Digital Commons Network^™

Cbx4 Promotes Antitumor Immunity By Suppressing Pdcd1 Expression In T Cells, Liwei Ren, Ziyin Li, Yu Zhou, Jun Zhang, Ziheng Zhao, Zhaofei Wu, Ye Zhao, Yurong Ju, Xuewen Pang, Xiuyuan Sun, Wei Wang, Yu Zhang

Faculty, Staff and Student Publications

E3 SUMO-protein ligase CBX4 (CBX4), a key component of polycomb-repressive complexes 1 (PRC1), has been reported to regulate a variety of genes implicated in tumor growth, metastasis, and angiogenesis. However, its role in T-cell-mediated antitumor immunity remains elusive. To shed light on this issue, we generated mice with T-cell-specific deletion of Cbx4. Tumor growth was increased in the knockout mice. Additionally, their tumor-infiltrating lymphocytes exhibited impaired tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) production, with an elevated programmed cell death protein 1 (PD-1) level. In fact, dysregulated Pdcd1 expression was observed in all major subsets of peripheral T cells from …

Enhanced Cd19 Activity In B Cells Contributes To Immunodeficiency In Mice Deficient In The Icf Syndrome Gene Zbtb24, Zhengzhou Ying, Swanand Hardikar, Joshua B Plummer, Tewfik Hamidi, Bin Liu, Yueping Chen, Jianjun Shen, Yunxiang Mu, Kevin M Mcbride, Taiping Chen

Faculty, Staff and Student Publications

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations in DNMT3B, ZBTB24, CDCA7, or HELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here, we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels …

Effect Of Epithelial-Specific Myd88 Signaling Pathway On Airway Inflammatory Response To Organic Dust Exposure, Amber N Johnson, John Dickinson, Amy Nelson, Rohit Gaurav, Katrina Kudrna, Scott E Evans, Katherine Janike, Todd A Wyatt, Jill A Poole

Faculty, Staff and Student Publications

The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE in vivo, the surfactant protein C protein (SPC) Cre+ embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre+, MyD88 floxed, …

Early-Life Stress Perturbs The Epigenetics Of Cd36 Concurrent With Adult Onset Of Nafld In Mice., Qi Fu, Jenna M. Frick, Maura F. O'Neil, Olivia C. Eller, E Matthew Morris, John P. Thyfault, Julie A. Christianson, Robert H. Lane

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in the U.S. and worldwide. The roles of early postnatal life stress (EPLS) and the fatty acid translocase (CD36) on the pathogenesis of adult-onset NAFLD remain unknown. We hypothesized that EPLS, in the form of neonatal maternal separation (NMS), would predispose mice towards developing adult NAFLD, increase hepatic CD36 expression, and differentially methylate Cd36 promoter concurrently.

METHODS: NMS was performed on mice from postnatal day 1 to 21 and a high-fat/high-sucrose (HFS) diet was started at 4 weeks of age to generate four experimental groups: Naive-control …

Clinical Exome Sequencing Efficacy And Phenotypic Expansions Involving Anomalous Pulmonary Venous Return, Emily A Huth, Xiaonan Zhao, Nichole Owen, Pamela N Luna, Ida Vogel, Inger L H Dorf, Shelagh Joss, Jill Clayton-Smith, Michael J Parker, Jacoba J Louw, Marc Gewillig, Jeroen Breckpot, Alison Kraus, Erina Sasaki, Usha Kini, Trent Burgess, Tiong Y Tan, Ruth Armstrong, Katherine Neas, Giovanni B Ferrero, Alfredo Brusco, Wihelmina S Kerstjens-Frederikse, Julia Rankin, Lindsey R Helvaty, Benjamin J Landis, Gabrielle C Geddes, Kim L Mcbride, Stephanie M Ware, Chad A Shaw, Seema R Lalani, Jill A Rosenfeld, Daryl A Scott

