subject:(Amino Acids Peptides AND Proteins)

University of Hong Kong

1. An, Ke. Conformational studies of hybrid aminoxy peptides & exploration of protein posttranslational modification by medium-chain fatty acid.

Degree: PhD, 2016, University of Hong Kong

URL: http://hdl.handle.net/10722/240680

► Conformations of aminoxy peptides with a wide range of backbones and substituents have been characterized over the past two decades. It has been discovered that… (more)

▼ Conformations of aminoxy peptides with a wide range of backbones and substituents have been characterized over the past two decades. It has been discovered that aminoxy peptides composed of α-, β-, and γ-aminoxy acids comprise a novel class of foldamers that adopt unique and stable secondary structures, such as turn, helix and sheet, in the solid state and in non-polar solutions. However, hybrid aminoxy peptides assembled by different types of aminoxy acid residues were largely unexplored. In Chapter 1, α- and cyclic β2,3-aminoxy acid residues were coupled to form hybrid aminoxy peptides and their secondary structures were investigated to find the structural relationship between aminoxy acid monomers and the resulting hybrid peptides. Compounds 1–12 were synthesized and their conformations were characterized by X-ray crystallography, 1D and 2D NMR spectroscopy and circular dichroism. Consistent results obtained from different methods establish that consecutive turns are conformationally stable and conserved in such hybrid peptides. In addition, novel helical and turn-like structures have been observed in the crystal structures of 5 and 8. The NOE patterns and CD spectra of other peptides were similar to those of 5 and 8, indicating that either helical or reverse turn structure is adopted by this series of peptides, regardless of the solvent, ring size and stereochemistry of cyclic β2,3-aminoxy acid residues. Protein posttranslational modification (PTM) has attracted much attention in current epigenetic research, especially on target profiling, mechanism and physiological functions. Several methods of profiling potential protein targets have been discovered with the rapid development of highly sensitive mass spectrometry detection and bioconjugation chemistry. The successful application of ‘chemical reporters’ in detecting protein lipidation by long-chain fatty acids has inspired us to explore any unknown but plausible PTM, such as medium-chain fatty acid lipidation, which is physiologically relevant yet rarely reported. In Chapter 2, several ‘chemical reporters’ were synthesized to explore potential protein lipidation by medium-chain fatty acids. Compounds alk-6, 7 and 8 were prepared and subjected to metabolic labeling in RAW264.7 cells. The resulting cell lysates were conjugated with rhodamine-N3, and fluorescent protein bands were visualized after SDS-PAGE. Alk-7 was found to uniquely give a novel fluorescent protein band at around 50 kDa, in dose- and time-dependent manners. This protein band showed resistance towards basic NH2OH nucleophilic replacement, which hinted that alk-7 might covalently modify proteins through amide bond, that is, either lysine or N-terminal amino acid residue was modified. After conjugating cell lysates with biotin-N3, streptavidin beads enrichment, trypsin digestion and mass spectrometry analysis, the newly alk-7 labeled protein band was identified as mitochondrial aldehyde dehydrogenase. Furthermore, it was validated through immunoblotting ALDH2 that this alk-7 labeling abundantly…

Subjects/Keywords: Amino acids; Peptides; Proteins - Analysis

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APA (6^th Edition):

An, K. (2016). Conformational studies of hybrid aminoxy peptides & exploration of protein posttranslational modification by medium-chain fatty acid. (Doctoral Dissertation). University of Hong Kong. Retrieved from http://hdl.handle.net/10722/240680

Chicago Manual of Style (16^th Edition):

An, Ke. “Conformational studies of hybrid aminoxy peptides & exploration of protein posttranslational modification by medium-chain fatty acid.” 2016. Doctoral Dissertation, University of Hong Kong. Accessed February 24, 2020. http://hdl.handle.net/10722/240680.

MLA Handbook (7^th Edition):

An, Ke. “Conformational studies of hybrid aminoxy peptides & exploration of protein posttranslational modification by medium-chain fatty acid.” 2016. Web. 24 Feb 2020.

Vancouver:

An K. Conformational studies of hybrid aminoxy peptides & exploration of protein posttranslational modification by medium-chain fatty acid. [Internet] [Doctoral dissertation]. University of Hong Kong; 2016. [cited 2020 Feb 24]. Available from: http://hdl.handle.net/10722/240680.

