Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Histopathologic And Proteogenomic Heterogeneity Reveals Features Of Clear Cell Renal Cell Carcinoma Aggressiveness, Yize Li, Tung-Shing M Lih, Saravana M Dhanasekaran, Rahul Mannan, Lijun Chen, Marcin Cieslik, Yige Wu, Rita Jiu-Hsien Lu, David J Clark, Iga Kołodziejczak, Runyu Hong, Siqi Chen, Yanyan Zhao, Seema Chugh, Wagma Caravan, Nataly Naser Al Deen, Noshad Hosseini, Chelsea J Newton, Karsten Krug, Yuanwei Xu, Kyung-Cho Cho, Yingwei Hu, Yuping Zhang, Chandan Kumar-Sinha, Weiping Ma, Anna Calinawan, Matthew A Wyczalkowski, Michael C Wendl, Yuefan Wang, Shenghao Guo, Cissy Zhang, Anne Le, Aniket Dagar, Alex Hopkins, Hanbyul Cho, Felipe Da Veiga Leprevost, Xiaojun Jing, Guo Ci Teo, Wenke Liu, Melissa A Reimers, Russell Pachynski, Alexander J Lazar, Arul M Chinnaiyan, Brian A Van Tine, Bing Zhang, Karin D Rodland, Gad Getz, D R Mani, Pei Wang, Feng Chen, Galen Hostetter, Mathangi Thiagarajan, W Marston Linehan, David Fenyö, Scott D Jewell, Gilbert S Omenn, Rohit Mehra, Maciej Wiznerowicz, Ana I Robles, Mehdi Mesri, Tara Hiltke, Eunkyung An, Henry Rodriguez, Daniel W Chan, Christopher J Ricketts, Alexey I Nesvizhskii, Hui Zhang, Li Ding, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Students Publications

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 …

Interdependent Progression Of Bidirectional Sister Replisomes In E Coli, Po Jui Chen, Anna B Mcmullin, Bryan J Visser, Qian Mei, Susan M Rosenberg, David Bates

Faculty, Staff and Students Publications

Bidirectional DNA replication complexes initiated from the same origin remain colocalized in a factory configuration for part or all their lifetimes. However, there is little evidence that sister replisomes are functionally interdependent, and the consequence of factory replication is unknown. Here, we investigated the functional relationship between sister replisomes in Escherichia coli, which naturally exhibits both factory and solitary configurations in the same replication cycle. Using an inducible transcription factor roadblocking system, we found that blocking one replisome caused a significant decrease in overall progression and velocity of the sister replisome. Remarkably, progression was impaired only if the block …

Technology Meets Tils: Deciphering T Cell Function In The -Omics Era, William H Hudson, Andreas Wieland

Faculty, Staff and Students Publications

T cells are at the centerstage of cancer immunology due to their ability to recognize mutations within tumor cells and directly mediate cancer cell killing. Immunotherapies to rejuvenate exhausted T cell responses have transformed the clinical management of several malignancies. In parallel, the development of novel multidimensional analysis platforms such as single-cell RNA-sequencing and high-dimensional flow cytometry has yielded unprecedented insights into immune cell biology. This convergence has revealed substantial heterogeneity of tumor-infiltrating immune cells, both within single tumors, across tumor types, and among cancer patients. Here, we discuss the opportunities and challenges of studying the complex tumor microenvironment with …

Echinococcus Multilocularis Calreticulin Interferes With C1q-Mediated Complement Activation, Siqi Xian, Lujuan Chen, Yan Yan, Jianfang Chen, Guixia Yu, Yuxiao Shao, Bin Zhan, Yanhai Wang, Limei Zhao

