Physical Sciences and Mathematics Commons^™

Unttangling Irregular Actin Cytoskeleton Architectures In Tomograms Of The Cell With Struwwel Tracer, Salim Sazzed, Peter Scheible, Jing He, Willy Wriggers

Computer Science Faculty Publications

In this work, we established, validated, and optimized a novel computational framework for tracing arbitrarily oriented actin filaments in cryo-electron tomography maps. Our approach was designed for highly complex intracellular architectures in which a long-range cytoskeleton network extends throughout the cell bodies and protrusions. The irregular organization of the actin network, as well as cryo-electron-tomography-specific noise, missing wedge artifacts, and map dimensions call for a specialized implementation that is both robust and efficient. Our proposed solution, Struwwel Tracer, accumulates densities along paths of a specific length in various directions, starting from locally determined seed points. The highest-density paths originating …

Inflammatory Response To Sleep Fragmentation In Skeletal, Cardiac, And Smooth Muscle Tissues In Female Mice, Patton Allen

Mahurin Honors College Capstone Experience/Thesis Projects

Sleep is a critical process that the body undergoes. When sleep is interrupted, so that an individual is awakened for some period before going back into sleep, the sleep can be described as fragmented. Studies in the past have shown that sleep fragmentation (SF) promotes an inflammatory environment, especially in the brain and peripheral tissue. However, studies have not been conducted to observe inflammatory responses in muscle. To examine this, C57BL/6J female mice were subjected to either a control group (no SF) or a SF group which involved using an automated SF chamber to disrupt sleep every 2 min over …

Nanoceria Distribution And Effects Are Mouse-Strain Dependent, Robert A. Yokel, Michael T. Tseng, D. Allan Butterfield, Matthew L. Hancock, Eric A. Grulke, Jason M. Unrine, Arnold J. Stromberg, Alan K. Dozier, Uschi M. Graham

Pharmaceutical Sciences Faculty Publications

Prior studies showed nanoparticle clearance was different in C57BL/6 versus BALB/c mice, strains prone to Th1 and Th2 immune responses, respectively. Objective: Assess nanoceria (cerium oxide, CeO₂ nanoparticle) uptake time course and organ distribution, cellular and oxidative stress, and bioprocessing as a function of mouse strain. Methods: C57BL/6 and BALB/c female mice were i.p. injected with 10 mg/kg nanoceria or vehicle and terminated 0.5 to 24 h later. Organs were collected for cerium analysis; light and electron microscopy with elemental mapping; and protein carbonyl, IL-1β, and caspase-1 determination. Results: Peripheral organ cerium significantly increased, generally more …

Chronic Muscle Weakness And Mitochondrial Dysfunction In The Absence Of Sustained Atrophy In A Preclinical Sepsis Model, Allison M. Owen, Samir P. Patel, Jeffrey D. Smith, Beverly K. Balasuriya, Stephanie F. Mori, Gregory S. Hawk, Arnold J. Stromberg, Naohide Kuriyama, Masao Kaneki, Alexander G. Rabchevsky, Timothy A. Butterfield, Karyn A. Esser, Charlotte A. Peterson, Marlene E. Starr, Hiroshi Saito

Physiology Faculty Publications

Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of …

Disruption Of The Hippocampal And Hypothalamic Blood-Brain Barrier In A Diet-Induced Obese Model Of Type Ii Diabetes: Prevention And Treatment By The Mitochondrial Carbonic Anhydrase Inhibitor, Topiramate, Therese S. Salameh, William G. Mortell, Aric F. Logsdon, D. Allan Butterfield, William A. Banks

Chemistry Faculty Publications

Background: Type II diabetes is a vascular risk factor for cognitive impairment and increased risk of dementia. Disruption of the blood–retinal barrier (BRB) and blood–brain barrier (BBB) are hallmarks of subsequent retinal edema and central nervous system dysfunction. However, the mechanisms by which diet or metabolic syndrome induces dysfunction are not understood. A proposed mechanism is an increase in reactive oxygen species (ROS) and oxidative stress. Inhibition of mitochondrial carbonic anhydrase (mCA) decreases ROS and oxidative stress. In this study, topiramate, a mCA inhibitor, was examined for its ability to protect the BRB and BBB in diet-induced obese type II …