Council of Science Editors:

An K. Conformational studies of hybrid aminoxy peptides & exploration of protein posttranslational modification by medium-chain fatty acid. [Doctoral Dissertation]. University of Hong Kong; 2016. Available from: http://hdl.handle.net/10722/240680

2. Souissi, Wided. Cytocidal activity of Cry41Aa, an anticancer toxin from Bacillus thuringiensis.

Degree: PhD, 2018, University of Sussex

URL: http://sro.sussex.ac.uk/id/eprint/80446/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.759607

► Bacillus thuringiensis (Bt) is a gram positive spore forming bacterium which produces intracellular protein crystals toxic to a wide variety of insect larvae and is… (more)

▼ Bacillus thuringiensis (Bt) is a gram positive spore forming bacterium which produces intracellular protein crystals toxic to a wide variety of insect larvae and is the most commonly used biological pesticide worldwide. More recently, Bt crystal proteins known as parasporins have been discovered, that have no known insecticidal activity but target some human cancer cells exhibiting strong cytocidal activities with different toxicity spectra and varied activity levels. Amongst these parasporins, parasporin-3 most closely resembles the commercially used insecticidal toxins and presents the narrowest activity spectrum, showing moderate cytotoxicity against only two cancer cell lines, HL-60 (Human promyelocytic leukemia cells) and HepG2 (Human liver cancer cells). Parasporin-3, also called Cry41Aa, has only been shown to exhibit cytocidal activity towards these two cell lines after being proteolytically cleaved. In order to understand this activation mechanism various mutations were made at the N- or C-terminal region of the protein and the toxicity against both HepG2 and HL-60 cell lines was evaluated. Our results indicate that only N-terminal cleavage is required for activation and that N-terminally deleted mutants show some toxicity without the need for proteolytic activation. Furthermore we have shown that the level of toxicity towards the two cell lines depends on the protease used to activate the toxin. Proteinase K-activated toxin was significantly more toxic towards HepG2 and HL-60 than trypsin-activated toxin. N-terminal sequencing of activated toxins showed that this difference in toxicity is associated with a difference of just two amino acids (serine and alanine at positions 59 and 60 respectively) which we hypothesize occlude a binding motif. Preliminary work carried out on binding showed a lack of correlation between binding and toxicity since toxin binds to both susceptible and non-susceptible cancer cell lines. In an attempt to better understand the mechanism of action of Cry41Aa against these cells, we evolved resistance in HepG2 through repeated exposure to increasing doses of the toxin. Morphological, physiological and genetic characteristics of the resistant cell line were compared with susceptible cells. Toxin was shown to bind to resistant HepG2 similarly to the susceptible line. RNA sequencing identified AQP9 as a potential mediator of resistance but extensive investigations failed to show a direct link. The involvement of certain intracellular signalling pathways were also investigated in order to understand cell responses to the toxin and showed that in response to the toxin p38, but not ERK1/2, is activated and in a dose dependent manner.

Subjects/Keywords: 572; QD0431 Proteins, peptides, amino acids, etc.

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APA (6^th Edition):

Souissi, W. (2018). Cytocidal activity of Cry41Aa, an anticancer toxin from Bacillus thuringiensis. (Doctoral Dissertation). University of Sussex. Retrieved from http://sro.sussex.ac.uk/id/eprint/80446/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.759607

Chicago Manual of Style (16^th Edition):

Souissi, Wided. “Cytocidal activity of Cry41Aa, an anticancer toxin from Bacillus thuringiensis.” 2018. Doctoral Dissertation, University of Sussex. Accessed February 24, 2020. http://sro.sussex.ac.uk/id/eprint/80446/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.759607.

MLA Handbook (7^th Edition):

Souissi, Wided. “Cytocidal activity of Cry41Aa, an anticancer toxin from Bacillus thuringiensis.” 2018. Web. 24 Feb 2020.

Vancouver:

Souissi W. Cytocidal activity of Cry41Aa, an anticancer toxin from Bacillus thuringiensis. [Internet] [Doctoral dissertation]. University of Sussex; 2018. [cited 2020 Feb 24]. Available from: http://sro.sussex.ac.uk/id/eprint/80446/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.759607.

Council of Science Editors:

Souissi W. Cytocidal activity of Cry41Aa, an anticancer toxin from Bacillus thuringiensis. [Doctoral Dissertation]. University of Sussex; 2018. Available from: http://sro.sussex.ac.uk/id/eprint/80446/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.759607

McMaster University

3. Scott, Benjamin M. Applying Phage Display to Screen a Library of α1-Proteinase Inhibitor Mutants for Improved Thrombin Binding Activity.

