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Articles 1 - 24 of 24
Full-Text Articles in Biophysics
Structural Characterization Of Peptide Nanoaggregates At Varying Concentrations And Their Impact On Cellular Responses, Malika Rozmetova
Structural Characterization Of Peptide Nanoaggregates At Varying Concentrations And Their Impact On Cellular Responses, Malika Rozmetova
Theses and Dissertations
Peptide nano-assemblies can regulate cellular pathways in a structure-dependent manner. Here, we show that the enzyme-responsive peptide NapFFK(NBD)Yp forms distinct nanoscale assemblies at different concentrations, triggering differential ER stress and extracellular vesicle release in MDA-MB231 cells. These results highlight the importance of supramolecular organization in peptide–cell interactions.
Protein-Metal Interactions Of A-Synuclein And Bioactive Transition Metals Via Molecular Dynamics, Gonzalo R. Vazquez
Protein-Metal Interactions Of A-Synuclein And Bioactive Transition Metals Via Molecular Dynamics, Gonzalo R. Vazquez
Theses and Dissertations
Parkinson’s Disease (PD) is a neurodegenerative movement disorder which has been found to target the dopaminergic neurons of the substantia nigra. It is characterized by the formation of masses known as Lewy Bodies, formed by aggregates of the intrinsically disordered protein (IDP) -synuclein (asyn). Research suggests that alpha synuclein can undergo aggregation in the presence of heavy metals, which may accumulate in the body through a variety of mechanisms. To study how metals may play a role in wildtype (WT) asyn aggregation, MD simulation of the protein was performed in the presence of bioactive transition metals including Fe2+, Fe3+, Cu+, …
Illuminating Function And Enabling Inhibition At The Protein-Membrane Interface Of Glutathione Peroxidase 4., Courtney L. Labrecque
Illuminating Function And Enabling Inhibition At The Protein-Membrane Interface Of Glutathione Peroxidase 4., Courtney L. Labrecque
Theses and Dissertations
Membrane proteins act as gateways to cells and are responsible not only for signaling, lipid transport, and cellular homeostasis, but they are also integral in disease pathologies. One class of membrane proteins, peripheral membrane proteins (PMPs), reside in aqueous compartments of the cell until they are recruited to the membrane to perform their function. Glutathione peroxidase 4 (GPx4) is a PMP enzyme responsible for engaging the membrane and reducing lipid hydroperoxides, thereby preventing cellular death via ferroptosis. Due to its central function surrounding ferroptosis, GPx4 is an interesting drug target that has recently gained interest for inflammatory diseases as well …
Mechanistic Analysis Of Four-Way Dna Junctions And Cytokine-Binding Aptamers For Therapeutic Interventions, Roaa S. Mahmoud
Mechanistic Analysis Of Four-Way Dna Junctions And Cytokine-Binding Aptamers For Therapeutic Interventions, Roaa S. Mahmoud
Theses and Dissertations
DNA is inherently dynamic and topologically diverse and can fold into many different structures. Besides the canonical Watson-Crick structure, other higher-order structures such as G-quadruplexes (G4), i-motifs (iM), and four-way DNA junctions are possible. Although these high-order DNA structures are known to form transiently, they are important due to the crucial roles they play in many cellular processes including DNA replication, recombination, and repair. Among these DNA structures, 4-way junctions (also known as Holliday junctions, HJ) which are formed during the repair of double-strand DNA breaks (DSBs) and interact with proteins have garnered significant attention due to their central role …
Eukaryotic Initiation Factor 4e (Eif4e) In Complex With Eif4e Binding Protein 1 (4e-Bp1) Binds With Higher Affinity To M7gpppn Cap Of A Subset Of Human Mrnas, Izza F. Nawaz
Theses and Dissertations
Fluorescence anisotropy binding assays were used to analyze the binding of eIF4E in complex with 4E-BP1 onto the 5’ m7G cap of a subset of mRNA that are known to carry cap-independent translation. These studies suggest that 4E-BP1 increases eIF4E binding affinity to 5’cap of both FGF-9 and HIF-1𝝰.
