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Teaching Observational Learning to Children with Autism: An In-vivo and Video-Model Assessment

Description: Observational learning (OL) occurs when an individual contacts reinforcement as a direct result of discriminating the observed consequences of other individuals' responses. Individuals with autism spectrum disorder (ASD) may have deficits in observational learning and previous research has demonstrated that teaching a series of prerequisite skills (i.e., attending, imitation, delayed imitation, and consequence discrimination) can result in observational learning. We sequentially taught these prerequisite skills for three young children with ASD across three play-based tasks. We assessed the direct and indirect effects of training by assessing OL before and after instruction across tasks and task variations (for two participants) during both in-vivo and video-model probes using a concurrent multiple-probe design. All participants acquired the prerequisite skills and demonstrated observational learning during probes of directly-trained tasks. Generalization results varied across participants. Observational learning generalized to one untrained task for one participant. For the other two participants, observational learning generalized to variations of the trained tasks but not to untrained tasks. Generalization additionally occurred during the in-vivo probes for both participants for whom we assessed this response. Implications of these findings, as well as directions for future research, are discussed.
Date: December 2017
Creator: Sansing, Elizabeth M
Partner: UNT Libraries

Potential Toxicity and Underlying Mechanisms Associated with Pulmonary Exposure to Iron Oxide Nanoparticles: Conflicting Literature and Unclear Risk

Description: This review article will focus on known risks following iron oxide nanoparticles (IONPs) exposure supported by human, animal, and cell culture-based studies, the potential challenges intrinsic to IONPs toxicity assessment, and how these may contribute to the poorly characterized IONPs toxicity profile.
Date: September 7, 2017
Creator: Kornberg, Tiffany G.; Stueckle, Todd A.; Antonini, James M.; Rojanasakul, Liying W.; Castranova, Vincent; Yang, Yong et al.
Partner: UNT College of Engineering

Delivery of CRISPR/Cas9 into Blood Cells of Zebrafish: Potential for Genome Editing in Somatic Cells

Description: Factor VIII is a clotting factor found on the intrinsic side of the coagulation cascade. A mutation in the factor VIII gene causes the disease Hemophilia A, for which there is no cure. The most common treatment is administration of recombinant factor VIII. However, this can cause an immune response that renders the treatment ineffective in certain hemophilia patients. For this reason a new treatment, or cure, needs to be developed. Gene editing is one solution to correcting the factor VIII mutation. CRISPR/Cas9 mediated gene editing introduces a double stranded break in the genomic DNA. Where this break occurs repair mechanisms cause insertions and deletions, or if a template oligonucleotide can be provided point mutations could be introduced or corrected. However, to accomplish this goal for editing factor VIII mutations, a way to deliver the components of CRISPR/Cas9 into somatic cells is needed. In this study, I confirmed that the CRISPR/Cas9 system was able to create a mutation in the factor VIII gene in zebrafish. I also showed that the components of CRISPR/Cas9 could be piggybacked by vivo morpholino into a variety of blood cells. This study also confirmed that the vivo morpholino did not interfere with the gRNA binding to the DNA, or Cas9 protein inducing the double stranded break.
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Date: August 2017
Creator: Schneider, Sara Jane
Partner: UNT Libraries

Cardiovascular function, compliance, and connective tissue remodeling in the turtle, Trachemys scripta, following thermal acclimation

Description: This article suggests that cold acclimation alters cardiac shunting patterns with an increased R-L shunt flow, achieved through reducing systemic resistance and increasing systemic blood flow.
Date: April 13, 2016
Creator: Keen, Adam N.; Shiels, Holly A. & Crossley, Dane A., II
Partner: UNT College of Arts and Sciences

Mammalian Tissue Response to Low Dose Ionizing Radiation: The Role of Oxidative Metabolism and Intercellular Communication

Description: The objective of the project was to elucidate the mechanisms underlying the biological effects of low dose/low dose rate ionizing radiation in organs/tissues of irradiated mice that differ in their susceptibility to ionizing radiation, and in human cells grown under conditions that mimic the natural in vivo environment. The focus was on the effects of sparsely ionizing cesium-137 gamma rays and the role of oxidative metabolism and intercellular communication in these effects. Four Specific Aims were proposed. The integrated outcome of the experiments performed to investigate these aims has been significant towards developing a scientific basis to more accurately estimate human health risks from exposures to low doses ionizing radiation. By understanding the biochemical and molecular changes induced by low dose radiation, several novel markers associated with mitochondrial functions were identified, which has opened new avenues to investigate metabolic processes that may be affected by such exposure. In particular, a sensitive biomarker that is differentially modulated by low and high dose gamma rays was discovered.
Date: January 16, 2013
Creator: Azzam, Edouard I.
Partner: UNT Libraries Government Documents Department