Faculty, Staff and Students Publications

As a zoonotic disease caused by Echinococcus multilocularis larvae, alveolar echinococcosis (AE) is one of the most severe forms of parasitic infection. Over a long evolutional process E. multilocularis has developed complex strategies to escape host immune attack and survive within a host. However, the mechanisms underlying immune evasion remain unclear. Here we investigated the binding activity of E. multilocularis calreticulin (EmCRT), a highly conserved Ca2+-binding protein, to human complement C1q and its ability to inhibit classical complement activation. ELISA, Far Western blotting and immunoprecipitation results demonstrated that both recombinant and natural EmCRTs bound to human C1q, …

Excretory/Secretory Proteome Of Females And Males Of The Hookworm Ancylostoma Ceylanicum, Samuel C Uzoechi, Bruce A Rosa, Kumar Sachin Singh, Young-Jun Choi, Bethany K Bracken, Paul J Brindley, R Reid Townsend, Robert Sprung, Bin Zhan, Maria-Elena Bottazzi, John M Hawdon, Yide Wong, Alex Loukas, Sergej Djuranovic, Makedonka Mitreva

Faculty, Staff and Students Publications

The dynamic host-parasite mechanisms underlying hookworm infection establishment and maintenance in mammalian hosts remain poorly understood but are primarily mediated by hookworm’s excretory/secretory products (ESPs), which have a wide spectrum of biological functions. We used ultra-high performance mass spectrometry to comprehensively profile and compare female and male ESPs from the zoonotic human hookworm Ancylostoma ceylanicum, which is a natural parasite of dogs, cats, and humans. We improved the genome annotation, decreasing the number of protein-coding genes by 49% while improving completeness from 92 to 96%. Compared to the previous genome annotation, we detected 11% and 10% more spectra in …

Establishing 3d Endometrial Organoids From The Mouse Uterus, Suni Tang, Sydney E Parks, Zian Liao, Dominique I Cope, Sarah E Blutt, Diana Monsivais

Faculty, Staff and Students Publications

Endometrial tissue lines the inner cavity of the uterus and is under the cyclical control of estrogen and progesterone. It is a tissue that is composed of luminal and glandular epithelium, a stromal compartment, a vascular network, and a complex immune cell population. Mouse models have been a powerful tool to study the endometrium, revealing critical mechanisms that control implantation, placentation, and cancer. The recent development of 3D endometrial organoid cultures presents a state-of-the-art model to dissect the signaling pathways that underlie endometrial biology. Establishing endometrial organoids from genetically engineered mouse models, analyzing their transcriptomes, and visualizing their morphology at …

Human Generation Times Across The Past 250,000 Years, Richard J Wang, Samer I Al-Saffar, Jeffrey Rogers, Matthew W Hahn

Faculty, Staff and Students Publications

The generation times of our recent ancestors can tell us about both the biology and social organization of prehistoric humans, placing human evolution on an absolute time scale. We present a method for predicting historical male and female generation times based on changes in the mutation spectrum. Our analyses of whole-genome data reveal an average generation time of 26.9 years across the past 250,000 years, with fathers consistently older (30.7 years) than mothers (23.2 years). Shifts in sex-averaged generation times have been driven primarily by changes to the age of paternity, although we report a substantial increase in female generation …

Civicdb 2022: Evolution Of An Open-Access Cancer Variant Interpretation Knowledgebase, Kilannin Krysiak, Arpad M Danos, Jason Saliba, Joshua F Mcmichael, Adam C Coffman, Susanna Kiwala, Erica K Barnell, Lana Sheta, Cameron J Grisdale, Lynzey Kujan, Shahil Pema, Jake Lever, Sarah Ridd, Nicholas C Spies, Veronica Andric, Andreea Chiorean, Damian T Rieke, Kaitlin A Clark, Caralyn Reisle, Ajay C Venigalla, Mark Evans, Payal Jani, Hideaki Takahashi, Avila Suda, Peter Horak, Deborah I Ritter, Xin Zhou, Benjamin J Ainscough, Sean Delong, Chimene Kesserwan, Mario Lamping, Haolin Shen, Alex R Marr, My H Hoang, Kartik Singhal, Mariam Khanfar, Brian V Li, Wan-Hsin Lin, Panieh Terraf, Laura B Corson, Yasser Salama, Katie M Campbell, Kirsten M Farncombe, Jianling Ji, Xiaonan Zhao, Xinjie Xu, Rashmi Kanagal-Shamanna, Ian King, Kelsy C Cotto, Zachary L Skidmore, Jason R Walker, Jinghui Zhang, Aleksandar Milosavljevic, Ronak Y Patel, Rachel H Giles, Raymond H Kim, Lynn M Schriml, Elaine R Mardis, Steven J M Jones, Gordana Raca, Shruti Rao, Subha Madhavan, Alex H Wagner, Malachi Griffith, Obi L Griffith

