Biochemistry, Biophysics, and Structural Biology Commons^™

A Rare Case Of Pancreatic Actinomyces, Marguerite Poche, Kyle Liu, Codey Pham, Shilpa Jain, Robert Sealock

Faculty, Staff and Students Publications

Actinomyces israelii is a filamentous, gram-positive anaerobic bacterium commonly found in the upper gastrointestinal tract, colon, and female genital tract. Rarely, actinomycosis can infect the pancreas most commonly after pancreatic instrumentation, often mimicking malignancy. We describe a case of a 26-year-old woman who presented with epigastric abdominal pain and nausea without prior pancreatic instrumentation. Abdominal imaging demonstrated a mass in the pancreatic head with fine-needle biopsy revealing Actinomyces. The patient was successfully treated with long-term antibiotic therapy resulting in resolution of the mass. Our case emphasizes the importance of considering nonmalignant etiologies in the differential diagnosis of pancreatic masses.

Impact Of Gastrointestinal Polymerase Chain Reaction Panels On Antibiotic Utilization In Hospitalized Adult Patients, Gillean A Kelly, Roumen Iordanov, Alex Franklin, Amna Ahmed, Krithika Srinivasan, Jesica Hayon, Todd Lasco, Rosie Amini, Sabra Shay, Prathit A Kulkarni, Mayar Al Mohajer

Faculty, Staff and Students Publications

Multiplex stool polymerase chain reaction (PCR) panels offer rapid comprehensive testing for patients with infectious diarrhea. We compared antibiotic utilization among hospitalized patients with suspected infectious diarrhea who underwent diagnostic testing with either a stool culture or stool PCR panel. No significant differences in antibiotic utilization were identified.

Second Virtual International Symposium On Cellular And Organismal Stress Responses, September 8-9, 2022, Patricija Van Oosten-Hawle, Sarah J Backe, Anat Ben-Zvi, Dimitra Bourboulia, Mara Brancaccio, Jeff Brodsky, Melody Clark, Giorgio Colombo, Marc B Cox, Paolo De Los Rios, Frank Echtenkamp, Adrienne Edkins, Brian Freeman, Pierre Goloubinoff, Walid Houry, Jill Johnson, Paul Lapointe, Wei Li, Valerie Mezger, Len Neckers, Nadinath B Nillegoda, Veena Prahlad, Adam Reitzel, Ruth Scherz-Shouval, Lea Sistonen, Francis T F Tsai, Mark R Woodford, Mehdi Mollapour, Andrew W Truman

Faculty, Staff and Students Publications

The Second International Symposium on Cellular and Organismal Stress Responses took place virtually on September 8-9, 2022. This meeting was supported by the Cell Stress Society International (CSSI) and organized by Patricija Van Oosten-Hawle and Andrew Truman (University of North Carolina at Charlotte, USA) and Mehdi Mollapour (SUNY Upstate Medical University, USA). The goal of this symposium was to continue the theme from the initial meeting in 2020 by providing a platform for established researchers, new investigators, postdoctoral fellows, and students to present and exchange ideas on various topics on cellular stress and chaperones. We will summarize the highlights of …

Targeting Hiv-1 Reservoirs In T Cell Subsets, Min Li, Marietta M Budai, Min Chen, Jin Wang

Faculty, Staff and Students Publications

The HIV-1 reservoirs harbor the latent proviruses that are integrated into the host genome. It is a challenging task to eradicate the proviruses in order to achieve an HIV cure. We have described a strategy for the clearance of HIV-1 infection through selective elimination of host cells harboring replication-competent HIV (SECH), by inhibition of autophagy and promotion of apoptosis during viral re-activation. HIV-1 can infect various CD4+ T cell subsets, but it is not known whether the SECH approach is equally effective in targeting HIV-1 reservoirs in these different subsets in vivo. In a humanized mouse model, we found …

Mortality Difference From Klebsiella Aerogenes Vs Enterobacter Cloacae Bloodstream Infections, Andrew Chou, Richard Sucgang, Richard J Hamill, Lynn Zechiedrich, Barbara W Trautner

