Digital Commons Network^™

Large Scale Dynamical Model Of Macrophage/Hiv Interactions, Sean T. Bresnahan, Matthew M. Froid

UNO Student Research and Creative Activity Fair

Properties emerge from the dynamics of large-scale molecular networks that are not discernible at the individual gene or protein level. Mathematical models - such as probabilistic Boolean networks - of molecular systems offer a deeper insight into how these emergent properties arise. Here, we introduce a non-linear, deterministic Boolean model of protein, gene, and chemical interactions in human macrophage cells during HIV infection. Our model is composed of 713 nodes with 1583 interactions between nodes and is responsive to 38 different inputs including signaling molecules, bacteria, viruses, and HIV viral particles. Additionally, the model accurately simulates the dynamics of over …

Scale-Invariance-Based Pre-Processing Drastically Improves Neural Network Learning: Case Study Of Diagnosing Lung Dysfunction In Children, Nancy Avila, Julio Urenda, Nelly Gordillo, Vladik Kreinovich

Departmental Technical Reports (CS)

To adequately treat different types of lung dysfunctions in children, it is important to properly diagnose the corresponding dysfunction, and this is not an easy task. Neural networks have been trained to perform this diagnosis, but they are not perfect in diagnostics: their success rate is 60%. In this paper, we show that by selecting an appropriate invariance-based pre-processing, we can drastically improve the diagnostic success, to 100% for diagnosing the presence of a lung dysfunction.

The Gradient Of The Reinforcement Landscape Influences Sensorimotor Learning, Joshua G.A. Cashaback, Christopher K. Lao, Dimitrios J. Palidis, Susan K. Coltman, Heather R. Mcgregor, Paul L. Gribble

Brain and Mind Institute Researchers' Publications

© 2019 Cashaback et al. Consideration of previous successes and failures is essential to mastering a motor skill. Much of what we know about how humans and animals learn from such reinforcement feedback comes from experiments that involve sampling from a small number of discrete actions. Yet, it is less understood how we learn through reinforcement feedback when sampling from a continuous set of possible actions. Navigating a continuous set of possible actions likely requires using gradient information to maximize success. Here we addressed how humans adapt the aim of their hand when experiencing reinforcement feedback that was associated with …

Longer Trinucleotide Repeats Of Androgen Receptor Gene: Infertility In Males, Mussarat Ashraf, Hemaila Tariq, Rehana Rehman

Department of Biological & Biomedical Sciences

No abstract provided.

Considerations For Implementing Precision Therapeutics For Children., Matthew J. Mclaughlin, Jonathan B. Wagner, Valentina Shakhnovich, Bruce Carleton, J Steven Leeder

Manuscripts, Articles, Book Chapters and Other Papers

Improving the utilization of pharmacologic agents in the pediatric population yields significant, perhaps life-long, benefits. Genetic factors related to the disposition of a medication or an alteration at the target receptor site contributes to the observed variability of exposure and response between individuals. An additional source of this variability specific to the pediatric population is ontogeny, where age-specific changes during development may require dose adjustments to obtain the same levels of drug exposure and response. With significant improvements in characterizing both the ontogeny and genetic contributions of drug metabolizing enzymes, the time is right to begin placing more emphasis on …

Role Of Sclerostin, Fibroblast Growth Factor-23, And Klotho In Hemodialysis Patients, Ahmed Hassan, Azza A. I. Elmenyawi

Journal of Medicine in Scientific Research

Introduction Chronic kidney disease–mineral bone disorder leads to decreasing bone health. Sclerostin is produced by osteocytes similar to fibroblast growth factor-23 (FGF-23) and might upregulate the FGF-23 production by the osteocyte. FGF-23 may act as a mineralization inhibitor. Klotho serves as an obligate coreceptor for the FGF-23 and represents a marker of chronic kidney disease–mineral bone disorder. Aim We examined the association between serum sclerostin, FGF-23, Klotho, parathyroid hormone, high-sensitivity C-reactive protein (hsCRP), and phosphorus levels in hemodialysis (HD) patients. Patients and methods A total of 63 HD patients in the National Institute of Urology and Nephrology and 20 controls …

