Medicine and Health Sciences Commons^™

The Next-Generation Dna Vaccine Platforms And Delivery Systems: Advances, Challenges And Prospects, Bowen Lu, Jing Ming Lim, Boyue Yu, Siyuan Song, Praveen Neeli, Navid Sobhani, Pavithra K, Srinivasa Reddy Bonam, Rajendra Kurapati, Junnian Zheng, Dafei Chai

Faculty, Staff and Students Publications

Vaccines have proven effective in the treatment and prevention of numerous diseases. However, traditional attenuated and inactivated vaccines suffer from certain drawbacks such as complex preparation, limited efficacy, potential risks and others. These limitations restrict their widespread use, especially in the face of an increasingly diverse range of diseases. With the ongoing advancements in genetic engineering vaccines, DNA vaccines have emerged as a highly promising approach in the treatment of both genetic diseases and acquired diseases. While several DNA vaccines have demonstrated substantial success in animal models of diseases, certain challenges need to be addressed before application in human subjects. …

Select Gut Microbiota Impede Rotavirus Vaccine Efficacy, Vu L Ngo, Yanling Wang, Yadong Wang, Zhenda Shi, Robert Britton, Jun Zou, Sasirekha Ramani, Baoming Jiang, Andrew T Gewirtz

Faculty, Staff and Students Publications

BACKGROUND & AIMS: The protection provided by rotavirus (RV) vaccines is highly heterogeneous among individuals. We hypothesized that microbiota composition might influence RV vaccine efficacy.

METHODS: First, we examined the potential of segmented filamentous bacteria (SFB) colonization to influence RV vaccine efficacy in mice. Next, we probed the influence of human microbiomes on RV vaccination via administering mice fecal microbial transplants (FMTs) from children with robust or minimal RV vaccine responsiveness. Post-FMT, mice were subjected to RV vaccination followed by RV challenge.

RESULTS: SFB colonization induced a phenotype that was reminiscent of RV vaccine failure (ie, failure to generate RV …

Siglec15, Negatively Correlated With Pd-L1 In Hcc, Could Induce Cd8+ T Cell Apoptosis To Promote Immune Evasion, Zheng Chen, Mincheng Yu, Bo Zhang, Lei Jin, Qiang Yu, Shuang Liu, Binghai Zhou, Jiuliang Yan, Wentao Zhang, Xiaoqiang Li, Yongfeng Xu, Yongsheng Xiao, Jian Zhou, Jia Fan, Mien-Chie Hung, Qinghai Ye, Hui Li, Lei Guo

Faculty, Staff and Student Publications

Functional roles of SIGLEC15 in hepatocellular carcinoma (HCC) were not clear, which was recently found to be an immune inhibitor with similar structure of inhibitory B7 family members. SIGLEC15 expression in HCC was explored in public databases and further examined by PCR analysis. SIGLEC15 and PD-L1 expression patterns were examined in HCC samples through immunohistochemistry. SIGLEC15 expression was knocked-down or over-expressed in HCC cell lines, and CCK8 tests were used to examine cell proliferative ability in vitro. Influences of SIGLEC15 expression on tumor growth were examined in immune deficient and immunocompetent mice respectively. Co-culture system of HCC cell lines and …

Β2-Glycoprotein I Promotes The Clearance Of Circulating Mitochondria, Swapan Kumar Dasgupta, Jahnavi Gollamudi, Stefanie Rivera, Ross A Poche, Rolando E Rumbaut, Perumal Thiagarajan

Faculty, Staff and Students Publications

β2-glycoprotein I (β2-Gp1) is a cardiolipin-binding plasma glycoprotein. It is evolutionarily conserved from invertebrates, and cardiolipin-bound β2-Gp1 is a major target of antiphospholipid antibodies seen in autoimmune disorders. Cardiolipin is almost exclusively present in mitochondria, and mitochondria are present in circulating blood. We show that β2-Gp1 binds to cell-free mitochondria (CFM) in the circulation and promotes its phagocytosis by macrophages at physiological plasma concentrations. Exogenous CFM had a short circulation time of less than 10 minutes in mice. Following infusion of CFM, β2-Gp1-deficient mice had significantly higher levels of transfused mitochondria at 5 minutes (9.9 ± 6.4 pg/ml versus 4.0 …