Faculty, Staff and Students Publications

Members of the order Enterobacterales, including Escherichia coli , Klebsiella species and Enterobacter species, are important pathogens in healthcare-associated infections. Higher mortality has been reported from infections due to Klebsiella pneumoniae than from E. coli , but prior studies comparing Enterobacter aerogenes (recently renamed Klebsiella aerogenes ) bacteraemia and Enterobacter cloacae complex bacteraemia have yielded conflicting results regarding whether clinical outcomes differ. We found bacteraemia with K. aerogenes was independently associated with greater risk of 30-day mortality than bacteraemia with Enterobacter cloacae complex.

Oral Gauze For Bleeding Control In Perioral And Perinasal Dermatologic Surgery, Riyad N H Seervai, Jose A Cervantes, Ikue Shimizu, Ida F Orengo

Faculty, Staff and Students Publications

The use of oral gauze is a quick, cheap, and effective method of preventing bleeding into the patient's mouth during dermatologic surgery. We recommend this technique combined with appropriate positioning for lesions in the perioral and perinasal regions. Similar approaches may be applied for the prevention of bleeding into the ear canal during facial/periauricular surgery.

Adeno-Associated Virus 8 Delivers An Immunomodulatory Peptide To Mouse Liver More Efficiently Than To Rat Liver, Yuqing Wang, Ayrea Hurley, Marco De Giorgi, Mark R Tanner, Rong-Chi Hu, Michael W Pennington, William R Lagor, Christine Beeton

Faculty, Staff and Students Publications

Targeting the Kv1.3 potassium channel has proven effective in reducing obesity and the severity of animal models of autoimmune disease. Stichodactyla toxin (ShK), isolated from the sea anemone Stichodactyla helianthus, is a potent blocker of Kv1.3. Several of its analogs are some of the most potent and selective blockers of this channel. However, like most biologics, ShK and its analogs require injections for their delivery, and repeated injections reduce patient compliance during the treatment of chronic diseases. We hypothesized that inducing the expression of an ShK analog by hepatocytes would remove the requirement for frequent injections and lead to a …

Quantitative Measurement Of Protac Intracellular Accumulation, Xin Yu, Jin Wang

Faculty, Staff and Students Publications

In recent years, Proteolysis Targeting Chimera (PROTAC) technology has emerged as one of the most promising approaches to remove disease-associated proteins by utilizing cells' own destruction machinery. To achieve successful degradation of a protein of interest (POI), the heterobifunctional PROTAC molecules must penetrate into the cells first, followed by target engagement and formation of the POI-PROTAC-E3 ligase complex. Based on this understanding, the assessment of cell permeability and in cell target engagement are of great importance to evaluate the efficacy of PROTAC candidates. PROTAC molecules can be classified as non-covalent and covalent, and covalent PROTACs can be further divided into …

Analysis Of Biologically Effective Dose For Retroactive Yttrium-90 Trans-Arterial Radioembolization Treatment Optimization, Mj Lindsey

CMC Senior Theses

Trans-arterial radioembolization (TARE) is a protracted modality of radiation therapy where radionuclides labeled with Yttrium-90 (⁹⁰Y) are inserted inside a patient's hepatic artery to treat hepatocellular carcinoma (HCC). While TARE has been shown to be a clinically effective and safe treatment, there is little understanding of the radiobiological relationship between absorbed dose and tissue response, and thus there is no dosimetric standard for treatment planning. The Biologically Effective Dose (BED) formalism, derived from the Linear-Quadratic model of radiobiology, is used to weigh the absorbed dose by the time pattern of delivery. BED is a virtual dose that can …

A Guide To Naming Eukaryotic Circular Rnas, Ling-Ling Chen, Albrecht Bindereif, Irene Bozzoni, Howard Y Chang, A Gregory Matera, Myriam Gorospe, Thomas B Hansen, Jørgen Kjems, Xu-Kai Ma, Jun Wei Pek, Nikolaus Rajewsky, Julia Salzman, Jeremy E Wilusz, Li Yang, Fangqing Zhao

