Digital Commons Network^™

Inhibition Of Cholesterol Biosynthesis Through Rnf145-Dependent Ubiquitination Of Scap, Li Zhang, Prashant Rajbhandari, Christina Priest, Jaspreet Sandhu, Xiaohui Wu, Ryan E. Temel, Antonio Castrillo, Thomas Q. De Aguiar Vallim, Tamer Sallam, Peter Tontonoz

Saha Cardiovascular Research Center Faculty Publications

Cholesterol homeostasis is maintained through concerted action of the SREBPs and LXRs. Here, we report that RNF145, a previously uncharacterized ER membrane ubiquitin ligase, participates in crosstalk between these critical signaling pathways. RNF145 expression is induced in response to LXR activation and high-cholesterol diet feeding. Transduction of RNF145 into mouse liver inhibits the expression of genes involved in cholesterol biosynthesis and reduces plasma cholesterol levels. Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma. Mechanistic studies show …

What’S In A Name?, Michael D. Schaller, Gary Mcdowell, André Porter, Dorothy Shippen, Katherine L. Friedman, Matthew S. Gentry, Tricia R. Serio, Wesley I. Sundquist

Molecular and Cellular Biochemistry Faculty Publications

Numerous concerns have been raised about the sustainability of the biomedical research enterprise in the United States. Improving the postdoctoral training experience is seen as a priority in addressing these concerns, but even identifying who the postdocs are is made difficult by the multitude of different job titles they can carry. Here, we summarize the detrimental effects that current employment structures have on training, compensation and benefits for postdocs, and argue that academic research institutions should standardize the categorization and treatment of postdocs. We also present brief case studies of two institutions that have addressed these challenges and can provide …

Effect Of Population, Collection Year, After-Ripening And Incubation Condition On Seed Germination Of Stipa Bungeana, Rui Zhang, Jerry M. Baskin, Carol C. Baskin, Qing Mo, Lijun Chen, Xiaowen Hu, Yanrong Wang

Biology Faculty Publications

Knowledge of the germination behavior of different populations of a species can be useful in the selection of appropriate seed sources for restoration. The aim of this study was to test the effect of seed population, collection year, after-ripening and incubation conditions on seed dormancy and germination of Stipa bungeana, a perennial grass used for revegetation of degraded grasslands on the Loess Plateau, China. Fresh S. bungeana seeds were collected from eight locally-adapted populations in 2015 and 2016. Dormancy and germination characteristics of fresh and 6-month-old dry-stored seeds were determined by incubating them over a range of alternating temperature …

Co-Opting Atp-Generating Glycolytic Enzyme Pgk1 Phosphoglycerate Kinase Facilitates The Assembly Of Viral Replicase Complexes, K. Reddisiva Prasanth, Chingkai Chuang, Peter D. Nagy

Plant Pathology Faculty Publications

The intricate interactions between viruses and hosts include exploitation of host cells for viral replication by using many cellular resources, metabolites and energy. Tomato bushy stunt virus (TBSV), similar to other (+)RNA viruses, induces major changes in infected cells that lead to the formation of large replication compartments consisting of aggregated peroxisomal and ER membranes. Yet, it is not known how TBSV obtains the energy to fuel these energy-consuming processes. In the current work, the authors discovered that TBSV co-opts the glycolytic ATP-generating Pgk1 phosphoglycerate kinase to facilitate the assembly of new viral replicase complexes. The recruitment of Pgk1 into …

Differential Roles For Inner Membrane Complex Proteins Across Toxoplasma Gondii And Sarcocystis Neurona Development, Rashmi Dubey, Brooke Harrison, Sriveny Dangoudoubiyam, Giulia Bandini, Katherine Cheng, Aziz Kosber, Carolina Agop-Nersesian, Daniel K. Howe, John Samuelson, David J. P. Ferguson, Marc-Jan Gubbels

