Digital Commons Network^™

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% …

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 …

Individual And Combined Antioxidant Activity Of Spices And Spice Phenolics, Mohammad B Hossain, Lubna Ahmed, Anna Belen Martin-Diana, Nigel P Brunton, Catherine Barry-Ryan

Faculty, Staff and Student Publications

The present study investigated the interaction effects (additive, synergistic, and antagonistic) of different groups of spices, their constituent phenolic compounds, and synthetic antioxidants on the total phenol (TP) content and antioxidant activity, as measured by the ferric-reducing antioxidant power (FRAP) of the mixtures. The results showed that there was an additive effect in all the groups studied, except for the group containing turmeric or curcumin. The groups containing turmeric or curcumin showed a moderate synergistic effect. Among the groups of spices, the highest summated TP (50.6 mg GAE/mL) and FRAP (106.2 mg Trolox/mL) values were observed in the group containing …

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 …

4d Lung Mri With High-Isotropic-Resolution Using Half-Spoke (Ute) And Full-Spoke 3d Radial Acquisition And Temporal Compressed Sensing Reconstruction, Can Wu, Guruprasad Krishnamoorthy, Victoria Yu, Ergys Subashi, Andreas Rimner, Ricardo Otazo

Faculty, Staff and Student Publications

Objective:

To develop a respiratory motion-resolved 4D MRI technique with high-isotropic-resolution (1.1 mm) using 3D radial sampling, camera-based respiratory motion sensing, and temporal compressed sensing reconstruction for lung cancer imaging.

Approach:

Free-breathing half- and full-spoke 3D golden-angle radial acquisitions were performed on eight healthy volunteers and eight patients with lung tumors of varying size. A back-and-forth k-space ordering between consecutive interleaves of the 3D radial acquisition was performed to minimize eddy current-related artifacts. Data were sorted into respiratory motion states using camera-based motion navigation and 4D images were reconstructed using temporal compressed sensing to reduce scan time. Normalized sharpness indices …

The Impact Of Covid-19 Pandemic Upon Non-Elective Admissions And Surgery At A Safety-Net Hospital, Aurelien Amiot, Jean-Francois Rahier, Filip Baert, Stephane Nahon, Ailsa Hart, Nikos Viazis, Livia Biancone, Eugeni Domenech, Catherine Reenears, Laurent Peyrin-Biroulet, Laurent Beaugerie, Johan Burisch, I-Care Collaborator Group

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: There are concerns regarding the potential impact of the COVID-19 outbreak on patients with inflammatory bowel disease [IBD]. We report on the impact of the COVID-19 outbreak in a European prospective cohort study of patients with IBD.

PATIENTS AND METHODS: We prospectively collected data from 5457 patients with IBD nested in the ongoing I-CARE project and still followed up in April 2020, with monthly online monitoring of clinical activity, treatment, imaging and endoscopy. Investigators were also contacted to report incidental cases.

RESULTS: In total, 233 [4.3%] reported COVID-19 and 12 [0.2%] severe COVID-19, with no COVID-19 deaths. …

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 …

Postbiotics Derived From L Paracasei Et-22 Inhibit The Formation Of S Mutans Biofilms And Bioactive Substances: An Analysis, Zhi Zhao, Jianmin Wu, Zhe Sun, Jinbo Fan, Fudong Liu, Wen Zhao, Wei-Hsien Liu, Ming Zhang, Wei-Lian Hung

Faculty, Staff and Student Publications

Globally, dental caries is one of the most common non-communicable diseases for patients of all ages; Streptococcus mutans (S. mutans) is its principal pathogen. Lactobacillus paracasei (L. paracasei) shows excellent anti-pathogens and immune-regulation functions in the host. The aim of this study is to evaluate the effects of L. paracasei ET-22 on the formation of S. mutans biofilms. The living bacteria, heat-killed bacteria, and secretions of L. paracasei ET-22 were prepared using the same number of bacteria. In vitro, they were added into artificial-saliva medium, and used to coculture with the S. mutans. Results showed …

