Digital Commons Network^™

Mutations In The Transcriptional Regulator Mecp2 Severely Impact Key Cellular And Molecular Signatures Of Human Astrocytes During Maturation, Jialin Sun, Sivan Osenberg, Austin Irwin, Li-Hua Ma, Nigel Lee, Yangfei Xiang, Feng Li, Ying-Wooi Wan, In-Hyun Park, Mirjana Maletic-Savatic, Nurit Ballas

Faculty, Staff and Students Publications

Mutations in the MECP2 gene underlie a spectrum of neurodevelopmental disorders, most commonly Rett syndrome (RTT). We ask whether MECP2 mutations interfere with human astrocyte developmental maturation, thereby affecting their ability to support neurons. Using human-based models, we show that RTT-causing MECP2 mutations greatly impact the key role of astrocytes in regulating overall brain bioenergetics and that these metabolic aberrations are likely mediated by dysfunctional mitochondria. During post-natal maturation, astrocytes rely on neurons to induce their complex stellate morphology and transcriptional changes. While MECP2 mutations cause cell-intrinsic aberrations in the astrocyte transcriptional landscape, surprisingly, they do not affect the neuron-induced …

Loss-Of-Function KCa2.2 Mutations Abolish Channel Activity, Young-Woo Nam, Mohammad Asikur Rahman, Grace Yang, Razan Orfali, Meng Cui, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca²⁺-activated potassium channels subtype 2 (K_Ca2.2, also called SK2) are operated exclusively by a Ca²⁺-calmodulin gating mechanism. Heterozygous genetic mutations of K_Ca2.2 channels have been associated with autosomal dominant neurodevelopmental disorders including cerebellar ataxia and tremor in humans and rodents. Taking advantage of these pathogenic mutations, we performed structure-function studies of the rat K_Ca2.2 channel. No measurable current was detected from HEK293 cells heterologously expressing these pathogenic K_Ca2.2 mutants. When co-expressed with the K_Ca2.2_WT channel, mutations of the pore-lining amino acid residues (I360M, Y362C, G363S …

Myelin Lipid Metabolism And Its Role In Myelination And Myelin Maintenance, Joseph A Barnes-Vélez, Fatma Betul Aksoy Yasar, Jian Hu

Faculty, Staff and Student Publications

Myelin is a specialized cell membrane indispensable for rapid nerve conduction. The high abundance of membrane lipids is one of myelin's salient features that contribute to its unique role as an insulator that electrically isolates nerve fibers across their myelinated surface. The most abundant lipids in myelin include cholesterol, glycosphingolipids, and plasmalogens, each playing critical roles in myelin development as well as function. This review serves to summarize the role of lipid metabolism in myelination and myelin maintenance, as well as the molecular determinants of myelin lipid homeostasis, with an emphasis on findings from genetic models. In addition, the implications …

Extracellular Matrix (Ecm) And Fibrosis In Adipose Tissue: Overview And Perspectives, Kai Sun, Xin Li, Philipp E Scherer

Faculty, Staff and Student Publications

Fibrosis in adipose tissue is a major driver of obesity-related metabolic dysregulation. It is characterized by an overaccumulation of extracellular matrix (ECM) during unhealthy expansion of adipose tissue in response to over nutrition. In obese adipose-depots, hypoxia stimulates multiple pro-fibrotic signaling pathways in different cell populations, thereby inducing the overproduction of the ECM components, including collagens, noncollagenous proteins, and additional enzymatic components of ECM synthesis. As a consequence, local fibrosis develops. The result of fibrosis-induced mechanical stress not only triggers cell necrosis and inflammation locally in adipose tissue but also leads to system-wide lipotoxicity and insulin resistance. A better understanding …

Effects Of Alginate Oligosaccharide On Testosterone-Induced Benign Prostatic Hyperplasia In Orchiectomized Rats, You-Jee Jang, Hye-Yeon Jung, Ju-Yeong Myeong, Kwang Hoon Song, Joseph Kwon, Duwoon Kim, Jae-Il Park

Faculty, Staff and Student Publications

Benign prostatic hyperplasia (BPH) is an age-related disease of the urinary system that affects elderly men. Current treatments for BPH are associated with several adverse effects, thus highlighting the need for alternative agents. Alginate oligosaccharide (AOS), a water-soluble functional oligomer derived from brown algae, inhibits prostate cancer cell proliferation. However, the effects of AOS on BPH and the underlying molecular mechanisms remain unclear. Therefore, here, we aimed to investigate the therapeutic potential of AOS in BPH by using human benign prostatic epithelial cells (BPH-1) and a rat model of testosterone-induced BPH. Treatment with AOS inhibited in vitro and in vivo …

