Protease-activated receptors (PARs) are a class of integral membrane proteins that are cleaved by a variety of proteases, most notably thrombin, to reveal a tethered ligand and promote activation. PARs are critical mediators of platelet function in hemostasis and thrombosis, and therefore are attractive targets for anti-platelet therapies. Animal models studying platelet PAR physiology have relied heavily on genetically modified mouse strains, which have provided ample insight but have some inherent limitations. The current review aims to summarize the notable PAR expression and functional differences between the mouse and human, in addition to highlighting some recently developed tools to further …

Tmem106b Regulates Microglial Proliferation And Survival In Response To Demyelination, Tingting Zhang, Weilun Pang, Tuancheng Feng, Jennifer Guo, Kenton Wu, Mariela Nunez Santos, Akshayakeerthi Arthanarisami, Alissa L Nana, Quynh Nguyen, Peter J Kim, Joanna L Jankowsky, William W Seeley, Fenghua Hu

Faculty, Staff and Students Publications

TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced microglia proliferation and activation and increased microglial apoptosis in response to demyelination. We also found an increase in lysosomal pH and a decrease in lysosomal enzyme activities in TMEM106B-deficient microglia. Furthermore, TMEM106B loss results in a significant decrease in the protein levels of TREM2, an innate immune receptor essential for microglia survival and activation. Specific ablation of TMEM106B …

Insights Into The Formation And Diversification Of A Novel Chiropteran Wing Membrane From Embryonic Development, Neal Anthwal, Daniel J Urban, Alexa Sadier, Risa Takenaka, Simon Spiro, Nancy Simmons, Richard R Behringer, Chris J Cretekos, John J Rasweiler, Karen E Sears

Faculty, Staff and Student Publications

BACKGROUND: Through the evolution of novel wing structures, bats (Order Chiroptera) became the only mammalian group to achieve powered flight. This achievement preceded the massive adaptive radiation of bats into diverse ecological niches. We investigate some of the developmental processes that underlie the origin and subsequent diversification of one of the novel membranes of the bat wing: the plagiopatagium, which connects the fore- and hind limb in all bat species.

RESULTS: Our results suggest that the plagiopatagium initially arises through novel outgrowths from the body flank that subsequently merge with the limbs to generate the wing airfoil. Our findings further …

Functional Characterization Of Age-Dependent P16 Epimutation Reveals Biological Drivers And Therapeutic Targets For Colorectal Cancer, Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Yunping Lei, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

METHODS: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA …

Infection Of Neonatal Mice With The Murine Norovirus Strain Wu23 Is A Robust Model To Study Norovirus Pathogenesis, Amy M Peiper, Emily W Helm, Quyen Nguyen, Matthew Phillips, Caroline G Williams, Dhairya Shah, Sarah Tatum, Neha Iyer, Marco Grodzki, Laura B Eurell, Aqsa Nasir, Megan T Baldridge, Stephanie M Karst

2020-Current year OA Pubs

Noroviruses are the leading cause of severe childhood diarrhea and foodborne disease worldwide. While they are a major cause of disease in all age groups, infections in the very young can be quite severe, with annual estimates of 50,000-200,000 fatalities in children under 5 years old. In spite of the remarkable disease burden associated with norovirus infections, very little is known about the pathogenic mechanisms underlying norovirus diarrhea, principally because of the lack of tractable small animal models. The development of the murine norovirus (MNV) model nearly two decades ago has facilitated progress in understanding host-norovirus interactions and norovirus strain …

Exercise Reprograms The Inflammatory Landscape Of Multiple Stem Cell Compartments During Mammalian Aging, Ling Liu, Soochi Kim, Matthew T Buckley, Jaime M Reyes, Jengmin Kang, Lei Tian, Mingqiang Wang, Alexander Lieu, Michelle Mao, Cristina Rodriguez-Mateo, Heather D Ishak, Mira Jeong, Joseph C Wu, Margaret A Goodell, Anne Brunet, Thomas A Rando

Faculty, Staff and Students Publications

Exercise has the ability to rejuvenate stem cells and improve tissue regeneration in aging animals. However, the cellular and molecular changes elicited by exercise have not been systematically studied across a broad range of cell types in stem cell compartments. We subjected young and old mice to aerobic exercise and generated a single-cell transcriptomic atlas of muscle, neural, and hematopoietic stem cells with their niche cells and progeny, complemented by whole transcriptome analysis of single myofibers. We found that exercise ameliorated the upregulation of a number of inflammatory pathways associated with old age and restored aspects of intercellular communication mediated …