EVALUATING THE EFFECTS OF FLY ASH EXPOSURE ON FISH EARLY LIFE STAGES: FATHEAD MINNOW EMBRYO-LARVAL TESTS

Description: On December 22, 2008, a dike containing fly ash and bottom ash in an 84-acre complex of the Tennessee Valley Authority's (TVA) Kingston Steam Plant in East Tennessee failed and released a large quantity of ash into the adjacent Emory River. Ash deposits extended as far as 4 miles upstream (Emory River mile 6) of the Plant, and some ash was carried as far downstream as Tennessee River mile 564 ({approx}4 miles downstream of the Tennessee River confluence with the Clinch River). A byproduct of coal burning power plants, fly ash contains a variety of metals and other elements which, at sufficient concentrations and in specific forms, can be toxic to biological systems. The effects of fly ash contamination on exposed fish populations depend on the magnitude and duration of exposure, with the most significant risk considered to be the effects of specific ash constituents, especially selenium, on fish early life stages. Uptake by adult female fish of fly ash constituents through the food chain and subsequent maternal transfer of contaminants to the developing eggs is thought to be the primary route of selenium exposure to larval fish (Woock and others 1987, Coyle and others 1993, Lemly 1999, Moscatello and others 2006), but direct contact of the fertilized eggs and developing embryos to ash constituents in river water and sediments is also a potential risk factor (Woock and others 1987, Coyle and others 1993, Jezierska and others 2009). To address the risk of fly ash from the Kingston spill to the reproductive health of downstream fish populations, ORNL has undertaken a series of studies in collaboration with TVA including: (1) a field study of the bioaccumulation of fly ash constituents in fish ovaries and the reproductive condition of sentinel fish species in reaches of the Emory and Clinch Rivers affected ...
Date: May 1, 2012
Creator: Greeley Jr, Mark Stephen; Elmore, Logan R & McCracken, Kitty
Partner: UNT Libraries Government Documents Department

Evaluating the Effects of the Kingston Fly Ash Release on Fish Reproduction: Spring 2009 - 2010 Studies

Description: On December 22, 2008, a dike containing fly ash and bottom ash at the Tennessee Valley Authority's (TVA) Kingston Fossil Plant in East Tennessee failed and released a large quantity of ash into the adjacent Emory River. Ash deposits from the spill extended 4 miles upstream of the facility to Emory River mile 6 and downstream to Tennessee River mile 564 ({approx}8.5 miles downstream of the confluence of the Emory River with the Clinch River, and {approx}4 miles downstream of the confluence of the Clinch River with the Tennessee River). A byproduct of coal combustion, fly ash contains a variety of metals and other elements which, at sufficient concentrations and in specific forms, can be harmful to biological systems. The ecological effects of fly ash contamination on exposed fish populations depend on the magnitude and duration of exposure, with the most significant risk considered to come from elevated levels of certain metals in the ash, particularly selenium, on fish reproduction and fish early life stages (Lemly 1993; Besser and others 1996). The ovaries of adult female fish in a lake contaminated by coal ash were reported to have an increased frequency of atretic oocytes (dead or damaged immature eggs) and reductions in the overall numbers of developing oocytes (Sorensen 1988) associated with elevated body burdens of selenium. Larval fish exposed to selenium through maternal transfer of contaminants to developing eggs in either contaminated bodies of water (Lemly 1999) or in experimental laboratory exposures (Woock and others 1987, Jezierska and others 2009) have significantly increased incidences of developmental abnormalities. Contact of fertilized eggs and developing embryos to ash in water and sediments may also pose an additional risk to the early life stages of exposed fish populations through direct uptake of metals and other ash constituents (Jezierska and others 2009). The ...
Date: May 1, 2012
Creator: Greeley Jr, Mark Stephen; Adams, Marshall & McCracken, Kitty
Partner: UNT Libraries Government Documents Department