Impacts Of Dietary Lysine And Crude Protein On Performance, Hepatic And Renal Functions, Biochemical Parameters, And Histomorphology Of Small Intestine, Liver, And Kidney In Broiler Chickens, Mohamed A Mousa, Ahamed S Asman, Reham M J Ali, Ramy K A Sayed, Kamlah A Majrashi, Khloud G Fakiha, Rashed A Alhotan, Shaimaa Selim

Faculty, Staff and Student Publications

The present study aimed to investigate the effects of increasing dietary lysine (Lys) levels with an adequate dietary crude protein (CP) content, as well as the effects of a reduction in dietary CP content with the recommended amino acid (AAs) level, on the performance, blood biochemical parameters, and histomorphology of the duodenum, liver, and kidney in broiler chickens. A total of 500 broiler chickens were randomly distributed into five dietary treatment groups, following a completely randomized design, where, at the beginning, the control group (C) was fed a diet containing the standard CP and Lys levels: 23% CP with 1.44% …

Glycolysis Regulates Kras Plasma Membrane Localization And Function Through Defined Glycosphingolipids, Junchen Liu, Ransome Van Der Hoeven, Walaa E Kattan, Jeffrey T Chang, Dina Montufar-Solis, Wei Chen, Maurice Wong, Yong Zhou, Carlito B Lebrilla, John F Hancock

Faculty, Staff and Student Publications

Oncogenic KRAS expression generates a metabolic dependency on aerobic glycolysis, known as the Warburg effect. We report an effect of increased glycolytic flux that feeds into glycosphingolipid biosynthesis and is directly linked to KRAS oncogenic function. High resolution imaging and genetic approaches show that a defined subset of outer leaflet glycosphingolipids, including GM3 and SM4, is required to maintain KRAS plasma membrane localization, with GM3 engaging in cross-bilayer coupling to maintain inner leaflet phosphatidylserine content. Thus, glycolysis is critical for KRAS plasma membrane localization and nanoscale spatial organization. Reciprocally oncogenic KRAS selectively upregulates cellular content of these same glycosphingolipids, whose …

Displaying And Delivering Viral Membrane Antigens Via Ww Domain–Activated Extracellular Vesicles, Sengjin Choi, Zhiping Yang, Qiyu Wang, Zhi Qiao, Maoyun Sun, Joshua Wiggins, Shi-Hua Xiang, Quan Lu

Nebraska Center for Virology: Faculty Publications

Membrane proteins expressed on the surface of enveloped viruses are conformational antigens readily recognized by B cells of the immune system. An effective vaccine would require the synthesis and delivery of these native conformational antigens in lipid membranes that preserve specific epitope structures. We have created an extracellular vesicle–based technology that allows viral membrane antigens to be selectively recruited onto the surface of WW domain–activated extracellular vesicles (WAEVs). Budding of WAEVs requires secretory carrier-associated membrane protein 3, which through its proline-proline-alanine-tyrosine motif interacts with WW domains to recruit fused viral membrane antigens onto WAEVs. Immunization with influenza and HIV viral …

Displaying And Delivering Viral Membrane Antigens Via Ww Domain–Activated Extracellular Vesicles, Sengjin Choi, Zhiping Yang, Qiyu Wang, Zhi Qiao, Maoyun Sun, Joshua Wiggins, Shi-Hua Xiang, Quan Lu

Nebraska Center for Virology: Faculty Publications

Membrane proteins expressed on the surface of enveloped viruses are conformational antigens readily recognized by B cells of the immune system. An effective vaccine would require the synthesis and delivery of these native conformational antigens in lipid membranes that preserve specific epitope structures. We have created an extracellular vesicle–based technology that allows viral membrane antigens to be selectively recruited onto the surface of WW domain–activated extracellular vesicles (WAEVs). Budding of WAEVs requires secretory carrier-associated membrane protein 3, which through its proline-proline-alanine-tyrosine motif interacts with WW domains to recruit fused viral membrane antigens onto WAEVs. Immunization with influenza and HIV viral …