Using Cancer Proteomics Data To Identify Gene Candidates For Therapeutic Targeting, Diana Monsivais, Sydney E Parks, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer …

Dimeric P53 Mutant Elicits Unique Tumor-Suppressive Activities Through An Altered Metabolic Program, Jovanka Gencel-Augusto, Xiaoping Su, Yuan Qi, Elizabeth M Whitley, Vinod Pant, Shunbin Xiong, Vrutant Shah, Jerome Lin, Encarnacion Perez, Marta L Fiorotto, Iqbal Mahmud, Abhinav K Jain, Philip L Lorenzi, Nicholas E Navin, Ellen R Richie, Guillermina Lozano

Faculty, Staff and Student Publications

Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li-Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence …

Bi-Allelic Variants In Ints11 Are Associated With A Complex Neurological Disorder, Burak Tepe, Erica L Macke, Marcello Niceta, Monika Weisz Hubshman, Oguz Kanca, Laura Schultz-Rogers, Yuri A Zarate, G Bradley Schaefer, Jorge Luis Granadillo De Luque, Daniel J Wegner, Benjamin Cogne, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Eric J Wagner, Lynn S Pais, Jennifer E Neil, Ganeshwaran H Mochida, Christopher A Walsh, Nurit Magal, Valerie Drasinover, Mordechai Shohat, Tanya Schwab, Chris Schmitz, Karl Clark, Anthony Fine, Brendan Lanpher, Ralitza Gavrilova, Pierre Blanc, Lydie Burglen, Alexandra Afenjar, Dora Steel, Manju A Kurian, Prab Prabhakar, Sophie Gößwein, Nataliya Di Donato, Enrico S Bertini, Undiagnosed Diseases Network, Michael F Wangler, Shinya Yamamoto, Marco Tartaglia, Eric W Klee, Hugo J Bellen

Faculty, Staff and Students Publications

The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog …

Driver Mutations Dictate The Immunologic Landscape And Response To Checkpoint Immunotherapy Of Glioblastoma., Alan T Yeo, Rushil Shah, Konstantinos Aliazis, Rinku Pal, Tuoye Xu, Piyan Zhang, Shruti Rawal, Christopher M Rose, Frederick S Varn, Vicky A Appleman, Joon Yoon, Hemant Varma, Steven P Gygi, Roel G W Verhaak, Vassiliki A Boussiotis, Al Charest

Faculty Research 2023

The composition of the tumor immune microenvironment (TIME) is considered a key determinant of patients' response to immunotherapy. The mechanisms underlying TIME formation and development over time are poorly understood. Glioblastoma (GBM) is a lethal primary brain cancer for which there are no curative treatments. GBMs are immunologically heterogeneous and impervious to checkpoint blockade immunotherapies. Utilizing clinically relevant genetic mouse models of GBM, we identified distinct immune landscapes associated with expression of EGFR wild-type and mutant EGFRvIII cancer driver mutations. Over time, accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) was more pronounced in EGFRvIII-driven GBMs and was correlated with resistance …

Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy In Melanoma, Gabriele Romano, Francesca Paradiso, Peng Li, Pooja Shukla, Lindsay N Barger, Olivia El Naggar, John P Miller, Roger J Liang, Timothy L Helms, Alexander J Lazar, Jennifer A Wargo, Francesca Taraballi, James C Costello, Lawrence N Kwong

Faculty, Staff and Student Publications

Patients with BRAF-mutant melanoma show substantial responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically "cold" after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines as …

Sexual Dimorphism In Bidirectional Sr-Mitochondria Crosstalk In Ventricular Cardiomyocytes, Richard T Clements, Radmila Terentyeva, Shanna Hamilton, Paul M L Janssen, Karim Roder, Benjamin Y Martin, Fruzsina Perger, Timothy G Schneider, Zuzana Nichtova, Anindhya S Das, Roland Veress, Beth S Lee, Do-Gyoon Kim, Gideon Koren, Matthew S Stratton, György Csordás, Federica Accornero, Andriy E Belevych, Sandor Gyorke, Dmitry Terentyev