Spleen Tyrosine Kinase/Fms-Like Tyrosine Kinase-3 Inhibition In Relapsed/Refractory B-Cell Lymphoma, Including Diffuse Large B-Cell Lymphoma: Updated Data With Mivavotinib (Tak-659/Cb-659), Leo I Gordon, Reem Karmali, Jason B Kaplan, Rakesh Popat, Howard A Burris, Silvia Ferrari, Sumit Madan, Manish R Patel, Giuseppe Gritti, Dima El-Sharkawi, F Ian Chau, John Radford, Jaime Pérez De Oteyza, Pier Luigi Zinzani, Swaminathan P Iyer, William Townsend, Harry Miao, Igor Proscurshim, Shining Wang, Shilpi Katyayan, Ying Yuan, Jiaxi Zhu, Kate Stumpo, Yaping Shou, Cecilia Carpio, Francesc Bosch

Faculty, Staff and Student Publications

We report an updated analysis from a phase I study of the spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 inhibitor mivavotinib, presenting data for the overall cohort of lymphoma patients, and the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; including an expanded cohort not included in the initial report). Patients with relapsed/refractory lymphoma for which no standard treatment was available received mivavotinib 60-120 mg once daily in 28-day cycles until disease progression/unacceptable toxicity. A total of 124 patients with lymphoma, including 89 with DLBCL, were enrolled. Overall response rates (ORR) in response-evaluable patients were 45% (43/95) …

Construction And Characterization Of Functional Ftsa Sandwich Fusions For Studies Of Ftsa Localization And Dynamics During Escherichia Coli Cell Division, Todd A Cameron, William Margolin

Faculty, Staff and Student Publications

FtsA, a homolog of actin, is essential for cell division of Escherichia coli and is widely conserved among many bacteria. FtsA helps to tether polymers of the bacterial tubulin homolog FtsZ to the cytoplasmic membrane as part of the cytokinetic Z ring. GFP fusions to FtsA have illuminated FtsA’s localization in live E. coli, but these fusions have not been fully functional and required the presence of the native FtsA. Here, we characterize “sandwich” fusions of E. coli FtsA to either mCherry or msfGFP that are functional for cell division and exhibit fluorescent rings at midcell that persist throughout …

Efficacy Of Kairomone Lures To Attract Parasitoids Of Halyomorpha Halys, Kate V Richardson, Diane G Alston, Lori R Spears

Faculty, Staff and Student Publications

In its native range, Halyomorpha halys (Stål) is suppressed by parasitoids in the genus Trissolcus (Hymenoptera: Scelionidae). Trissolcus native to Utah have demonstrated low parasitism of H. halys, while adventive Trissolcus japonicus (Ashmead) have shown parasitism of up to 20%. Custom rubber septa lures containing stink bug kairomones, n-tridecane (attractant), and (E)-2-decenal (repellent), at 100%, 90%, and 80% levels of attractant (10 mg load rate), were placed adjacent to sentinel H. halys egg masses in northern Utah field trials. Egg masses were evaluated for the presence and intensity (proportion of parasitized eggs) of parasitism. Parasitism by T. japonicus and …

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, …

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 …

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 …

Facebook Intervention For Young-Onset Melanoma Survivors And Families: Protocol For A Randomized Controlled Trial, Sharon Manne, Sherry Pagoto, Susan Peterson, Carolyn Heckman, Deborah Kashy, Adam Berger, Christina Studts, Rosalyn Negrón, David Buller, Lisa Paddock, Joseph Gallo, Alexandria Kulik, Sara Frederick, Morgan Pesanelli, Mara Domider, Marissa Grosso

Faculty, Staff and Student Publications

Background: Individuals diagnosed with melanoma before the age of 40 years (young-onset melanoma survivors) and their first-degree relatives (FDRs) are a growing population at risk for developing recurrent melanoma or new melanomas. Regular surveillance using clinical skin examination (CSE) and skin self-examination (SSE) and engagement in preventive behaviors including sun protection are recommended. Given the growing population of survivors and their families who are at increased risk, it is surprising that no behavioral interventions have been developed and evaluated to improve risk-reduction behaviors.