Degree: MSc, 2013, McMaster University

URL: http://hdl.handle.net/11375/13367

► α₁-proteinase inhibitor (α₁-PI) is the most abundant serine protease inhibitor (serpin) in plasma. The α₁-PI M358R mutant exhibits greatly increased rates of thrombin inhibition… (more)

▼ α₁-proteinase inhibitor (α₁-PI) is the most abundant serine protease inhibitor (serpin) in plasma. The α₁-PI M358R mutant exhibits greatly increased rates of thrombin inhibition compared to wild type α₁-PI, which predominantly inhibits neutrophil elastase. M358R (P1) lies at the reactive centre (P1-P1’) bond of the reactive centre loop (RCL) of α₁-PI, cleaved by cognate proteases as they become trapped in the serpin-type inhibitory complex. The relationship between RCL structure and serpin inhibitor function is incompletely understood and has not been subjected to saturation mutagenesis. α₁-PI M358R is a less potent inhibitor of thrombin than natural thrombin-inhibitory serpins, suggesting room for engineered improvement into an antithrombotic protein drug. Phage display is a powerful tool for screening mutant protein libraries, but only one serpin (PAI-1) has previously been mutated and expressed in this manner. In this study the T7Select10-3b (Novagen) phage display system was used to express α₁-PI variants and PAI-1, fused to the first 348 residues of the T7 10B coat protein. Following confirmation that α₁-PI M358R retained inhibitory activity when fused to T7Select10-3b phage, this system was used to express a library of α₁-PI mutant proteins with all possible codon combinations at positions P2 (P357) and P1 (M358) (441 mutants). The library was biopanned using a novel technique in order to amplify only the α₁-PI P2P1 mutants capable of forming stable complexes with thrombin. The P357/M358R mutant was the only P2P1 mutant enriched, indicating that the α₁-PI M358R protein has the optimal P2P1 sequence for thrombin inhibition. A second T7Select10-3b library of α₁-PI mutant proteins was generated to identify the optimal sequence at positions P7 through to P3 (amino acids 352-356) for thrombin inhibition. The P2 and P1 positions were maintained at P357/M358R, while all possible codon combinations at positions P7 through to P3 were represented (>4.08 million mutants). The library was biopanned using the protocol developed for the P2P1 library, before sequences were inserted into an E. coli expression vector and α₁-PI M358R P7-P3 mutants were screened for thrombin inhibitory activity. 80 individual colonies were screened, yielding 22 unique P7-P3 mutants with thrombin inhibitory activity greater than the M358R RCL sequence. The consensus observed in sequences with improved activity matched thrombin’s known substrate specificity and also general RCL trends: P7-Not Aromatic/P6-Hydrophobic/P5-T or S/P4-Hydrophobic/P3-Not Aromatic. Kinetic characterization of selected mutants with improved thrombin inhibitory activity yielded two mutants, P7-P3 sequence DITMA and AAFVS, with a second order rate constant of 1.0 x 10⁶ M^-1s^-1. This represents a >2-fold increase in the rate of thrombin inhibition versus α₁-PI… Advisors/Committee Members: Sheffield, William P., Junop, Murray, Bramson, Jonathan, Medical Sciences (Thrombosis & Haemostasis & Atherosclerosis).

Subjects/Keywords: protein engineering; thrombin; phage display; coagulation; serpin; thrombin inhibitor; Amino Acids, Peptides, and Proteins; Amino Acids, Peptides, and Proteins

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Scott, B. M. (2013). Applying Phage Display to Screen a Library of α1-Proteinase Inhibitor Mutants for Improved Thrombin Binding Activity. (Masters Thesis). McMaster University. Retrieved from http://hdl.handle.net/11375/13367

Chicago Manual of Style (16^th Edition):

Scott, Benjamin M. “Applying Phage Display to Screen a Library of α1-Proteinase Inhibitor Mutants for Improved Thrombin Binding Activity.” 2013. Masters Thesis, McMaster University. Accessed February 24, 2020. http://hdl.handle.net/11375/13367.

MLA Handbook (7^th Edition):

Scott, Benjamin M. “Applying Phage Display to Screen a Library of α1-Proteinase Inhibitor Mutants for Improved Thrombin Binding Activity.” 2013. Web. 24 Feb 2020.

Vancouver:

Scott BM. Applying Phage Display to Screen a Library of α1-Proteinase Inhibitor Mutants for Improved Thrombin Binding Activity. [Internet] [Masters thesis]. McMaster University; 2013. [cited 2020 Feb 24]. Available from: http://hdl.handle.net/11375/13367.