A Review Of Calcineurin Biophysics With Implications For Cardiac Physiology, Ryan B. Williams
A Review Of Calcineurin Biophysics With Implications For Cardiac Physiology, Ryan B. Williams
Theses and Dissertations
Calmodulin is a prevalent calcium sensing protein found in all cells. Three genes exist for calmodulin and all three of these genes encode for the exact same protein sequence. Recently mutations in the amino acid sequence of calmodulin have been identified in living human patients. Thus far, patients harboring these mutations in the calmodulin sequence have only displayed an altered cardiac related phenotype. Calcineurin is involved in many key physiological processes and its activity is regulated by calcium and calmodulin. In order to assess whether or not calcineurin contributes to calmodulinopathy (a pathological state arising from dysfunctional calmodulin), a comprehensive …
A Computational Investigation Of The Biophysical Mechanisms Underlying Thermotaxis In The Afd Neurons Of Caenorhabditis Elegans, Zachary Mobille
A Computational Investigation Of The Biophysical Mechanisms Underlying Thermotaxis In The Afd Neurons Of Caenorhabditis Elegans, Zachary Mobille
Theses and Dissertations
Thermotaxis in the nematode Caenorhabditis elegans (C. elegans) is studied at the cellular scale of the amphid finger-like ciliated (AFD) neurons, which have previously been shown to be essential for thermoreception. The voltage and calcium signals of AFD during temperature stimuli are described with ordinary differential equations. The primary calcium model is a modified version of that published by Kuramochi and Doi in 2017 to explain the calcium responses of the chemosensitive amphid single-ciliated right (ASER) neuron to fluctuations in extracellular salt concentration. To account for the effects of temperature, changes to the stimuli conditions under which inactivation takes place …
Muscarinic Excitation Of Dopamine Neurons In The Ventral Tegmental Area Via Activation Of A Trpc-Like Cation Conductance, Yu Tzu Chen
Theses and Dissertations
Dopaminergic (DA) neurons in the ventral tegmental area (VTA) play a crucial role in reward and motivational behaviors, including the development of drug addictions. VTA DA neurons receive excitatory cholinergic inputs from the mesopontine tegmentum. Blockage of the M5 muscarinic receptor in DA neurons has been shown to attenuate drug-induced DA release and abuse-related behaviors, but the molecular mechanism is unknown. In this study, experiments were designed to identify the electrophysiological effects of muscarinic agonism in the modulation of action potential kinetics and firing patterns in VTA DA neurons of mice. Pharmacology of the muscarinic receptor-evoked current was also characterized. …
Conformational Modulation Of Α-Helical N-Acetylated Α-Synuclein, Ricardo Fernandez
Conformational Modulation Of Α-Helical N-Acetylated Α-Synuclein, Ricardo Fernandez
Theses and Dissertations
Human N-acetylated α-synuclein (NAcαSyn) has long been accepted as an intrinsically disordered protein (IDP) predominantly found in terminal nerve regions in healthy subjects. NAcαSyn structural fluidity enables the formation of transient or dynamic assemblies. Some of these assemblies may serve functional, yet undefined purposes. NAcαSyn is highly susceptible to the surrounding environment, leading to misfolding under high cytosolic oxidative stress conditions, which in turn assemble in the form of toxic oligomers or amyloid fibrils. These NAcαSyn inclusions along with their accretion and migration within neurons, are pathological hallmarks of Parkinson’s disease (PD), dementia, and multiple …
Characterization Of Cytochrome P450 3a4 Structure And Ligand Binding Mechanism In Anionic Nanodiscs, David T. Sweeney
Characterization Of Cytochrome P450 3a4 Structure And Ligand Binding Mechanism In Anionic Nanodiscs, David T. Sweeney
Theses and Dissertations
The Cytochromes P450 superfamily are ubiquitous throughout life and are present in some viruses. Humans encode for 57 of these enzymes that are involved in the metabolism of ~90% of all chemicals. These membrane-bound monooxygenase enzymes utilize a heme protoporphyrin at their active site to activate molecular oxygen and oxidize their substrates through an intermediate deemed nature's most powerful oxidizer. They are a powerful system at our disposal yet understanding of their structure and ligand binding mechanisms in the presence of a lipid bilayer remains poorly understood. The focus of this work is on Cytochrome P450 3A4 (CYP3A4). We set …