Objective: We describe the rationale and methodology for a randomized controlled trial evaluating the efficacy of a …

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 …

Mixcan: A Framework For Cell-Type-Aware Transcriptome-Wide Association Studies With An Application To Breast Cancer, Xiaoyu Song, Jiayi Ji, Joseph H Rothstein, Stacey E Alexeeff, Lori C Sakoda, Adriana Sistig, Ninah Achacoso, Eric Jorgenson, Alice S Whittemore, Robert J Klein, Laurel A Habel, Pei Wang, Weiva Sieh

Faculty, Staff and Student Publications

Human bulk tissue samples comprise multiple cell types with diverse roles in disease etiology. Conventional transcriptome-wide association study approaches predict genetically regulated gene expression at the tissue level, without considering cell-type heterogeneity, and test associations of predicted tissue-level expression with disease. Here we develop MiXcan, a cell-type-aware transcriptome-wide association study approach that predicts cell-type-level expression, identifies disease-associated genes via combination of cell-type-level association signals for multiple cell types, and provides insight into the disease-critical cell type. As a proof of concept, we conducted cell-type-aware analyses of breast cancer in 58,648 women and identified 12 transcriptome-wide significant genes using MiXcan compared …

Association Between E-Cigarette Use Behaviors And Anxiety/Depression Among Black/African American Adults Based On Sexual Identity, David Adzrago, Melissa B Harrell, Kayo Fujimoto, Antwan Jones, J Michael Wilkerson

Faculty, Staff and Student Publications

Limited studies have examined disparities in e-cigarette use among Black/African American adults by sexual identity and whether the relationship between symptoms of anxiety/depression and e-cigarette use varies by sexual identity. We examined the association between e-cigarette use behaviors (never, former, and current use) and anxiety/depression among a nationally representative sample of Black/African American adults who identified as a sexual minority (lesbian/gay, bisexual, and others) or heterosexual individuals. We combined cross-sectional data from the 2011 to 2020 Health Information National Trends Survey (n = 6267), which is a nationally representative data set. We computed weighted e-cigarette use prevalence and multinomial logistic …

Epigenomic Charting And Functional Annotation Of Risk Loci In Renal Cell Carcinomaepigenomic Charting And Functional Annotation Of Risk Loci In Renal Cell Carcinoma, Amin H Nassar, Sarah Abou Alaiwi, Sylvan C Baca, Elio Adib, Rosario I Corona, Ji-Heui Seo, Marcos A S Fonseca, Sandor Spisak, Talal El Zarif, Viktoria Tisza, David A Braun, Heng Du, Monica He, Abdallah Flaifel, Michel Alchoueiry, Thomas Denize, Sayed G Matar, Andres Acosta, Sachet Shukla, Yue Hou, John Steinharter, Gabrielle Bouchard, Jacob E Berchuck, Edward O'Connor, Connor Bell, Pier Vitale Nuzzo, Gwo-Shu Mary Lee, Sabina Signoretti, Michelle S Hirsch, Mark Pomerantz, Elizabeth Henske, Alexander Gusev, Kate Lawrenson, Toni K Choueiri, David J Kwiatkowski, Matthew L Freedman

Faculty, Staff and Student Publications

While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC. We confirm histology-specific MTFs via immunohistochemistry including a ccRCC-specific TF, BHLHE41. FOXI1 overexpression with knock-down of EPAS1 in the 786-O ccRCC cell line induces transcriptional …

Synthesize Heterogeneous Biological Knowledge Via Representation Learning For Alzheimer’S Disease Drug Repurposing, Kang-Lin Hsieh, German Plascencia-Villa, Ko-Hong Lin, George Perry, Xiaoqian Jiang, Yejin Kim

Faculty, Staff and Student Publications

Developing drugs for treating Alzheimer's disease has been extremely challenging and costly due to limited knowledge of underlying mechanisms and therapeutic targets. To address the challenge in AD drug development, we developed a multi-task deep learning pipeline that learns biological interactions and AD risk genes, then utilizes multi-level evidence on drug efficacy to identify repurposable drug candidates. Using the embedding derived from the model, we ranked drug candidates based on evidence from post-treatment transcriptomic patterns, efficacy in preclinical models, population-based treatment effects, and clinical trials. We mechanistically validated the top-ranked candidates in neuronal cells, identifying drug combinations with efficacy in …

Acquired Genomic Alterations On First-Line Chemotherapy With Cetuximab In Advanced Colorectal Cancer: Circulating Tumor Dna Analysis Of The Calgb/Swog-80405 Trial (Alliance), Kanwal Raghav, Fang-Shu Ou, Alan P Venook, Federico Innocenti, Ryan Sun, Heinz-Josef Lenz, Scott Kopetz