Faculty, Staff and Students Publications

Alternative splicing of eukaryotic transcripts often leads to production of multiple mature RNAs from a single gene locus. In addition to encoding linear RNAs, genes can produce stable circular RNAs (circRNAs) that are often co-expressed with their cognate linear RNAs. Multiple distinct circRNAs are frequently generated from a gene locus via back-splicing, with each mature transcript having a potentially unique function due to its distinct combination of exons and sometimes retained introns. However, names currently given to circRNAs are often ambiguous and lack consistency across studies. Here, we call on the community to embrace standards for naming circRNAs so that …

Engineered Cd4 T Cells Expressing A Membrane Anchored Viral Inhibitor Restrict Hiv-1 Through Cis And Trans Mechanisms, Weiming Wang, Khanghy Truong, Chaobaihui Ye, Suman Sharma, Huan He, Lihong Liu, Michael Wen, Anisha Misra, Paul Zhou, Jason T Kimata

Faculty, Staff and Students Publications

HIV-1 infection of target cells can occur through either cell-free virions or cell-cell transmission in a virological synapse, with the latter mechanism of infection reported to be 100- to 1,000-fold more efficient. Neutralizing antibodies and entry inhibitors effectively block cell-free HIV-1, but with few exceptions, they display much less inhibitory activity against cell-mediated HIV-1 transmission. Previously, we showed that engineering HIV-1 target cells by genetically linking single-chain variable fragments (scFvs) of antibodies to glycosyl phosphatidylinositol (GPI) potently blocks infection by cell-free virions and cell-mediated infection by immature dendritic cell (iDC)-captured HIV-1. Expression of scFvs on CD4

Structural Basis Of Ferroportin Inhibition By Minihepcidin Pr73, Azaan Saalim Wilbon, Jiemin Shen, Piotr Ruchala, Ming Zhou, Yaping Pan

Faculty, Staff and Students Publications

Ferroportin (Fpn) is the only known iron exporter in humans and is essential for maintaining iron homeostasis. Fpn activity is suppressed by hepcidin, an endogenous peptide hormone, which inhibits iron export and promotes endocytosis of Fpn. Hepcidin deficiency leads to hemochromatosis and iron-loading anemia. Previous studies have shown that small peptides that mimic the first few residues of hepcidin, i.e., minihepcidins, are more potent than hepcidin. However, the mechanism of enhanced inhibition by minihepcidins remains unclear. Here, we report the structure of human ferroportin in complex with a minihepcidin, PR73 that mimics the first 9 residues of hepcidin, at 2.7 …

How Do Necrotic Cells Expose Phosphatidylserine To Attract Their Predators-What’S Unique And What’S In Common With Apoptotic Cells, Yoshitaka Furuta, Zheng Zhou

Faculty, Staff and Students Publications

Phosphatidylserine (PS) is a lipid component of the plasma membrane. It is asymmetrically distributed to the inner leaflet in live cells. In cells undergoing apoptosis, phosphatidylserine is exposed to the outer surfaces. The exposed phosphatidylserine acts as an evolutionarily conserved “eat-me” signal that attracts neighboring engulfing cells in metazoan organisms, including the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and mammals. During apoptosis, the exposure of phosphatidylserine to the outer surface of a cell is driven by the membrane scramblases and flippases, the activities of which are regulated by caspases. Cells undergoing necrosis, a kind of cell …

Development Of A Peripheral Blood Transcriptomic Gene Signature To Predict Bronchopulmonary Dysplasia, Alvaro Moreira, Miriam Tovar, Alisha M Smith, Grace C Lee, Justin A Meunier, Zoya Cheema, Axel Moreira, Caitlyn Winter, Shamimunisa B Mustafa, Steven Seidner, Tina Findley, Joe G N Garcia, Bernard Thébaud, Przemko Kwinta, Sunil K Ahuja