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Calcium transfer into the mitochondrial matrix during sarcoplasmic reticulum (SR) Ca²⁺ release is essential to boost energy production in ventricular cardiomyocytes (VCMs) and match increased metabolic demand. Mitochondria from female hearts exhibit lower mito-[Ca²⁺] and produce less reactive oxygen species (ROS) compared to males, without change in respiration capacity. We hypothesized that in female VCMs, more efficient electron transport chain (ETC) organization into supercomplexes offsets the deficit in mito-Ca²⁺ accumulation, thereby reducing ROS production and stress-induced intracellular Ca²⁺ mishandling. Experiments using mitochondria-targeted biosensors confirmed lower mito-ROS and mito-[Ca²⁺] in female rat VCMs challenged …

Reduction Of Paraoxonase Expression Followed By Inactivation Across Independent Semiaquatic Mammals Suggests Stepwise Path To Pseudogenization., Allie M Graham, Jerrica M Jamison, Marisol Bustos, Charlotte Cournoyer, Alexa Michaels, Jason S Presnell, Rebecca Richter, Daniel E Crocker, Ari Fustukjian, Margaret E Hunter, Lorrie D Rea, Judit Marsillach, Clement E Furlong, Wynn K Meyer, Nathan L Clark

Faculty Research 2023

Convergent adaptation to the same environment by multiple lineages frequently involves rapid evolutionary change at the same genes, implicating these genes as important for environmental adaptation. Such adaptive molecular changes may yield either change or loss of protein function; loss of function can eliminate newly deleterious proteins or reduce energy necessary for protein production. We previously found a striking case of recurrent pseudogenization of the Paraoxonase 1 (Pon1) gene among aquatic mammal lineages-Pon1 became a pseudogene with genetic lesions, such as stop codons and frameshifts, at least four times independently in aquatic and semiaquatic mammals. Here, we assess the landscape …

Very-Long-Chain Fatty Acids Induce Glial-Derived Sphingosine-1-Phosphate Synthesis, Secretion, And Neuroinflammation, Hyung-Lok Chung, Qi Ye, Ye-Jin Park, Zhongyuan Zuo, Jung-Wan Mok, Oguz Kanca, Sudhir Gopal Tattikota, Shenzhao Lu, Nobert Perrimon, Hyun Kyoung Lee, Hugo J Bellen

Faculty, Staff and Students Publications

VLCFAs (very-long-chain fatty acids) are the most abundant fatty acids in myelin. Hence, during demyelination or aging, glia are exposed to higher levels of VLCFA than normal. We report that glia convert these VLCFA into sphingosine-1-phosphate (S1P) via a glial-specific S1P pathway. Excess S1P causes neuroinflammation, NF-κB activation, and macrophage infiltration into the CNS. Suppressing the function of S1P in fly glia or neurons, or administration of Fingolimod, an S1P receptor antagonist, strongly attenuates the phenotypes caused by excess VLCFAs. In contrast, elevating the VLCFA levels in glia and immune cells exacerbates these phenotypes. Elevated VLCFA and S1P are also …

Whole-Exome Sequencing Prioritizes Candidate Genes For Hereditary Cataract In The Emory Mouse Mutant, Thomas M Bennett, Yuefang Zhou, Kacie J Meyer, Michael G Anderson, Alan Shiels

2020-Current year OA Pubs

The Emory cataract (Em) mouse mutant has long been proposed as an animal model for age-related or senile cataract in humans-a leading cause of visual impairment. However, the genetic defect(s) underlying the autosomal dominant Em phenotype remains elusive. Here, we confirmed development of the cataract phenotype in commercially available Em/J mice [but not ancestral Carworth Farms White (CFW) mice] at 6-8 months of age and undertook whole-exome sequencing of candidate genes for Em. Analysis of coding and splice-site variants did not identify any disease-causing/associated mutations in over 450 genes known to underlie inherited and age-related forms of cataract and other …

Katp Channels Are Necessary For Glucose-Dependent Increases In Amyloid-Β And Alzheimer's Disease-Related Pathology, John Grizzanti, William R. Moritz, Molly Stanley, Emily E. Caesar, Maria S. Remedi, Celeste M. Karch, Colin G. Nichols, David M. Holtzman, Et Al.