Multimodality Imaging with Silica-Based Targeted Nanoparticle Platforms

Description: Objectives: To synthesize and characterize a C-Dot silica-based nanoparticle containing 'clickable' groups for the subsequent attachment of targeting moieties (e.g., peptides) and multiple contrast agents (e.g., radionuclides with high specific activity) [1,2]. These new constructs will be tested in suitable tumor models in vitro and in vivo to ensure maintenance of target-specificity and high specific activity. Methods: Cy5 dye molecules are cross-linked to a silica precursor which is reacted to form a dye-rich core particle. This core is then encapsulated in a layer of pure silica to create the core-shell C-Dot (Figure 1) [2]. A 'click' chemistry approach has been used to functionalize the silica shell with radionuclides conferring high contrast and specific activity (e.g. 64Cu and 89Zr) and peptides for tumor targeting (e.g. cRGD and octreotate) [3]. Based on the selective Diels-Alder reaction between tetrazine and norbornene, the reaction is bioorthogonal, highyielding, rapid, and water-compatible. This radiolabeling approach has already been employed successfully with both short peptides (e.g. octreotate) and antibodies (e.g. trastuzumab) as model systems for the ultimate labeling of the nanoparticles [1]. Results: PEGylated C-Dots with a Cy5 core and labeled with tetrazine have been synthesized (d = 55 nm, zeta potential = -3 mV) reliably and reproducibly and have been shown to be stable under physiological conditions for up to 1 month. Characterization of the nanoparticles revealed that the immobilized Cy5 dye within the C-Dots exhibited fluorescence intensities over twice that of the fluorophore alone. The nanoparticles were successfully radiolabeled with Cu-64. Efforts toward the conjugation of targeting peptides (e.g. cRGD) are underway. In vitro stability, specificity, and uptake studies as well as in vivo imaging and biodistribution investigations will be presented. Conclusions: C-Dot silica-based nanoparticles offer a robust, versatile, and multi-functional platform to enhance in vivo detection sensitivity and non-invasively assay receptor expression/status of tumor ...
Date: April 9, 2012
Creator: Lewis, Jason S.
Partner: UNT Libraries Government Documents Department

Preparation of Radiopharmaceuticals Labeled with Metal Radionuclides

Description: The overall goal of this project was to develop methods for the production of metal-based radionuclides, to develop metal-based radiopharmaceuticals and in a limited number of cases, to translate these agents to the clinical situation. Initial work concentrated on the application of the radionuclides of Cu, Cu-60, Cu-61 and Cu-64, as well as application of Ga-68 radiopharmaceuticals. Initially Cu-64 was produced at the Missouri University Research Reactor and experiments carried out at Washington University. A limited number of studies were carried out utilizing Cu-62, a generator produced radionuclide produced by Mallinckrodt Inc. (now Covidien). In these studies, copper-62-labeled pyruvaldehyde Bis(N{sup 4}-methylthiosemicarbazonato)-copper(II) was studied as an agent for cerebral myocardial perfusion. A remote system for the production of this radiopharmaceutical was developed and a limited number of patient studies carried out with this agent. Various other copper radiopharmaceuticals were investigated, these included copper labeled blood imaging agents as well as Cu-64 labeled antibodies. Cu-64 labeled antibodies targeting colon cancer were translated to the human situation. Cu-64 was also used to label peptides (Cu-64 octriatide) and this is one of the first applications of a peptide radiolabeled with a positron emitting metal radionuclide. Investigations were then pursued on the preparation of the copper radionuclides on a small biomedical cyclotron. A system for the production of high specific activity Cu-64 was developed and initially the Cu-64 was utilized to study the hypoxic imaging agent Cu-64 ATSM. Utilizing the same target system, other positron emitting metal radionuclides were produced, these were Y-86 and Ga-66. Radiopharmaceuticals were labeled utilizing both of these radionuclides. Many studies were carried out in animal models on the uptake of Cu-ATSM in hypoxic tissue. The hypothesis is that Cu-ATSM retention in vivo is dependent upon the oxygen retention of the tissue and the significantly greater retention amounting in hypoxic tissue. ...
Date: February 16, 2012
Creator: Welch, M.J.
Partner: UNT Libraries Government Documents Department

Development of Reagents for Application of At-211 to Targeted Radionuclide Therapy of Cancer