Faculty, Staff and Students Publications

Bronchopulmonary dysplasia (BPD) is the most common lung disease of extreme prematurity, yet mechanisms that associate with or identify neonates with increased susceptibility for BPD are largely unknown. Combining artificial intelligence with gene expression data is a novel approach that may assist in better understanding mechanisms underpinning chronic lung disease and in stratifying patients at greater risk for BPD. The objective of this study is to develop an early peripheral blood transcriptomic signature that can predict preterm neonates at risk for developing BPD. Secondary analysis of whole blood microarray data from 97 very low birth weight neonates on day of …

Combating Hypertension Beyond Genome-Wide Association Studies: Microbiome And Artificial Intelligence As Opportunities For Precision Medicine, Sachin Aryal, Ishan Manandhar, Xue Mei, Beng S Yeoh, Ramakumar Tummala, Piu Saha, Islam Osman, Jasenka Zubcevic, David J Durgan, Matam Vijay-Kumar, Bina Joe

Faculty, Staff and Students Publications

The single largest contributor to human mortality is cardiovascular disease, the top risk factor for which is hypertension (HTN). The last two decades have placed much emphasis on the identification of genetic factors contributing to HTN. As a result, over 1,500 genetic alleles have been associated with human HTN. Mapping studies using genetic models of HTN have yielded hundreds of blood pressure (BP) loci but their individual effects on BP are minor, which limits opportunities to target them in the clinic. The value of collecting genome-wide association data is evident in ongoing research, which is beginning to utilize these data …

Open-Source, Highly Efficient, Post-Acquisition Synchronization For 4d Dual-Contrast Imaging Of The Mouse Embryonic Heart Over Development With Optical Coherence Tomography, Andre C Faubert, Irina V Larina, Shang Wang

Faculty, Staff and Students Publications

Dynamic imaging of the beating embryonic heart in 3D is critical for understanding cardiac development and defects. Optical coherence tomography (OCT) plays an important role in embryonic heart imaging with its unique imaging scale and label-free contrasts. In particular, 4D (3D + time) OCT imaging enabled biomechanical analysis of the developing heart in various animal models. While ultrafast OCT systems allow for direct volumetric imaging of the beating heart, the imaging speed remains limited, leading to an image quality inferior to that produced by post-acquisition synchronization. As OCT systems become increasingly available to a wide range of biomedical researchers, a …

Optical Coherence Tomography For Dynamic Investigation Of Mammalian Reproductive Processes, Kohei Umezu, Irina V Larina

Faculty, Staff and Students Publications

The biological events associated with mammalian reproductive processes are highly dynamic and tightly regulated by molecular, genetic, and biomechanical factors. Implementation of live imaging in reproductive research is vital for the advancement of our understanding of normal reproductive physiology and for improving the management of reproductive disorders. Optical coherence tomography (OCT) is emerging as a promising tool for dynamic volumetric imaging of various reproductive processes in mice and other animal models. In this review, we summarize recent studies employing OCT-based approaches toward the investigation of reproductive processes in both, males and females. We describe how OCT can be applied to …

Treatment Of Severe Covid-19 Infection With Remdesivir In Peritoneal Dialysis, Ryan Geffin, Shazia Raheem, Lavannya M Pandit, Andrew S Hunter, Michael W Holliday, Aditya V Rao, Maulin K Shah

Faculty, Staff and Students Publications

End-stage kidney disease (ESKD) has been shown to be correlated with an increased risk of COVID-19 infection and mortality. Remdesivir is an effective non-EUA U.S. Food and Drug Administration (FDA)-approved antiviral agent for the treatment of COVID-19 in hospitalized adult and pediatric patients, though a lack of data has prevented its use in patients with severe kidney disease including dialysis patients. Some observational studies report the use of remdesivir in hemodialysis patients, but there are no reports of patients treated with remdesivir on peritoneal dialysis. Dialysis modalities may affect drug pharmacokinetics, and safety and efficiency of remdesivir in peritoneal dialysis …