Council of Science Editors:

Scott BM. Applying Phage Display to Screen a Library of α1-Proteinase Inhibitor Mutants for Improved Thrombin Binding Activity. [Masters Thesis]. McMaster University; 2013. Available from: http://hdl.handle.net/11375/13367

4. Brewer, Daniel Niron. Elucidation of the Role of the Exocyst Subunit Sec6p in Exocytosis: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, Biochemistry and Molecular Pharmacology, 2009, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/446

► Trafficking of protein and lipid cargo through the secretory pathway in eukaryotic cells is mediated by membrane-bound vesicles. Secretory vesicles are targeted to sites… (more)

▼ Trafficking of protein and lipid cargo through the secretory pathway in eukaryotic cells is mediated by membrane-bound vesicles. Secretory vesicles are targeted to sites of exocytosis on the plasma membrane in part by a conserved multi-subunit protein complex termed the exocyst. In addition to tethering vesicles to the plasma membrane, the exocyst complex and components therein may also add a layer of regulation by directly controlling assembly of the SNARE complex, which is required for membrane fusion, as well as other regulatory factors such as Sec1p. In the past, we have shown that Sec6p interacts with Sec9p in vivo and that that interaction retards binary SNARE complex formation in a SNARE assembly assay. Though many interactions have been mapped using in vitro methods, confirming them in vivoand placing them into the context of a complete model that accounts for all observed interactions (and lack of interactions) has proven difficult. In order to address these problems, I have studied the interactions between Sec6p and other factors involved in exocytosis at the plasma membrane via in vivo methods. My hypothesis was that Sec6p interaction with Sec9p and subsequent inhibition of SNARE complex assembly in vitro was an intermediate state and Sec6p was part of a set of cofactors that accelerated SNARE complex assembly in vivo. To test this hypothesis I showed that the interaction between the plasma membrane t-SNARE Sec9p and the yeast exocyst subunit Sec6p can be observed in vivoand designed point mutations to disrupt that interaction. Interestingly, I also showed that Sec6p:Sec9p interaction involves the free pool of Sec6p rather than the exocyst bound fraction of Sec6p. Point mutations in the N-terminal domain of Sec6p result in temperature sensitive growth and secretion defects, without loss of Sec6p-Sec9p interaction. However, at the non-permissive temperature, the exocyst subunits Sec5p, Sec10p and Sec15p are mislocalized and are absent from the exocyst complex. The resulting subcomplex, containing Sec3p, Sec8p, Exo70p and Exo84p, remains stably assembled and localized at sites of polarized secretion. This subcomplex is likely due to disruption of interaction between Sec6p and Sec5p, and may be similar to that observed at restrictive temperatures in the sec6-54temperature sensitive mutant. Additionally, one of the sec6 temperature sensitive mutants displays a loss of binding to the yeast regulatory protein Sec1p. In vitro binding studies indicate a direct interaction between Sec1p and the free pool of the wild-type Sec6p protein, suggesting close interplay between Sec6p and Sec1p in the regulation of SNARE complexes. A coherent model which incorporates all these interactions has continued to be elusive. However, the results I have found do suggest several hypotheses which should prove testable in the future. Advisors/Committee Members: Mary Munson PhD.

Subjects/Keywords: SNARE Proteins; Vesicular Transport Proteins; Exocytosis; Amino Acids, Peptides, and Proteins; Cells; Genetic Phenomena

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Brewer, D. N. (2009). Elucidation of the Role of the Exocyst Subunit Sec6p in Exocytosis: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/446

Chicago Manual of Style (16^th Edition):

Brewer, Daniel Niron. “Elucidation of the Role of the Exocyst Subunit Sec6p in Exocytosis: A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/446.

MLA Handbook (7^th Edition):

Brewer, Daniel Niron. “Elucidation of the Role of the Exocyst Subunit Sec6p in Exocytosis: A Dissertation.” 2009. Web. 24 Feb 2020.

Vancouver:

Brewer DN. Elucidation of the Role of the Exocyst Subunit Sec6p in Exocytosis: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/446.

Council of Science Editors:

Brewer DN. Elucidation of the Role of the Exocyst Subunit Sec6p in Exocytosis: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/446

5. Ley, Nathan Benjamin. Investigations into fragment ligand binding using quantitative STD and WaterLOGSY NMR spectroscopy.

