Medical Specialties Commons^™

Ceramide Synthase Tlcd3b Is A Novel Gene Associated With Human Recessive Retinal Dystrophy, Renae Elaine Bertrand, Jun Wang, Kaitlyn H Xiong, Chinthana Thangavel, Xinye Qian, Rola Ba-Abbad, Qingnan Liang, Renata T Simões, Shirley A M Sampaio, Keren J Carss, F Lucy Raymond, Anthony G Robson, Andrew R Webster, Gavin Arno, Fernanda Belga Ottoni Porto, Rui Chen

Faculty, Staff and Students Publications

PURPOSE: Previous studies suggest that ceramide is a proapoptotic lipid as high levels of ceramides can lead to apoptosis of neuronal cells, including photoreceptors. However, no pathogenic variant in ceramide synthases has been identified in human patients and knockout of various ceramide synthases in mice has not led to photoreceptor degeneration.

METHODS: Exome sequencing was used to identify candidate disease genes in patients with vision loss as confirmed by standard evaluation methods, including electroretinography (ERG) and optical coherence tomography. The vision loss phenotype in mice was evaluated by ERG and histological analyses.

RESULTS: Here we have identified four patients with …

Inhibition Of Camkk2 Impairs Autophagy And Castration-Resistant Prostate Cancer Via Suppression Of Ampk-Ulk1 Signaling, Chenchu Lin, Alicia M Blessing, Thomas L Pulliam, Yan Shi, Sandi R Wilkenfeld, Jenny J Han, Mollianne M Murray, Alexander H Pham, Kevin Duong, Sonja N Brun, Reuben J Shaw, Michael M Ittmann, Daniel E Frigo

Faculty, Staff and Students Publications

Previous work has suggested androgen receptor (AR) signaling mediates prostate cancer progression in part through the modulation of autophagy. However, clinical trials testing autophagy inhibition using chloroquine derivatives in men with castration-resistant prostate cancer (CRPC) have yet to yield promising results, potentially due to the side effects of this class of compounds. We hypothesized that identification of the upstream activators of autophagy in prostate cancer could highlight alternative, context-dependent targets for blocking this important cellular process during disease progression. Here, we used molecular, genetic and pharmacological approaches to elucidate an AR-mediated autophagy cascade involving Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2; …

Hands-On Training About Overfitting, Janez Demšar, Blaž Zupan

Faculty, Staff and Students Publications

Overfitting is one of the critical problems in developing models by machine learning. With machine learning becoming an essential technology in computational biology, we must include training about overfitting in all courses that introduce this technology to students and practitioners. We here propose a hands-on training for overfitting that is suitable for introductory level courses and can be carried out on its own or embedded within any data science course. We use workflow-based design of machine learning pipelines, experimentation-based teaching, and hands-on approach that focuses on concepts rather than underlying mathematics. We here detail the data analysis workflows we use …

The Crosstalk Between Cardiomyocyte Calcium And Inflammasome Signaling Pathways In Atrial Fibrillation, Xiaolei Wang, Xiaohui Chen, Dobromir Dobrev, Na Li

Faculty, Staff and Students Publications

Atrial fibrillation (AF) is the most frequent arrhythmia in adults. The prevalence and incidence of AF is going to increase substantially over the next a few decades. Because AF increases the risk of stroke, heart failure, dementia, and others, it severely impacts the quality of life, morbidity and mortality. Although the pathogenesis of AF is multifaceted and complex, focal ectopic activity and reentry are considered as the fundamental proarrhythmic mechanisms underlying AF development. Over the past 2 decades, large amount of evidence points to the key role of intracellular Ca2+ dysregulation in both initiation and maintenance of AF. More recently, …

Deficiency Of Stat1 In Cd11c+ Cells Alters Adipose Tissue Inflammation And Improves Metabolic Dysfunctions In Mice Fed A High-Fat Diet, Antu Antony, Zeqin Lian, Xiaoyuan Dai Perrard, Jerry Perrard, Hua Liu, Aaron R Cox, Pradip Saha, Lothar Hennighausen, Sean M Hartig, Christie M Ballantyne, Huaizhu Wu

