Other Biochemistry, Biophysics, and Structural Biology Commons^™

Building Digital Twins Of The Human Immune System: Toward A Roadmap, Reinhard Laubenbacher, Anna Niarakis, Tomas Helikar, G. An, B. Shapiro, R. S. Malik-Sheriff, T. J. Sego, P. Macklin, J. A. Glazier

Biochemistry -- Faculty Publications

Digital twins, customized simulation models pioneered in industry, are beginning to be deployed in medicine and healthcare, with some major successes, for instance in cardiovascular diagnostics and in insulin pump control. Personalized computational models are also assisting in applications ranging from drug development to treatment optimization. More advanced medical digital twins will be essential to making precision medicine a reality. Because the immune system plays an important role in such a wide range of diseases and health conditions, from fighting pathogens to autoimmune disorders, digital twins of the immune system will have an especially high impact. However, their development presents …

Fish Oil Intake During Gestation And Lactation Attenuated Stz-Induced Diabetes Inmale Offspring Via Activation Of Brown Fat And Modulating Oxylipin Profile, Rong Fan, Shalom Thomas, Mikyoung You, Zhuoheng Li, Brandt Bessell, Bhanwar Lal Puniya, Tomáš Helikar, Zhenhua Liu, Soonkyu Chung

Biochemistry -- Faculty Publications

Fish oil (FO) has been demonstrated to activate brown thermogenesis and attenuate inflammation in the brown adipose tissue (BAT). Previously, we have reported thatmaternal FO supplementation promotes BAT activity of the weaned mice pups. However, whether maternal FO intake could confer sustainable metabolic benefits to offspring remains uncovered. Therefore, this study aimed to determine the differential impact of maternal FO during pregnancy versus lactation on BAT transcriptome and evaluate the role of bioactive lipid metabolites derived from maternal FO supplementation on the extended metabolic benefits of older pups in the context of type 1 diabetes (T1D).

Conclusions: Our results suggested …

Coordination Of Metal Center Biogenesis In Human Cytochrome C Oxidase, Eva Nývltová, Jonathan Dietz, Javier Seravalli, Oleh Khalimonchuk, Antoni Barrientos

Biochemistry -- Faculty Publications

Mitochondrial cytochrome c oxidase (CcO) or respiratory chain complex IV is a heme aa3- copper oxygen reductase containing metal centers essential for holo-complex biogenesis and enzymatic function that are assembled by subunit-specific metallochaperones. The enzyme has two copper sites located in the catalytic core subunits. The COX1 subunit harbors the CuB site that tightly associates with heme a3 while the COX2 subunit contains the binuclear CuA site. Here, we report that in human cells the CcO copper chaperones form macromolecular assemblies and cooperate with several twin CX9C proteins to control heme a biosynthesis and coordinate copper transfer sequentially to the …

Arginine Catabolism And Polyamine Biosynthesis Pathway Disparities Within Francisella Tularensis Subpopulations, Yinshi Yue, Bhanwar Lal Puniya, Tomáš Helikar, Benjamin Girardo, Steven H. Hinrichs, Marilyn A. Larson

Biochemistry -- Faculty Publications

Francisella tularensis is a highly infectious zoonotic pathogen with as few as 10 organisms causing tularemia, a disease that is fatal if untreated. Although F. tularensis subspecies tularensis (type A) and subspecies holarctica (type B) share over 99.5% average nucleotide identity, notable differences exist in genomic organization and pathogenicity. The type A clade has been further divided into subtypes A.I and A.II, with A.I strains being recognized as some of the most virulent bacterial pathogens known. In this study, we report on major disparities that exist between the F. tularensis subpopulations in arginine catabolism and subsequent polyamine biosynthesis. The genes …

Addressing Barriers In Comprehensiveness, Accessibility, Reusability, Interoperability And Reproducibility Of Computational Models In Systems Biology, Anna Niarakis, Dagmar Waltemath, James Glazier, Falk Schreiber, Sarah M. Keating, David Nickerson, Claudine Chaouiya, Anne Siegel, Vincent Noël, Henning Hermjakob, Tomáš Helikar, Sylvain Soliman, Laurence Calzone

Biochemistry -- Faculty Publications

Computational models are often employed in systems biology to study the dynamic behaviours of complex systems. With the rise in the number of computational models, finding ways to improve the reusability of these models and their ability to reproduce virtual experiments becomes critical. Correct and effective model annotation in community-supported and standardised formats is necessary for this improvement. Here,we present recent efforts toward a common framework for annotated, accessible, reproducible and interoperable computational models in biology, and discuss key challenges of the field.