Faculty, Staff and Students Publications

Anomalous pulmonary venous return (APVR) frequently occurs with other congenital heart defects (CHDs) or extra-cardiac anomalies. While some genetic causes have been identified, the optimal approach to genetic testing in individuals with APVR remains uncertain, and the etiology of most cases of APVR is unclear. Here, we analyzed molecular data from 49 individuals to determine the diagnostic yield of clinical exome sequencing (ES) for non-isolated APVR. A definitive or probable diagnosis was made for 8 of those individuals yielding a diagnostic efficacy rate of 16.3%. We then analyzed molecular data from 62 individuals with APVR accrued from three databases to …

Ezh2 Cooperates With Brd4-Nut To Drive Nut Carcinoma Growth By Silencing Key Tumor Suppressor Genes, Yeying Huang, R Taylor Durall, Nhi M Luong, Hans J Hertzler, Julianna Huang, Prafulla C Gokhale, Brittaney A Leeper, Nicole S Persky, David E Root, Praju V Anekal, Paula D L M Montero Llopis, Clement N David, Jeffery L Kutok, Alejandra Raimondi, Karan Saluja, Jia Luo, Cynthia A Zahnow, Biniam Adane, Kimberly Stegmaier, Catherine E Hawkins, Christopher Ponne, Quan Le, Geoffrey I Shapiro, Madeleine E Lemieux, Kyle P Eagen, Christopher A French

Faculty, Staff and Student Publications

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NC that can impede BRD4-NUT’s ability to activate genes, but the efficacy of BETi as monotherapy are limited. Here, we demonstrated that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple …

Complex Evolutionary History With Extensive Ancestral Gene Flow In An African Primate Radiation, Axel Jensen, Frances Swift, Dorien De Vries, Robin M D Beck, Lukas F K Kuderna, Sascha Knauf, Idrissa S Chuma, Julius D Keyyu, Andrew C Kitchener, Kyle Farh, Jeffrey Rogers, Tomas Marques-Bonet, Kate M Detwiler, Christian Roos, Katerina Guschanski

Faculty, Staff and Students Publications

Understanding the drivers of speciation is fundamental in evolutionary biology, and recent studies highlight hybridization as an important evolutionary force. Using whole-genome sequencing data from 22 species of guenons (tribe Cercopithecini), one of the world's largest primate radiations, we show that rampant gene flow characterizes their evolutionary history and identify ancient hybridization across deeply divergent lineages that differ in ecology, morphology, and karyotypes. Some hybridization events resulted in mitochondrial introgression between distant lineages, likely facilitated by cointrogression of coadapted nuclear variants. Although the genomic landscapes of introgression were largely lineage specific, we found that genes with immune functions were overrepresented …

Microbial Stimulation Of Oxytocin Release From The Intestinal Epithelium Via Secretin Signaling, Heather A Danhof, Jihwan Lee, Aanchal Thapa, Robert A Britton, Sara C Di Rienzi

Faculty, Staff and Students Publications

Intestinal microbes impact the health of the intestine and organs distal to the gut. Limosilactobacillus reuteri is a human intestinal microbe that promotes normal gut transit, the anti-inflammatory immune system, wound healing, normal social behavior in mice, and prevents bone reabsorption. Oxytocin impacts these functions and oxytocin signaling is required for L. reuteri-mediated wound healing and social behavior; however, the events in the gut leading to oxytocin stimulation and beneficial effects are unknown. Here we report evolutionarily conserved oxytocin production in the intestinal epithelium through analysis of single-cell RNA-Seq datasets and imaging of human and mouse intestinal tissues. Moreover, …

Microbial Products Linked To Steatohepatitis Are Reduced By Deletion Of Nuclear Hormone Receptor Shp In Mice, Ryan Mifflin, Jung Eun Park, Mikang Lee, Prasant Kumar Jena, Yu-Jui Yvonne Wan, Hazel A Barton, Mirjavid Aghayev, Takhar Kasumov, Li Lin, Xinwen Wang, Robert Novak, Feng Li, He Huang, Leah P Shriver, Yoon-Kwang Lee