Effect Of Different Doses Of Low-Intensity Laser Therapy On Total Active Range Of Motion After Hand Flexor Tendon Repair, Amir A. Saidi, Amir N. Wadee, Eid R. Abd El Azim, Feify A. Badawy, Osama F. Al Balah, Wadida H. Elsayed

Journal of Medicine in Scientific Research

Objective To investigate the difference between the effects of different doses of low-level laser therapy (4 or 1 J/cm²) on the return of hand active range of motion (ROM) after flexor tendon repair. Participants and methods A small trial was conducted on 33 patients with 45 injured fingers of both sexes who underwent primary repair after complete cut of hand flexor tendon. Their age ranged from 20 to 40 years old. They were recruited from the plastic surgery department. The treatment began the first day postoperatively after permission by surgeons using Duran protocol and splinting. Transcutaneous electrical nerve …

Significance Of Matrix Metalloproteinase-9 Expression In The Ectopic Endometrial Tissue Of Women With Endometriosis, Abd Elatif M. Elbalshy, Ashraf M. Kansouh, Samar E. Ghanem

Journal of Medicine in Scientific Research

Background Degradation of the extracellular matrix is a basic step in the formation of endometriosis. The extracellular matrix degradation operated by matrix metalloproteinases (MMPs) Because matrix metalloproteinases (MMPs) are essential in orchestrating proper physiological functioning of the endometrium. MMP-9 is affected by many factors such as prostaglandin E2, tumor necrosis factor-α, interleukin 1β, interferon-γ, and tissue inhibitors of matrix metalloproteinase. Objective The aim of the present study was to evaluate MMP-9 forms in the ectopic and eutopic endometrial tissue of women with endometriosis. Patients and methods The study was carried upon 56 patients. Patients were divided into two groups (study …

Design And Actuation Of A Fabric-Based Worm-Like Robot, Akhil Kandhari, Anna Mehringer, Hillel J. Chiel, Roger D. Quinn, Kathryn A. Daltorio

Faculty Scholarship

Soft-bodied animals, such as earthworms, are capable of contorting their body to squeeze through narrow spaces, create or enlarge burrows, and move on uneven ground. In many applications such as search and rescue, inspection of pipes and medical procedures, it may be useful to have a hollow-bodied robot with skin separating inside and outside. Textiles can be key to such skins. Inspired by earthworms, we developed two new robots: FabricWorm and MiniFabricWorm. We explored the application of fabric in soft robotics and how textile can be integrated along with other structural elements, such as three-dimensional (3D) printed parts, linear springs, …

Use Of 3d Imaging For Providing Insights Into High-Order Structure Of Mitotic Chromosomes, Mohammad Yusuf, Kohei Kaneyoshi, Kiichi Fukui, Ian Robinson

Centre for Regenerative Medicine & Stem Cell Research

The high-order structure of metaphase chromosomes remains still under investigation, especially the 30-nm structure that is still controversial. Advanced 3D imaging has provided useful information for our understanding of this detailed structure. It is evident that new technologies together with improved sample preparations and image analyses should be adequately combined. This mini review highlights 3D imaging used for chromosome analysis so far with future imaging directions also highlighted.

Probable Donor-Derived Human Adenovirus Type 34 Infection In 2 Kidney Transplant Recipients From The Same Donor., Matthew A. Pettengill, Tara M. Babu, Paritosh Prasad, Sally Chuang, Michael G. Drage, Marilyn Menegus, Daryl M. Lamson, Xiaoyan Lu, Dean Erdman, Nicole Pecora

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Human adenovirus type 34 (HAdV-34) infection is a recognized cause of transplant-associated hemorrhagic cystitis and, in rare cases, tubulointerstitial nephritis. The source of such infections is often difficult to assess, that is, whether acquired as a primary infection, exposure to a pathogen in the transplanted organ, or reactivation of an endogenous latent infection. We present here 2 cases of likely transplant-acquired HAdV-34 infection from the same organ donor, manifesting as tubulointerstitial nephritis in 1.