2020-Current year OA Pubs

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-β (Aβ) release, offering a mechanistic link between type 2 diabetes and Alzheimer's disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal …

A Review Of The Neural Basis Underlying The Acoustic Startle Response With A Focus On Recent Developments In Mammals, Alice Zheng, Susanne Schmid

Anatomy and Cell Biology Publications

The startle response consists of whole-body muscle contractions, eye-blink, accelerated heart rate, and freezing in response to a strong, sudden stimulus. It is evolutionarily preserved and can be observed in any animal that can perceive sensory signals, indicating the important protective function of startle. Startle response measurements and its alterations have become a valuable tool for exploring sensorimotor processes and sensory gating, especially in the context of pathologies of psychiatric disorders. The last reviews on the neural substrates underlying acoustic startle were published around 20 years ago. Advancements in methods and techniques have since allowed new insights into acoustic startle …

A Multi-Lab Experimental Assessment Reveals That Replicability Can Be Improved By Using Empirical Estimates Of Genotype-By-Lab Interaction., Iman Jaljuli, Neri Kafkafi, Eliezer Giladi, Ilan Golani, Illana Gozes, Elissa J Chesler, Molly A. Bogue, Yoav Benjamini

Faculty Research 2023

The utility of mouse and rat studies critically depends on their replicability in other laboratories. A widely advocated approach to improving replicability is through the rigorous control of predefined animal or experimental conditions, known as standardization. However, this approach limits the generalizability of the findings to only to the standardized conditions and is a potential cause rather than solution to what has been called a replicability crisis. Alternative strategies include estimating the heterogeneity of effects across laboratories, either through designs that vary testing conditions, or by direct statistical analysis of laboratory variation. We previously evaluated our statistical approach for estimating …

Dilemmas Of Difference And Nonhuman Animals: Applying Insights From Feminist Philosophy To Animal Rights Law, Ethan Charles Shopmeyer

Undergraduate Honors Thesis Collection

Martha Minow’s concept of dilemmas of difference, widely influential in feminist philosophy of law, exposes how hidden patriarchal norms are reified in legal institutions and harmfully categorize oppressed groups. Though Minow primarily focuses on how such dilemmas impact interpersonal relationships, I argue that her work can be applied to the relationship between nonhuman animals, human beings, and our legal institutions. Just as certain patriarchal norms establish categories that mask the true roots of difference and thus make it more difficult for non-dominant groups to obtain justice, so too do implicit anthropocentric norms mark out nonhuman animals as different from human …

Mincle-Gsdmd-Mediated Release Of Il-1Β Small Extracellular Vesicles From Hepatic Macrophages In Ethanol-Induced Liver Injury, Quanri Zhang, Weiwei Liu, Katarzyna Bulek, Han Wang, Megan R Mcmullen, Xiaoqin Wu, Nicole Welch, Renliang Zhang, Jaividhya Dasarathy, Srinivasan Dasarathy, Laura E Nagy, Xiaoxia Li

Faculty, Staff and Student Publications

BACKGROUND: Macrophage-inducible C-type lectin (Mincle) is expressed on hepatic macrophages and senses ethanol (EtOH)-induced danger signals released from dying hepatocytes and promotes IL-1β production. However, it remains unclear what and how EtOH-induced Mincle ligands activate downstream signaling events to mediate IL-1β release and contribute to alcohol-associated liver disease (ALD). In this study, we investigated the association of circulating β-glucosylceramide (β-GluCer), an endogenous Mincle ligand, with severity of ALD and examined the mechanism by which β-GluCer engages Mincle on hepatic macrophages to release IL-1β in the absence of cell death and exacerbates ALD.

METHOD AND RESULTS: Concentrations of β-GluCer were increased …

Fully Human Monoclonal Antibody Targeting Activated Adam10 On Colorectal Cancer Cells, Nayanendu Saha, Du-San Baek, Rachelle P Mendoza, Dorothea Robev, Yan Xu, Yehuda Goldgur, M Jason De La Cruz, Elisa De Stanchina, Peter W Janes, Kai Xu, Dimiter S Dimitrov, Dimitar B Nikolov