Comparative Exploration Of Mammalian Deafness Gene Homologues In The Drosophila Auditory Organ Shows Genetic Correlation Between Insect And Vertebrate Hearing, Daniel C Sutton, Jonathan C Andrews, Dylan M Dolezal, Ye Jin Park, Hongjie Li, Daniel F Eberl, Shinya Yamamoto, Andrew K Groves

Faculty, Staff and Students Publications

Johnston's organ, the Drosophila auditory organ, is anatomically very different from the mammalian organ of Corti. However, recent evidence indicates significant cellular and molecular similarities exist between vertebrate and invertebrate hearing, suggesting that Drosophila may be a useful platform to determine the function of the many mammalian deafness genes whose underlying biological mechanisms are poorly characterized. Our goal was a comprehensive screen of all known orthologues of mammalian deafness genes in the fruit fly to better understand conservation of hearing mechanisms between the insect and the fly and ultimately gain insight into human hereditary deafness. We used bioinformatic comparisons to …

Inference Of Phylogenetic Trees Directly From Raw Sequencing Reads Using Read2tree, David Dylus, Adrian Altenhoff, Sina Majidian, Fritz J Sedlazeck, Christophe Dessimoz

Faculty, Staff and Students Publications

Current methods for inference of phylogenetic trees require running complex pipelines at substantial computational and labor costs, with additional constraints in sequencing coverage, assembly and annotation quality, especially for large datasets. To overcome these challenges, we present Read2Tree, which directly processes raw sequencing reads into groups of corresponding genes and bypasses traditional steps in phylogeny inference, such as genome assembly, annotation and all-versus-all sequence comparisons, while retaining accuracy. In a benchmark encompassing a broad variety of datasets, Read2Tree is 10-100 times faster than assembly-based approaches and in most cases more accurate-the exception being when sequencing coverage is high and reference …

Neuronal Ablation Of Ghsr Mitigates Diet-Induced Depression And Memory Impairment Via Ampk-Autophagy Signaling-Mediated Inflammation, Hongying Wang, Zheng Shen, Chia-Shan Wu, Pengfei Ji, Ji Yeon Noh, Cédric G Geoffroy, Sunja Kim, David Threadgill, Jianrong Li, Yu Zhou, Xiaoqiu Xiao, Hui Zheng, Yuxiang Sun

Faculty, Staff and Students Publications

Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the …

Lung Infection With Classical Klebsiella Pneumoniae Strains Establishes Robust Macrophage-Dependent Protection Against Heterologous Reinfection, Joseph J Mackel, Casey L G Mick, Emily Guo, David A Rosen

2020-Current year OA Pubs

At present, there is no approved vaccine for prevention of infection by the opportunistic bacterium Klebsiella pneumoniae (Kp); success in treating these infections is increasingly challenged by the spread of antibiotic resistance. Preclinical investigation of adaptive immunity elicited by lung infection with live classical Kp may reveal host mechanisms of protection against this pathogen. Here, we utilize multiple virulent classical Kp strains to demonstrate that following lung infection, surviving wild-type mice develop protective immunity against both homologous and heterologous (heterotypic) reinfection. For Kp strains with low capacity to disseminate from the lung, this immunity is B-cell-independent. We further demonstrate that …

A Novel Crispr/Cas9-Mediated Mouse Model Of Colon Carcinogenesis, Hajime Kashima, Anthony Fischer, Daniel A Veronese-Paniagua, Vered A Gazit, Changqing Ma, Yan Yan, Marc S Levin, Blair B Madison, Deborah C Rubin

2020-Current year OA Pubs

BACKGROUND & AIMS: Human sporadic colorectal cancer (CRC) results from a multistep pathway with sequential acquisition of specific genetic mutations in the colorectal epithelium. Modeling CRC in vivo is critical for understanding the tumor microenvironment. To accurately recapitulate human CRC pathogenesis, mouse models must include these multi-step genetic abnormalities. The aim of this study was to generate a sporadic CRC model that more closely mimics this multi-step process and to use this model to study the role of a novel Let7 target PLAGL2 in CRC pathogenesis.