Faculty, Staff and Students Publications

CD11c+ macrophages/dendritic cells (MDCs) are increased and display the classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into the M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed a high-fat diet (HFD). Compared with littermate controls, cKO mice fed an HFD (16 …

Is Covid-19-Induced Platelet Activation A Cause Of Concern For Patients With Cancer?, Lenard M Lichtenberger, K Vinod Vijayan

Faculty, Staff and Students Publications

Patients with cancer are more susceptible to be infected by SARS-CoV-2 and develop severe outcomes including ICU admittance, mechanical ventilator support, and a high rate of mortality. Like mid-to late-stage cancer, SARS-CoV-2 infection is associated with platelet hyperactivity, systemic inflammation, thrombotic complications, and coagulopathy. Platelets also promote cancer cell growth, survival in circulation, and angiogenesis at sites of metastases. In this article, we will discuss the potential for platelets in the development of systemic inflammation and thrombosis in SARS-CoV-2-infected patients with cancer, with the concern that the platelet-induced pathogenic events are likely magnified in cancer patients with COVID-19.

Tools For Visualizing And Analyzing Fourier Space Sampling In Cryo-Em, Philip R Baldwin, Dmitry Lyumkis

Faculty, Staff and Students Publications

A complete understanding of how an orientation distribution contributes to a cryo-EM reconstruction remains lacking. It is necessary to begin critically assessing the set of views to gain an understanding of its effect on experimental reconstructions. Toward that end, we recently suggested that the type of orientation distribution may alter resolution measures in a systematic manner. We introduced the sampling compensation factor (SCF), which incorporates how the collection geometry might change the spectral signal-to-noise ratio (SSNR), irrespective of the other experimental aspects. We show here that knowledge of the sampling restricted to spherical surfaces of sufficiently large radii in Fourier …

A Biallelic Pathogenic Variant In The Ogdh Gene Results In A Neurological Disorder With Features Of A Mitochondrial Disease, Zheng Yie Yap, Klaudia Strucinska, Satoshi Matsuzaki, Sukyeong Lee, Yue Si, Kenneth Humphries, Mark A Tarnopolsky, Wan Hee Yoon

Faculty, Staff and Students Publications

2-Oxoglutarate dehydrogenase (OGDH) is a rate-limiting enzyme in the mitochondrial TCA cycle, encoded by the OGDH gene. α-Ketoglutarate dehydrogenase (OGDH) deficiency was previously reported in association with developmental delay, hypotonia, and movement disorders and metabolic decompensation, with no genetic data provided. Using whole exome sequencing, we identified two individuals carrying a homozygous missense variant c.959A>G (p.N320S) in the OGDH gene. These individuals presented with global developmental delay, elevated lactate, ataxia and seizure. Fibroblast analysis and modeling of the mutation in Drosophila were used to evaluate pathogenicity of the variant. Skin fibroblasts from subject # 2 showed a decrease in …

On The Application, Reporting, And Sharing Of In Silico Simulations For Genetic Studies, Kaleigh Riggs, Huann-Sheng Chen, Melissa Rotunno, Bing Li, Naoko I Simonds, Leah E Mechanic, Bo Peng

Faculty, Staff and Students Publications

In silico simulations play an indispensable role in the development and application of statistical models and methods for genetic studies. Simulation tools allow for the evaluation of methods and investigation of models in a controlled manner. With the growing popularity of evolutionary models and simulation-based statistical methods, genetic simulations have been applied to a wide variety of research disciplines such as population genetics, evolutionary genetics, genetic epidemiology, ecology, and conservation biology. In this review, we surveyed 1409 articles from five journals that publish on major application areas of genetic simulations. We identified 432 papers in which genetic simulations were used …

Fusobacteriumnucleatum Adheres To Clostridioides Difficile Via The Radd Adhesin To Enhance Biofilm Formation In Intestinal Mucus, Melinda A Engevik, Heather A Danhof, Jennifer Auchtung, Bradley T Endres, Wenly Ruan, Eugénie Bassères, Amy C Engevik, Qinglong Wu, Maribeth Nicholson, Ruth Ann Luna, Kevin W Garey, Sue E Crawford, Mary K Estes, Renate Lux, Mary Beth Yacyshyn, Bruce Yacyshyn, Tor Savidge, Robert A Britton, James Versalovic

Faculty, Staff and Students Publications

Background:

Although Clostridioides difficile infection (CDI) is known to involve the disruption of the gut microbiota, little is understood regarding how mucus-associated microbes interact with C. difficile. We hypothesized that select mucus-associated bacteria would promote C. difficile colonization and biofilm formation.