Degree: PhD, 2015, University of Kent

URL: https://kar.kent.ac.uk/50197/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.659558

► Ligand-observed NMR spectroscopy is frequently employed in early-stage drug discovery, often as an initial screen to narrow the field of potential drug-like molecules. However, its… (more)

▼ Ligand-observed NMR spectroscopy is frequently employed in early-stage drug discovery, often as an initial screen to narrow the field of potential drug-like molecules. However, its use is limited to this early stage. More information regarding binding mode can be extracted from these experiments via quantification, and this should help extend the remit of these experiments beyond simple screening functions. Initially, it was shown that the amount of signal that could be produced from an STD NMR experiment could be dramatically increased by careful consideration of the selective saturation pulse. By systematically shortening the Gaussian pulse and positioning it at specific offset positions, it was shown that these dramatic increases in signal are genuine and need not result in false positives. Quantitative STD NMR spectroscopy as applied to Hsp90 and a series of small fragment ligands provided evidence to suggest that the precise inter-atomic distances between a protein and ligand within a crystal structure correlate with both initial rates of STD build up, and T1-adjusted STD values. This precise correlation has implications for chemotype clustering and initial binding mode selection, something which should be useful in the absence of a crystal structure. Taking the same quantitative principles and applying to LOGSY experiments elucidated another, discrete property of protein-ligand binding. Examining the ‘LOGSY difference’ signal for protons of a ligand allows us to see what protons are in close proximity to conserved, bound water at the protein-ligand binding interface. This is fundamentally different to the information gained from STD experiments. Applying the insights to a protein of a different nature, Ras, it was shown that quantitative STD can be applied to proteins of both different size and structure. Furthermore, more evidence was acquired to suggest that conserved, bound water in the binding site really is responsible for generating LOGSY signal. In the absence of these molecules, as in Ras, proximity of a proton to an exchangeable tends to dominate. In addition we were able to show that these quantitative methods can be used together to help eliminate incorrect computationally generated docking poses. The work presented in this thesis provides evidence for the advantages of STD and LOGSY NMR spectroscopy in fragment-based drug discovery. The information that can be extracted from relatively simple ligand-observed NMR experiments should be used to provide more evidence at an earlier stage of the drug discovery process, hopefully reducing late-stage attrition and helping us get to the therapeutic drug molecules we need a little more quickly.

Subjects/Keywords: 500; QD431 Organic Chemistry- Biochemistry- Proteins; peptides; amino acids

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APA (6^th Edition):

Ley, N. B. (2015). Investigations into fragment ligand binding using quantitative STD and WaterLOGSY NMR spectroscopy. (Doctoral Dissertation). University of Kent. Retrieved from https://kar.kent.ac.uk/50197/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.659558

Chicago Manual of Style (16^th Edition):

Ley, Nathan Benjamin. “Investigations into fragment ligand binding using quantitative STD and WaterLOGSY NMR spectroscopy.” 2015. Doctoral Dissertation, University of Kent. Accessed February 24, 2020. https://kar.kent.ac.uk/50197/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.659558.

MLA Handbook (7^th Edition):

Ley, Nathan Benjamin. “Investigations into fragment ligand binding using quantitative STD and WaterLOGSY NMR spectroscopy.” 2015. Web. 24 Feb 2020.

Vancouver:

Ley NB. Investigations into fragment ligand binding using quantitative STD and WaterLOGSY NMR spectroscopy. [Internet] [Doctoral dissertation]. University of Kent; 2015. [cited 2020 Feb 24]. Available from: https://kar.kent.ac.uk/50197/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.659558.

Council of Science Editors:

Ley NB. Investigations into fragment ligand binding using quantitative STD and WaterLOGSY NMR spectroscopy. [Doctoral Dissertation]. University of Kent; 2015. Available from: https://kar.kent.ac.uk/50197/ ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.659558

University of Limerick

6. Cunha Neves, Adriana. Extraction, purification and characterisation of biofunctional peptides from marine processing co-products.

Degree: 2015, University of Limerick

URL: http://hdl.handle.net/10344/4793

► Large quantities of marine processing by-products such as salmon trimmings, or undersized, fouled and cracked mussels as well as mussel byssus are generated annually. Currently… (more)