METHODS: We generated a CRISPR/Cas9 somatic mutagenesis mouse model that is inducible and multiplexed …

Mapping Of A Hybrid Insulin Peptide In The Inflamed Islet Β-Cells From Nod Mice, Janet M Wenzlau, Orion J Peterson, Anthony N Vomund, James E Dilisio, Anita Hohenstein, Kathryn Haskins, Xiaoxiao Wan

2020-Current year OA Pubs

There is accumulating evidence that pathogenic T cells in T1D recognize epitopes formed by post-translational modifications of β-cell antigens, including hybrid insulin peptides (HIPs). The ligands for several CD4 T-cell clones derived from the NOD mouse are HIPs composed of a fragment of proinsulin joined to peptides from endogenous β-cell granule proteins. The diabetogenic T-cell clone BDC-6.9 reacts to a fragment of C-peptide fused to a cleavage product of pro-islet amyloid polypeptide (6.9HIP). In this study, we used a monoclonal antibody (MAb) to the 6.9HIP to determine when and where HIP antigens are present in NOD islets during disease progression …

Transcriptomic Profiling Of Thymic Dysregulation And Viral Tropism After Neonatal Roseolovirus Infection, Andrei Belean, Eden Xue, Benjamin Cisneros, Elisha D O Roberson, Michael A Paley, Tarin M Bigley

2020-Current year OA Pubs

INTRODUCTION: Herpesviruses, including the roseoloviruses, have been linked to autoimmune disease. The ubiquitous and chronic nature of these infections have made it difficult to establish a causal relationship between acute infection and subsequent development of autoimmunity. We have shown that murine roseolovirus (MRV), which is highly related to human roseoloviruses, induces thymic atrophy and disruption of central tolerance after neonatal infection. Moreover, neonatal MRV infection results in development of autoimmunity in adult mice, long after resolution of acute infection. This suggests that MRV induces durable immune dysregulation.

METHODS: In the current studies, we utilized single-cell RNA sequencing (scRNAseq) to study …

Loss Of Β-Cell Identity And Dedifferentiation, Not An Irreversible Process?, Sumit Patel, Maria S Remedi

2020-Current year OA Pubs

Type 2 diabetes (T2D) is a polygenic metabolic disorder characterized by insulin resistance in peripheral tissues and impaired insulin secretion by the pancreas. While the decline in insulin production and secretion was previously attributed to apoptosis of insulin-producing β-cells, recent studies indicate that β-cell apoptosis rates are relatively low in diabetes. Instead, β-cells primarily undergo dedifferentiation, a process where they lose their specialized identity and transition into non-functional endocrine progenitor-like cells, ultimately leading to β-cell failure. The underlying mechanisms driving β-cell dedifferentiation remain elusive due to the intricate interplay of genetic factors and cellular stress. Understanding these mechanisms holds the …

Hormonal And Circuit Mechanisms Controlling Female Sexual Behavior, Sayaka Inoue

2020-Current year OA Pubs

Sexual behavior is crucial for reproduction in many animals. In many vertebrates, females exhibit sexual behavior only during a brief period surrounding ovulation. Over the decades, studies have identified the roles of ovarian sex hormones, which peak in levels around the time of ovulation, and the critical brain regions involved in the regulation of female sexual behavior. Modern technical innovations have enabled a deeper understanding of the neural circuit mechanisms controlling this behavior. In this review, I summarize our current knowledge and discuss the neural circuit mechanisms by which female sexual behavior occurs in association with the ovulatory phase of …

A Neural Mechanism For Conserved Value Computations Integrating Information And Rewards, Ethan S Bromberg-Martin, Yang-Yang Feng, Takaya Ogasawara, J Kael White, Kaining Zhang, Ilya E Monosov

2020-Current year OA Pubs

Behavioral and economic theory dictate that we decide between options based on their values. However, humans and animals eagerly seek information about uncertain future rewards, even when this does not provide any objective value. This implies that decisions are made by endowing information with subjective value and integrating it with the value of extrinsic rewards, but the mechanism is unknown. Here, we show that human and monkey value judgements obey strikingly conserved computational principles during multi-attribute decisions trading off information and extrinsic reward. We then identify a neural substrate in a highly conserved ancient structure, the lateral habenula (LHb). LHb …

Hyperbaric Oxygen Augments Susceptibility To C. Difficile Infection By Impairing Gut Microbiota Ability To Stimulate The Hif-1Α-Il-22 Axis In Ilc3, José L Fachi, Laís P Pral, Helder C Assis, Sarah Oliveira, Vinícius R Rodovalho, Jefferson A C Dos Santos, Mariane F Fernandes, Valquíria A Matheus, Renata Sesti-Costa, Paulo J Basso, Marina Flóro E Silva, Niels O S Câmara, Selma Giorgio, Marco Colonna, Marco A R Vinolo