Faculty, Staff and Students Publications

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination …

Rare Eif4a2 Variants Are Associated With A Neurodevelopmental Disorder Characterized By Intellectual Disability, Hypotonia, And Epilepsy, Maimuna S Paul, Anna R Duncan, Casie A Genetti, Hongling Pan, Adam Jackson, Patricia E Grant, Jiahai Shi, Michele Pinelli, Nicola Brunetti-Pierri, Alexandra Garza-Flores, Dave Shahani, Russell P Saneto, Giuseppe Zampino, Chiara Leoni, Emanuele Agolini, Antonio Novelli, Ulrike Blümlein, Tobias B Haack, Wolfram Heinritz, Eva Matzker, Bader Alhaddad, Rami Abou Jamra, Tobias Bartolomaeus, Saber Alhamdan, Raphael Carapito, Bertrand Isidor, Seiamak Bahram, Alyssa Ritter, Kosuke Izumi, Ben Pode Shakked, Ortal Barel, Bruria Ben Zeev, Amber Begtrup, Deanna Alexis Carere, Sureni V Mullegama, Timothy Blake Palculict, Daniel G Calame, Katharina Schwan, Alicia R P Aycinena, Rasa Traberg, Genomics England Research Consortium, Sofia Douzgou, Harrison Pirt, Naila Ismayilova, Siddharth Banka, Hsiao-Tuan Chao, Pankaj B Agrawal

Faculty, Staff and Students Publications

Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. …

Feasibility And Preclinical Efficacy Of Cd7-Unedited Cd7 Car T Cells For T Cell Malignancies, Norihiro Watanabe, Feiyan Mo, Rong Zheng, Royce Ma, Vanesa C Bray, Dayenne G Van Leeuwen, Juntima Sritabal-Ramirez, Hongxiang Hu, Sha Wang, Birju Mehta, Madhuwanti Srinivasan, Lauren D Scherer, Huimin Zhang, Sachin G Thakkar, Laquisa C Hill, Helen E Heslop, Chonghui Cheng, Malcolm K Brenner, Maksim Mamonkin

Faculty, Staff and Students Publications

Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR T cells or their excessive differentiation driven by constant CAR signaling. Expression of CARs targeting CD7, a pan-T cell antigen highly expressed in T cell malignancies and some myeloid leukemias, produces robust fratricide and often requires additional mitigation strategies, such as CD7 gene editing. In this study, we show fratricide of CD7 CAR T cells can be fully prevented using ibrutinib and dasatinib, the pharmacologic inhibitors of key CAR/CD3ζ signaling kinases. Supplementation with ibrutinib and dasatinib rescued the …

A Low-Fat/Sucrose Diet Rich In Complex Carbohydrates Reverses High-Fat/Sucrose Diet-Induced Corneal Dysregulation, Prince K Akowuah, Carolina Lema, Rolando E Rumbaut, Alan R Burns

Faculty, Staff and Students Publications

High-fat/sucrose diet feeding in mice causes loss of corneal nerve function and impairs corneal wound healing. While changing to a diet with a low fat/sugar composition and enrichments in complex carbohydrates mitigates the reduction in nerve function, it remains to be determined if it has an effect on corneal wound healing. In this study, 6-week-old C57BL/6 male mice were fed either a normal diet or a high-fat/sucrose diet for 20 weeks. A third group (diet reversal) was placed on a high-fat/sucrose diet for 10 weeks followed by a normal diet for an additional 10 weeks. A central corneal epithelial abrasion …