Maxwell H. Gluck Equine Research Center Faculty Publications

The inner membrane complex (IMC) of apicomplexan parasites contains a network of intermediate filament-like proteins. The 14 alveolin domain-containing IMC proteins in Toxoplasma gondii fall into different groups defined by their distinct spatiotemporal dynamics during the internal budding process of tachyzoites. Here, we analyzed representatives of different IMC protein groups across all stages of the Toxoplasma life cycle and during Sarcocystis neurona asexual development. We found that across asexually dividing Toxoplasma stages, IMC7 is present exclusively in the mother’s cytoskeleton, whereas IMC1 and IMC3 are both present in mother and daughter cytoskeletons (IMC3 is strongly enriched in daughter buds). In …

Deletion Of The Nr4a Nuclear Receptor Nor1 In Hematopoietic Stem Cells Reduces Inflammation But Not Abdominal Aortic Aneurysm Formation, Hua Qing, Karrie L. Jones, Elizabeth B. Heywood, Hong Lu, Alan Daugherty, Dennis Bruemmer

Pharmacology and Nutritional Sciences Faculty Publications

Background: The NR4A3 orphan nuclear hormone receptor, NOR1, functions as a constitutively active transcription factor to regulate inflammation, proliferation, and cell survival during pathological vascular remodeling. Inflammatory processes represent key mechanisms leading to abdominal aortic aneurysm (AAA) formation. However, a role of NOR1 in AAA formation has not been investigated previously.

Methods: Inflammatory gene expression was analyzed in bone marrow-derived macrophages isolated from NOR1-deficient mice. Low-density lipoprotein receptor-deficient (LDLr^−/−) mice were irradiated and reconstituted with hematopoietic stem cells obtained from NOR1−/− or wild-type littermate mice. Animals were infused with angiotensin II and fed a diet enriched in saturated …

Harnessing The Data Revolution, Chaitan Baru

Commonwealth Computational Summit

Harnessing Data for 21st Century Science and Engineering (aka Harnessing the Data Revolution, HDR) is one of NSF's six "Big Research Ideas," aimed at supporting fundamental research in data science and engineering; developing a cohesive, federated approach to the research data infrastructure needed to power this revolution; and developing of a 21st-century data-capable workforce. HDR will enable new modes of data-driven discovery allowing researchers to ask and answer new questions in frontier science and engineering, generate new knowledge and understanding by working with domain experts, and accelerate discovery and innovation. This initiative builds on NSF's history of data science investments. …

Analysis Of Complex Vertebrate Genomes: Computational Challenges And Solutions, Jeramiah J. Smith

Commonwealth Computational Summit

No abstract provided.

Accurate And Scalable Query Over Large Rna‐Seq Experiments, Jinze Liu

Commonwealth Computational Summit

No abstract provided.

Integrative Computational Modeling For Developing Means To Manipulate Biological Cells And For Solving Complex Engineering Problems, Yu Zhao, Guigen Zhang

Commonwealth Computational Summit

A brief discussion on reductive vs integrative investigation

A case study: how integrative computational modeling helps advance the understanding and application of dielectrophoresis (DEP) in various situations

Other applications in advancing the design and development of nanopore, medical devices, novel materials, actuation devices, and coupled spectroscopic techniques, etc.

Registration And Grouping Algorithms In Protein Nmr Derived Peak Lists And Their Application In Protein Nmr Reference Correction, Andrey Smelter, Xi Chen, Eric C. Rouchka, Hunter N. B. Moseley

Commonwealth Computational Summit

Nuclear magnetic resonance spectroscopy of proteins (protein NMR) is a powerful analytical technique for studying structure and dynamics of proteins. Almost all aspects of protein NMR have been accelerated by the development of software tools that enable the analysis of NMR spectral data and its utilization in studying protein structure and dynamics. This includes software for raw NMR processing, spectral visualization, protein resonance assignment, and structure determination. However, full automation of protein NMR data analysis is still a work in progress and data analysis still requires an expert NMR spectroscopist utilizing an array of software tools.