▼ Large quantities of marine processing by-products such as salmon trimmings, or undersized, fouled and cracked mussels as well as mussel byssus are generated annually. Currently these components are discarded or used as fertilizers, animal feed or are sold on for fish oil extraction. However, it is becoming more evident that marine processing by-products are rich reservoirs of structurally diverse biofunctional components such as proteins, peptides and amino acids. These marine processing by-products can contain significant levels of protein (10-23 % (w/w)) and may act as substrates for the generation of bioactive peptides. The potential of by-products of the fish and shellfish industries to generate peptides with angiotensin-converting-enzyme (ACE) and dipeptidyl peptidase IV (DPP-IV) inhibitory and antioxidant activities was assessed. The extraction of protein, gelatin and collagen from the marine by-products, salmon trimmings (ST), mussel meat (MM) and mussel byssus (MB) respectively was optimized and hydrolysates were generated from these extracts. All the hydrolysates generated had ACE and DPP-IV inhibitory and antioxidant activities, although higher in vitro DPP-IV and ACE inhibitory and antioxidant activity levels were seen in ST-derived hydrolysates compared to MM or MB-derived hydrolysates. The most potent multifunctional hydrolysates were the ST proteins hydrolysed with Corolase PP® for 1 h (STP-C1, ACE IC50= 0.96 ± 0.11 mg mL-1; DPP-IV IC50= 0.30 ± 0.01 mg mL-1; ORAC value= 601.47 ± 85.13 μmol TE g-1) and the ST gelatin hydrolysed with Corolase PP® for 1 h (STG-C1, ACE IC50= 0.19 ± 0.05 mg mL-1; DPP-IV IC50= 0.08 ± 0.01 mg mL-1; ORAC value= 540.94 ± 9.57 μmol TE g-1). Furthermore, the STP-C1 and STG-C1 showed no significant change in the bioactivities when subjected to simulated gastrointestinal digestion. The fractionation of these hydrolysates showed that small peptides (mainly dipeptides) rich in proline, tyrosine and phenylalanine, were present in the most potent fractions. The characteristics of these peptides are linked with ACE and DPP-IV inhibition, and antioxidant activities. Based on the in vitro results presented above, marine by-products may have potential as value-added sources of antioxidant, anti-diabetic and cardioprotective functional food ingredients. Advisors/Committee Members: Fitzgerald, Richard J..

Subjects/Keywords: marine processing co-products; proteins; peptides; amino acids; fish

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cunha Neves, A. (2015). Extraction, purification and characterisation of biofunctional peptides from marine processing co-products. (Thesis). University of Limerick. Retrieved from http://hdl.handle.net/10344/4793

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Cunha Neves, Adriana. “Extraction, purification and characterisation of biofunctional peptides from marine processing co-products.” 2015. Thesis, University of Limerick. Accessed February 24, 2020. http://hdl.handle.net/10344/4793.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Cunha Neves, Adriana. “Extraction, purification and characterisation of biofunctional peptides from marine processing co-products.” 2015. Web. 24 Feb 2020.

Vancouver:

Cunha Neves A. Extraction, purification and characterisation of biofunctional peptides from marine processing co-products. [Internet] [Thesis]. University of Limerick; 2015. [cited 2020 Feb 24]. Available from: http://hdl.handle.net/10344/4793.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Cunha Neves A. Extraction, purification and characterisation of biofunctional peptides from marine processing co-products. [Thesis]. University of Limerick; 2015. Available from: http://hdl.handle.net/10344/4793

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

7. Kolpak, Adrianne L. The Role of Macropinocytosis in Sonic Hedgehog-Induced Axon Growth and Guidance: A Dissertation.

Degree: Interdisciplinary Graduate Program, Medicine; Cell Biology, 2009, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/451

► Axon pathfinding is an important process required for the establishment of proper neuronal connections during development. An increasing number of secreted and membrane-anchored molecules… (more)

▼ Axon pathfinding is an important process required for the establishment of proper neuronal connections during development. An increasing number of secreted and membrane-anchored molecules have been identified as axon guidance cues, which can act as positive or negative factors to increase or decrease the growth of axons and influence the direction of axonal growth. These axon guidance factors present in the extracellular environment interact with receptors present on the growth cone, a structure located at the tip of the axon which functions as the motor unit for the axon. Upon binding to their receptors on the growth cone, the guidance factors then elicit an intracellular signaling cascade within the axon that ultimately influences the direction of axon growth, often through a direct, non-transcriptional mechanism. In this dissertation, we show that Sonic hedgehog (Shh) acts as an axon guidance factor for chick retinal ganglion cell (RGC) axons in a concentration-dependent manner. At a low concentration, Shh functions as a positive factor that induces axon growth and attractive turning while, at a high concentration, Shh functions as a negative factor that induces axon retraction and repulsive axon turning. We further characterized the effects of Shh on macropinocytosis, a fluid-phase type of endocytosis, in the axons. A high concentration of Shh significantly increased macropinocytosis in the axons. Macropinocytosis resulted in the generation of large, dextran-positive, clathrinindependent vesicles in the axonal growth cones, prior to growth cone collapse, axon retraction and repulsive axon turning. These vesicles were found to require dynamic F-actin, nonmuscle myosin II and dynamin for their formation but were formed independently of PI3 kinase signaling. Interestingly, a low concentration of Shh had an opposite effect on macropinocytosis. A low concentration of Shh and soluble laminin decreased macropinocytosis and additionally increased the turnover of these vesicles within the axons, suggesting positive axon guidance factors can additionally regulate downstream processing or maturation of these vesicles. The effect of Shh on regulating the motility of macropinosomes within the axons was investigated. A low concentration of Shh appeared to increase the motility of these vesicles along axonal microtubules in a cAMPdependent manner. However, a high concentration of Shh did not appear to affect the motility of the macropinosomes, suggesting that it likely plays a more predominant role in the formation of these vesicles within the growth cone. When we began this work, a large body of research existed describing the effects of guidance factors on regulating the cytoskeleton during axon motility. However, the role of membrane trafficking events during axon growth and guidance were very poorly characterized. Since we began this project, an increasing number of reports have shown that endo- and exocytosis are important for axon growth and, here, we show that macropinocytosis induced by negative… Advisors/Committee Members: Zheng-Zheng Bao, Ph.D..