Description: This grant covered only a period of 4 months as the major portion of the award was returned to DOE due to an award of funding from NIH that covered the same research objectives. A letter regarding the termination of the research is attached as the last page of the Final Report. The research conducted was limited due to the short period of this grant, but the results obtained in that period are outlined in the Final Report. The studies addressed in the research effort were directed at a problem that is of critical importance to the in vivo application of the alpha-particle emitting radionuclide At-211. That problem, low in vivo stability of many astatinated molecules, severely limits the use of At-211 in therapeutic applications. The advances sought in the studies were expected to expand the types of biomolecules that can be used as carriers of At-211, and provide improved in vivo targeting of the radiation dose compared with the dose delivered to normal tissue.
Date: December 23, 2011
Creator: Wilbur, D. Scott
Partner: UNT Libraries Government Documents Department

Final Report for research grant entitled "Development of Reagents for Application of At-211 and Bi-213 to Targeted Radiotherapy of Cancer"

Description: This grant was a one-year extension of another grant with the same title (DE-FG03-98ER62572). The objective of the studies was to continue in vivo evaluation of reagents to determine which changes in structure were most favorable for in vivo use. The focus of our studies was development and optimization of reagents for pretargeting alpha-emitting radionuclides At-211 or Bi-213 to cancer cells. Testing of the reagents was conducted in vitro and in animal model systems. During the funding period, all three specific aims set out in the proposed studies were worked on, and some additional studies directed at development of a method for direct labeling of proteins with At-211 were investigated. We evaluated reagents in two different approaches in 'two step' pretargeting protocols. These approaches are: (1) delivery of the radionuclide on recombinant streptavidin to bind with pretargeted biotinylated monoclonal antibody (mAb), and alternatively, (2) delivery of the radionuclide on a biotin derivative to bind with pretargeted antibody-streptavidin conjugates. The two approaches were investigated as it was unclear which will be superior for the short half-lived alpha-emitting radionuclides.
Date: December 23, 2011
Creator: Wilbur, D. Scott
Partner: UNT Libraries Government Documents Department

METHOD FOR SIMULTANEOUS 90SR AND 137CS IN-VIVO MEASUREMENTS OF SMALL ANIMALS AND OTHER ENVIRONMENTAL MEDIA DEVELOPED FOR THE CONDITIONS OF THE CHERNOBYL EXCLUSION ZONE

Description: To perform in vivo simultaneous measurements of the {sup 90}Sr and {sup 137}Cs content in the bodies of animals living in the Chernobyl Exclusion Zone (ChEZ), an appropriate method and equipment were developed and installed in a mobile gamma beta spectrometry laboratory. This technique was designed for animals of relatively small sizes (up to 50 g). The {sup 90}Sr content is measured by a beta spectrometer with a 0.1 mm thick scintillation plastic detector. The spectrum processing takes into account the fact that the measured object is 'thick-layered' and contains a comparable quantity of {sup 137}Cs, which is a characteristic condition of the ChEZ. The {sup 137}Cs content is measured by a NaI scintillation detector that is part of the combined gamma beta spectrometry system. For environmental research performed in the ChEZ, the advantages of this method and equipment (rapid measurements, capability to measure live animals directly in their habitat, and the capability of simultaneous {sup 90}Sr and {sup 137}Cs measurements) far outweigh the existing limitations (considerations must be made for background radiation and the animal size, skeletal shape and body mass). The accuracy of these in vivo measurements is shown to be consistent with standard spectrometric and radiochemical methods. Apart from the in vivo measurements, the proposed methodology, after a very simple upgrade that is also described in the article, works even more accurately with samples of other media, such as soil and plants.
Date: October 1, 2011
Creator: Farfan, E. & Jannik, T.
Partner: UNT Libraries Government Documents Department

Visually Relating Gene Expression and in vivo DNA Binding Data

Description: Gene expression and in vivo DNA binding data provide important information for understanding gene regulatory networks: in vivo DNA binding data indicate genomic regions where transcription factors are bound, and expression data show the output resulting from this binding. Thus, there must be functional relationships between these two types of data. While visualization and data analysis tools exist for each data type alone, there is a lack of tools that can easily explore the relationship between them. We propose an approach that uses the average expression driven by multiple of ciscontrol regions to visually relate gene expression and in vivo DNA binding data. We demonstrate the utility of this tool with examples from the network controlling early Drosophila development. The results obtained support the idea that the level of occupancy of a transcription factor on DNA strongly determines the degree to which the factor regulates a target gene, and in some cases also controls whether the regulation is positive or negative.
Date: September 20, 2011
Creator: Huang, Min-Yu; Mackey, Lester; Ker?; nen, Soile V. E.; Weber, Gunther H.; Jordan, Michael I. et al.
Partner: UNT Libraries Government Documents Department