2020-Current year OA Pubs

Hyperbaric oxygen (HBO) therapy is a well-established method for improving tissue oxygenation and is typically used for the treatment of various inflammatory conditions, including infectious diseases. However, its effect on the intestinal mucosa, a microenvironment known to be physiologically hypoxic, remains unclear. Here, we demonstrated that daily treatment with hyperbaric oxygen affects gut microbiome composition, worsening antibiotic-induced dysbiosis. Accordingly, HBO-treated mice were more susceptible to

The Type Ii Raf Inhibitor Tovorafenib In Relapsed/Refractory Pediatric Low-Grade Glioma: The Phase 2 Firefly-1 Trial, Lindsay B Kilburn, Mohamed S Abdelbaki, Et Al.

2020-Current year OA Pubs

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m

A Structure-Function Analysis Of Hepatocyte Arginase 2 Reveals Mitochondrial Ureahydrolysis As A Determinant Of Glucose Oxidation, Yiming Zhang, Jiameng Sun, Henry D Wasserman, Joshua A Adams, Cassandra B Higgins, Shannon C Kelly, Louise Lantier, Brian J Debosch

2020-Current year OA Pubs

BACKGROUND & AIMS: Restoring hepatic and peripheral insulin sensitivity is critical to prevent or reverse metabolic syndrome and type 2 diabetes. Glucose homeostasis comprises in part the complex regulation of hepatic glucose production and insulin-mediated glucose uptake and oxidation in peripheral tissues. We previously identified hepatocyte arginase 2 (Arg2) as an inducible ureahydrolase that improves glucose homeostasis and enhances glucose oxidation in multiple obese, insulin-resistant models. We therefore examined structure-function determinants through which hepatocyte Arg2 governs systemic insulin action and glucose oxidation.

METHODS: To do this, we generated mice expressing wild-type murine Arg2, enzymatically inactive Arg2 (Arg2

RESULTS: We show …

Ddr2-Regulated Arginase Activity In Ovarian Cancer-Associated Fibroblasts Promotes Collagen Production And Tumor Progression, Favour A Akinjiyan, Zainab Ibitoye, Peinan Zhao, Leah P Shriver, Gary J Patti, Gregory D Longmore, Katherine C Fuh

2020-Current year OA Pubs

Ovarian cancer has poor survival outcomes particularly for advanced stage, metastatic disease. Metastasis is promoted by interactions of stromal cells, such as cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), with tumor cells. CAFs play a key role in tumor progression by remodeling the TME and extracellular matrix (ECM) to result in a more permissive environment for tumor progression. It has been shown that fibroblasts, in particular myofibroblasts, utilize metabolism to support ECM remodeling. However, the intricate mechanisms by which CAFs support collagen production and tumor progression are poorly understood. In this study, we show that the fibrillar collagen receptor, …

The Forkhead Transcription Factor Foxj1 Controls Vertebrate Olfactory Cilia Biogenesis And Sensory Neuron Differentiation, Dheeraj Rayamajhi, Steven L. Brody, Et Al.

2020-Current year OA Pubs

In vertebrates, olfactory receptors localize on multiple cilia elaborated on dendritic knobs of olfactory sensory neurons (OSNs). Although olfactory cilia dysfunction can cause anosmia, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a forkhead domain-containing transcription factor traditionally linked with motile cilia biogenesis, is expressed in OSNs and required for olfactory epithelium (OE) formation. In keeping with the immotile nature of olfactory cilia, we observed that ciliary motility genes are repressed in zebrafish, mouse, and human OSNs. Strikingly, we also found that besides ciliogenesis, Foxj1 controls the …

Translatability Of Findings From Cynomolgus Monkey To Human Suggests A Mechanistic Role For Il-21 In Promoting Immunogenicity To An Anti-Pd-1/Il-21 Mutein Fusion Protein, Mark A Kroenke, Ramaswamy Govindan, Et Al.