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Acquired genomic alterations (Acq-GAs), specifically RAS, BRAF, and EGFR-ectodomain mutations and ERBB2 and MET amplifications, are recognized as major mechanisms of resistance to later-line anti-EGFR-antibody therapy in metastatic colorectal cancer (mCRC). However, data regarding …

Resistance Mechanisms To Anti–Epidermal Growth Factor Receptor Therapy In Ras/Raf Wild-Type Colorectal Cancer Vary By Regimen And Line Of Therapy, Christine M Parseghian, Ryan Sun, Melanie Woods, Stefania Napolitano, Hey Min Lee, Jumanah Alshenaifi, Jason Willis, Shakayla Nunez, Kanwal P Raghav, Van K Morris, John P Shen, Madhulika Eluri, Alexey Sorokin, Preeti Kanikarla, Eduardo Vilar, Marko Rehn, Agnes Ang, Teresa Troiani, Scott Kopetz

Faculty, Staff and Student Publications

Purpose: Acquired resistance to anti-epidermal growth factor receptor (EGFR) inhibitor (EGFRi) therapy in colorectal cancer (CRC) has previously been explained by the model of acquiring new mutations in KRAS/NRAS/EGFR, among other MAPK-pathway members. However, this was primarily on the basis of single-agent EGFRi trials and little is known about the resistance mechanisms of EGFRi combined with effective cytotoxic chemotherapy in previously untreated patients.

Methods: We analyzed paired plasma samples from patients with RAS/BRAF/EGFR wild-type metastatic CRC enrolled in three large randomized trials evaluating EGFRi in the first line in combination with chemotherapy and as a single agent in third …

Outcomes Of Surgical Treatment For Extradural Benign Primary Spinal Tumors In Patients Younger Than 25 Years: An Ambispective International Multicenter Study, Alexander C Disch, Stefano Boriani, Aron Lazary, Laurence D Rhines, Alessandro Luzzati, Ziya L Gokaslan, Charles G Fisher, Michael G Fehlings, Michelle J Clarke, Dean Chou, Nicole M Germscheid, Klaus-Dieter Schaser, Jeremy J Reynolds, The Ao Spine Knowledge Forum Tumor

Faculty, Staff and Student Publications

Extradural primary spinal tumors were retrospectively analyzed from a prospective database of 1495 cases. All subjects with benign primary tumors under the age of 25 years, who were enrolled between 1990 and 2012 (Median FU was 2.4 years), were identified. Patient- and case-related characteristics were collected and statistically analyzed. Results: 161 patients (66f;95m; age 17.0 ± 4.7 years at time of diagnosis) were identified. The most common tumors were osteoblastomas n = 53 (32.9%), osteoid osteomas n = 45 (28.0%), and aneurysmal bone cysts n = 32 (19.9%). The tumor grade, according to the Enneking Classification S1/S2/S3, was 14/73/74 (8.7/45.3/46.0%), …

Hypoxia Truncates And Constitutively Activates The Key Cholesterol Synthesis Enzyme Squalene Monooxygenase, Hudson W Coates, Isabelle M Capell-Hattam, Ellen M Olzomer, Ximing Du, Rhonda Farrell, Hongyuan Yang, Frances L Byrne, Andrew J Brown

Faculty, Staff and Student Publications

Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-dependent enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show hypoxia is a physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6 and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates …

Integrated Mrna Sequence Optimization Using Deep Learning, Haoran Gong, Jianguo Wen, Ruihan Luo, Yuzhou Feng, Jingjing Guo, Hongguang Fu, Xiaobo Zhou

Faculty, Staff and Student Publications

The coronavirus disease of 2019 pandemic has catalyzed the rapid development of mRNA vaccines, whereas, how to optimize the mRNA sequence of exogenous gene such as severe acute respiratory syndrome coronavirus 2 spike to fit human cells remains a critical challenge. A new algorithm, iDRO (integrated deep-learning-based mRNA optimization), is developed to optimize multiple components of mRNA sequences based on given amino acid sequences of target protein. Considering the biological constraints, we divided iDRO into two steps: open reading frame (ORF) optimization and 5' untranslated region (UTR) and 3'UTR generation. In ORF optimization, BiLSTM-CRF (bidirectional long-short-term memory with conditional random …