The Gastrointestinal-Brain-Microbiota Axis: A Promising Therapeutic Target For Ischemic Stroke, Yan-Hao Wei, Ren-Tang Bi, Yan-Mei Qiu, Chun-Lin Zhang, Jian-Zhuang Li, Ya-Nan Li, Bo Hu

Faculty, Staff and Student Publications

Ischemic stroke is a highly complex systemic disease characterized by intricate interactions between the brain and gastrointestinal tract. While our current understanding of these interactions primarily stems from experimental models, their relevance to human stroke outcomes is of considerable interest. After stroke, bidirectional communication between the brain and gastrointestinal tract initiates changes in the gastrointestinal microenvironment. These changes involve the activation of gastrointestinal immunity, disruption of the gastrointestinal barrier, and alterations in gastrointestinal microbiota. Importantly, experimental evidence suggests that these alterations facilitate the migration of gastrointestinal immune cells and cytokines across the damaged blood-brain barrier, ultimately infiltrating the ischemic brain. …

A Novel Use Of Bar Code Medication Administration Data To Assess Nurse Staffing And Workload, Melissa K Knox, Paras D Mehta, Lynette E Dorsey, Christine Yang, Laura A Petersen

Faculty, Staff and Students Publications

OBJECTIVE: The aim of the study is to introduce an innovative use of bar code medication administration (BCMA) data, medication pass analysis, that allows for the examination of nurse staffing and workload using data generated during regular nursing workflow.

METHODS: Using 1 year (October 1, 2014-September 30, 2015) of BCMA data for 11 acute care units in one Veterans Affairs Medical Center, we determined the peak time for scheduled medications and included medications scheduled for and administered within 2 hours of that time in analyses. We established for each staff member their daily peak-time medication pass characteristics (number of patients, …

Neprilysin Inhibitors In Heart Failure: The Science, Mechanism Of Action, Clinical Studies, And Unanswered Questions, Biykem Bozkurt, Ajith P Nair, Arunima Misra, Claire Z Scott, Jamal H Mahar, Savitri Fedson

Faculty, Staff and Students Publications

This article provides a contemporary review and a new perspective on the role of neprilysin inhibition in heart failure (HF) in the context of recent clinical trials and addresses potential mechanisms and unanswered questions in certain HF patient populations. Neprilysin is an endopeptidase that cleaves a variety of peptides such as natriuretic peptides, bradykinin, adrenomedullin, substance P, angiotensin I and II, and endothelin. It has a broad role in cardiovascular, renal, pulmonary, gastrointestinal, endocrine, and neurologic functions. The combined angiotensin receptor and neprilysin inhibitor (ARNi) has been developed with an intent to increase vasodilatory natriuretic peptides and prevent counterregulatory activation …

Native Bk Polyomavirus Nephropathy In An Orthotopic Heart Transplant Patient, Zachary M Thompson, George Ajene, Prathit A Kulkarni, Nidhi Aggarwal, Savitri Fedson, Maulin K Shah

Faculty, Staff and Students Publications

BK polyomavirus nephropathy (BKVN) is a common cause of nephropathy in kidney transplant patients and is typically seen within the first year after transplantation. BK polyomavirus nephropathy can occur in the native kidneys of patients with nonrenal solid-organ transplants (NRSOT). However, this is rare, especially outside the early post-transplant period, and BKVN is not usually considered in the differential diagnosis for acute kidney injury in NRSOT patients. We present a case of a 75-year-old man who had undergone orthotopic heart transplant 13 years prior with stable allograft function who developed progressive renal dysfunction in the setting of recent unilateral obstructive …

Feasibility And Effectiveness Of A Worksite-Weight-Loss Program For Cancer Prevention Among School-District Employees With Overweight And Obesity, Che Young Lee, Michael C Robertson, Hannah Johnston, Thuan Le, Margaret Raber, Ruth Rechis, Katherine Oestman, Alise Neff, Amber Macneish, Karen M Basen-Engquist