Faculty, Staff and Students Publications

Deletion of the nuclear hormone receptor small heterodimer partner (Shp) ameliorates the development of obesity and nonalcoholic steatohepatitis (NASH) in mice. Liver-specific SHP plays a significant role in this amelioration. The gut microbiota has been associated with these metabolic disorders, and the interplay between bile acids (BAs) and gut microbiota contributes to various metabolic disorders. Since hepatic SHP is recognized as a critical regulator in BA synthesis, we assessed the involvement of gut microbiota in the antiobesity and anti-NASH phenotype of Shp−/− mice. Shp deletion significantly altered the levels of a few conjugated BAs. Sequencing the 16S …

Development Of Canagliflozin Nanocrystals Sublingual Tablets In The Presence Of Sodium Caprate Permeability Enhancer: Formulation Optimization, Characterization, Sammar Fathy Elhabal, Mohamed A El-Nabarawi, Nashwa Abdelaal, Mohamed Fathi Mohamed Elrefai, Shrouk A Ghaffar, Mohamed Mansour Khalifa, Passant M Mohie, Dania S Waggas, Ahmed Mohsen Elsaid Hamdan, Samar Zuhair Alshawwa, Essa M Saied, Nahla A Elzohairy, Tayseer Elnawawy, Rania A Gad, Nehal Elfar, Hanaa Mohammed, Mohammad Ahmad Khasawneh

Faculty, Staff and Students Publications

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor (SGLT2) that lowers albuminuria in type-2 diabetic patients, cardiovascular, kidney, and liver disease. CFZ is classified as class IV in the Biopharmaceutical Classification System (BCS) and is characterized by low permeability, solubility, and bioavailability, most likely attributed to hepatic first-pass metabolism. Nanocrystal-based sublingual formulations were developed in the presence of sodium caprate, as a wetting agent, and as a permeability enhancer. This formulation is suitable for children and adults and could enhance solubility, permeability, and avoid enterohepatic circulation due to absorption through the sublingual mucosa. In the present study, formulations containing various surfactants …

Steroid Receptor Coactivator-2 Drives Epithelial Reprogramming That Enables Murine Embryo Implantation, Vineet K Maurya, Maria M Szwarc, David M Lonard, Ramakrishna Kommagani, San Pin Wu, Bert W O'Malley, Francesco J Demayo, John P Lydon

Faculty, Staff and Students Publications

Although we have shown that steroid receptor coactivator-2 (SRC-2), a member of the p160/SRC family of transcriptional coregulators, is essential for decidualization of both human and murine endometrial stromal cells, SRC-2’s role in the earlier stages of the implantation process have not been adequately addressed. Using a conditional SRC-2 knockout mouse (SRC-2 ^d/d) in timed natural pregnancy studies, we show that endometrial SRC-2 is required for embryo attachment and adherence to the luminal epithelium. Implantation failure is associated with the persistent expression of Mucin 1 and E-cadherin on the apical surface and basolateral adherens junctions of the SRC-2 …

The Brd4-Nut Fusion Alone Drives Malignant Transformation Of Nut Carcinoma, R Taylor Durall, Julianna Huang, Luke Wojenski, Yeying Huang, Prafulla C Gokhale, Brittaney A Leeper, Joshua O Nash, Pedro L Ballester, Scott Davidson, Adam Shlien, Emmanuel Sotirakis, Fabien Bertaux, Vincent Dubus, Jia Luo, Catherine J Wu, Derin B Keskin, Kyle P Eagen, Geoffrey I Shapiro, Christopher A French

Faculty, Staff and Students Publications

NUT carcinoma (NC) is an aggressive squamous carcinoma defined by the BRD4-NUT fusion oncoprotein. Routinely effective systemic treatments are unavailable for most NC patients. The lack of an adequate animal model precludes identifying and leveraging cell-extrinsic factors therapeutically in NC. Here, we created a genetically engineered mouse model (GEMM) of NC that forms a Brd4::NUTM1 fusion gene upon tamoxifen induction of Sox2-driven Cre. The model displayed complete disease penetrance, with tumors arising from the squamous epithelium weeks after induction and all mice succumbing to the disease shortly thereafter. Closely resembling human NC (hNC), GEMM tumors (mNC) were poorly differentiated squamous …