Methods/Results:

To create a model of the human intestinal mucus layer and gut microbiota, we used bioreactors inoculated with healthy human feces, treated with clindamycin and infected with C. difficile with the addition of human MUC2-coated coverslips. C. difficile was found to colonize and form biofilms on MUC2-coated coverslips and 16S rRNA sequencing revealed a unique biofilm profile …

Evaluating The Revised American Society For Gastrointestinal Endoscopy Guidelines For Common Bile Duct Stone Diagnosis, Jake S Jacob, Michelle E Lee, Erin Y Chew, Aaron P Thrift, Robert J Sealock

Faculty, Staff and Students Publications

BACKGROUND/AIMS: The American Society for Gastrointestinal Endoscopy (ASGE) revised its guidelines for risk stratification of patients with suspected choledocholithiasis. This study aimed to assess the diagnostic performance of the revision and to compare it to the previous guidelines.

METHODS: We conducted a retrospective cohort study of 267 patients with suspected choledocholithiasis. We identified high-risk patients according to the original and revised guidelines and examined the diagnostic accuracy of both guidelines. We measured the association between individual criteria and choledocholithiasis.

RESULTS: Under the original guidelines, 165 (62%) patients met the criteria for high risk, of whom 79% had confirmed choledocholithiasis. The …

Pegylated Arginine Deiminase Depletes Plasma Arginine But Maintains Tissue Arginine Availability In Young Pigs, Mahmoud A Mohammad, Inka C Didelija, Barbara Stoll, Trung C Nguyen, Juan C Marini

Faculty, Staff and Students Publications

Pegylated arginine deiminase (ADI-PEG20) results in the depletion of arginine with the production of isomolar amounts of citrulline. This citrulline has the potential to be utilized by the citrulline recycling pathway regenerating arginine and sustaining tissue arginine availability. The goal of this research was to test the hypothesis that ADI-PEG20 depletes circulating arginine in pigs but maintains tissue arginine concentration and function, and to characterize the kinetics of citrulline and arginine. Two multitracer approaches (bolus dose and primed-continuous infusion) were used to investigate the metabolism of arginine and citrulline in Control (

A Prospective Surveillance Study On The Kinetics Of The Humoral Immune Response To The Respiratory Syncytial Virus Fusion Protein In Adults In Houston, Texas, Brittani N Blunck, Letisha Aideyan, Xunyan Ye, Vasanthi Avadhanula, Laura Ferlic-Stark, Lynn Zechiedrich, Brian E Gilbert, Pedro A Piedra

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV)-specific serum antibody has been correlated to protection of infection and reduction of severe disease, but reinfection is still frequent. In this study, we evaluated RSV-specific serum antibody activity following natural RSV re-infection to examine the longevity of the humoral immune response in adults. Nineteen healthy adult volunteers under sixty-five years of age were enrolled during the 2018-2019 RSV season in Houston, TX. Blood was collected at three study visits. The kinetics of RSV-neutralizing, RSV F site-specific competitive, and RSV-binding antibodies in serum samples were measured by microneutralization and enzyme-linked immunosorbent assays. Three distinct profiles of RSV-specific …

Vulvar Lichen Sclerosus In Women Of Reproductive Age, Elysha Kolitz, Laura Gammon, Melissa Mauskar

Faculty, Staff and Students Publications

Vulvar lichen sclerosus (vLS) is an inflammatory skin condition that predominantly affects the vulvar and perianal regions. Approximately 50% of cases present prior to menopause; however, there is a paucity of data on vLS in women of reproductive age as well as during their pregnancies. A retrospective review was performed at two tertiary referral centers to better describe cases of vLS in women of reproductive age. Thirty-three patients with a mean age of 40 years met inclusion criteria. In this group, vulvar pruritus was the most common presenting symptom (52%); 61% had biopsy-proven vLS, 42% had at least one autoimmune …