Faculty, Staff and Students Publications

The effects of Vibrant Lives, a 6-month worksite-weight-loss program, were examined in a cohort of school-district employees with overweight or obesity. The VL Basic (VLB) participants received materials and tailored text messages, the VL Plus (VLP) participants additionally received WIFI-enabled activity monitors and scales and participated in health challenges throughout the school year, and the VL Plus with Support (VLP + S) participants additionally received coaching support. The levels of program satisfaction and retention and changes in weight, physical activity (PA), and diet were compared across groups using Pearson chi-square tests, repeated-measure mixed models, and logistic regression. After the program, …

Impact Of Covid-19 On A Worksite Weight Loss Program For Employees With Overweight And Obesity, Che Young Lee, Michael C Robertson, Kendahl Servino, Thuan Le, Margaret Raber, Katherine Oestman, Karen M Basen-Engquist

Faculty, Staff and Students Publications

OBJECTIVE: The COVID-19 pandemic has been shown to be negatively associated with physical activity engagement, adherence to healthy diet, and weight management among people with obesity. The current study examined COVID-19-related changes in weight, physical activity (PA), and diet among employees with obesity or overweight who participated in Vibrant Lives (VL), a worksite weight loss program.

METHODS: School district employees participated in the 6-month VL weight loss program and were categorized into non-COVID-era participants and COVID-era participants. Participants completed questionnaires about PA and dietary intake at baseline and follow-up. COVID-era participants reported the effects of pandemic on their behaviors. Changes …

Systemic Delivery Of Divalent Europium From Ligand Screening With Implications To Direct Imaging Of Hypoxia, Md Mamunur Rashid, Brooke A Corbin, Pavan Jella, Caitlyn J Ortiz, Md Abul Hassan Samee, Robia G Pautler, Matthew J Allen

Faculty, Staff and Students Publications

Hypoxia is a hallmark of many diseases, including cancer, arthritis, heart and kidney diseases, and diabetes, and it is often associated with disease aggressiveness and poor prognosis. Consequently, there is a critical need for imaging hypoxia in a noninvasive and direct way to diagnose, stage, and monitor the treatment and development of new therapies for these diseases. Eu-containing contrast agents for magnetic resonance imaging have demonstrated potential for in vivo imaging of hypoxia via changes in metal oxidation state from +2 to +3, but rapid oxidation in blood limits EuII-containing complexes to only studies compatible with direct injection to sites. …

Tiam1-Mediated Synaptic Plasticity Underlies Comorbid Depression-Like And Ketamine Antidepressant-Like Actions In Chronic Pain, Qin Ru, Yungang Lu, Ali Bin Saifullah, Francisco A Blanco, Changqun Yao, Juan P Cata, De-Pei Li, Kimberley F Tolias, Lingyong Li

Faculty, Staff and Students Publications

Chronic pain often leads to depression, increasing patient suffering and worsening prognosis. While hyperactivity of the anterior cingulate cortex (ACC) appears to be critically involved, the molecular mechanisms underlying comorbid depressive symptoms in chronic pain remain elusive. T cell lymphoma invasion and metastasis 1 (Tiam1) is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendrite, spine, and synapse development during brain development. Here, we show that Tiam1 orchestrates synaptic structural and functional plasticity in ACC neurons via actin cytoskeleton reorganization and synaptic N-methyl-d-aspartate receptor (NMDAR) stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain-induced depressive-like behaviors. …

A Gating Lever And Molecular Logic Gate That Couple Voltage And Calcium Sensor Activation To Opening In Bk Potassium Channels, Liang Sun, Frank T Horrigan

Faculty, Staff and Students Publications

BK channels uniquely integrate voltage and calcium signaling in diverse cell types through allosteric activation of their K+-conducting pore by structurally distinct V and Ca2+ sensor domains. Here, we define mechanisms and interaction pathways that link V sensors to the pore by analyzing effects on allosteric coupling of point mutations in the context of Slo1 BK channel structure. A gating lever, mediated by S4/S5 segment interaction within the transmembrane domain, rotates to engage and stabilize the open conformation of the S6 inner pore helix upon V sensor activation. In addition, an indirect pathway, mediated by the carboxyl-terminal cytosolic domain (CTD) …