While manual resonance assignment …

The Lamprey Genome: Illuminating Genomic Change Across Eons And Embryogenesis, Jeramiah J. Smith, Courtney K. M. Waterbury, Melissa C. Keinath, Cody B. Saraceno, Vladimir A. Timoshevskiy, Nataliya Y. Timoshevskaya

Commonwealth Computational Summit

The lamprey genome provides unique insights into both the deep evolutionary history of vertebrate genomes and the maintenance of genome structure/integrity over development. The lamprey lineage diverged from all other vertebrates approximately 500 million years ago. As such, comparisons between lamprey and other vertebrates permit reconstruction of ancient duplication and rearrangement events that defined the fundamental architecture and gene content of all extant vertebrate genomes. Lamprey also undergoes programmatic changes genome structure that result in the physical elimination of ~20% of its genomic DNA (~0.5Gb from a ~2 Gb genome) from all somatic cell lineages during early embryonic development. Here, …

Structure-Based Drug Discovery: Computational Virtual Screening, Robert C. Monsen, Lynn Deleeuw, Jon Maguire, William L. Dean, Robert D. Gray, Jonathan B. Chaires, John O. Trent

Commonwealth Computational Summit

No abstract provided.

Bio-Inspired Disaster Response Networks, Vijay K. Shah, Simone Silvestri, Sajal K. Das, Satyaki Roy

Commonwealth Computational Summit

Large-scale natural disasters (e.g., Earthquake, Hurricane) –

• Three times as many disasters between 1980 and 2016 compared to 1940-1980. (EM-DAT – The International Disaster Database)
• Since 1990, 217 million people affected each year. (The New England Journal of Medicine)

Aftermath a disaster,

• Loss of human lives and property
• Lack of food, clean drinking water, shelter etc.
• Disruption of infrastructure networks (e.g. cellular towers) and other public infrastructures (e.g. power sources) – Our focus !

Use Of Hpc To Analyze Changes In Gene Expression During Fruit Fly Spermiogenesis, Sepideh Dadkhah, Douglas A. Harrison, Jeramiah J. Smith

Commonwealth Computational Summit

In the fruit fly, Drosophila melanogaster, JAK/STAT signaling during spermiogenesis is known to play a crucial role in the maintenance of stem cells of the testis. Recent studies in our lab have shown that activation of the JAK/STAT pathway in somatic cyst cells is also required for the later stages of spermiogenesis like individualization.

The main goal of this project is to characterize the events downstream of JAK/STAT signaling in spermiogenesis and more specifically to determine the mechanism by which JAK/STAT activation regulates individualization, a later stage in spermiogenesis where 64 individual spermatids are formed from a 64-interconnected spermatid …

Aberrant Coordination Geometries Discovered In Most Abundant Metalloproteins, Sen Yao, Robert M. Flight, Eric C. Rouchka, Hunter N. B. Moseley

Commonwealth Computational Summit

Metalloproteins play crucial biochemical roles in our body and are essential across all domains of life. The structural environment around a metal ion, especially the coordination geometry (CG), is both sequentially and functionally relevant. Studies of the metalloprotein’s CG will greatly help alleviate the imbalance between the ample sequence data available and the insufficient knowledge on protein functions. Current methodologies in characterizing metalloproteins’ CG consider only previously reported CG (canonical CG) models based primarily on nonbiological chemical context. Exceptions to these canonical CG models can greatly hamper the ability to characterize metalloproteins both structurally and functionally.

Integrative Computational Modeling For Developing Means To Manipulate Biological Cells And For Solving Complex Engineering Problems, Yu Zhao, Guigen Zhang

Commonwealth Computational Summit

Computational modeling has become more widely used to guide the design of microfluidic devices for manipulating cells using Dielectrophoresis (DEP), and devise novel means for advancing the study of cellular science and engineering. Conventionally, cells are treated as volumeless points in the system, which allows study of the movement of groups of particles under the effect of field. However, this approach often neglects the distortion effect of particle on external field, as well as interactions among particles. Moreover, it ignores the complex inner structures of cell, which are the causes of distinctive cell behavior. To more accurately model the behavior …