Continuous-Flow Left Ventricular Assist Device Therapy In Adults With Transposition Of The Great Vessels, Tadahisa Sugiura, Chitaru Kurihara, Masashi Kawabori, Andre C Critsinelis, Andrew B Civitello, Jeffrey A Morgan, O H Frazier

Faculty, Staff and Students Publications

An increasing number of children with congenital heart disease are surviving into adulthood and subsequently developing end-stage heart failure. Two example populations are adults who have been previously operated on for congenitally corrected transposition of the great arteries (CCTGA) and transposition of the great arteries (TGA). Implantation of a continuous flow left ventricular assist device (CF-LVAD) in these patients can present unusual anatomical and physiologic challenges. In this report, we describe outcomes of CF-LVAD implantation in three such patients. These cases demonstrate the feasibility of implanting a CF-LVAD in patients who have undergone surgery for CCTGA and/or TGA.

The Mitochondrial Protease Lonp1 Promotes Proteasome Inhibitor Resistance In Multiple Myeloma, Laure Maneix, Melanie A Sweeney, Sukyeong Lee, Polina Iakova, Shannon E Moree, Ergun Sahin, Premal Lulla, Sarvari V Yellapragada, Francis T F Tsai, Andre Catic

Faculty, Staff and Students Publications

Multiple myeloma and its precursor plasma cell dyscrasias affect 3% of the elderly population in the US. Proteasome inhibitors are an essential part of several standard drug combinations used to treat this incurable cancer. These drugs interfere with the main pathway of protein degradation and lead to the accumulation of damaged proteins inside cells. Despite promising initial responses, multiple myeloma cells eventually become drug resistant in most patients. The biology behind relapsed/refractory multiple myeloma is complex and poorly understood. Several studies provide evidence that in addition to the proteasome, mitochondrial proteases can also contribute to protein quality control outside of …

Mapk4 Promotes Prostate Cancer By Concerted Activation Of Androgen Receptor And Akt, Tao Shen, Wei Wang, Wolong Zhou, Ilsa Coleman, Qinbo Cai, Bingning Dong, Michael M Ittmann, Chad J Creighton, Yingnan Bian, Yanling Meng, David R Rowley, Peter S Nelson, David D Moore, Feng Yang

Faculty, Staff and Students Publications

Prostate cancer (PCa) is the second leading cause of cancer death in American men. Androgen receptor (AR) signaling is essential for PCa cell growth/survival and remains a key therapeutic target for lethal castration-resistant PCa (CRPC). GATA2 is a pioneer transcription factor crucial for inducing AR expression/activation. We recently reported that MAPK4, an atypical MAPK, promotes tumor progression via noncanonical activation of AKT. Here, we demonstrated that MAPK4 activated AR by enhancing GATA2 transcriptional expression and stabilizing GATA2 protein through repression of GATA2 ubiquitination/degradation. MAPK4 expression correlated with AR activation in human CRPC. Concerted activation of both GATA2/AR and AKT by …

Targeting Nsd2-Mediated Src-3 Liquid-Liquid Phase Separation Sensitizes Bortezomib Treatment In Multiple Myeloma, Jing Liu, Ying Xie, Jing Guo, Xin Li, Jingjing Wang, Hongmei Jiang, Ziyi Peng, Jingya Wang, Sheng Wang, Qian Li, Linquan Ye, Yuping Zhong, Qiguo Zhang, Xiaozhi Liu, David M Lonard, Jin Wang, Bert W O'Malley, Zhiqiang Liu

Faculty, Staff and Students Publications

Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid-liquid phase separation to supranormally modify histone …

The Rac-Gef Tiam1 Promotes Dendrite And Synapse Stabilization Of Dentate Granule Cells And Restricts Hippocampal-Dependent Memory Functions, Jinxuan Cheng, Federico Scala, Francisco A Blanco, Sanyong Niu, Karen Firozi, Laura Keehan, Shalaka Mulherkar, Emmanouil Froudarakis, Lingyong Li, Joseph G Duman, Xiaolong Jiang, Kimberley F Tolias