Control Of Craniofacial Development By The Collagen Receptor, Discoidin Domain Receptor 2, Fatma F Mohamed, Chunxi Ge, Shawn A Hallett, Alec C Bancroft, Randy T Cowling, Noriaki Ono, Abdul-Aziz Binrayes, Barry Greenberg, Benjamin Levi, Vesa M Kaartinen, Renny T Franceschi

Faculty, Staff and Student Publications

Development of the craniofacial skeleton requires interactions between progenitor cells and the collagen-rich extracellular matrix (ECM). The mediators of these interactions are not well-defined. Mutations in the discoidin domain receptor 2 gene (DDR2), which encodes a non-integrin collagen receptor, are associated with human craniofacial abnormalities, such as midface hypoplasia and open fontanels. However, the exact role of this gene in craniofacial morphogenesis is not known. As will be shown, Ddr2-deficient mice exhibit defects in craniofacial bones including impaired calvarial growth and frontal suture formation, cranial base hypoplasia due to aberrant chondrogenesis and delayed ossification at growth plate …

Cortical Connectomic Mediations On Gamma Band Synchronization In Schizophrenia, Xiaoming Du, Stephanie Hare, Ann Summerfelt, Bhim M Adhikari, Laura Garcia, Wyatt Marshall, Peng Zan, Mark Kvarta, Eric Goldwaser, Heather Bruce, Si Gao, Hemalatha Sampath, Peter Kochunov, Jonathan Z Simon, L Elliot Hong

Faculty, Staff and Student Publications

Aberrant gamma frequency neural oscillations in schizophrenia have been well demonstrated using auditory steady-state responses (ASSR). However, the neural circuits underlying 40 Hz ASSR deficits in schizophrenia remain poorly understood. Sixty-six patients with schizophrenia spectrum disorders and 85 age- and gender-matched healthy controls completed one electroencephalography session measuring 40 Hz ASSR and one imaging session for resting-state functional connectivity (rsFC) assessments. The associations between the normalized power of 40 Hz ASSR and rsFC were assessed via linear regression and mediation models. We found that rsFC among auditory, precentral, postcentral, and prefrontal cortices were positively associated with 40 Hz ASSR in …

Circadian Rhythms As Modulators Of Brain Health During Development And Throughout Aging, Rachel Van Drunen, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

The circadian clock plays a prominent role in neurons during development and throughout aging. This review covers topics pertinent to the role of 24-h rhythms in neuronal development and function, and their tendency to decline with aging. Pharmacological or behavioral modification that augment the function of our internal clock may be central to decline of cognitive disease and to future chronotherapy for aging-related diseases of the central nervous system.

A Comprehensive Assessment Of Cell Type-Specific Differential Expression Methods In Bulk Data, Guanqun Meng, Wen Tang, Emina Huang, Ziyi Li, Hao Feng

Faculty, Staff and Student Publications

Accounting for cell type compositions has been very successful at analyzing high-throughput data from heterogeneous tissues. Differential gene expression analysis at cell type level is becoming increasingly popular, yielding biomarker discovery in a finer granularity within a particular cell type. Although several computational methods have been developed to identify cell type-specific differentially expressed genes (csDEG) from RNA-seq data, a systematic evaluation is yet to be performed. Here, we thoroughly benchmark six recently published methods: CellDMC, CARseq, TOAST, LRCDE, CeDAR and TCA, together with two classical methods, csSAM and DESeq2, for a comprehensive comparison. We aim to systematically evaluate the performance …

Ccsynergy: An Integrative Deep-Learning Framework Enabling Context-Aware Prediction Of Anti-Cancer Drug Synergy, Sayed-Rzgar Hosseini, Xiaobo Zhou

Faculty, Staff and Student Publications

Combination therapy is a promising strategy for confronting the complexity of cancer. However, experimental exploration of the vast space of potential drug combinations is costly and unfeasible. Therefore, computational methods for predicting drug synergy are much needed for narrowing down this space, especially when examining new cellular contexts. Here, we thus introduce CCSynergy, a flexible, context aware and integrative deep-learning framework that we have established to unleash the potential of the Chemical Checker extended drug bioactivity profiles for the purpose of drug synergy prediction. We have shown that CCSynergy enables predictions of superior accuracy, remarkable robustness and improved context generalizability …