Osteoblasts Are "Educated" By Crosstalk With Metastatic Breast Cancer Cells In The Bone Tumor Microenvironment., Alexus D. Kolb, Alison B. Shupp, Dimpi Mukhopadhyay, Frank C. Marini, Karen M. Bussard

Department of Cancer Biology Faculty Papers

INTRODUCTION: In a cancer-free environment in the adult, the skeleton continuously undergoes remodeling. Bone-resorbing osteoclasts excavate erosion cavities, and bone-depositing osteoblasts synthesize osteoid matrix that forms new bone, with no net bone gain or loss. When metastatic breast cancer cells invade the bone, this balance is disrupted. Patients with bone metastatic breast cancer frequently suffer from osteolytic bone lesions that elicit severe bone pain and fractures. Bisphosphonate treatments are not curative. Under ideal circumstances, osteoblasts would synthesize new matrix to fill in erosion cavities caused by osteoclasts, but this is not what occurs. Our prior evidence demonstrated that osteoblasts are …

Saturated Fatty Acid Activates T Cell Inflammation Through A Nicotinamide Nucleotide Transhydrogenase (Nnt)-Dependent Mechanism, Grace Mccambridge, Madhur Agrawal, Alanna Keady, Philip A. Kern, Hatice Hasturk, Barbara S. Nikolajczyk, Leena P. Bharath

Pharmacology and Nutritional Sciences Faculty Publications

Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated bioenergetics play in the inflammatory response of immune cells in obesity is untested. Our objective was to determine how free fatty acids (FFAs) regulate inflammation through impacts on mitochondria and redox homeostasis of peripheral blood mononuclear cells (PBMCs). PBMCs from lean subjects were activated with a T cell-specific stimulus in the presence or absence of generally pro-inflammatory …

Ephrin-B3 Controls Excitatory Synapse Density Through Cell-Cell Competition For Ephbs., Nathan T. Henderson, Sylvain J. Le Marchand, Martin Hruska, Simon Hippenmeyer, Liqun Luo, Matthew B. Dalva

Department of Neuroscience Faculty Papers

Cortical networks are characterized by sparse connectivity, with synapses found at only a subset of axo-dendritic contacts. Yet within these networks, neurons can exhibit high connection probabilities, suggesting that cell-intrinsic factors, not proximity, determine connectivity. Here, we identify ephrin-B3 (eB3) as a factor that determines synapse density by mediating a cell-cell competition that requires ephrin-B-EphB signaling. In a microisland culture system designed to isolate cell-cell competition, we find that eB3 determines winning and losing neurons in a contest for synapses. In a Mosaic Analysis with Double Markers (MADM) genetic mouse model system in vivo the relative levels of eB3 control …

Student-Faculty Collaborative Research Grant Report, Megan Bestwick

Post-Grant Reports

Mitochondria are essential organelles in most eukaryotic cells because of their role in metabolism and the production of ATP by the oxidative phosphorylation (OXPHOS) pathway, as well as other key cellular processes. Metal cofactors, such as copper (Cu) and iron (Fe), are incorporated into OXPHOS protein complexes of yeast located within the inner membrane of the mitochondria. Misincorporation or modulation of these available metals in mitochondrial enzymes leads to the production of reactive oxygen species (ROS). ROS are reactive molecules containing oxygen such as peroxides, superoxide, and hydroxyl radicals. Yeast are a good model for studying aging and the effect …

Innovation And Competition In Advanced Therapy Medicinal Products, Enrique Seoane-Vazquez, Vaishali Shukla, Rosa Rodriguez-Monguio

Pharmacy Faculty Articles and Research

"Advanced therapy medicinal products (ATMPs), including gene therapy, cell therapy, and tissue engineering products, represent a paradigm shift in health care as they have great potential for preventing and treating many diseases (Food and Drug Administration (FDA), 2013). By way of example, only 367 (8.0%) of the 4,603 rare diseases and conditions listed by the NIH Genetic and Rare Diseases Information Center had at least one FDA-approved drug therapy in early 2018. An estimated 3,038 (66.0%) of those rare diseases and conditions are congenital and genetic diseases that could potentially be treated by gene therapy. There are already ATMPs under …