Estradiol Mediates Colonic Epithelial Protection In Aged Mice After Stroke And Is Associated With Shifts In The Gut Microbiome, Juneyoung Lee, Pedram Peesh, Victoria Quaicoe, Chunfeng Tan, Anik Banerjee, Patrick Mooz, Bhanu P Ganesh, Joseph Petrosino, Robert M Bryan, Louise D Mccullough, Venugopal Reddy Venna

Faculty, Staff and Student Publications

The gut is a major source of bacteria and antigens that contribute to neuroinflammation after brain injury. Colonic epithelial cells (ECs) are responsible for secreting major cellular components of the innate defense system, including antimicrobial proteins (AMP) and mucins. These cells serve as a critical regulator of gut barrier function and maintain host-microbe homeostasis. In this study, we determined post-stroke host defense responses at the colonic epithelial surface in mice. We then tested if the enhancement of these epithelial protective mechanisms is beneficial in young and aged mice after stroke. AMPs were significantly increased in the colonic ECs of young …

Crispr-Cas9-Based Functional Interrogation Of Unconventional Translatome Reveals Human Cancer Dependency On Cryptic Non-Canonical Open Reading Frames, Caishang Zheng, Yanjun Wei, Peng Zhang, Kangyu Lin, Dandan He, Hongqi Teng, Ganiraju Manyam, Zhao Zhang, Wen Liu, Hye Rin Lindsay Lee, Ximing Tang, Wei He, Nelufa Islam, Antrix Jain, Yulun Chiu, Shaolong Cao, Yarui Diao, Sherita Meyer-Gauen, Magnus Höök, Anna Malovannaya, Wenbo Li, Ming Hu, Wenyi Wang, Han Xu, Scott Kopetz, Yiwen Chen

Faculty, Staff and Student Publications

Emerging evidence suggests that cryptic translation beyond the annotated translatome produces proteins with developmental or physiological functions. However, functions of cryptic non-canonical open reading frames (ORFs) in cancer remain largely unknown. To fill this gap and systematically identify colorectal cancer (CRC) dependency on non-canonical ORFs, we apply an integrative multiomic strategy, combining ribosome profiling and a CRISPR-Cas9 knockout screen with large-scale analysis of molecular and clinical data. Many such ORFs are upregulated in CRC compared to normal tissues and are associated with clinically relevant molecular subtypes. We confirm the in vivo tumor-promoting function of the microprotein SMIMP, encoded by a …

Nonsense Variant Prdm16-Q187x Causes Impaired Myocardial Development And Tgf-Β Signaling Resulting In Noncompaction Cardiomyopathy In Humans And Mice, Bo Sun, Omid M T Rouzbehani, Ryan J Kramer, Rajeshwary Ghosh, Robin M Perelli, Sage Atkins, Amir Nima Fatahian, Kathryn Davis, Marta W Szulik, Michael A Goodman, Marissa A Hathaway, Ellenor Chi, Tarah A Word, Hari Tunuguntla, Susan W Denfield, Xander H T Wehrens, Kevin J Whitehead, Hala Y Abdelnasser, Junco S Warren, Mingfu Wu, Sarah Franklin, Sihem Boudina, Andrew P Landstrom

Faculty, Staff and Students Publications

BACKGROUND: PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human cardiomyopathy development is unclear. This study aims to determine the impact of PRDM16 loss-of-function variants on cardiomyopathy in humans.

METHODS: Individuals with PRDM16 variants were identified and consented. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated from a proband hosting a Q187X nonsense variant as an in vitro model and underwent proliferative and transcriptional analyses. CRISPR-mediated knock-in mouse model hosting the Prdm16Q187X allele was generated …

Optimized Strategy For Real-Time Qpcr Detection Of Onchocerca Volvulus Dna In Pooled Simulium Sp. Blackfly Vectors, Mary Doherty, Peter U. Fischer, Et Al.