Interclass Gpcr Heteromerization Affects Localization And Trafficking, Rudy Toneatti
Interclass Gpcr Heteromerization Affects Localization And Trafficking, Rudy Toneatti
Theses and Dissertations
Class A serotonin (5-hydroxytryptamine) 2A (5-HT2AR) and class C metabotropic glutamate 2 receptors (mGluR2) are seven transmembrane receptors (7TMRs or G protein-coupled receptors – GPCRs) involved in multiple neuropsychiatric disorders including schizophrenia. Previous findings from our laboratory reported that 5-HT2AR and mGluR2 are dysregulated in the prefrontal cortex of patients suffering from this psychiatric condition, although 5-HT2AR’s expression was recovered in antipsychotic-medicated patients. Genome-wide association studies on schizophrenia reported that endosomal trafficking that regulates cell surface abundance of another 7TMR implicated in this disease (dopamine D2 receptor) can be altered. Ligand-activated receptors, including the …
Snow-Albedo Feedback In Northern Alaska: How Vegetation Influences Snowmelt, Lucas C. Reckhaus
Snow-Albedo Feedback In Northern Alaska: How Vegetation Influences Snowmelt, Lucas C. Reckhaus
Theses and Dissertations
This paper investigates how the snow-albedo feedback mechanism of the arctic is changing in response to rising climate temperatures. Specifically, the interplay of vegetation and snowmelt, and how these two variables can be correlated. This has the potential to refine climate modelling of the spring transition season. Research was conducted at the ecoregion scale in northern Alaska from 2000 to 2020. Each ecoregion is defined by distinct topographic and ecological conditions, allowing for meaningful contrast between the patterns of spring albedo transition across surface conditions and vegetation types. The five most northerly ecoregions of Alaska are chosen as they encompass …
Biometal-Induced Structural Consequences Of Α-Synuclein – The Parkinson’S Disease Protein, Dinendra L. Abeyawardhane
Biometal-Induced Structural Consequences Of Α-Synuclein – The Parkinson’S Disease Protein, Dinendra L. Abeyawardhane
Theses and Dissertations
The pre-synaptic protein α-Synuclein (αS) is often linked to the pathology of Parkinson’s disease (PD), an age-related neurodegenerative disorder. Lewy bodies, the cytopathological hallmarks of PD, are found to be rich in aggregates of misfolded αS protein. Metal dyshomeostasis has also been linked to PD due to the accumulation of iron in the substantia nigra pars compacta, and diminished copper levels reported in this same region. Metal dyshomeostasis in the brain coupled with oxidative stress can enhance the aggregation of αS. Recently, it was confirmed that mammalian αS is universally acetylated at the N-terminus, a common post-translational modification in …
Electrostatic Networks And Mechanisms Of Δph-Dependent Gating In The Human Voltage-Gated Proton Channel Hv1, Ashley L. Bennett
Electrostatic Networks And Mechanisms Of Δph-Dependent Gating In The Human Voltage-Gated Proton Channel Hv1, Ashley L. Bennett
Theses and Dissertations
The structure of the voltage-gated proton (H+) channel Hv1 is homologous to the voltage sensor domain (VSD) of tetrameric voltage-gated Na+, K+ and Ca2+ channels (VGCs), but lacks a pore domain and instead forms a homodimer. Similar to other VSD proteins, Hv1 is gated by changes in membrane potential (V), but unlike VGCs, voltage-dependent gating in Hv1 is modulated by changes in the transmembrane pH gradient (DpH = pHo - pHi). In Hv1, pHo or pHi changes shift the open probability (POPEN)-V relation by ~40 mV per …
Signaling Through Homomeric And Heteromeric Cannabinoid Cb1 Receptors, Guoqing Xiang
Signaling Through Homomeric And Heteromeric Cannabinoid Cb1 Receptors, Guoqing Xiang
Theses and Dissertations