Faculty, Staff and Student Publications

Metastasis and chemoresistance in colorectal cancer are mediated by certain poorly differentiated cancer cells, known as cancer stem cells, that are maintained by Notch downstream signaling initiated upon Notch cleavage by the metalloprotease ADAM10. It has been shown that ADAM10 overexpression correlates with aberrant signaling from Notch, erbBs, and other receptors, as well as a more aggressive metastatic phenotype, in a range of cancers including colon, gastric, prostate, breast, ovarian, uterine, and leukemia. ADAM10 inhibition, therefore, stands out as an important and new approach to deter the progression of advanced CRC. For targeting the ADAM10 substrate-binding region, which is located …

A Parathyroid Hormone/Salt-Inducible Kinase Signaling Axis Controls Renal Vitamin D Activation And Organismal Calcium Homeostasis, Sung-Hee Yoon, Mark B Meyer, Carlos Arevalo, Murat Tekguc, Chengcheng Zhang, Jialiang S Wang, Christian D Castro Andrade, Katelyn Strauss, Tadatoshi Sato, Nancy A Benkusky, Seong Min Lee, Rebecca Berdeaux, Marc Foretz, Thomas B Sundberg, Ramnik J Xavier, Charles H Adelmann, Daniel J Brooks, Anthony Anselmo, Ruslan I Sadreyev, Ivy A Rosales, David E Fisher, Navin Gupta, Ryuji Morizane, Anna Greka, J Wesley Pike, Michael Mannstadt, Marc N Wein

Faculty, Staff and Student Publications

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell–derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, …

Targeting Pd-L2-Rgmb Overcomes Microbiome-Related Immunotherapy Resistance, Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Wen Zheng, Martin W Lafleur, Sarah B Johnson, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe

Faculty, Staff and Student Publications

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and …

Updated Analysis To Reject The Laboratory-Engineering Hypothesis Of Sars-Cov-2, Fuqing Wu

Faculty, Staff and Student Publications

A clear understanding of the origin of SARS-CoV-2 is important for future pandemic preparedness. Here, I provided an updated analysis of the type IIS endonuclease maps in genomes of alphacoronavirus, betacoronavirus, and SARS-CoV-2. Scenarios to engineer SARS-CoV-2 in the laboratory and the associated workload was also discussed. The analysis clearly shows that the endonuclease fingerprint does not indicate a synthetic origin of SARS-CoV-2 and engineering a SARS-CoV-2 virus in the laboratory is extremely challenging both scientifically and financially. On the contrary, current scientific evidence does support the animal origin of SARS-CoV-2.