Faculty, Staff and Students Publications

The dentate gyrus (DG) controls information flow into the hippocampus and is critical for learning, memory, pattern separation, and spatial coding, while DG dysfunction is associated with neuropsychiatric disorders. Despite its importance, the molecular mechanisms regulating DG neural circuit assembly and function remain unclear. Here, we identify the Rac-GEF Tiam1 as an important regulator of DG development and associated memory processes. In the hippocampus, Tiam1 is predominantly expressed in the DG throughout life. Global deletion of Tiam1 in male mice results in DG granule cells with simplified dendritic arbors, reduced dendritic spine density, and diminished excitatory synaptic transmission. Notably, DG …

Vertical Sleeve Gastrectomy Confers Metabolic Improvements By Reducing Intestinal Bile Acids And Lipid Absorption In Mice, Lili Ding, Eryun Zhang, Qiaoling Yang, Lihua Jin, Kyle M Sousa, Bingning Dong, Yangmeng Wang, Jui Tu, Xiaoxiao Ma, Jingyan Tian, Hongli Zhang, Zhipeng Fang, Ana Guan, Yixin Zhang, Zhengtao Wang, David D Moore, Li Yang, Wendong Huang

Faculty, Staff and Students Publications

Vertical sleeve gastrectomy (VSG) is a highly effective bariatric surgery that sustainably treats obesity and type 2 diabetes (T2D). However, the underlying mechanisms governing its metabolic benefits remain unclear. In this study, we have used four different genetically modified mouse lines to understand the link between bile acid circulation and metabolic effects of VSG. Instead of directly activating the nuclear bile acid receptor farnesoid X receptor (Fxr) in the liver or intestine, VSG reduces intestinal levels of bile acids, thereby decreasing fat absorption in the intestine. Given the rising popularity of bariatric surgeries to treat obesity and associated T2D, the …

Association Of Nt-Probnp, Blood Pressure, And Cardiovascular Events: The Aric Study, Aliza Hussain, Wensheng Sun, Anita Deswal, James A De Lemos, John W Mcevoy, Ron C Hoogeveen, Kunihiro Matsushita, David Aguilar, Biykem Bozkurt, Salim S Virani, Amil M Shah, Elizabeth Selvin, Chiadi Ndumule, Christie M Ballantyne, Vijay Nambi

Faculty, Staff and Students Publications

BACKGROUND: Although intensive blood pressure reduction has cardiovascular benefits, the absolute benefit is greater in those at higher cardiovascular disease (CVD) risk.

OBJECTIVES: This study examined whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) helps identify subjects at higher risk for CVD events across systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse pressure (PP) categories.

METHODS: Participants from the ARIC (Atherosclerosis Risk In Communities) study visit 4 (1996 to 98) were grouped according to SBP, DBP, or PP categories and further stratified by NT-proBNP categories. Cox regression models were used to estimate hazard ratios for incident CVD (coronary heart disease, …

Hermansky-Pudlak Syndrome-2 Alters Mitochondrial Homeostasis In The Alveolar Epithelium Of The Lung, Karina Cuevas-Mora, Willy Roque, Hoora Shaghaghi, Bernadette R Gochuico, Ivan O Rosas, Ross Summer, Freddy Romero

Faculty, Staff and Students Publications

BACKGROUND: Mitochondrial dysfunction has emerged as an important player in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a common cause of idiopathic interstitial lung disease in adults. Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that causes a similar type of pulmonary fibrosis in younger adults, although the role of mitochondrial dysfunction in this condition is not understood.

METHODS: We performed a detailed characterization of mitochondrial structure and function in lung tissues and alveolar epithelial cells deficient in the adaptor protein complex 3 beta 1 (Ap3b1) subunit, the gene responsible for causing subtype 2 of HPS (HPS-2).