Discovery Of Sex-Specific Regions In A Salamander Genome, Nataliya Y. Timoshevskaya, Melissa C. Keinath, Jeramiah J. Smith

Commonwealth Computational Summit

Biological Aspects:

Salamander (Ambystoma mexicanum) has a gigantic genome: ~32,000,000,000 bases (10X of size of human genome)

Sex is determined by a pair of morphologically identical chromosomes:

• ZZ in male
• ZW in female

Object:

• Find (if there are any) genomic differences between chromosomes W and Z

Workflow:

1. Sequencing and de novo assembly of the reference salamander genome
2. Alignment of short sequences from male and female genomes to the reference
3. Coverage analysis

Compositions And Methods Of Modulating 15-Pgdh Activity, Sanford Markowitz, James K. V. Willson, Bruce A. Posner, Joseph Ready, Yongyou Zhang, Hsin-Hsiung Tai, Monika Antczak, Stanton Gerson, Kibeom Bae, Sung Yeun Yang, Amar Desai

Pharmaceutical Sciences Faculty Patents

Compounds and methods of modulating 15-PGDH activity, modulating tissue prostaglandin levels, treating disease, diseases disorders, or conditions in which it is desired to modulate 15-PGDH activity and/or prostaglandin levels include 15-PGDH inhibitors and 15-PGDH activators described herein.

A Latent Propriospinal Network Can Restore Diaphragm Function After High Cervical Spinal Cord Injury, Jared M. Cregg, Kevin A. Chu, Lydia E. Hager, Rachel S. J. Maggard, Daimen R. Stoltz, Michaela Edmond, Warren J. Alilain, Polyxeni Philippidou, Lynn T. Landmesser, Jerry Silver

Spinal Cord and Brain Injury Research Center Faculty Publications

Spinal cord injury (SCI) above cervical level 4 disrupts descending axons from the medulla that innervate phrenic motor neurons, causing permanent paralysis of the diaphragm. Using an ex vivo preparation in neonatal mice, we have identified an excitatory spinal network that can direct phrenic motor bursting in the absence of medullary input. After complete cervical SCI, blockade of fast inhibitory synaptic transmission caused spontaneous, bilaterally coordinated phrenic bursting. Here, spinal cord glutamatergic neurons were both sufficient and necessary for the induction of phrenic bursts. Direct stimulation of phrenic motor neurons was insufficient to evoke burst activity. Transection and pharmacological manipulations …

Nanoparticle Delivery Of Mir-34a Eradicates Long-Term-Cultured Breast Cancer Stem Cells Via Targeting C22orf28 Directly, Xiaoti Lin, Weiyu Chen, Fengqin Wei, Binhua P. Zhou, Mien-Chie Hung, Xiaoming Xie

Molecular and Cellular Biochemistry Faculty Publications

Rationale: Cancer stem cells (CSCs) have been implicated as the seeds of therapeutic resistance and metastasis, due to their unique abilities of self-renew, wide differentiation potentials and resistance to most conventional therapies. It is a proactive strategy for cancer therapy to eradicate CSCs. Methods: Tumor tissue-derived breast CSCs (BCSC), including XM322 and XM607, were isolated by fluorescence-activated cell sorting (FACS); while cell line-derived BCSC, including MDA-MB-231.SC and MCF-7.SC, were purified by magnetic-activated cell sorting (MACS). Analyses of microRNA and mRNA expression array profiles were performed in multiple breast cell lines. The mentioned nanoparticles were constructed following the standard molecular cloning …

Diverse Amide Analogs Of Sulindac For Cancer Treatment And Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

Pharmaceutical Sciences Faculty Publications

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivoantitumor activity that was comparable to sulindac in a human colon tumorxenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good …

Glycolytic Reprogramming Through Pck2 Regulates Tumor Initiation Of Prostate Cancer Cells, Jiangsha Zhao, Jieran Li, Teresa W.M. Fan, Steven X. Hou