2020-Current year OA Pubs

BACKGROUND: Onchocerca volvulus is a filarial parasite that is a major cause of dermatitis and blindness in endemic regions primarily in sub-Saharan Africa. Widespread efforts to control the disease caused by O. volvulus infection (onchocerciasis) began in 1974 and in recent years, following successful elimination of transmission in much of the Americas, the focus of efforts in Africa has moved from control to the more challenging goal of elimination of transmission in all endemic countries. Mass drug administration (MDA) with ivermectin has reached more than 150 million people and elimination of transmission has been confirmed in four South American countries, …

Endothelial Adam10 Utilization Defines A Molecular Pathway Of Vascular Injury In Mice With Bacterial Sepsis, Danielle N. Alfano, Mark J. Miller, Juliane Bubeck-Wardenburg

2020-Current year OA Pubs

The endothelium plays a critical role in the host response to infection and has been a focus of investigation in sepsis. While it is appreciated that intravascular thrombus formation, severe inflammation, and loss of endothelial integrity impair tissue oxygenation during sepsis, the precise molecular mechanisms that lead to endothelial injury remain poorly understood. We demonstrate here that endothelial ADAM10 was essential for the pathogenesis of Staphylococcus aureus sepsis, contributing to α-toxin-mediated (Hla-mediated) microvascular thrombus formation and lethality. As ADAM10 is essential for endothelial development and homeostasis, we examined whether other major human sepsis pathogens also rely on ADAM10-dependent pathways in …

Purification Of Modified Mammalian Actin Isoforms For In Vitro Reconstitution Assays, David J Kast, Silvia Jansen

2020-Current year OA Pubs

In vitro reconstitution assays using purified actin have greatly improved our understanding of cytoskeletal dynamics and their regulation by actin-binding proteins. However, early purification methods consisted of harsh conditions to obtain pure actin and often did not include correct maturation and obligate modification of the isolated actin monomers. Novel insights into the folding requirements and N-terminal processing of actin as well as a better understanding of the interaction of actin with monomer sequestering proteins such as DNaseI, profilin and gelsolin, led to the development of more gentle approaches to obtain pure recombinant actin isoforms with known obligate modifications. This review …

Neurofibromin 1 Mutations Impair The Function Of Human Induced Pluripotent Stem Cell-Derived Microglia, Leonard D Kuhrt, Edyta Motta, Nirmeen Elmadany, Hannah Weidling, Raphaela Fritsche-Guenther, Ibrahim E Efe, Olivia Cobb, Jit Chatterjee, Lucy G Boggs, Marina Schnauß, Sebastian Diecke, Marcus Semtner, Corina Anastasaki, David H Gutmann, Helmut Kettenmann

2020-Current year OA Pubs

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by germline mutations in the neurofibromin 1 (NF1) gene. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could reflect the effect of NF1 mutation on microglia function. Using heterozygous Nf1-mutant mice, we previously demonstrated that impaired purinergic signaling underlies deficits in microglia process extension and phagocytosis in situ. To determine whether these abnormalities are also observed in human microglia in the setting of NF1, we leveraged an engineered isogenic series of human induced pluripotent stem cells to generate human …

Single-Cell Analysis Of Chromatin Accessibility In The Adult Mouse Brain, Songpeng Zu, Yang Eric Li, Et Al.

2020-Current year OA Pubs

Recent advances in single-cell technologies have led to the discovery of thousands of brain cell types; however, our understanding of the gene regulatory programs in these cell types is far from complete

Conserved And Divergent Gene Regulatory Programs Of The Mammalian Neocortex, Nathan R Zemke, Daofeng Li, Xiaoyu Zhuo, Vincent Xu, Ting Wang, Et Al.

2020-Current year OA Pubs

Divergence of cis-regulatory elements drives species-specific traits

Trehalose Enhances Mitochondria Deficits In Human Npc1 Mutant Fibroblasts But Disrupts Mouse Purkinje Cell Dendritic Growth Ex Vivo., Collin M Macleod, Fawad A K Yousufzai, Liam T Spencer, Sarah Kim, Lucianne A Rivera-Rosario, Zerian D Barrera, Lindsay Walsh, Claude Krummenacher, Benjamin Carone, Ileana Soto