Subtype And Site Specific-Induced Metabolic Vulnerabilities In Prostate Cancer, Federica Mossa, Daniele Robesti, Ramachandran Sumankalai, Eva Corey, Mark Titus, Yuqi Kang, Jianhua Zhang, Alberto Briganti, Francesco Montorsi, Christopher P Vellano, Joseph R Marszalek, Daniel E Frigo, Christopher J Logothetis, Taranjit S Gujral, Eleonora Dondossola

Faculty, Staff and Student Publications

Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer [androgen receptor-expressing prostate cancer (ARPC) and aggressive variant prostate cancer (AVPC)]. Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation (OXPHOS) in ARPC tumor samples compared with AVPC. Unbiased screening of metabolic signaling pathways in patient-derived xenograft models by proteomic analyses further supported an enrichment of OXPHOS in ARPC compared with AVPC, and a skewing toward …

Increased Camkk2 Expression Is An Adaptive Response That Maintains The Fitness Of Tumor-Infiltrating Natural Killer Cells, Patrick K Juras, Luigi Racioppi, Debarati Mukherjee, Sandeep Artham, Xia Gao, Laura Akullian D'Agostino, Ching-Yi Chang, Donald P Mcdonnell

Faculty, Staff and Students Publications

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been interest in developing CaMKK2 inhibitors as potential anticancer therapeutics. One impediment to clinical development of these agents is that the roles of CaMKK2 in other cellular compartments within the tumor immune microenvironment remain to be established. We report herein that CaMKK2 is expressed at low basal levels in natural killer (NK) …

Mitochondrial Dysfunction Reactivates Α-Fetoprotein Expression That Drives Copper-Dependent Immunosuppression In Mitochondrial Disease Models, Kimberly A Jett, Zakery N Baker, Amzad Hossain, Aren Boulet, Paul A Cobine, Sagnika Ghosh, Philip Ng, Orhan Yilmaz, Kris Barreto, John Decoteau, Karen Mochoruk, George N Ioannou, Christopher Savard, Sai Yuan, Osama Hmh Abdalla, Christopher Lowden, Byung-Eun Kim, Hai-Ying Mary Cheng, Brendan J Battersby, Vishal M Gohil, Scot C Leary

Faculty, Staff and Students Publications

Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identified a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that resulted in atrophy of the spleen and thymus and caused a peripheral white blood cell deficiency. We demonstrated that the leukopenia was caused by α-fetoprotein, which required copper and the cell surface receptor CCR5 to promote white blood cell death. We further showed that α-fetoprotein expression was upregulated in several cell types upon inhibition of oxidative …

Follistatin Regulates The Specification Of The Apical Cochlea Responsible For Low-Frequency Hearing In Mammals, Hei Yeun Koo, Min-A Kim, Hyehyun Min, Jae Yeon Hwang, Meenakshi Prajapati-Dinubila, Kwan Soo Kim, Martin M Matzuk, Juw Won Park, Angelika Doetzlhofer, Un-Kyung Kim, Jinwoong Bok

Faculty, Staff and Students Publications

The cochlea's ability to discriminate sound frequencies is facilitated by a special topography along its longitudinal axis known as tonotopy. Auditory hair cells located at the base of the cochlea respond to high-frequency sounds, whereas hair cells at the apex respond to lower frequencies. Gradual changes in morphological and physiological features along the length of the cochlea determine each region's frequency selectivity, but it remains unclear how tonotopy is established during cochlear development. Recently, sonic hedgehog (SHH) was proposed to initiate the establishment of tonotopy by conferring regional identity to the primordial cochlea. Here, using mouse genetics, we provide in …