RESULTS: We …

Common Questions And Misconceptions About Creatine Supplementation: What Does The Scientific Evidence Really Show?, Jose Antonio, Darren G Candow, Scott C Forbes, Bruno Gualano, Andrew R Jagim, Richard B Kreider, Eric S Rawson, Abbie E Smith-Ryan, Trisha A Vandusseldorp, Darryn S Willoughby, Tim N Ziegenfuss

Faculty, Staff and Students Publications

Supplementing with creatine is very popular amongst athletes and exercising individuals for improving muscle mass, performance and recovery. Accumulating evidence also suggests that creatine supplementation produces a variety of beneficial effects in older and patient populations. Furthermore, evidence-based research shows that creatine supplementation is relatively well tolerated, especially at recommended dosages (i.e. 3-5 g/day or 0.1 g/kg of body mass/day). Although there are over 500 peer-refereed publications involving creatine supplementation, it is somewhat surprising that questions regarding the efficacy and safety of creatine still remain. These include, but are not limited to: 1. Does creatine lead to water retention? 2. …

Cryo-Electron Tomography Of Candida Glabrata Plasma Membrane Proteins, Cristina Jiménez-Ortigosa, Jennifer Jiang, Muyuan Chen, Xuyuan Kuang, Kelley R Healey, Paul Castellano, Nikpreet Boparai, Steven J Ludtke, David S Perlin, Wei Dai

Faculty, Staff and Students Publications

Fungal plasma membrane proteins have long been recognized as targets for the development of antifungal agents. Despite recent progress in experimental approaches and computational structural predictions, our knowledge of the structural dynamics and spatial distribution of these membrane proteins in the context of their native lipid environment remains limited. By applying cryo-electron tomography (cryoET) and subtomogram analysis, we aim to characterize the structural characteristics and spatial distribution of membrane proteins present in Candida glabrata plasma membranes. This study has resulted in the identification of the membrane-embedded structure of the fungal H+-ATPase, Pma1. Tomograms of the plasma membrane revealed that Pma1 …

Addressing Artificial Intelligence Bias In Retinal Diagnostics, Philippe Burlina, Neil Joshi, William Paul, Katia D Pacheco, Neil M Bressler

Faculty, Staff and Students Publications

PURPOSE: This study evaluated generative methods to potentially mitigate artificial intelligence (AI) bias when diagnosing diabetic retinopathy (DR) resulting from training data imbalance or domain generalization, which occurs when deep learning systems (DLSs) face concepts at test/inference time they were not initially trained on.

METHODS: The public domain Kaggle EyePACS dataset (88,692 fundi and 44,346 individuals, originally diverse for ethnicity) was modified by adding clinician-annotated labels and constructing an artificial scenario of data imbalance and domain generalization by disallowing training (but not testing) exemplars for images of retinas with DR warranting referral (DR-referable) from darker-skin individuals, who presumably have greater …

Efficacy And Safety Of The Mrna-1273 Sars-Cov-2 Vaccine, Lindsey R Baden, Hana M El Sahly, Brandon Essink, Karen Kotloff, Sharon Frey, Rick Novak, David Diemert, Stephen A Spector, Nadine Rouphael, C Buddy Creech, John Mcgettigan, Shishir Khetan, Nathan Segall, Joel Solis, Adam Brosz, Carlos Fierro, Howard Schwartz, Kathleen Neuzil, Larry Corey, Peter Gilbert, Holly Janes, Dean Follmann, Mary Marovich, John Mascola, Laura Polakowski, Julie Ledgerwood, Barney S Graham, Hamilton Bennett, Rolando Pajon, Conor Knightly, Brett Leav, Weiping Deng, Honghong Zhou, Shu Han, Melanie Ivarsson, Jacqueline Miller, Tal Zaks, Cove Study Group

Faculty, Staff and Students Publications

BACKGROUND: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19.