College of Science & Mathematics Departmental Research

Lysosomes play important roles in catabolism, nutrient sensing, metabolic signaling, and homeostasis. NPC1 deficiency disrupts lysosomal function by inducing cholesterol accumulation that leads to early neurodegeneration in Niemann-Pick type C (NPC) disease. Mitochondria pathology and deficits in NPC1 deficient cells are associated with impaired lysosomal proteolysis and metabolic signaling. It is thought that activation of the transcription factor TFEB, an inducer of lysosome biogenesis, restores lysosomal-autophagy activity in lysosomal storage disorders. Here, we investigated the effect of trehalose, a TFEB activator, in the mitochondria pathology of NPC1 mutant fibroblasts in vitro and in mouse developmental Purkinje cells ex vivo. We …

Loss Of The Methylarginine Reader Function Of Snd1 Confers Resistance To Hepatocellular Carcinoma, Tanner Wright, Yalong Wang, Sabrina A Stratton, Manu Sebastian, Bin Liu, David G Johnson, Mark T Bedford

Faculty, Staff and Student Publications

Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that 'reads' methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. Although SND1 can drive hepatocellular carcinoma (HCC), it is unclear whether the SND1 Tudor domain is needed to promote HCC. We sought to identify the biological role of the SND1 Tudor domain in normal and tumorigenic settings by developing two genetically engineered SND1 mouse models, an Snd1 knockout (Snd1 KO) and an Snd1 Tudor domain-mutated (Snd1 KI) mouse, whose mutant SND1 can …

Autogenous Reproduction By Ornithodoros Turicata (Ixodida: Argasidae) Females And Vertical Transmission Of The Tick-Borne Pathogen Borrelia Turicatae (Spirochaetales: Borreliaceae), Serhii Filatov, Aparna Krishnavajhala, Job E Lopez

Faculty, Staff and Students Publications

Ornithodoros turicata is a vector of relapsing fever spirochetes in North America and transmits Borrelia turicatae to a variety of vertebrate hosts. The remarkably long lifespan of O. turicata and its ability to maintain spirochetes horizontally (between life stages) and vertically (to progeny) promote the perpetuation of B. turicatae in nature. Nevertheless, the reproductive biology of O. turicata is poorly understood. In this report, we collected ticks from a park within a neighborhood of Austin, TX. They were reared to adulthood, and male ticks were individually housed with females. We observed autogenous reproduction, which is the ability to produce eggs …

Global Genetic Diversity, Introgression, And Evolutionary Adaptation Of Indicine Cattle Revealed By Whole Genome Sequencing., Ningbo Chen, Xiaoting Xia, Quratulain Hanif, Fengwei Zhang, Ruihua Dang, Bizhi Huang, Yang Lyu, Xiaoyu Luo, Hucai Zhang, Huixuan Yan, Shikang Wang, Fuwen Wang, Jialei Chen, Xiwen Guan, Yangkai Liu, Shuang Li, Liangliang Jin, Pengfei Wang, Luyang Sun, Jicai Zhang, Jianyong Liu, Kaixing Qu, Yanhong Cao, Junli Sun, Yuying Liao, Zhengzhong Xiao, Ming Cai, Lan Mu, Amam Zonaed Siddiki, Muhammad Asif, Shahid Mansoor, Masroor Ellahi Babar, Tanveer Hussain, Gamamada Liyanage Lalanie Pradeepa Silva, Neena Amatya Gorkhali, Endashaw Terefe, Gurja Belay, Abdulfatai Tijjani, Tsadkan Zegeye, Mebrate Genet Gebre, Yun Ma, Yu Wang, Yongzhen Huang, Xianyong Lan, Hong Chen, Nicola Rambaldi Migliore, Giulia Colombo, Ornella Semino, Alessandro Achilli, Mikkel-Holger S Sinding, Johannes A Lenstra, Haijian Cheng, Wenfa Lu, Olivier Hanotte, Jianlin Han, Yu Jiang, Chuzhao Lei

Faculty Research 2023

Indicine cattle, also referred to as zebu (Bos taurus indicus), play a central role in pastoral communities across a wide range of agro-ecosystems, from extremely hot semiarid regions to hot humid tropical regions. However, their adaptive genetic changes following their dispersal into East Asia from the Indian subcontinent have remained poorly documented. Here, we characterize their global genetic diversity using high-quality whole-genome sequencing data from 354 indicine cattle of 57 breeds/populations, including major indicine phylogeographic groups worldwide. We reveal their probable migration into East Asia was along a coastal route rather than inland routes and we detected introgression from other …

Genetic Separation Of Brca1 Functions Reveal Mutation-Dependent Polθ Vulnerabilities, John J Krais, Et Al.