Displaying And Delivering Viral Membrane Antigens Via Ww Domain–Activated Extracellular Vesicles, Sengjin Choi, Zhiping Yang, Qiyu Wang, Zhi Qiao, Maoyun Sun, Joshua Wiggins, Shi-Hua Xiang, Quan Lu

School of Veterinary and Biomedical Sciences: Faculty Publications

Membrane proteins expressed on the surface of enveloped viruses are conformational antigens readily recognized by B cells of the immune system. An effective vaccine would require the synthesis and delivery of these native conformational antigens in lipid membranes that preserve specific epitope structures. We have created an extracellular vesicle–based technology that allows viral membrane antigens to be selectively recruited onto the surface of WW domain–activated extracellular vesicles (WAEVs). Budding of WAEVs requires secretory carrier-associated membrane protein 3, which through its proline-proline-alanine-tyrosine motif interacts with WW domains to recruit fused viral membrane antigens onto WAEVs. Immunization with influenza and HIV viral …

Vaccines Against Group B Coxsackieviruses And Their Importance, Kiruthiga Mone, Ninaad Lasrado, Meghna Sur, Jay Reddy

School of Veterinary and Biomedical Sciences: Faculty Publications

The group B coxsackieviruses (CVBs) exist in six serotypes (CVB1 to CVB6). Disease associations have been reported for most serotypes, and multiple serotypes can cause similar diseases. For example, CVB1, CVB3, and CVB5 are generally implicated in the causation of myocarditis, whereas CVB1 and CVB4 could accelerate the development of type 1 diabetes (T1D). Yet, no vaccines against these viruses are currently available. In this review, we have analyzed the attributes of experimentally tested vaccines and discussed their merits and demerits or limitations, as well as their impact in preventing infections, most importantly myocarditis and T1D.

Inhibition Of Colorectal Cancer Tumorigenesis By Ursolic Acid And Doxorubicin Is Mediated By Targeting The Akt Signaling Pathway And Activating The Hippo Signaling Pathway, Dan Hu, Ruo Yu Meng, Thi Van Nguyen, Ok Hee Chai, Byung Hyun Park, Ju-Seog Lee, Soo Mi Kim

Faculty, Staff and Student Publications

Colorectal cancer (CRC) is one of the deadliest malignant tumors worldwide and its prevalence is increasing in South Korea. The efficacy of combined treatment with natural product‑derived and chemotherapy agents including curcumin combined with 5‑fluorouracil, resveratrol combined with cisplatin and epigallocatechin‑3‑gallate (EGCG) combined with cisplatin in preventing cancer progression and killing cancer cells has emerged. The Akt and Hippo signaling pathways serve a key role in colorectal tumor growth; however, the exact role of the crosstalk between Akt and Hippo signaling pathways in CRC remains poorly elucidated. The combined effect of UA and DOX on the cell proliferation, apoptosis, migration …

Monitoring And Modulating Diet And Gut Microbes To Enhance Response And Reduce Toxicity To Cancer Treatment, Anne Knisely, Yongwoo David Seo, Jennifer A Wargo, Manoj Chelvanambi

Faculty, Staff and Student Publications

The gut microbiome comprises a diverse array of microbial species that have been shown to dynamically modulate host immunity both locally and systemically, as well as contribute to tumorigenesis. In this review, we discuss the scientific evidence on the role that gut microbes and diet play in response and toxicity to cancer treatment. We highlight studies across multiple cancer cohorts that have shown an association between particular gut microbiome signatures and an improved response to immune checkpoint blockade, chemotherapy, and adoptive cell therapies, as well as the role of particular microbes in driving treatment-related toxicity and how the microbiome can …

Integration Of Transcriptome-Wide Association Study With Neuronal Dysfunction Assays Provides Functional Genomics Evidence For Parkinson’S Disease Genes, Jiayang Li, Bismark Kojo Amoh, Emma Mccormick, Akash Tarkunde, Katy Fan Zhu, Alma Perez, Megan Mair, Justin Moore, Joshua M Shulman, Ismael Al-Ramahi, Juan Botas

Faculty, Staff and Students Publications

Genome-wide association studies (GWAS) have markedly advanced our understanding of the genetics of Parkinson's disease (PD), but they currently do not account for the full heritability of PD. In many cases it is difficult to unambiguously identify a specific gene within each locus because GWAS does not provide functional information on the identified candidate loci. Here we present an integrative approach that combines transcriptome-wide association study (TWAS) with high-throughput neuronal dysfunction analyses in Drosophila to discover and validate candidate PD genes. We identified 160 candidate genes whose misexpression is associated with PD risk via TWAS. Candidates were validated using orthogonal …

Supplementing Glycine And N-Acetylcysteine (Glynac) In Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, And Aging Hallmarks: A Randomized Clinical Trial, Premranjan Kumar, Chun Liu, James Suliburk, Jean W Hsu, Raja Muthupillai, Farook Jahoor, Charles G Minard, George E Taffet, Rajagopal V Sekhar

Faculty, Staff and Students Publications

BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.