Apoptotic Cell Death In Disease-Current Understanding Of The Nccd 2023, Ilio Vitale, Federico Pietrocola, Emma Guilbaud, Stuart A Aaronson, John M Abrams, Dieter Adam, Massimiliano Agostini, Patrizia Agostinis, Emad S Alnemri, Lucia Altucci, Ivano Amelio, David W Andrews, Rami I Aqeilan, Eli Arama, Eric H Baehrecke, Siddharth Balachandran, Daniele Bano, Nickolai A Barlev, Jiri Bartek, Nicolas G Bazan, Christoph Becker, Francesca Bernassola, Mathieu J M Bertrand, Marco E Bianchi, Mikhail V Blagosklonny, J Magarian Blander, Giovanni Blandino, Klas Blomgren, Christoph Borner, Carl D Bortner, Pierluigi Bove, Patricia Boya, Catherine Brenner, Petr Broz, Thomas Brunner, Rune Busk Damgaard, George A Calin, Michelangelo Campanella, Eleonora Candi, Michele Carbone, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Guo-Qiang Chen, Quan Chen, Youhai H Chen, Emily H Cheng, Jerry E Chipuk, John A Cidlowski, Aaron Ciechanover, Gennaro Ciliberto, Marcus Conrad, Juan R Cubillos-Ruiz, Peter E Czabotar, Vincenzo D'Angiolella, Mads Daugaard, Ted M Dawson, Valina L Dawson, Ruggero De Maria, Bart De Strooper, Klaus-Michael Debatin, Ralph J Deberardinis, Alexei Degterev, Giannino Del Sal, Mohanish Deshmukh, Francesco Di Virgilio, Marc Diederich, Scott J Dixon, Brian D Dynlacht, Wafik S El-Deiry, John W Elrod, Kurt Engeland, Gian Maria Fimia, Claudia Galassi, Carlo Ganini, Ana J Garcia-Saez, Abhishek D Garg, Carmen Garrido, Evripidis Gavathiotis, Motti Gerlic, Sourav Ghosh, Douglas R Green, Lloyd A Greene, Hinrich Gronemeyer, Georg Häcker, György Hajnóczky, J Marie Hardwick, Ygal Haupt, Sudan He, David M Heery, Michael O Hengartner, Claudio Hetz, David A Hildeman, Hidenori Ichijo, Satoshi Inoue, Marja Jäättelä, Ana Janic, Bertrand Joseph, Philipp J Jost, Thirumala-Devi Kanneganti, Michael Karin, Hamid Kashkar, Thomas Kaufmann, Gemma L Kelly, Oliver Kepp, Adi Kimchi, Richard N Kitsis, Daniel J Klionsky, Ruth Kluck, Dmitri V Krysko, Dagmar Kulms, Sharad Kumar, Sergio Lavandero, Inna N Lavrik, John J Lemasters, Gianmaria Liccardi, Andreas Linkermann, Stuart A Lipton, Richard A Lockshin, Carlos López-Otín, Tom Luedde, Marion Macfarlane, Frank Madeo, Walter Malorni, Gwenola Manic, Roberto Mantovani, Saverio Marchi, Jean-Christophe Marine, Seamus J Martin, Jean-Claude Martinou, Pier G Mastroberardino, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Gerry Melino, Sonia Melino, Edward A Miao, Ute M Moll, Cristina Muñoz-Pinedo, Daniel J Murphy, Maria Victoria Niklison-Chirou, Flavia Novelli, Gabriel Núñez, Andrew Oberst, Dimitry Ofengeim, Joseph T Opferman, Moshe Oren, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M Penninger, Francesca Pentimalli, David M Pereira, Shazib Pervaiz, Marcus E Peter, Paolo Pinton, Giovanni Porta, Jochen H M Prehn, Hamsa Puthalakath, Gabriel A Rabinovich, Krishnaraj Rajalingam, Kodi S Ravichandran, Markus Rehm, Jean-Ehrland Ricci, Rosario Rizzuto, Nirmal Robinson, Cecilia M P Rodrigues, Barak Rotblat, Carla V Rothlin, David C Rubinsztein, Thomas Rudel, Alessandro Rufini, Kevin M Ryan, Kristopher A Sarosiek, Akira Sawa, Emre Sayan, Kate Schroder, Luca Scorrano, Federico Sesti, Feng Shao, Yufang Shi, Giuseppe S Sica, John Silke, Hans-Uwe Simon, Antonella Sistigu, Anastasis Stephanou, Brent R Stockwell, Flavie Strapazzon, Andreas Strasser, Liming Sun, Erwei Sun, Qiang Sun, Gyorgy Szabadkai, Stephen W G Tait, Daolin Tang, Nektarios Tavernarakis, Carol M Troy, Boris Turk, Nicoletta Urbano, Peter Vandenabeele, Tom Vanden Berghe, Matthew G Vander Heiden, Jacqueline L Vanderluit, Alexei Verkhratsky, Andreas Villunger, Silvia Von Karstedt, Anne K Voss, Karen H Vousden, Domagoj Vucic, Daniela Vuri, Erwin F Wagner, Henning Walczak, David Wallach, Ruoning Wang, Ying Wang, Achim Weber, Will Wood, Takahiro Yamazaki, Huang-Tian Yang, Zahra Zakeri, Joanna E Zawacka-Pankau, Lin Zhang, Haibing Zhang, Boris Zhivotovsky, Wenzhao Zhou, Mauro Piacentini, Guido Kroemer, Lorenzo Galluzzi

Faculty, Staff and Student Publications

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. …

Potent Antitumor Activity Of Ensartinib In Met Exon 14 Skipping-Mutated Non-Small Cell Lung Cancer, Yang Xia, Rui Jin, Miao Li, Fen Lan, Hao Zhu, Yinghui Yu, Da Miao, Qiyuan Wang, Yi Zhou, Giovanni Selvaggi, Songmin Ying, Jianjun Zhang, Huahao Shen, Xiuning Le, Wen Li