Treatment Combinations For Alzheimer’S Disease: Current And Future Pharmacotherapy Options, Jeffrey L. Cummings, Gary Tong, Clive Ballard

Integrated Health Sciences Faculty Research

Although Alzheimer’s disease (AD) is the world’s leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that …

Yap1-Lats2 Feedback Loop Dictates Senescent Or Malignant Cell Fate To Maintain Tissue Homeostasis, Chunbo He, Xiangmin Lv, Cong Huang, Guohua Hua, Bowen Ma, Xingcheng Chen, Peter C. Angeletti, Jixin Dong, Jin Zhou, Zhengfeng Wang, Bo R. Rueda, John S. Davis, Cheng Wang

Nebraska Center for Virology: Faculty Publications

Dysfunction of the homeostasis-maintaining systems in specific cell types or tissues renders the organism susceptible to a range of diseases, including cancers. One of the emerging mechanisms for maintaining tissue homeostasis is cellular senescence. Here, we report that the Hippo pathway plays a critical role in controlling the fate of ovarian cells. Hyperactivation of Yes-associated protein 1 (YAP1), the major effector of the Hippo pathway, induces senescence in cultured primary human ovarian surface epithelial cells (hOSEs). Large tumor suppressor 2 (LATS2), the primary upstream negative regulator of YAP1, is elevated in both YAP1-induced and natural replicative-triggered senescence. Deletion of LATS2 …

Tradd Regulates Perinatal Development And Adulthood Survival In Mice Lacking Ripk1 And Ripk3., John P. Dowling, Mohamed Alsabbagh, Christina Del Casale, Zheng-Gang Liu, Jianke Zhang

Department of Microbiology and Immunology Faculty Papers

TRADD is an adaptor for TNFR1-induced apoptosis and NFκB activation. However, TRADD-deficient mice undergo normal development and contain normal lymphoid populations, which contrasts with an embryonic defect in mice lacking FADD, the shared adaptor mediating apoptosis. Recent studies indicate FADD suppresses embryonic necroptosis mediated by RIPK1. TRADD was suggested to also mediate necroptosis. Here we report that targeting TRADD fails to rescue Fadd ^−/− embryos from necroptosis, and ablation of TRADD rescues Ripk1 ^−/− mice from perinatal lethality when RIPK3-mediated necroptosis is disabled. The resulting Ripk1 ^−/− Ripk3 ^−/− Tradd ^−/− mice survive until early adulthood, but die thereafter. A …

Is Retinal Metabolic Dysfunction At The Center Of The Pathogenesis Of Age-Related Macular Degeneration?, Thierry Léveillard, Nancy J. Philp, Florian Sennlaub

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The retinal pigment epithelium (RPE) forms the outer blood⁻retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE. Lactate taken up by the RPE is converted to pyruvate and metabolized …

Cyclin D1 Integrates G9a-Mediated Histone Methylation., Zhiping Li, Xuanmao Jiao, Gabriele Di Sante, Adam Ertel, Mathew C. Casimiro, Min Wang, Sanjay Katiyar, Xiaoming Ju, D. V. Klopfenstein, Aydin Tozeren, William Dampier, Iouri Chepelev, Albert Jeltsch, Richard G. Pestell

Department of Cancer Biology Faculty Papers

Lysine methylation of histones and non-histone substrates by the SET domain containing protein lysine methyltransferase (KMT) G9a/EHMT2 governs transcription contributing to apoptosis, aberrant cell growth, and pluripotency. The positioning of chromosomes within the nuclear three-dimensional space involves interactions between nuclear lamina (NL) and the lamina-associated domains (LAD). Contact of individual LADs with the NL are dependent upon H3K9me2 introduced by G9a. The mechanisms governing the recruitment of G9a to distinct subcellular sites, into chromatin or to LAD, is not known. The cyclin D1 gene product encodes the regulatory subunit of the holoenzyme that phosphorylates pRB and NRF1 thereby governing cell-cycle …