Antisense Oligonucleotide Therapy Rescues Disturbed Brain Rhythms And Sleep In Juvenile And Adult Mouse Models Of Angelman Syndrome, Dongwon Lee, Wu Chen, Heet Naresh Kaku, Xinming Zhuo, Eugene S Chao, Armand Soriano, Allen Kuncheria, Stephanie Flores, Joo Hyun Kim, Armando Rivera, Frank Rigo, Paymaan Jafar-Nejad, Arthur L Beaudet, Matthew S Caudill, Mingshan Xue

Faculty, Staff and Students Publications

UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the UBE3A antisense transcript (UBE3A-ATS). This leaves neurons susceptible to loss-of-function of maternal UBE3A. Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal UBE3A deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal UBE3A by suppressing UBE3A-ATS. Prior studies show that many neurological phenotypes of maternal Ube3a knockout mice can only be rescued by reinstating Ube3a expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here, we …

Leukocytes As Mediators Of Gut-Brain Communication, Dilini Ekanayake

Biomedical Sciences Posters and Presentations

Food allergies

▪ Reactions range from mild/delayed to severe/rapid. ▪ People with mild allergic reactions have increased re-exposure risks. ▪ Cow’s milk allergy tends to manifest with milder allergic reactions.

Cow’s milk allergy (CMA)

▪ CMA has been associated with behavioral and neurological disorders. ▪ How allergic inflammatory signals from the gut reach the brain is unclear

Continuous Consumption Of Whey Protein Affects Motor And Cognitive Functions In A Mouse Model Of Cow’S Milk Hypersensitivity, Geetika Verma

Biomedical Sciences Posters and Presentations

Hypersensitization to a food allergen can occur in the absence of immediate allergic reactions, a condition referred to as asymptomatic sensitization. Using mice asymptomatically sensitized to a bovine whey allergen, β-lactoglobulin (BLG, Bos d 5), we have previously shown that chronic exposure to the allergen results in behavior changes with increased neuroinflammation and cortical demyelination. However, whether allergen avoidance can resolve these pathologies is unknown. Thus, we aimed to compare immunological and behavioral changes in sham- or BLG-sensitized mice with or without the removal of dietary whey after the mice had consumed either a control diet (CTL) or a whey-protein-containing …

Continued Food-Allergen Consumption Exacerbates Beta-Amyloid Accumulation In Allergen-Sensitized Appnl-G-Fmice., Afrina Brishti

Biomedical Sciences Posters and Presentations

Alzheimer’s disease (AD) is the most common neurodegenerative disease, with β-amyloid(Aβ) plaque deposition being one of the hallmark pathologies. However, the etiology of AD remains elusive. While chronic inflammation from recurrent infections or injury seems to contribute to AD development, it is unclear whether atopic diseases, such as allergies, are associated with AD. We previously reported that continuous consumption of a whey protein(WP) -containing diet led to lasting neuro inflammation in C57BL/6J mice that were sensitized but tolerant to a bovine milk allergen, β-lactoglobulin (BLG;Bosd5). Thus, we hypothesized that the persisting neuroinflammation due to repeated allergen consumption would exacerbate AD …

Histamine H3 Receptor Antagonism Mitigates Food-Hypersensitivity-Associated Depressive Behavior And Neuropathology In A Mouse Model Of Cow’S Milk Allergy, Danielle Germundson-Hermanson

Biomedical Sciences Posters and Presentations

Background Histamine is best known for causing allergy symptoms, but it also regulates blood-brain barrier permeability1 and oligodendrocyte differentiation2. Thus, brain histamine levels are tightly controlled.

Previous Findings We demonstrated that histamine and histamine H3 receptor (H3R) levels were elevated in a mouse model of cow’s milk allergy (CMA) in association with intracranial mast cell activation, depression-like behaviors, and cortical demyelination3,4.

Gaps in Knowledge In humans, food allergies are often associated with neuropsychiatric disorders5-7, but the involvement of allergy induced histamine in triggering behavioral changes is unclear.

Hypothesis Repeated allergen consumption can lead to central histaminergic dysfunction through H3R, ultimately …