Toxicology and Cancer Biology Faculty Publications

Tumor-initiating cells (TICs) play important roles in tumor progression and metastasis. Identifying the factors regulating TICs may open new avenues in cancer therapy. Here, we show that TIC-enriched prostate cancer cell clones use more glucose and secrete more lactate than TIC-low clones. We determined that elevated levels of phosphoenolpyruvate carboxykinase isoform 2 (PCK2) are critical for the metabolic switch and the maintenance of TICs in prostate cancer. Information from prostate cancer patient databases revealed that higher PCK2 levels correlated with more aggressive tumors and lower survival rates. PCK2 knockdown resulted in low TIC numbers, increased cytosolic acetyl-CoA and cellular protein …

No Difference In Myosin Kinetics And Spatial Distribution Of The Lever Arm In The Left And Right Ventricles Of Human Hearts, Divya Duggal, S. Requena, Janhavi Nagwekar, Sangram Raut, Ryan Rich, Hriday Das, Vipul Patel, Ignacy Gryczynski, Rafal Fudala, Zygmunt Gryczynski, Cheavar Blair, Kenneth S. Campbell, Julian Borejdo

Physiology Faculty Publications

The systemic circulation offers larger resistance to the blood flow than the pulmonary system. Consequently, the left ventricle (LV) must pump blood with more force than the right ventricle (RV). The question arises whether the stronger pumping action of the LV is due to a more efficient action of left ventricular myosin, or whether it is due to the morphological differences between ventricles. Such a question cannot be answered by studying the entire ventricles or myocytes because any observed differences would be wiped out by averaging the information obtained from trillions of myosin molecules present in a ventricle or myocyte. …

The Molecular Mechanism Of N-Acetylglucosamine Side-Chain Attachment To The Lancefield Group A Carbohydrate In Streptococcus Pyogenes, Jeffrey Rush, Rebecca J. Edgar, Pan Deng, Jing Chen, Haining Zhu, Nina M. Van Sorge, Andrew J. Morris, Konstantin V. Korotkov, Natalia Korotkova

Molecular and Cellular Biochemistry Faculty Publications

In many Lactobacillales species (i.e. lactic acid bacteria), peptidoglycan is decorated by polyrhamnose polysaccharides that are critical for cell envelope integrity and cell shape and also represent key antigenic determinants. Despite the biological importance of these polysaccharides, their biosynthetic pathways have received limited attention. The important human pathogen, Streptococcus pyogenes, synthesizes a key antigenic surface polymer, the Lancefield group A carbohydrate (GAC). GAC is covalently attached to peptidoglycan and consists of a polyrhamnose polymer, with N-acetylglucosamine (GlcNAc) side chains, which is an essential virulence determinant. The molecular details of the mechanism of polyrhamnose modification with GlcNAc are …

Image-Based Analysis To Dissect Vertical Distribution And Horizontal Asymmetry Of Conspecific Root System Interactions In Response To Planting Densities, Nutrients And Root Exudates In Arabidopsis Thaliana, Jane Geisler-Lee, Xian Liu, Wei Rang, Jayanthan Raveendiran, Marisa Blake Szubryt, David John Gibson, Matt Geisler, Qiang Cheng

Institute for Biomedical Informatics Faculty Publications

Intraspecific competition is an important plant interaction that has been studied extensively aboveground, but less so belowground, due to the difficulties in accessing the root system experimentally. Recent in vivo and in situ automatic imaging advances help understand root system architecture. In this study, a portable imaging platform and a scalable transplant technique were applied to test intraspecific competition in Arabidopsis thaliana. A single green fluorescent protein labeled plant was placed in the center of a grid of different planting densities of neighboring unlabeled plants or empty spaces, into which different treatments were made to the media. The root …