Cannabis (Marijuana) has multiple effects on the human body, such as analgesia, euphoria and memory impairment. Delta-9 tetrahydrocannabinol (D9-THC), the active ingredient in cannabis, binds to cannabinoid receptors, seven-transmembrane G protein-coupled receptors (GPCRs) that mediate a variety of physiological functions. GPCRs were believed to function only in homomeric forms, however, recent findings show that different GPCRs can also form heteromeric complexes that may expand their signaling properties. In this study, we focused on Cannabinoid CB1 receptor (CB1R) heteromers with the mu-opioid receptor (MOR) and the Dopamine type 2 receptor (D2R), respectively. We utilized a variety of techniques, such as the …
Nicotinic Acetylcholine Receptor Dependent Effects Of Nicotine On Hek293t And Hbo Cells, James D. Larsen
Nicotinic Acetylcholine Receptor Dependent Effects Of Nicotine On Hek293t And Hbo Cells, James D. Larsen
Theses and Dissertations
T2R receptors are the classical bitter taste receptors which detect and transduce bitter taste in a subset of taste receptor cells (TRCs). The TRPM5-dependent T2Rs are G-protein coupled receptors (GPCRs) and are linked to G protein, gustducin to initiate an intracellular signaling cascade for the transduction of bitter tastants. Nicotine is bitter. However, at present the transduction mechanisms for the detection of nicotine in are poorly understood. Previous studies from our laboratory using TRPM5 knockout (KO) mice demonstrated that the T2R pathway is insufficient in explaining the taste perception of nicotine. TRPM5 KO mice elicited chorda tympani (CT) taste nerve …
The Mechanistic Requirements Of Passive H+ Import Through The Na, K-Atpase, Kevin S. Stanley
The Mechanistic Requirements Of Passive H+ Import Through The Na, K-Atpase, Kevin S. Stanley
Theses and Dissertations
This work focuses on the elucidation of the mechanism of passive proton import through the Na,K-ATPase. This enzyme uses the energy in ATP hydrolysis to exchange three intracellular Na+ for two extracellular K+ to maintain ion gradients within the cell, and while in the absence of physiological external Na+ and K+, the phosphorylated externally open (E2P) conformation passively imports protons, generating an inward current (IH). Chapter one reports on the effects of intracellular cations and nucleotides to shift the Na,K-ATPase into the E2P conformation. We identified that a combination of either internal Na+ and ATP or K+ and Pi. In …
Identification Of Expression And Function Of The Glucagon-Like Peptide-1 Receptor In Gastrointestinal Smooth Muscle, Alexander T. May
Identification Of Expression And Function Of The Glucagon-Like Peptide-1 Receptor In Gastrointestinal Smooth Muscle, Alexander T. May
Theses and Dissertations
In response to ingestion of nutrients, enteroendocrine L cells secrete the incretin hormone, glucagon-like peptide-1 (GLP-1), to enhance glucose-dependent insulin release. Therapies related to GLP-1 are approved for type 2 diabetes. The GLP-1 receptor (GLP-1R) is expressed in cells of the gastrointestinal tract and elsewhere. In pancreatic beta cells, GLP-1R are coupled to the Gs/cAMP/PKA pathway. The expression and function of GLP-1R in gastrointestinal smooth muscle are not known. Aim. To test the hypothesis that GLP-1 regulates smooth muscle function by acting on GLP-1R expressed on smooth muscle. Methods. Smooth muscle cells (SMC) were isolated and cultured. Expression of GLP-1R …
N-Alkyl 4-Methylamphetamine Enantiomers And The Implication For Potential Modulation Of Abuse Liability And Enhancement Of Psychoactive Drug Targeting., Ramsey Sitta
Theses and Dissertations
Drugs of abuse have a long history in humanity. Currently however, a subject of great interest is the phenylalkylamine family of drugs. Not only is the abuse liability of interest but also the potential therapeutic expansion of the capabilities of this family of drugs by utilizing the unique stereospecific effects of the newly discovered hybrid compounds. Based upon prior data of N-Alkyl 4-MA the enantiomers of N-Methyl, N-Ethyl, and N-Propyl were analyzed in hDAT, hNET, and hSERT. It was found that there was a negative correlation between chain length and potency and dopaminergic component. In agreement with the currently established …
A Mechanistic Study Of An Ipsc Model For Leigh’S Disease Caused By Mtdna Mutataion (8993 T>G), John P. Galdun