Subjects/Keywords: Pinocytosis; Axons; Growth Cones; Hedgehog Proteins; Amino Acids, Peptides, and Proteins; Cells; Nervous System

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kolpak, A. L. (2009). The Role of Macropinocytosis in Sonic Hedgehog-Induced Axon Growth and Guidance: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/451

Chicago Manual of Style (16^th Edition):

Kolpak, Adrianne L. “The Role of Macropinocytosis in Sonic Hedgehog-Induced Axon Growth and Guidance: A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/451.

MLA Handbook (7^th Edition):

Kolpak, Adrianne L. “The Role of Macropinocytosis in Sonic Hedgehog-Induced Axon Growth and Guidance: A Dissertation.” 2009. Web. 24 Feb 2020.

Vancouver:

Kolpak AL. The Role of Macropinocytosis in Sonic Hedgehog-Induced Axon Growth and Guidance: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/451.

Council of Science Editors:

Kolpak AL. The Role of Macropinocytosis in Sonic Hedgehog-Induced Axon Growth and Guidance: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/451

8. Melanson, Suzanne Marie. Functional Interaction of BPV-1 E2 with the Papillomavirus Genome: A Dissertation.

Degree: Immunology and Microbiology, Department of Medicine, 2009, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/410

► The bovine papillomavirus type 1 E2 protein is a multifunctional early viral protein with roles in all phases of the cell cycle. E2 is… (more)

Subjects/Keywords: DNA-Binding Proteins; Nuclear Proteins; Transcription Factors; Viral Proteins; Bovine papillomavirus; Amino Acids, Peptides, and Proteins; Cells; Genetic Phenomena; Viruses

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APA (6^th Edition):

Melanson, S. M. (2009). Functional Interaction of BPV-1 E2 with the Papillomavirus Genome: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/410

Chicago Manual of Style (16^th Edition):

Melanson, Suzanne Marie. “Functional Interaction of BPV-1 E2 with the Papillomavirus Genome: A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/410.

MLA Handbook (7^th Edition):

Melanson, Suzanne Marie. “Functional Interaction of BPV-1 E2 with the Papillomavirus Genome: A Dissertation.” 2009. Web. 24 Feb 2020.

Vancouver:

Melanson SM. Functional Interaction of BPV-1 E2 with the Papillomavirus Genome: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/410.

Council of Science Editors:

Melanson SM. Functional Interaction of BPV-1 E2 with the Papillomavirus Genome: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/410

9. Clingman, Carina C. A Feedback Loop Couples Musashi-1 Activity to Omega-9 Fatty Acid Biosynthesis: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, Biochemistry and Molecular Pharmacology, 2014, U of Massachusetts : Med

URL: http://escholarship.umassmed.edu/gsbs_diss/718

► All living creatures change their gene expression program in response to nutrient availability and metabolic demands. Nutrients and metabolites can directly control transcription and… (more)

Subjects/Keywords: Fatty Acids; Gene Expression Regulation; RNA; RNA-Binding Proteins; Stem Cells; Amino Acids, Peptides, and Proteins; Biochemistry; Molecular Biology

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APA (6^th Edition):

Clingman, C. C. (2014). A Feedback Loop Couples Musashi-1 Activity to Omega-9 Fatty Acid Biosynthesis: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from http://escholarship.umassmed.edu/gsbs_diss/718

Chicago Manual of Style (16^th Edition):

Clingman, Carina C. “A Feedback Loop Couples Musashi-1 Activity to Omega-9 Fatty Acid Biosynthesis: A Dissertation.” 2014. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. http://escholarship.umassmed.edu/gsbs_diss/718.