Scientists from different systems biology fields have long been developing community-driven guidelines and best practices for annotation, …

Feedlot Diets Containing Different Starch Levels And Additives Change The Cecal Proteome Involved In Cattle’S Energy Metabolism And Inflammatory Response, Leone Campos Rocha, Andrey Sávio De Almeida Assunção, Renata Aparecida Martins, Victor Valério De Carvalho, Alexandre Perdigão2, Marília Afonso Rabelo Buzalaf, Jiri Adamec, Camila Pereira Braga, Danilo Domingues Millen, José Cavalcante Souza Vieira, Pedro De Magalhães Padilha

Biochemistry -- Faculty Publications

Diets for feedlot cattle must be a higher energy density, entailing high fermentable carbohydrate content. Feed additives are needed to reduce possible metabolic disorders. This study aimed to analyze the post-rumen effects of different levels of starch (25%, 35%, and 45%) and additives (monensin or a blend of essential oils and exogenous α-amylase) in diets for Nellore feedlot cattle. The cecum tissue proteome was analyzed via two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and then differentially expressed protein spots were identified with liquid chromatography–tandem mass spectrometry (LC–MS/MS). The use of blends of essential oils associated with α-amylase as a feed additive promoted …

Recognition Of Extracellular Dna By Type Iv Pili Promotes Biofilm Formation By Clostridioides Difficile, Leslie A. Ronish, Ben Sidner, Yafan Yu, Kurt H. Piepenbrink

Biochemistry -- Faculty Publications

Clostridioides difficile is a Gram-positive bacillus, which is a frequent cause of gastrointestinal infections triggered by the depletion of the gut microbiome. Because of the frequent recurrence of these infections after antibiotic treatment, mechanisms of C. difficile persistence and recurrence, including biofilm formation, are of increasing interest. Previously, our group and others found that type IV pili, filamentous helical appendages polymerized from protein subunits, promoted microcolony and biofilm formation in C. difficile. In Gram-negative bacteria, the ability of type IV pili to mediate bacterial self-association has been explained through interactions between the pili of adjacent cells, but type …

The Role Of Irf-1 In Spontaneous Mouse Glioma, Aakash B. Vaidya

Theses and Dissertations

Glioblastoma Multiforme has been shown to be one of the deadliest primary brain cancers. One of the reasons why GBM is so deadly, is a unique immunosuppressive tumor microenvironment that promotes GBM growth and progression. Both astrocyte and microglia have been implicated in immunosuppression. In this study, we explored the role of Interferon Regulatory Factor 1 (IRF-1) in astrocytes and glioma cells on the growth of spontaneous glioma tumors. IRF-1 is regulated by the JAK/STAT pathway and induces expression of Programmed death ligand 1 (PD-L1). PD-L1 downregulates immune responses to glioma. We found that IRF-1 had no effect on spontaneous …

Functional Foods: Promising Therapeutics For Nigerian Children With Sickle Cell Diseases, Oladeji John Alabi, Fikayo Noah Adegboyega, Dolapo Samuel Olawoyin, Oluwakemi Arinola Babatunde

Biochemistry -- Faculty Publications

Sickle cell disease (SCD), also known as sickle cell anemia (SCA) is one of the structural hemoglobinopathies that occurs due to a single nucleotide mutation from GAG to GTG, which changes the amino acid of a β-globin chain of hemoglobin (Hb) from glutamate to valine. This singular mutation results to disorderliness in red blood cells (RBCs) with advent of changes in RBC morphology and other pathological conditions. In the 1980s, intermittent red blood cell transfusions, opioids, and penicillin prophylaxis were the only available therapy for SCA and were commonly reserved for acute, life threatening complications. So far, the US Food …

Metabolic Synergy Between Human Symbionts Bacteroides And Methanobrevibacter, Jennie L. Catlett, Sean Carr, Mikaela Cashman, Megan D. Smith, Mary Walter, Zahmeeth Sakkaff, Christine A. Kelley, Massimiliano Pierobon, Myra B. Cohen, Nicole R. Buan

Biochemistry -- Faculty Publications

ABSTRACT Trophic interactions between microbes are postulated to determine whether a host microbiome is healthy or causes predisposition to disease. Two abundant taxa, the Gram-negative heterotrophic bacterium Bacteroides thetaiotaomicron and the methanogenic archaeon Methanobrevibacter smithii, are proposed to have a synergistic metabolic relationship. Both organisms play vital roles in human gut health; B. thetaiotaomicron assists the host by fermenting dietary polysaccharides, whereas M. smithii consumes end-stage fermentation products and is hypothesized to relieve feedback inhibition of upstream microbes such as B. thetaiotaomicron. To study their metabolic interactions, we defined and optimized a coculture system and used software testing …