2020-Current year OA Pubs

Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq

Genetic Separation Of Brca1 Functions Reveal Mutation-Dependent Polθ Vulnerabilities, John J. Krais, David J. Glass, Ilse Chudoba, Yifan Wang, Wanjuan Feng, Dennis Simpson, Pooja Patel, Zemin Liu, Ryan Neumann-Domer, Robert G. Betsch, Andrea J. Bernhardy, Alice M. Bradbury, Jason Conger, Wei-Ting Yueh, Joseph Nacson, Richard T. Pomerantz, Gaorav P. Gupta, Joseph R. Testa, Neil Johnson

Department of Biochemistry and Molecular Biology Faculty Papers

Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq−/− cells were viable, but grew slowly and had chromosomal instability. Brca1 mutant cells proficient in DNA end resection were …

Dopamine, Norepinephrine And Serotonin Participate Differently In Methylphenidate Action In Concomitant Behavioral And Ventral Tegmental Area, Locus Coeruleus And Dorsal Raphe Neuronal Study In Young Rats, Cruz Reyes-Vasquez, Zachary Jones, Bin Tang, Nachum Dafny

Faculty, Staff and Student Publications

Methylphenidate (MPD), known as Ritalin, is a psychostimulant used to treat children, adults, and the elderly. MPD exerts its effects through increasing concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the synaptic cleft. Concomitant behavioral and neuronal recording from the ventral tegmental area (VTA), locus coeruleus (LC), and from the dorsal raphe (DR) nucleus, which are the sources of DA, NE, and 5-HT to the mesocorticolimbic circuit, were investigated following acute and repetitive (chronic) saline, 0.6, 2.5, or 10.0 mg/kg MPD. Animals received daily saline or MPD administration on experimental days 1 to 6 (ED1–6), followed by a …

Hyperleptinemia Contributes To Antipsychotic Drug-Associated Obesity And Metabolic Disorders, Shangang Zhao, Qian Lin, Wei Xiong, Li Li, Leon Straub, Dinghong Zhang, Rizaldy Zapata, Qingzhang Zhu, Xue-Nan Sun, Zhuzhen Zhang, Jan-Bernd Funcke, Chao Li, Shiuhwei Chen, Yi Zhu, Nisi Jiang, Guannan Li, Ziying Xu, Steven C Wyler, May-Yun Wang, Juli Bai, Xianlin Han, Christine M Kusminski, Ningyan Zhang, Zhiqiang An, Joel K Elmquist, Olivia Osborn, Chen Liu, Philipp E Scherer

Faculty, Staff and Students Publications

Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution of this hyperleptinemia to weight gain and metabolic deterioration has not been defined. Here, with an established mouse model that recapitulates antipsychotic drug-induced obesity and insulin resistance, we not only confirm that hyperleptinemia occurs before weight gain but also demonstrate that hyperleptinemia contributes directly …

Vaginal Microbial Dynamics And Pathogen Colonization In A Humanized Microbiota Mouse Model, Marlyd E Mejia, Vicki Mercado-Evans, Jacob J Zulk, Samantha Ottinger, Korinna Ruiz, Mallory B Ballard, Stephanie W Fowler, Robert A Britton, Kathryn A Patras

Faculty, Staff and Students Publications

Vaginal microbial composition is associated with differential risk of urogenital infection. Although Lactobacillus spp. are thought to confer protection against infection, the lack of in vivo models resembling the human vaginal microbiota remains a prominent barrier to mechanistic discovery. Using 16S rRNA amplicon sequencing of C57BL/6J female mice, we found that vaginal microbial composition varies within and between colonies across three vivaria. Noting vaginal microbial plasticity in conventional mice, we assessed the vaginal microbiome of humanized microbiota mice (