Novel Fluconazole Derivatives With Promising Antifungal Activity, Nishad Thamban Chandrika, Sanjib K. Shrestha, Huy X. Ngo, Kaitlind C. Howard, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activities of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against …

Polymer Micelle Formulation For The Proteasome Inhibitor Drug Carfilzomib: Anticancer Efficacy And Pharmacokinetic Studies In Mice, Ji Eun Park, Se-Eun Chun, Derek Alexander Reichel, Jee Sun Min, Su-Chan Lee, Songhee Han, Gongmi Ryoo, Yunseok Oh, Shin-Hyung Park, Heon-Min Ryu, Kyung Bo Kim, Ho-Young Lee, Soo Kyung Bae, Younsoo Bae, Wooin Lee

Pharmaceutical Sciences Faculty Publications

Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic …

Agonist-Mediated Activation Of Sting Induces Apoptosis In Malignant B Cells, Chih-Hang Anthony Tang, Joseph A. Zundell, Sujeewa Ranatunga, Cindy Lin, Yulia Nefedova, Juan R. Del Valle, Chih-Chi Andrew Hu

Chemistry Faculty Publications

Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In Eμ-TCL1 mice with chronic lymphocytic leukemia, injection of …

Correlation Of Maximal Inspiratory Pressure To Transdiaphragmatic Twitch Pressure In Intensive Care Unit Patients, Gerald S. Supinski, Philip M. Westgate, Leigh Ann Callahan

Internal Medicine Faculty Publications

Background: Respiratory muscle weakness contributes to respiratory failure in ICU patients. Unfortunately, assessment of weakness is difficult since the most objective test, transdiaphragmatic pressure in response to phrenic nerve stimulation (PdiTw), is difficult to perform. While most clinicians utilize maximum inspiratory pressure (Pimax) to assess strength, the relationship of this index to PdiTw has not been evaluated in a large ICU population. The purpose of the present study was to assess both PdiTw and Pimax in ICU patients to determine how these indices correlate with each other, what factors influence these indices, and how well these indices predict outcomes.

Methods: …

Measuring The Role Of Inhibition In Auditory Discrimination In Mice, Tazima Nur

Graduate Theses and Dissertations

Understanding how inhibitory neurons affect sensory information processing in the cerebral cortex is an ongoing goal of both neuroscience and statistical physics research. In this master's thesis research project, an experimental system has been designed and built for studying how auditory dynamic range depends on inhibitory neurons, based on observations of mouse behavior. In this thesis, firstly, the topic of inhibition and information processing has been introduced. Then two papers related to inhibition and dynamic range has been reviewed in detail. One of the papers is an experimental work that analyzes the affect of inhibition on dynamic range. The other …

Pubertal And Adult Leydig Cell Function In Mullerian Inhibiting Substance-Deficient Mice, Xiufeng Wu, Ramamani Arumugam, Stephen Baker, Mary Lee

Mary M. Lee

Mullerian inhibiting substance (MIS) causes Mullerian duct regression during sexual differentiation and regulates postnatal Leydig cell development. MIS knockout (MIS-KO) mice with targeted deletions of MIS develop Leydig cell hyperplasia, but their circulating androgen concentrations are reportedly unaltered. We compared reproductive hormone profiles, androgen biosynthesis, and the expression of key steroidogenic and metabolic enzymes in MIS-KO and wild-type (WT) mice at puberty (36 d) and sexual maturity (60 d). In pubertal animals, basal testosterone and LH concentrations in plasma were lower in MIS-KO than WT mice, whereas human chorionic gonadotropin-stimulated testosterone concentrations were similar. In adults, basal LH, and both …