2020-Current year OA Pubs

AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were …

Neurosteroids Mediate And Modulate The Effects Of Pro-Inflammatory Stimulation And Toll-Like Receptors On Hippocampal Plasticity And Learning, Yukitoshi Izumi, Kazuko A. O'Dell, Anil G. Cashikar, Steven M. Paul, Douglas F. Covey, Steven J. Mennerick, Charles F. Zorumski

2020-Current year OA Pubs

Pro-inflammatory changes contribute to multiple neuropsychiatric illnesses. Understanding how these changes are involved in illnesses and identifying strategies to alter inflammatory responses offer paths to potentially novel treatments. We previously found that acute pro-inflammatory stimulation with high (μg/ml) lipopolysaccharide (LPS) for 10-15 min dampens long-term potentiation (LTP) in the hippocampus and impairs learning. Effects of LPS involved non-canonical inflammasome signaling but were independent of toll-like receptor 4 (TLR4), a known LPS receptor. Low (ng/ml) LPS also inhibits LTP when administered for 2-4 h, and here we report that this LPS exposure requires TLR4. We also found that effects of low …

Control Of Acute Myeloid Leukemia And Generation Of Immune Memory In Vivo Using Amv564, A Bivalent Bispecific Cd33 X Cd3 T Cell Engager, Linda G. Eissenberg, Julie K. Ritchey, Michael P. Rettig, Dilan A. Patel, Kiran Vij, Feng Gao, Victoria Smith, Tae H Han, John F. Dipersio

2020-Current year OA Pubs

Off-the-shelf immunotherapeutics that suppress tumor growth and provide durable protection against relapse could enhance cancer treatment. We report preclinical studies on a CD33 x CD3 bivalent bispecific diabody, AMV564, that not only suppresses tumor growth, but also facilitates memory responses in a mouse model of acute myelogenous leukemia (AML). Mechanistically, a single 5-day treatment with AMV564 seems to reduce tumor burden by redirection of T cells, providing a time window for allogeneic or other T cells that innately recognize tumor antigens to become activated and proliferate. When the concentration of bispecific becomes negligible, the effector: target ratio has also shifted, …

Stat1 Employs Myeloid Cell-Extrinsic Mechanisms To Regulate The Neutrophil Response And Provide Protection Against Invasive Klebsiella Pneumoniae Lung Infection, Shekina Gonzalez-Ferrer, Zeyu Xiong, Atish Gheware, Janet S Lee, Et Al.

2020-Current year OA Pubs

Klebsiella pneumoniae (KP) is an extracellular Gram-negative bacterium that causes infections in the lower respiratory and urinary tracts and the bloodstream. STAT1 is a master transcription factor that acts to maintain T cell quiescence under homeostatic conditions. Although STAT1 helps defend against systemic spread of acute KP intrapulmonary infection, whether STAT1 regulation of T cell homeostasis impacts pulmonary host defense during acute bacterial infection and injury is less clear. Using a clinical KP respiratory isolate and a pneumonia mouse model, we found that STAT1 deficiency led to an early neutrophil-dominant transcriptional profile and neutrophil recruitment in the lung preceding widespread …

Traversing The Bench To Bedside Journey For Inkt Cell Therapies, Julie O'Neal, Melissa Mavers, Reyka G Jayasinghe, John F Dipersio

2020-Current year OA Pubs

Invariant natural killer T (iNKT) cells are immune cells that harness properties of both the innate and adaptive immune system and exert multiple functions critical for the control of various diseases. Prevention of graft-versus-host disease (GVHD) by iNKT cells has been demonstrated in mouse models and in correlative human studies in which high iNKT cell content in the donor graft is associated with reduced GVHD in the setting of allogeneic hematopoietic stem cell transplants. This suggests that approaches to increase the number of iNKT cells in the setting of an allogeneic transplant may reduce GVHD. iNKT cells can also induce …

Systematic Computer-Aided Disulfide Design As A General Strategy To Stabilize Prefusion Class I Fusion Proteins, Karen J Gonzalez, Kevin C Yim, Jorge C G Blanco, Marina S Boukhvalova, Eva-Maria Strauch

2020-Current year OA Pubs

Numerous enveloped viruses, such as coronaviruses, influenza, and respiratory syncytial virus (RSV), utilize class I fusion proteins for cell entry. During this process, the proteins transition from a prefusion to a postfusion state, undergoing substantial and irreversible conformational changes. The prefusion conformation has repeatedly shown significant potential in vaccine development. However, the instability of this state poses challenges for its practical application in vaccines. While non-native disulfides have been effective in maintaining the prefusion structure, identifying stabilizing disulfide bonds remains an intricate task. Here, we present a general computational approach to systematically identify prefusion-stabilizing disulfides. Our method assesses the geometric …