Lpa Disruption With Aav-Crispr Potently Lowers Plasma Apo(A) In Transgenic Mouse Model: A Proof-Of-Concept Study, Alexandria M Doerfler, So Hyun Park, Julia M Assini, Amer Youssef, Lavanya Saxena, Adam B Yaseen, Marco De Giorgi, Marcel Chuecos, Ayrea E Hurley, Ang Li, Santica M Marcovina, Gang Bao, Michael B Boffa, Marlys L Koschinsky, William R Lagor

Faculty, Staff and Students Publications

Lipoprotein(a) (Lp(a)) represents a unique subclass of circulating lipoprotein particles and consists of an apolipoprotein(a) (apo(a)) molecule covalently bound to apolipoprotein B-100. The metabolism of Lp(a) particles is distinct from that of low-density lipoprotein (LDL) cholesterol, and currently approved lipid-lowering drugs do not provide substantial reductions in Lp(a), a causal risk factor for cardiovascular disease. Somatic genome editing has the potential to be a one-time therapy for individuals with extremely high Lp(a). We generated an LPA transgenic mouse model expressing apo(a) of physiologically relevant size. Adeno-associated virus (AAV) vector delivery of CRISPR-Cas9 was used to disrupt the LPA transgene in …

An Elf4 Hypomorphic Variant Results In Nk Cell Deficiency, Sandra Andrea Salinas, Emily M Mace, Matilde I Conte, Chun Shik Park, Yu Li, Joshua I Rosario-Sepulveda, Sanjana Mahapatra, Emily K Moore, Evelyn R Hernandez, Ivan K Chinn, Abigail E Reed, Barclay J Lee, Alexander Frumovitz, Richard A Gibbs, Jennifer E Posey, Lisa R Forbes Satter, Akaluck Thatayatikom, Eric J Allenspach, Theodore G Wensel, James R Lupski, H Daniel Lacorazza, Jordan S Orange

Faculty, Staff and Students Publications

NK cell deficiencies (NKD) are a type of primary immune deficiency in which the major immunologic abnormality affects NK cell number, maturity, or function. Since NK cells contribute to immune defense against virally infected cells, patients with NKD experience higher susceptibility to chronic, recurrent, and fatal viral infections. An individual with recurrent viral infections and mild hypogammaglobulinemia was identified to have an X-linked damaging variant in the transcription factor gene ELF4. The variant does not decrease expression but disrupts ELF4 protein interactions and DNA binding, reducing transcriptional activation of target genes and selectively impairing ELF4 function. Corroborating previous murine models …

Proteasome Inhibitors Silence Oncogenes In Multiple Myeloma Through Localized Histone Deacetylase 3 (Hdac3) Stabilization And Chromatin Condensation, Laure Maneix, Polina Iakova, Shannon E Moree, Joanne I Hsu, Ragini M Mistry, Fabio Stossi, Premal Lulla, Zheng Sun, Ergun Sahin, Sarvari V Yellapragada, André Catic

Faculty, Staff and Students Publications

Proteasome inhibitors have become the standard of care for multiple myeloma (MM). Blocking protein degradation particularly perturbs the homeostasis of short-lived polypeptides such as transcription factors and epigenetic regulators. To determine how proteasome inhibitors directly impact gene regulation, we performed an integrative genomics study in MM cells. We discovered that proteasome inhibitors reduce the turnover of DNA-associated proteins and repress genes necessary for proliferation through epigenetic silencing. Specifically, proteasome inhibition results in the localized accumulation of histone deacetylase 3 (HDAC3) at defined genomic sites, which reduces H3K27 acetylation and increases chromatin condensation. The loss of active chromatin at super-enhancers critical …