Insights Into Land Plant Evolution Garnered From The Marchantia Polymorpha Genome, John L. Bowman, Takayuki Kohchi, Katsuyuki T. Yamato, Jerry Jenkins, Shengqiang Shu, Kimitsune Ishizaki, Shohei Yamaoka, Ryuichi Nishihama, Yasukazu Nakamura, Frédéric Berger, Catherine Adam, Shiori Sugamata Aki, Felix Althoff, Takashi Araki, Mario A. Arteaga-Vazquez, Sureshkumar Balasubrmanian, Kerrie Barry, Diane Bauer, Christian R. Boehm, Liam Briginshaw, Juan Caballero-Perez, Bruno Catarino, Feng Chen, Shota Chiyoda, Mansi Chovatia, Kevin M. Davies, Mihails Delmans, Taku Demura, Tom Dierschke, Liam Dolan, Tomokazu Kawashima

Plant and Soil Sciences Faculty Publications

The evolution of land flora transformed the terrestrial environment. Land plants evolved from an ancestral charophycean alga from which they inherited developmental, biochemical, and cell biological attributes. Additional biochemical and physiological adaptations to land, and a life cycle with an alternation between multicellular haploid and diploid generations that facilitated efficient dispersal of desiccation tolerant spores, evolved in the ancestral land plant. We analyzed the genome of the liverwort Marchantia polymorpha, a member of a basal land plant lineage. Relative to charophycean algae, land plant genomes are characterized by genes encoding novel biochemical pathways, new phytohormone signaling pathways (notably auxin), …

Temporal Transcriptomic Profiling Of The Ant-Feeding Assassin Bug Acanthaspis Cincticrus Reveals A Biased Expression Of Genes Associated With Predation In Nymphs, Fei Kou, Hu Li, Shujuan Li, Huaizhu Xun, Yinqiao Zhang, Ziqiang Sun, Xuguo Zhou, Wanzhi Cai

Entomology Faculty Publications

Acanthaspis cincticrus (Stål) is an assassin bug with a specialized camouflaging behavior to ambush ants in the nymphal stages. In this study, we comprehensively sequenced all the life stages of A. cincticrus, including the eggs, five nymph instars, female and male adults using Illumina HiSeq technology. We obtained 176 million clean sequence reads. The assembled 84,055 unigenes were annotated and classified functionally based on protein databases. Among the unigenes, 29.03% were annotated by one or more databases, suggesting their well-conserved functions. Comparison of the gene expression profiles in the egg, nymph and adult stages revealed certain bias. Functional enrichment …

1H, 15N, And 13C Chemical Shift Assignments Of The Regulatory Domain Of Human Calcineurin, Dinesh K. Yadav, Sri Ramya Tata, John Hunt, Erik C. Cook, Trevor P. Creamer, Nicholas C. Fitzkee

Center for Structural Biology Faculty Publications

Calcineurin (CaN) plays an important role in T-cell activation, cardiac system development and nervous system function. Previous studies have demonstrated that the regulatory domain (RD) of CaN binds calmodulin (CaM) towards the N-terminal end. Calcium-loaded CaM activates the serine/threonine phosphatase activity of CaN by binding to the RD, although the mechanistic details of this interaction remain unclear. It is thought that CaM binding at the RD displaces the auto-inhibitory domain (AID) from the active site of CaN, activating phosphatase activity. In the absence of calcium-loaded CaM, the RD is disordered, and binding of CaM induces folding in the RD. In …

Hne-Modified Proteins In Down Syndrome: Involvement In Development Of Alzheimer Disease Neuropathology, Eugenio Barone, Elizabeth Head, D. Allan Butterfield, Marzia Perluigi

Sanders-Brown Center on Aging Faculty Publications

Down syndrome (DS), trisomy of chromosome 21, is the most common genetic form of intellectual disability. The neuropathology of DS involves multiple molecular mechanisms, similar to AD, including the deposition of beta-amyloid (Aβ) into senile plaques and tau hyperphosphorylating in neurofibrillary tangles. Interestingly, many genes encoded by chromosome 21, in addition to being primarily linked to amyloid-beta peptide (Aβ) pathology, are responsible for increased oxidative stress (OS) conditions that also result as a consequence of reduced antioxidant system efficiency. However, redox homeostasis is disturbed by overproduction of Aβ, which accumulates into plaques across the lifespan in DS as well as …