Faculty, Staff and Student Publications

Met proto-oncogene exon 14 skipping (METex14) mutations are targetable driver genes in approximately 3% of non-small-cell lung cancers (NSCLCs). Ensartinib, a type Ia MET inhibitor, is a multi-kinase inhibitor that has been approved for ALK-positive NSCLCs. Ensartinib was administered for compassionate use (cohort 1) and in a phase II clinical trial (cohort 2) to patients with METex14 mutant NSCLCs, with ORR as a primary endpoint. Molecular simulation was conducted to evaluate ensartinib c-MET interaction, and cell lines, patient-derived organoids (PDOs), and xenograft models were used to test the effectiveness of ensartinib. Among 29 evaluable patients, the ORR and DCR of …

Sting Agonist-Loaded Mesoporous Manganese-Silica Nanoparticles For Vaccine Applications, Cheng Xu, Hannah E Dobson, Mengjie Yu, Wang Gong, Xiaoqi Sun, Kyung Soo Park, Andrew Kennedy, Xingwu Zhou, Jin Xu, Yao Xu, Andrew W Tai, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Cyclic dinucleotides (CDNs), as one type of Stimulator of Interferon Genes (STING) pathway agonist, have shown promising results for eliciting immune responses against cancer and viral infection. However, the suboptimal drug-like properties of conventional CDNs, including their short in vivo half-life and poor cellular permeability, compromise their therapeutic efficacy. In this study, we have developed a manganese-silica nanoplatform (MnOx@HMSN) that enhances the adjuvant effects of CDN by achieving synergy with Mn2+ for vaccination against cancer and SARS-CoV-2. MnOx@HMSN with large mesopores were efficiently co-loaded with CDN and peptide/protein antigens. MnOx@HMSN(CDA) amplified the activation of the STING pathway and enhanced the …

Redox Phospholipidomics Discovers Pro-Ferroptotic Death Signals In A375 Melanoma Cells In Vitro And In Vivo, Yulia Y Tyurina, Alexandr A Kapralov, Vladimir A Tyurin, Galina Shurin, Andrew A Amoscato, Dhivyaa Rajasundaram, Hua Tian, Yuri L Bunimovich, Yulia Nefedova, William G Herrick, Ralph E Parchment, James H Doroshow, Hulya Bayir, Apurva K Srivastava, Valerian E Kagan

Faculty, Staff and Student Publications

Growing cancer cells effectively evade most programs of regulated cell death, particularly apoptosis. This necessitates a search for alternative therapeutic modalities to cause cancer cell's demise, among them - ferroptosis. One of the obstacles to using pro-ferroptotic agents to treat cancer is the lack of adequate biomarkers of ferroptosis. Ferroptosis is accompanied by peroxidation of polyunsaturated species of phosphatidylethanolamine (PE) to hydroperoxy- (-OOH) derivatives, which act as death signals. We demonstrate that RSL3-induced death of A375 melanoma cells in vitro was fully preventable by ferrostatin-1, suggesting their high susceptibility to ferroptosis. Treatment of A375 cells with RSL3 caused a significant …

Enhancing Oral Delivery Of Plant-Derived Vesicles For Colitis, Yuan Liu, Adrian Lankenau Ahumada, Emine Bayraktar, Paul Schwartz, Mamur Chowdhury, Sixiang Shi, Manu M Sebastian, Htet Khant, Natalia De Val, Nazende Nur Bayram, Guodong Zhang, Thanh Chung Vu, Zuliang Jie, Nicholas B Jennings, Cristian Rodriguez-Aguayo, Jody Swain, Elaine Stur, Lingegowda S Mangala, Yutuan Wu, Supriya Nagaraju, Brooke Ermias, Chun Li, Gabriel Lopez-Berestein, Janet Braam, Anil K Sood

Faculty, Staff and Student Publications

Plant-derived vesicles (PDVs) are attractive for therapeutic applications, including as potential nanocarriers. However, a concern with oral delivery of PDVs is whether they would remain intact in the gastrointestinal tract. We found that 82% of cabbage PDVs were destroyed under conditions mimicking the upper digestive tract. To overcome this limitation, we developed a delivery method whereby lyophilized Eudragit S100-coated cabbage PDVs were packaged into a capsule (Cap-cPDVs). Lyophilization and suspension of PDVs did not have an appreciable impact on PDV structure, number, or therapeutic effect. Additionally, packaging the lyophilized Eudragit S100-coated PDVs into capsules allowed them to pass through the …