Recarving The Future: Bridging Car T-Cell Therapy Gaps With Synthetic Biology, Engineering, And Economic Insights, Alaa Ali, John F Dipersio

2020-Current year OA Pubs

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, offering remarkable remission rates in otherwise refractory conditions. However, its expansion into broader oncological applications faces significant hurdles, including limited efficacy in solid tumors, safety concerns related to toxicity, and logistical challenges in manufacturing and scalability. This review critically examines the latest advancements aimed at overcoming these obstacles, highlighting innovations in CAR T-cell engineering, novel antigen targeting strategies, and improvements in delivery and persistence within the tumor microenvironment. We also discuss the development of allogeneic CAR T cells as off-the-shelf therapies, strategies to mitigate adverse effects, and …

Leishmania Major Surface Components And Dkk1 Signalling Via Lrp6 Promote Migration And Longevity Of Neutrophils In The Infection Site, Olivia C Ihedioha, Haley Q Marcarian, Anutr Sivakoses, Stephen M Beverley, Diane Mcmahon-Pratt, Alfred L M Bothwell

2020-Current year OA Pubs

BACKGROUND: Host-related factors highly regulate the increased circulation of neutrophils during

RESULTS: In this study, we further explored the potential role of DKK1-LRP6 signalling in the migration and longevity of activated neutrophils in the infection site using BALB/c mice with PMNs deficient in LRP6 (LRP6

CONCLUSION: Our results suggest that DKK1 signalling and

Beta Cell Primary Cilia Mediate Somatostatin Responsiveness Via Sstr3, Samantha E Adamson, Zipeng A Li, Jing W Hughes

2020-Current year OA Pubs

Somatostatin is a paracrine modulator of insulin secretion and beta cell function with pleotropic effects on glucose homeostasis. The mechanism of somatostatin-mediated communication between delta and beta cells is not well-understood, which we address in this study via the ciliary somatostatin receptor 3 (SSTR3). Primary cilia are membrane organelles that act as signaling hubs in islets by virtue of their subcellular location and enrichment in signaling proteins such as G-protein coupled receptors (GPCRs). We show that SSTR3, a ciliary GPCR, mediates somatostatin suppression of insulin secretion in mouse islets. Quantitative analysis of calcium flux using a mouse model of genetically …

Genetic Inactivation Of Β-Catenin Is Salubrious, Whereas Its Activation Is Deleterious In Desmoplakin Cardiomyopathy, Melis Olcum, Siyang Fan, Leila Rouhi, Sirisha Cheedipudi, Benjamin Cathcart, Hyun-Hwan Jeong, Zhongming Zhao, Priyatansh Gurha, Ali J Marian

Faculty, Staff and Student Publications

AIMS: Mutations in the DSP gene encoding desmoplakin, a constituent of the desmosomes at the intercalated discs (IDs), cause a phenotype that spans arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy. It is typically characterized by biventricular enlargement and dysfunction, myocardial fibrosis, cell death, and arrhythmias. The canonical wingless-related integration (cWNT)/β-catenin pathway is implicated in the pathogenesis of ACM. The β-catenin is an indispensable co-transcriptional regulator of the cWNT pathway and a member of the IDs. We genetically inactivated or activated β-catenin to determine its role in the pathogenesis of desmoplakin cardiomyopathy.

METHODS AND RESULTS: The Dsp gene was conditionally deleted in …

P53r245w Mutation Fuels Cancer Initiation And Metastases In Nash-Driven Liver Tumorigenesis, Denada Dibra, Mihai Gagea, Yuan Qi, Gilda P Chau, Xiaoping Su, Guillermina Lozano

Faculty, Staff and Student Publications

Obesity is a significant global health concern. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are common risk factors for hepatocellular carcinoma (HCC) and are closely associated with metabolic comorbidities, including obesity and diabetes. The TP53 tumor suppressor is the most frequently mutated gene in liver cancers, with half of these alterations being missense mutations. These mutations produce highly abundant proteins in cancer cells which have both inhibitory effects on wildtype (WT) p53, and gain-of-function (GOF) activities that contribute to tumor progression. A Western diet increases p53 activity in the liver. To elucidate the functional consequences of Trp53 mutations in …