Identification Of Novel Regulatory Genes In Apap Induced Hepatocyte Toxicity By A Genome-Wide Crispr-Cas9 Screen., Katherine Shortt, Daniel P. Heruth, Nini Zhang, Weibin Wu, Shipra Singh, Ding-You Li, Li Qin Zhang, Gerald J. Wyckoff, Lei S Qi, Craig A. Friesen, Shui Qing Ye

Manuscripts, Articles, Book Chapters and Other Papers

Acetaminophen (APAP) is a commonly used analgesic responsible for more than half of acute liver failure cases. Identification of previously unknown genetic risk factors would provide mechanistic insights and novel therapeutic targets for APAP-induced liver injury. This study used a genome-wide CRISPR-Cas9 screen to evaluate genes that are protective against, or cause susceptibility to, APAP-induced liver injury. HuH7 human hepatocellular carcinoma cells containing CRISPR-Cas9 gene knockouts were treated with 15 mM APAP for 30 minutes to 4 days. A gene expression profile was developed based on the 1) top screening hits, 2) overlap of expression data from APAP overdose studies, …

Dynamic Light Scattering Optical Coherence Tomography To Probe Motion Of Subcellular Scatterers., Nico J J Arezza, Marjan Razani, Michael C Kolios

Medical Biophysics Publications

Optical coherence tomography (OCT) is used to provide anatomical information of biological systems but can also provide functional information by characterizing the motion of intracellular structures. Dynamic light scattering OCT was performed on intact, control MCF-7 breast cancer cells and cells either treated with paclitaxel to induce apoptosis or deprived of nutrients to induce oncosis. Autocorrelations (ACs) of the temporal fluctuations of OCT intensity signals demonstrate a significant decrease in decorrelation time after 24 h in both the paclitaxel-treated and nutrient-deprived cell groups but no significant differences between the two groups. The acquired ACs were then used as input for …

Efficacy Of Combination Of Immunotherapies In A Murine In A Murine Squamous Cell Carcinoma Model, E. Correia, C. Portocarrero, U. Rodeck

Phase 1

Introduction: Head and neck squamous cell carcinomas (HNSCCs) are a type of neoplasm found in the epithelium of the oral cavity, oropharynx, nasopharynx, larynx, or hypopharynx. Recent evidence has demonstrated that 70-90% of HNSCC are associated with Human Papillomavirus (HPV), particularly strain 16 producing oncogenic proteins E6/E7. Currently, HNSCCs are treated with surgery, chemotherapy, and radiation, however immunotherapy with immune checkpoint (PD-1) blocking agents promises to improve outcomes in HNSCC.

Objective: This study examined the therapeutic effects of dual and triple combination immunotherapies in a mouse model of HPV-associated HNSCC.

Methods: Treatment modalities included a tumor vaccine (attenuated Listeria monocytogenes …

Initial Characterization Of The Indole-3-Carboxamide Bic-154 As A Fast Onset And Reversible Orai Channel Blocker, Tetyana Zhelay, Kalina Szteyn, Elisa Liardo, Jae Eun Cheong, Steffi Koerner, Anil Ekkati, Lijun Sun, J. Ashot Kozak

Neuroscience, Cell Biology & Physiology Faculty Publications

Calcium ion elevations are required for human T-lymphocyte proliferation in response to antigen recognition by a T-cell receptor. Calcium influx through the plasma membrane is necessary for efficient T-cell proliferation and effector function. The calcium channels responsible for Ca2+ influx in lymphocytes have been identified and Orai interacting with ER Ca2+ sensor STIM were shown to be crucial for persistent calcium mobilization. Loss-of-function mutations in Orai1 or STIM1 result in severe combined immunodeficiency (SCID) with muscle hypotonia. Suppression of calcium influx through Orai/STIM channels gives rise to various lymphoproliferative defects. Thus, deletion of Orai or STIM in mice results in …