METHODS: Twenty-four …

A Data-Driven Approach To Construct A Molecular Map Of Trypanosoma Cruzi To Identify Drugs And Vaccine Targets, Swarsat Kaushik Nath, Preeti Pankajakshan, Trapti Sharma, Priya Kumari, Sweety Shinde, Nikita Garg, Kartavya Mathur, Nevidita Arambam, Divyank Harjani, Manpriya Raj, Garwit Kwatra, Sayantan Venkatesh, Alakto Choudhoury, Saima Bano, Prashansa Tayal, Mahek Sharan, Ruchika Arora, Ulrich Strych, Peter J Hotez, Maria Elena Bottazzi, Kamal Rawal

Faculty, Staff and Students Publications

Chagas disease (CD) is endemic in large parts of Central and South America, as well as in Texas and the southern regions of the United States. Successful parasites, such as the causative agent of CD, Trypanosoma cruzi have adapted to specific hosts during their phylogenesis. In this work, we have assembled an interactive network of the complex relations that occur between molecules within T. cruzi. An expert curation strategy was combined with a text-mining approach to screen 10,234 full-length research articles and over 200,000 abstracts relevant to T. cruzi. We obtained a scale-free network consisting of 1055 nodes …

Supplementing Glycine And N-Acetylcysteine (Glynac) In Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, And Aging Hallmarks: A Randomized Clinical Trial, Premranjan Kumar, Chun Liu, James Suliburk, Jean W Hsu, Raja Muthupillai, Farook Jahoor, Charles G Minard, George E Taffet, Rajagopal V Sekhar

Faculty, Staff and Students Publications

BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.

METHODS: Twenty-four …

Supplementing Glycine And N-Acetylcysteine (Glynac) In Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, And Aging Hallmarks: A Randomized Clinical Trial, Premranjan Kumar, Chun Liu, James Suliburk, Jean W Hsu, Raja Muthupillai, Farook Jahoor, Charles G Minard, George E Taffet, Rajagopal V Sekhar

Faculty, Staff and Students Publications

BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.

METHODS: Twenty-four …

Supplementing Glycine And N-Acetylcysteine (Glynac) In Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, And Aging Hallmarks: A Randomized Clinical Trial, Premranjan Kumar, Chun Liu, James Suliburk, Jean W Hsu, Raja Muthupillai, Farook Jahoor, Charles G Minard, George E Taffet, Rajagopal V Sekhar

Faculty, Staff and Students Publications

BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.

METHODS: Twenty-four …

Engineered Protac-Cid Systems For Mammalian Inducible Gene Regulation, Dacheng Ma, Qichen Yuan, Fei Peng, Victor Paredes, Hongzhi Zeng, Emmanuel C Osikpa, Qiaochu Yang, Advaith Peddi, Anika Patel, Megan S Liu, Zheng Sun, Xue Gao

Faculty, Staff and Students Publications

Gene regulation via chemically induced dimerization (CID) is useful for biomedical research. However, the number, type, versatility, and in vivo applications of CID tools remain limited. Here, we demonstrate the development of proteolysis-targeting chimera-based scalable CID (PROTAC-CID) platforms by systematically engineering the available PROTAC systems for inducible gene regulation and gene editing. Further, we show orthogonal PROTAC-CIDs that can fine-tune gene expression at gradient levels or multiplex biological signals with different logic gating operations. Coupling the PROTAC-CID platform with genetic circuits, we achieve digitally inducible expression of DNA recombinases, base- and prime-editors for transient genome manipulation. Finally, we package a …

Gut Microbiota And Microbiota-Derived Metabolites Promotes Endometriosis, Sangappa B Chadchan, Sumanta K Naik, Pooja Popli, Chandni Talwar, Satwikreddy Putluri, Chandrasekhar R Ambati, Michael A Lint, Andrew L Kau, Christina L Stallings, Ramakrishna Kommagani