In Vivo Monitoring Program Manual, PNL-MA-574, Rev 5.1

Description: The following sections provide an overview of the administration for the In Vivo Monitoring Program (IVMP) for Hanford. This includes the organizational structure and program responsibilities; coordination of in vivo measurements; scheduling measurements; performing measurements; reporting results; and quality assurance.
Date: September 12, 2011
Creator: Lynch, Timothy P.
Partner: UNT Libraries Government Documents Department

Calibration of the Accuscan II In Vivo System for Whole Body Counting

Description: This report describes the April 2011 calibration of the Accuscan II HpGe In Vivo system for whole body counting. The source used for the calibration was a NIST traceable BOMAB manufactured by DOE as INL2006 BOMAB containing Eu-154, Eu-155, Eu-152, Sb-125 and Y-88 with energies from 27 keV to 1836 keV with a reference date of 11/29/2006. The actual usable energy range was 86.5 keV to 1597 keV on 4/21/2011. The BOMAB was constructed inside the Accuscan II counting 'tub' in the order of legs, thighs, abdomen, thorax/arms, neck, and head. Each piece was taped to the backwall of the counter. The arms were taped to the thorax. The phantom was constructed between the v-ridges on the backwall of the Accuscan II counter. The energy and efficiency calibrations were performed using the INL2006 BOMAB. The calibrations were performed with the detectors in the scanning mode. This report includes an overview introduction and records for the energy/FWHM and efficiency calibration including performance verification and validation counting. The Accuscan II system was successfully calibrated for whole body counting and verified in accordance with ANSI/HPS N13.30-1996 criteria.
Date: August 1, 2011
Creator: Perry, Orval R. & Georgeson, David L.
Partner: UNT Libraries Government Documents Department

MULTIDENTATE TEREPHTHALAMIDATE AND HYDROXYPYRIDONATE LIGANDS: TOWARDS NEW ORALLY ACTIVE CHELATORS

Description: The limitations of current therapies for the treatment of iron overload or radioisotope contamination have stimulated efforts to develop new orally bioavailable iron and actinide chelators. Siderophore-inspired tetradentate, hexadentate and octadentate terephthalamidate and hydroxypyridonate ligands were evaluated in vivo as selective and efficacious iron or actinide chelating agents, with several metal loading and ligand assessment procedures, using {sup 59}Fe, {sup 238}Pu, and {sup 241}Am as radioactive tracers. The compounds presented in this study were compared to commercially available therapeutic sequestering agents [deferoxamine (DFO) for iron and diethylenetriaminepentaacetic acid (DPTA) for actinides] and are unrivaled in terms of affinity, selectivity and decorporation efficacy, which attests to the fact that high metal affinity may overcome the low bioavailability properties commonly associated to multidenticity.
Date: July 13, 2011
Creator: Abergel, Rebecca J. & Raymond, Kenneth N.
Partner: UNT Libraries Government Documents Department

Calibration of the Accuscan II IN Vivo System for High Energy Lung Counting

Description: This report describes the April 2011 calibration of the Accuscan II HpGe In Vivo system for high energy lung counting. The source used for the calibration was a NIST traceable lung set manufactured at the University of Cincinnati UCLL43AMEU & UCSL43AMEU containing Am-241 and Eu-152 with energies from 26 keV to 1408 keV. The lung set was used in conjunction with a Realistic Torso phantom. The phantom was placed on the RMC II counting table (with pins removed) between the v-ridges on the backwall of the Accuscan II counter. The top of the detector housing was positioned perpendicular to the junction of the phantom clavicle with the sternum. This position places the approximate center line of the detector housing with the center of the lungs. The energy and efficiency calibrations were performed using a Realistic Torso phantom (Appendix I) and the University of Cincinnati lung set. This report includes an overview introduction and records for the energy/FWHM and efficiency calibration including performance verification and validation counting. The Accuscan II system was successfully calibrated for high energy lung counting and verified in accordance with ANSI/HPS N13.30-1996 criteria.
Date: July 1, 2011
Creator: Perry, Ovard R. & Georgeson, David L.
Partner: UNT Libraries Government Documents Department