Development, Structure, And Mechanism Of Synthetic Antibodies That Target Claudin And Clostridium Perfringens Enterotoxin Complexes, Benjamin J. Orlando, Pawel K. Dominik, Sourav Roy, Chinemerem P. Ogbu, Satchal K. Erramilli, Anthony A. Kossiakoff, Alex J. Vecchio

Biochemistry -- Faculty Publications

Strains of Clostridium perfringens produce a two-domain enterotoxin (CpE) that afflicts humans and domesticated animals, causing prevalent gastrointestinal illnesses. CpE’s C-terminal domain (cCpE) binds cell surface receptors, followed by a restructuring of its N-terminal domain to form a membranepenetrating β-barrel pore, which is toxic to epithelial cells of the gut. The claudin family of membrane proteins are known receptors for CpE and also control the architecture and function of cell-cell contacts (tight junctions) that create barriers to intercellular molecular transport. CpE binding and assembly disables claudin barrier function and induces cytotoxicity via β-pore formation, disrupting gut homeostasis; however, a structural …

The Follicular Lymphoma Epigenome Regulates Its Microenvironment, Rada Amin, Mounia S. Braza

Biochemistry -- Faculty Publications

Follicular lymphoma (FL) is a B-cell non-Hodgkin lymphoma of germinal center (GC) origin with a distinctive tumor microenvironment (TME) and a unique spectrum of mutations. Despite the important therapeutic advances, FL is still incurable. During B-cell development, the GC reaction is a complex multistep process in which epigenetic regulators dynamically induce or suppress transcriptional programs. In FL, epigenetic gene mutations perturb the regulation of these programs, changing GC B-cell function and skewing differentiation towards tumor cells and altering the microenvironment interactions. FL pathogenesis and malignant transformation are promoted by epigenetic reprogramming of GC B cells that alters the immunological synapse …

A Link Between Methylglyoxal And Heart Failure During Hiv-1 Infection, Prasanta K. Dasg, Fadhel A. Alomar, Jesse L. Cox, Joellyn Mcmillan, Bryan T. Hackfort, Edward Makarov, Brenda Morsey, Howard S. Fox, Howard E. Gendelman, Santhi Gorantla, Keshore R. Bidasee

Biochemistry -- Faculty Publications

Early-onset heart failure (HF) continues to be a major cause of morbidity and mortality in people living with human immunodeficiency virus type one (HIV-1) infection (PLWH), yet the molecular causes for this remain poorly understood. Herein NOD.Cg- Prkdc^scidIl2rg^tm1Wjl/SzJ humanized mice (Hu-mice), plasma from PLWH, and autopsied cardiac tissues from deceased HIV seropositive individuals were used to assess if there is a link between the glycolysis byproduct methylglyoxal (MG) and HF in the setting of HIV-1 infection. At five weeks post HIV infection, Hu-mice developed grade III-IV diastolic dysfunction (DD) with an associated two-fold increase in plasma …

The Application Of Mathematical Optimization And Flavor-Detection Technologies For Modeling Aroma Of Hops, Yutong Liu

Dissertations, Theses, & Student Research in Food Science and Technology

In recent years, proprietary hops (Citra, Simcoe, and Mosaic) become the most sought-after hops among brewers due to their excellent aroma. However, they are restricted to the owners unless other growers purchase the costly licensing agreements. Many public hops are available to the growers without any additional costs, but their aroma is difficult to match to the proprietary hops. Although proprietary and public hop varieties are unique in their aroma profiles, all hops varieties contain similar volatile compounds, merely differ in the quantity of different individual compounds. The main objective of this thesis was to investigate the feasibility of matching …

Erecta Family Genes Regulate The Shoot Apical Meristem And Organ Formation, Daniel A. Degennaro

Doctoral Dissertations

Plants are sessile and must adjust their organ growth to their environments. A reservoir of stem cells in the shoot apical meristem (SAM) supplies cells for differentiation into organs. The SAM must balance organ production with stem cell maintenance. The ERECTA family (ERfs) encodes the leucine-rich repeat receptor-like kinases ERECTA (ER), ERECTA-LIKE 1 (ERL1), and ERL2. ERf signaling regulates organ initiation and stem cell maintenance. Results presented in this work include the following:

1) WUSCHEL (WUS) and CLAVATA3 (CLV3) make up a negative feedback loop to maintain SAM size. WUS and CLV3 expression localization is critical for …