Synthesis, Biological Evaluation And Molecular Modeling Studies Of Novel Chromone/Aza-Chromone Fused Α-Aminophosphonates As Src Kinase Inhibitors, S. Bapat, N. Viswanadh, M. Mujahid, Amir Nasrolahi Shirazi, Rakesh Tiwari, Keykavous Parang, M. Karthikeyan, M. Muthukrishnan, Renu Vyas

Pharmacy Faculty Articles and Research

A series of novel chromone/aza-chromone fused α-aminophosphonate derivatives were synthesized in good yields using silica chloride as the catalyst. All the synthesized compounds were tested for their c-Src kinase inhibitory activity. Aza-chromone compound showed Src kinase inhibition with an IC50 value of 15.8 µM. The compounds were subjected to molecular docking and dynamics simulations to study the atomic level interactions with an unphosphorylated proto-oncogenic tyrosine protein kinase Src (PDB code 1Y57) as well as phosphorylated tyrosine protein kinase Src (PDB code 2H8H). Docking and molecular dynamic results revealed phosphorylated Src tyrosine kinase protein better results than unphosphorylated tyrosine Src kinase …

The Underdeveloped Innate Immunity In Embryonic Stem Cells: The Molecular Basis And Biological Perspectives From Early Embryogenesis, Yan-Lin Guo

Faculty Publications

Embryonic stem cells (ESCs) have been intensively studied as a promising cell source for regenerative medicine. The rapid advancements in the field have not only proven the feasibility of ESC‐based cell therapy, but also led to a better understanding of pluripotent stem cells (PSCs) as a unique cell population at an early stage of embryogenesis. Recent studies have revealed that both human and mouse ESCs have attenuated innate immune responses to infectious agents and inflammatory cytokines. These findings raise interesting questions about the rationale for ESCs, the PSCs experimentally derived from preimplantation stage embryos, to not have an innate defense …

The Morphology And Evolution Of The Primate Brachial Plexus, Brian M. Shearer

Dissertations, Theses, and Capstone Projects

Primate evolutionary history is inexorably linked to the evolution of a broad array of locomotor adaptations that have facilitated the clade’s invasion of new niches. Researchers studying the evolution of primates and of their individual locomotor adaptations have traditionally relied on bony morphology – a practical choice given the virtual non-existence of any other type of tissue in the fossil record. However, this focus downplays the potential importance of the many other structures involved in locomotion, such as muscle, cartilage, and neural tissue, which may each be influenced by separate selective forces because of their different roles in facilitating movement. …

Investigating Gαs Pepducin’S Effect On Β2ar Signaling For Chf Pharmacology, Nida Bajwa, Nathan Hopfinger, Charles Scott

Phase 1

Introduction: Congestive heart failure affects nearly six million Americans and significantly impairs their quality of life. New and better interventions are needed to improve HF patients’ survival and outcomes. Pharmacologics that bias β2AR signaling towards arrestin, which promotes cardiomyocyte survival and contractility, may offer advantages over traditional β-blockers.

Objective: It has been demonstrated that peptides mimicking the C-terminus of the Gα_s subunit block downstream signaling of GPCRs. The study’s objective is to determine if a pepducin derived from the C-terminus of the Gα_s subunit of the β2AR could block G_s signaling but maintain arrestin-recruitment, thereby producing a …

Use Of Novel Anthropomorphic Breast Ultrasound Phantoms For Radiology Resident Education, Jacinta Browne, Chris Gu, Robert Fazzio, Andrew J. Fagan, Donald Tradup, Nicholas Hangiandreou

Articles

Purpose: This study evaluated the training and assessment role of anthropomorphic breast ultrasound phantoms which simulated both the morphological and sonographic characteristics of breast tissue, including lesions, in a group of radiology residents at a large academic medical center. Methods: This was a prospective study involving 9 residents across all years (2^nd–4^th year) of a radiology residency program. Baseline assessments of all residents ability to detect and characterize lesions in P-I were carried out, followed by a two-hour teaching session on the same phantom. All residents underwent a post-training, final assessment on P-II to evaluate changes in …