Calibration of the Accuscan II In Vivo System for I-125 Thyroid Counting

Description: This report describes the March 2011 calibration of the Accuscan II HpGe In Vivo system for I-125 thyroid counting. The source used for the calibration was a DOE manufactured Am-241/Eu-152 source contained in a 22 ml vial BEA Am-241/Eu-152 RMC II-1 with energies from 26 keV to 344 keV. The center of the detector housing was positioned 64 inches from the vault floor. This position places the approximate center line of the detector housing at the center line of the source in the phantom thyroid tube. The energy and efficiency calibration were performed using an RMC II phantom (Appendix J). Performance testing was conducted using source BEA Am-241/Eu-152 RMC II-1 and Validation testing was performed using an I-125 source in a 30 ml vial (I-125 BEA Thyroid 002) and an ANSI N44.3 phantom (Appendix I). This report includes an overview introduction and records for the energy/FWHM and efficiency calibration including performance verification and validation counting. The Accuscan II system was successfully calibrated for counting the thyroid for I-125 and verified in accordance with ANSI/HPS N13.30-1996 criteria.
Date: July 1, 2011
Creator: Perry, Ovard R. & Georgeson, David L.
Partner: UNT Libraries Government Documents Department

Calibration of the Accuscan II In Vivo System for I-131 Thyroid Counting

Description: This report describes the March 2011 calibration of the Accuscan II HpGe In Vivo system for I-131 thyroid counting. The source used for the calibration was an Analytics mixed gamma source 82834-121 distributed in an epoxy matrix in a Wheaton Liquid Scintillation Vial with energies from 88.0 keV to 1836.1 keV. The center of the detectors was position 64-feet from the vault floor. This position places the approximate center line of the detectors at the center line of the source in the thyroid tube. The calibration was performed using an RMC II phantom (Appendix J). Validation testing was performed using a Ba-133 source and an ANSI N44.3 Phantom (Appendix I). This report includes an overview introduction and records for the energy/FWHM and efficiency calibrations including verification counting. The Accuscan II system was successfully calibrated for counting the thyroid for I-131 and verified in accordance with ANSI/HPS N13.30-1996 criteria.
Date: July 1, 2011
Creator: Perry, Orval R. & Georgeson, David L.
Partner: UNT Libraries Government Documents Department

Reenacting the birth of an intron

Description: An intron is an extended genomic feature whose function requires multiple constrained positions - donor and acceptor splice sites, a branch point, a polypyrimidine tract and suitable splicing enhancers - that may be distributed over hundreds or thousands of nucleotides. New introns are therefore unlikely to emerge by incremental accumulation of functional sub-elements. Here we demonstrate that a functional intron can be created de novo in a single step by a segmental genomic duplication. This experiment recapitulates in vivo the birth of an intron that arose in the ancestral jawed vertebrate lineage nearly half a billion years ago.
Date: July 1, 2011
Creator: Hellsten, Uffe; Aspden, Julie L.; Rio, Donald C. & Rokhsar, Daniel S.
Partner: UNT Libraries Government Documents Department

ChIP-seq Mapping of Distant-Acting Enhancers and Their In Vivo Activities

Description: The genomic location and function of most distant-acting transcriptional enhancers in the human genome remains unknown We performed ChIP-seq for various transcriptional coactivator proteins (such as p300) directly from different embryonic mouse tissues, identifying thousands of binding sitesTransgenic mouse experiments show that p300 and other co-activator peaks are highly predictive of genomic location AND tissue-specific activity patterns of distant-acting enhancersMost enhancers are active only in one or very few tissues Genomic location of tissue-specific p300 peaks correlates with tissue-specific expression of nearby genes Most binding sites are conserved, but the global degree of conservation varies between tissues
Date: June 1, 2011
Creator: Visel, Axel & Pennacchio, Len A.
Partner: UNT Libraries Government Documents Department

Mesoporous silica nanoparticles as smart and safe devices for regulating blood biomolecule levels