Stabilin Receptors Clear Lps And Control Systemic Inflammation, Fatima Cabral, Mustafa Al-Rahem, John Skaggs, Thushara A. Thomas, Naresh Kumar, Qian Wu, Paolo Fadda, Lianbo Yu, John M. Robinson, Jonghan Kim, Ekta Pandey, Xinghui Sun, Wael N. Jarjour, Murugesan V.S. Rajaram, Edward N. Harris, Latha P. Ganesan

Biochemistry -- Faculty Publications

Lipopolysaccharides (LPSs) cause lethal endotoxemia if not rapidly cleared from blood circulation. Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanisms. We discovered that LPS clearance through LSEC involves endocytosis and lysosomal inactivation via Stabilin-1 and 2 (Stab1 and Stab2) but does not involve TLR4. Cytokine production was inversely related to clearance/endocytosis of LPS by LSEC. When exposed to LPS, Stabilin double knockout mice (Stab DK) and Stab1 KO, but not Stab2 KO, showed significantly enhanced systemic inflammatory cytokine production and early death compared with WT mice. Stab1 KO is not significantly different from Stab DK in circulatory …

Binding Affinity And Interaction Of Sars-Cov-2 Epitopes With Major Histocompatibility Complex, Sareena Kandavalli, James Stewart, Mohammed A. Halim

Symposium of Student Scholars

SARS CoV-2 has been affecting the world since 2019. It caused 245 million cases of infection and around 5 million deaths worldwide. The most important strategies for the development of vaccines against SARS-CoV-2 are inactivated or weakened virus, replicating or non-replicating viral vector-based approaches, DNA, RNA, virus particle like approaches and epitope-based approaches. The epitope-based approach is rapid, accurate, cost-effective, and reliable against pathogens. By presenting epitopes (antigen peptides) on antigen-presenting cells (APCs), the major histocompatibility complex (MHC), also recognized as the human leukocyte antigen (HLA) system in humans, plays an essential role in triggering T-cell immune responses. The focus …

Computational Simulation Of The Lung Doses Of Air-Borne Fine And Ultrafine Particles Inhaled By Humans At Industrial Workplaces, Mohammed Ali

Technology Faculty Publications and Presentations

This study correlates computational predictions with in-vivo experimental results of inhaled fine and ultrafine particulate matters (PMs) transport, dissemination, and deposition in the human respiratory airways. Epidemiological studies suggest that workplace exposure of anthropogenic pollutant PMs as a risk factor for increased susceptibility to acute broncho-pulmonary infections. However, investigations on detailed human inhalation and PM transport processes are restrictive from time, cost, and ethical perspectives. To overcome this problem, computational simulation of particle deposition based on the Multiple Path Particle Dosimetry (MPPD) model was employed. Here, the physical, mechanical, and electrical properties of PMs of carbon black and nanoparticles from …

Physiological Roles Of Mammalian Transmembrane Adenylyl Cyclase Isoforms, Katrina F. Ostrom, Justin E. Lavigne, Tarsis F. Brust, Roland Seifert, Carmen Dessauer, Val J. Watts, Rennolds S. Ostrom

Pharmacy Faculty Articles and Research

Adenylyl cyclases (ACs) catalyze the conversion of ATP to the ubiquitous second messenger cAMP. Mammals possess nine isoforms of transmembrane ACs, dubbed AC1-9, that serve as major effector enzymes of G protein-coupled receptors. The transmembrane ACs display varying expression patterns across tissues, giving potential for them having a wide array of physiologic roles. Cells express multiple AC isoforms, implying that ACs have redundant functions. Furthermore, all transmembrane ACs are activated by Gα_s so it was long assumed that all ACs are activated by Gα_s-coupled GPCRs. AC isoforms partition to different microdomains of the plasma membrane and form …

Dynamic Evolution And Correlation Between Metabolites And Microorganisms During Manufacturing Process And Storage Of Fu Brick Tea, Jing Li, Ran Xu, Joseph Brake, Lizeng Cheng, Jie Wu, Xiaobin Wu

Biochemistry -- Faculty Publications

Fu brick tea (FBT) is one of the major brands of dark tea. Microbial fermentation is considered the key step in the development of the special characteristics of FBT. The systemic corelationship of the microbiome and metabolomics during manufacture of Fu brick tea is not fully understood. In this study, we comprehensively explored the microbiome and metabolite dynamic evolution during the FBT manufacturing processes, and revealed decisive factors for the quality and safety of FBT based on the grouped methods of metabolomics combined with biochemical measurements, microbiome sequencing combined with quantitative polymerase chain reaction (PCR), and multiplex analysis. Both the …