METHODS: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. …

Eosinophils Attenuate Hepatic Ischemia-Reperfusion Injury In Mice Through St2-Dependent Il-13 Production, Yaochun Wang, Yang Yang, Meng Wang, Shuhong Wang, Jong-Min Jeong, Long Xu, Yankai Wen, Christoph Emontzpohl, Constance Lynn Atkins, Kevin Duong, Nicolas F Moreno, Xiaoyi Yuan, David R Hall, Wasim Dar, Dechun Feng, Bin Gao, Yong Xu, Zoltan Czigany, Sean P Colgan, J Steve Bynon, Shizuo Akira, Jared M Brown, Holger K Eltzschig, Elizabeth A Jacobsen, Cynthia Ju

Faculty, Staff and Students Publications

Eosinophils are a myeloid cell subpopulation that mediates type 2 T helper cell immune responses. Unexpectedly, we identified a rapid accumulation of eosinophils in 22 human liver grafts after hepatic transplantation. In contrast, no eosinophils were detectable in healthy liver tissues before transplantation. Studies with two genetic mouse models of eosinophil deficiency and a mouse model of antibody-mediated eosinophil depletion revealed exacerbated liver injury after hepatic ischemia and reperfusion. Adoptive transfer of bone marrow-derived eosinophils normalized liver injury of eosinophil-deficient mice and reduced hepatic ischemia and reperfusion injury in wild-type mice. Mechanistic studies combining genetic and adoptive transfer approaches identified …

Lkb1 And Ampk Instruct Cone Nuclear Position To Modify Visual Function, Courtney A Burger, Nicholas E Albrecht, Danye Jiang, Justine H Liang, Ross A Poché, Melanie A Samuel

Faculty, Staff and Students Publications

Cone photoreceptors detect light and are responsible for color vision. These cells display a distinct polarized morphology where nuclei are precisely aligned in the apical retina. However, little is known about the mechanisms involved in cone nuclear positioning or the impact of this organization on retina function. We show that the serine/threonine kinase LKB1 and one of its substrates, AMPK, regulate cone nuclear positioning. In the absence of either molecule, cone nuclei are misplaced along the axon, resulting in altered nuclear lamination. LKB1 is required specifically in cones to mediate this process, and disruptions in nuclear alignment result in reduced …

X-Aptamers Targeting Thy-1 Membrane Glycoprotein In Pancreatic Ductal Adenocarcinoma, Hongyu Wang, Xin Li, Lisa A Lai, Teresa A Brentnall, David W Dawson, Kimberly A Kelly, Ru Chen, Sheng Pan

Faculty, Staff and Students Publications

Modified DNA aptamers incorporated with amino-acid like side chains or drug-like ligands can offer unique advantages and enhance specificity as affinity ligands. Thy-1 membrane glycoprotein (THY1 or CD90) was previously identified as a biomarker candidate of neovasculature in pancreatic ductal adenocarcinoma (PDAC). The current study developed and evaluated modified DNA X-aptamers targeting THY1 in PDAC. The expression and glycosylation of THY1 in PDAC tumor tissues were assessed using immunohistochemistry and quantitative proteomics. Bead-based X-aptamer library that contains 108 different sequences was used to screen for high affinity THY1 X-aptamers. The sequences of the X-aptamers were analyzed with the next-generation sequencing. …

Intestinal Stem Cell-Derived Enteroids From Morbidly Obese Patients Preserve Obesity-Related Phenotypes: Elevated Glucose Absorption And Gluconeogenesis, Nesrin M Hasan, Kelli F Johnson, Jianyi Yin, Nicholas W Baetz, Lea Fayad, Vadim Sherman, Sarah E Blutt, Mary K Estes, Vivek Kumbhari, Nicholas C Zachos, Olga Kovbasnjuk

Faculty, Staff and Students Publications

OBJECTIVE: The mechanisms behind the efficacy of bariatric surgery (BS) for treating obesity and type 2 diabetes, particularly with respect to the influence of the small bowel, remain poorly understood. In vitro and animal models are suboptimal with respect to their ability to replicate the human intestinal epithelium under conditions induced by obesity. Human enteroids have the potential to accelerate the development of less invasive anti-obesity therapeutics if they can recapitulate the pathophysiology of obesity. Our aim was to determine whether adult stem cell-derived enteroids preserve obesity-characteristic patient-specific abnormalities in carbohydrate absorption and metabolism.

METHODS: We established 24 enteroid lines …