Description: Stimuli-responsive end-capped MSN materials are promising drug carriers that securely deliver a large payload of drug molecules without degradation or premature release. A general review of the recent progress in this field is presented, including a summary of a series of hard and soft caps for drug encapsulation and a variety of internal and external stimuli for controlled release of different therapeutics, a discussion of the biocompatibility of MSN both in vitro and in vivo, and a description of the sophisticated stimuli-responsive systems with novel capping agents and controlled release mechanism. The unique internal and external surfaces of MSN were utilized for the development of a glucose-responsive double delivery system end-capped with insulin. This unique system consists of functionalized MSNs capable of releasing insulin when the concentration of sugar in blood exceeds healthy levels. The insulin-free nanoparticles are then up taken by pancreatic cells, and release inside of them another biomolecule that stimulates the production of more insulin. The in vivo application of this system for the treatment of diabetes requires further understanding on the biological behaviors of these nanoparticles in blood vessels. The research presented in this dissertation demonstrated the size and surface effects on the interaction of MSNs with red blood cell membranes, and discovered how the surface of the nanoparticles can be modified to improve their compatibility with red blood cells and avoid their dangerous side effects. In order to optimize the properties of MSN for applying them as efficient intracellular drug carriers it is necessary to understand the factors that can regulate their internalization into and exocytosis out of the cells. The correlation between the particle morphology and aggregation of MSNs to the effectiveness of cellular uptake is discussed and compared with different cell lines. The differences in the degree of exocytosis of MSNs between healthy ...
Date: May 15, 2011
Creator: Zhao, Yan
Partner: UNT Libraries Government Documents Department

Self-assembled pentablock copolymers for selective and sustained gene delivery

Description: The poly(diethylaminoethyl methacrylate) (PDEAEM) - Pluronic F127 - PDEAEM pentablock copolymer (PB) gene delivery vector system has been found to possess an inherent selectivity in transfecting cancer cells over non-cancer cells in vitro, without attaching any targeting ligands. In order to understand the mechanism of this selective transfection, three possible intracellular barriers to transfection were investigated in both cancer and non-cancer cells. We concluded that escape from the endocytic pathway served as the primary intracellular barrier for PB-mediated transfection. Most likely, PB vectors were entrapped and rendered non-functional in acidic lysosomes of non-cancer cells, but survived in less acidic lysosomes of cancer cells. The work highlights the importance of identifying intracellular barriers for different gene delivery systems and provides a new paradigm for designing targeting vectors based on intracellular differences between cell types, rather than through the use of targeting ligands. The PB vector was further developed to simultaneously deliver anticancer drugs and genes, which showed a synergistic effect demonstrated by significantly enhanced gene expression in vitro. Due to the thermosensitive gelation behavior, the PB vector packaging both drug and gene was also investigated for its in vitro sustained release properties by using polyethylene glycol diacrylate as a barrier gel to mimic the tumor matrix in vivo. Overall, this work resulted in the development of a gene delivery vector for sustained and selective gene delivery to tumor cells for cancer therapy.
Date: May 15, 2011
Creator: Zhang, Bingqi
Partner: UNT Libraries Government Documents Department

Studies of the structure and function of Mms6, a bacterial protein that promotes the formation of magnetic nanoparticles

Description: Here we report structural and functional studies of Mms6, a biomineralization protein that can promote the formation in vitro of magnetic nanoparticles with sizes and morphologies similar to the magnetites synthesized by magnetotactic bacteria. We found the binding pattern of Mms6 to ferric ion to be two-phase and multivalent. We quantatively determined that Mms6 binds one Fe{sup 3+} with a very high affinity (K{sub d} = 10{sup -16} M). The second phase of iron binding is multivalent and cooperative with respect to iron with a K{sub d} in the {mu}M range and a stoichiometry of about 20 ferric ion per protein molecule. We found that Mms6 exists in large particles of two sizes, one consisting of 20-40 monomeric units and the other of 200 units. From proteolytic digestion, ultracentrifugation and liposome fusion studies, we found that Mms6 forms a large micellar quaternary structure with the N-terminal domain self-assembling into a uniformly sized micelle and the C-terminal domain on the surface. The two-phase iron-binding pattern may be relevant to iron crystal formation. We propose that the first high affinity phase may stabilize a new conformation of the C-terminal domain that allows interaction with other C-terminal domains leading to a structural change in the multimeric protein complex that enables the second low affinity iron binding phase to organize iron and initiate crystal formation. We also observed a dimeric apparent molecular mass of the Mms6 C-terminal peptide (C21Mms6). We speculate that the C-terminal domain may form higher order quaternary arrangements on the surface of the micelle or when anchored to a membrane by the N-terminal domain. The change in fluorescence quenching in the N-terminal domain with iron binding suggests a structural integrity between the C- and N-terminal domains. The slow change in trp fluorescence as a function of time after adding iron suggests ...
Date: May 15, 2011
Creator: Wang, Lijun
Partner: UNT Libraries Government Documents Department