A Mechanistic Study Of An Ipsc Model For Leigh’S Disease Caused By Mtdna Mutataion (8993 T>G), John P. Galdun
Theses and Dissertations
Mitochondrial diseases encompass a broad range of devastating disorders that typically affect tissues with high-energy requirements. These disorders have been difficult to diagnose and research because of the complexity of mitochondrial genetics, and the large variability seen among patient populations. We have devised and carried out a mechanistic study to generate a cell based model for Leigh’s disease caused by mitochondrial DNA mutation 8993 T>G. Leigh’s disease is a multi-organ system disorder that depends heavily on the mutation burden seen within various tissues. Using new reprogramming and sequencing technologies, we were able to show that Leigh’s disease patient fibroblasts …
Probing Allosteric, Partial Inhibition Of Thrombin Using Novel Anticoagulants, Stephen S. Verespy Iii
Probing Allosteric, Partial Inhibition Of Thrombin Using Novel Anticoagulants, Stephen S. Verespy Iii
Theses and Dissertations
Thrombin is the key protease that regulates hemostasis; the delicate balance between procoagulation and anticoagulation of blood. In clotting disorders, like deep vein thrombosis or pulmonary embolism, procoagulation is up-regulated, but propagation of clotting can be inhibited with drugs targeting the proteases involved, like thrombin. Such drugs however, have serious side effects (e.g., excessive bleeding) and some require monitoring during the course of treatment. The reason for these side effects is the mechanism by which the drugs’ act. The two major mechanisms are direct orthosteric and indirect allosteric inhibition, which will completely abolish the protease’s activity. Herein we sought an …
High Affinity Block Of Icl,Swell By Thiol-Reactive Small Molecules, Sung H. Park
High Affinity Block Of Icl,Swell By Thiol-Reactive Small Molecules, Sung H. Park
Theses and Dissertations
Ebselen (Ebs) is considered as a glutathione peroxidase (GPx) mimetic and primarily thought to function by scavenging intracellular reactive oxygen species (ROS). Previous to our work, Deng et al. (2010a) demonstrated complete block of ICl,swell with 15 microM Ebs following endothelin-1 (ET-1) induced activation of the current in cardiomyocytes. This block was presumed to take effect mainly via the quenching of ROS. Nonetheless, our work with DI TNC1 astrocytes strongly emphasizes that Ebs might function by an alternative mechanism based on its kinetic profile in blocking ICl,swell. Our experiments showed that 45 nM Ebs can fully block …
Effects Of Pulsed Electric Fields On Mammalian Cell Membranes, Guy K. Smith
Effects Of Pulsed Electric Fields On Mammalian Cell Membranes, Guy K. Smith
Theses and Dissertations
The effect of pulsed electric fields on cell membranes were studied to investigate the effects of an electric field, per se, on biological systems, without the densometric and other technical problems associated with other forms of nonionizing radiation. Exposure of mouse splenocytes to a high voltage pulse resulted in an increase in membrane permeability to K+ that was dependent on both the electric field strength and the pulse duration. Exposure to a 2 μsec, 3.0 kV/cm pulse elicited a 50% loss of intracellular K+ indicating that the critical transmembrane potential (Vm) at breakdown was 1.26 volts …
Effects Of Glucocorticoid Treatment On The Properties Of Single Notor Units In Cat Hindlinb Huscles, Andrew James Robinson
Effects Of Glucocorticoid Treatment On The Properties Of Single Notor Units In Cat Hindlinb Huscles, Andrew James Robinson
Theses and Dissertations
The administration of glucocorticoids has been shown to induce atrophy and weakness in whole skeletal muscle. These effects frequently appear to be more pronounced in pale muscle than in red muscle. The present study was undertaken to examine the effects of steroid treatment on the contractile, electrical, and fatigue properties of single meter units in pale and red cat hindlimb muscles. Single motor units in the medial gastrocnemius (MG) and soleus muscles were isolated using techniques developed by McPhedran, et al., (1965). The properties of a large number of motor units were examined in normal animals and were compared to …