Faculty, Staff and Students Publications

Endometriosis is a pathological condition of the female reproductive tract characterized by the existence of endometrium-like tissue at ectopic sites, affecting 10% of women between the age 15 and 49 in the USA. However, currently there is no reliable non-invasive method to detect the presence of endometriosis without surgery and many women find hormonal therapy and surgery as ineffective in avoiding the recurrences. There is a lack of knowledge on the etiology and the factors that contribute to the development of endometriosis. A growing body of recent evidence suggests an association between gut microbiota and endometriosis pathophysiology. However, the direct …

Gut Microbiota And Microbiota-Derived Metabolites Promotes Endometriosis, Sangappa B Chadchan, Sumanta K Naik, Pooja Popli, Chandni Talwar, Satwikreddy Putluri, Chandrasekhar R Ambati, Michael A Lint, Andrew L Kau, Christina L Stallings, Ramakrishna Kommagani

Faculty, Staff and Students Publications

Endometriosis is a pathological condition of the female reproductive tract characterized by the existence of endometrium-like tissue at ectopic sites, affecting 10% of women between the age 15 and 49 in the USA. However, currently there is no reliable non-invasive method to detect the presence of endometriosis without surgery and many women find hormonal therapy and surgery as ineffective in avoiding the recurrences. There is a lack of knowledge on the etiology and the factors that contribute to the development of endometriosis. A growing body of recent evidence suggests an association between gut microbiota and endometriosis pathophysiology. However, the direct …

Interfering With Lipid Metabolism Through Targeting Ces1 Sensitizes Hepatocellular Carcinoma For Chemotherapy, Gang Li, Xin Li, Iqbal Mahmud, Jazmin Ysaguirre, Baharan Fekry, Shuyue Wang, Bo Wei, Kristin L Eckel-Mahan, Philip L Lorenzi, Richard Lehner, Kai Sun

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. In this study, we found that carboxylesterase 1 (CES1) is expressed at various levels in HCC. We further revealed that blockage of CES1 by pharmacological and genetical approaches leads to altered lipid profiles that are directly linked to impaired mitochondrial function. Mechanistically, lipidomic analyses indicated that lipid signaling molecules, including polyunsaturated fatty acids (PUFAs), which activate PPARα/γ, were dramatically reduced upon CES1 inhibition. As a result, the expression of SCD, …

Cbx5 Loss Drives Egfr Inhibitor Resistance And Results In Therapeutically Actionable Vulnerabilities In Lung Cancer, Suresh Bugide, Yvonne J K Edwards, Romi Gupta, Michael R Green, Narendra Wajapeyee

Faculty, Staff and Student Publications

Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFRi) are approved for treating EGFR-mutant lung adenocarcinoma (LUAD), emergence of acquired resistance limits their clinical benefits. Several mechanisms for acquired resistance to EGFRi in LUAD have been identified; however, the molecular basis for this resistance remains unknown in ~30% of LUAD. Chromatin and DNA modifiers and their regulators play important roles in determining response to anticancer therapies. Therefore, to identify nongenetic mechanisms of EGFRi resistance in LUAD, we performed an epigenome-wide shRNA screen targeting 363 human epigenetic regulator genes. This screen identified loss of the transcriptional repressor chromobox homolog 5 …

A Novel Defined Tlr3 Agonist As An Effective Vaccine Adjuvant, Kwang Hyun Ko, Seung Bin Cha, Seung-Hwan Lee, Hyun Shik Bae, Chul Soo Ham, Min-Gyu Lee, Dong-Ho Kim, Seung Hyun Han

Faculty, Staff and Student Publications

Synthetic double-stranded RNA analogs recognized by Toll-like receptor 3 (TLR3) are an attractive adjuvant candidate for vaccines, especially against intracellular pathogens or tumors, because of their ability to enhance T cell and antibody responses. Although poly(I:C) is a representative dsRNA with potent adjuvanticity, its clinical application has been limited due to heterogeneous molecular size, inconsistent activity, poor stability, and toxicity. To overcome these limitations, we developed a novel dsRNA-based TLR3 agonist named NexaVant (NVT) by using PCR-coupled bidirectional in vitro transcription. Agarose gel electrophoresis and reverse phase-HPLC analysis demonstrated that NVT is a single 275-kDa homogeneous molecule. NVT appears to …

Recent Advances In Understanding Of Pathogenesis Of Alcohol-Associated Liver Disease, Xiaoqin Wu, Xiude Fan, Tatsunori Miyata, Adam Kim, Christina K Cajigas-Du Ross, Semanti Ray, Emily Huang, Moyinoluwa Taiwo, Rakesh Arya, Jianguo Wu, Laura E Nagy

Faculty, Staff and Student Publications

Alcohol-associated liver disease (ALD) is one of the major diseases arising from chronic alcohol consumption and is one of the most common causes of liver-related morbidity and mortality. ALD includes asymptomatic liver steatosis, fibrosis, cirrhosis, and alcohol-associated hepatitis and its complications. The progression of ALD involves complex cell-cell and organ-organ interactions. We focus on the impact of alcohol on dysregulation of homeostatic mechanisms and regulation of injury and repair in the liver. In particular, we discuss recent advances in understanding the disruption of balance between programmed cell death and prosurvival pathways, such as autophagy and membrane trafficking, in the pathogenesis …

Genetics And Pathogenesis Of Parkinson's Syndrome, Hui Ye, Laurie A Robak, Meigen Yu, Matthew Cykowski, Joshua M Shulman

Faculty, Staff and Students Publications

Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson's syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central and peripheral nervous systems, the distribution varies and other pathologies commonly modify PD or trigger similar manifestations. Nearly all PD is genetically influenced. More than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common …

Tmem161b Regulates Cerebral Cortical Gyration, Sonic Hedgehog Signaling, And Ciliary Structure In The Developing Central Nervous System, Shyam K Akula, Jack H Marciano, Youngshin Lim, David Exposito-Alonso, Norma K Hylton, Grace H Hwang, Jennifer E Neil, Nicole Dominado, Rosie K Bunton-Stasyshyn, Janet H T Song, Maya Talukdar, Aloisia Schmid, Lydia Teboul, Alisa Mo, Taehwan Shin, Benjamin Finander, Samantha G Beck, Rebecca C Yeh, Aoi Otani, Xuyu Qian, Ellen M Degennaro, Fowzan S Alkuraya, Sateesh Maddirevula, Gregory D Cascino, Caterina Giannini, Undiagnosed Diseases Network, Lindsay C Burrage, Jill A Rosenfield, Shamika Ketkar, Gary D Clark, Carlos Bacino, Richard A Lewis, Rosalind A Segal, J Fernando Bazan, Kelly A Smith, Jeffrey A Golden, Ginam Cho, Christopher A Walsh

Faculty, Staff and Students Publications

Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B, which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret …

Reducing Tracheal Complications In Endotracheal Intubation Patients Using Automated Cuff Pressure Modulation, Shrihan G. Babu

Journal of the South Carolina Academy of Science

Endotracheal tube intubation is the third most frequent procedure, performed approximately 13-20 million times yearly in the United States (Mosier et al., 2020). Despite the regularity of the procedure, intubation-related complications such as tracheal injuries, laryngeal injuries, and ventilator-associated pneumonia are ubiquitous due to improper cuff pressure management methods (Ganti et al., 2018). Current techniques, such as the pilot balloon and minimal leak technique, have proven ineffective and inconsistent in managing pressure. As a result, over 71.6% of intubation patients have abnormally high cuff pressures (Ramírez, 2014). Therefore, the purpose of this research was to design an endotracheal tube with …

The Nfib/Carm1 Partnership Is A Driver In Preclinical Models Of Small Cell Lung Cancer, Guozhen Gao, Simone Hausmann, Natasha M Flores, Ana Morales Benitez, Jianjun Shen, Xiaojie Yang, Maria D Person, Sitaram Gayatri, Donghang Cheng, Yue Lu, Bin Liu, Pawel K Mazur, Mark T Bedford

Faculty, Staff and Student Publications

The coactivator associated arginine methyltransferase (CARM1) promotes transcription, as its name implies. It does so by modifying histones and chromatin bound proteins. We identified nuclear factor I B (NFIB) as a CARM1 substrate and show that this transcription factor utilizes CARM1 as a coactivator. Biochemical studies reveal that tripartite motif 29 (TRIM29) is an effector molecule for methylated NFIB. Importantly, NFIB harbors both oncogenic and metastatic activities, and is often overexpressed in small cell lung cancer (SCLC). Here, we explore the possibility that CARM1 methylation of NFIB is important for its transforming activity. Using a SCLC mouse model, we show …