MLA Handbook (7^th Edition):

Clingman, Carina C. “A Feedback Loop Couples Musashi-1 Activity to Omega-9 Fatty Acid Biosynthesis: A Dissertation.” 2014. Web. 24 Feb 2020.

Vancouver:

Clingman CC. A Feedback Loop Couples Musashi-1 Activity to Omega-9 Fatty Acid Biosynthesis: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2014. [cited 2020 Feb 24]. Available from: http://escholarship.umassmed.edu/gsbs_diss/718.

Council of Science Editors:

Clingman CC. A Feedback Loop Couples Musashi-1 Activity to Omega-9 Fatty Acid Biosynthesis: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2014. Available from: http://escholarship.umassmed.edu/gsbs_diss/718

Wilfrid Laurier University

10. Rice, Kyle. Characterization of the Microbial Phosphonate-Activating PntC Enzymes.

Degree: 2019, Wilfrid Laurier University

URL: https://scholars.wlu.ca/etd/2163

► New strategies are urgently needed to combat infectious diseases in an era of rising antibiotic resistance. Furthermore, an emerging appreciation for the human microbiome’s role… (more)

▼ New strategies are urgently needed to combat infectious diseases in an era of rising antibiotic resistance. Furthermore, an emerging appreciation for the human microbiome’s role in maintaining health motivates discovery of species-specific antibiotics that minimally disrupt our native bacterial communities. Small molecule modifications to bacterial cell surfaces represent a potentially rich source of new targets for next generation antibiotics, as these molecules mediate virulence and evasion of the host immune response. Phosphocholine (PCho) is a rare cell surface modification that contributes to virulence, and modifications with phosphonates like 2-aminoethylphosphonate (AEP) are even more unusual and therefore provide opportunities for species- and pathway-specific targeting. Cytidylyltransferase enzymes are required to activate these unique substrates. The cytidylyltransferase LicC was previously known to activate PCho through addition of a cytidine monophosphate (CMP) moiety, and here we demonstrate that the homologous protein that we have termed PntC activates AEP. PntC homologs and resulting cell-surface phosphonate modifications have been identified across diverse phyla of bacteria. Among these bacterial species are the known pathogens Atopobium rimae, Olsenella uli, Treponema denticola, and Streptococcus pneumoniae. NMR analysis and continuous spectrophotometric assays were performed to compare LicC from S. pneumoniae (Spn-LicC) to PntCs from the Gram positive A. rimae (Ari-PntC) and Gram negative T. denticola (Tde-PntC). The results demonstrated that: (i) PntC enzymes generate a previously unreported compound CMP-AEP; (ii) PntCs exhibit specificity towards CTP and Mg2+; (iii) PntCs possess >400-fold preference for AEP over PCho, while LicC exhibits a 200-fold preference for PCho over AEP; and (iv) LicC is capable of accepting a range of larger substrates. These findings have provided insight into the activity and versatility of these proteins to utilize uncommon molecular substrates, setting the stage for the development of molecular probes and effective protein-specific inhibitors designed to halt the overall phosphonate-tailoring pathway which could ultimately disrupt the ability of the pathogen to confer virulence in a host.

Subjects/Keywords: Nucleotidyltransferase; Enzyme Kinetics; Proteins; Amino Acids, Peptides, and Proteins; Biochemistry; Enzymes and Coenzymes; Nucleic Acids, Nucleotides, and Nucleosides; Other Chemistry

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APA (6^th Edition):

Rice, K. (2019). Characterization of the Microbial Phosphonate-Activating PntC Enzymes. (Thesis). Wilfrid Laurier University. Retrieved from https://scholars.wlu.ca/etd/2163

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Rice, Kyle. “Characterization of the Microbial Phosphonate-Activating PntC Enzymes.” 2019. Thesis, Wilfrid Laurier University. Accessed February 24, 2020. https://scholars.wlu.ca/etd/2163.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Rice, Kyle. “Characterization of the Microbial Phosphonate-Activating PntC Enzymes.” 2019. Web. 24 Feb 2020.

Vancouver:

Rice K. Characterization of the Microbial Phosphonate-Activating PntC Enzymes. [Internet] [Thesis]. Wilfrid Laurier University; 2019. [cited 2020 Feb 24]. Available from: https://scholars.wlu.ca/etd/2163.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Rice K. Characterization of the Microbial Phosphonate-Activating PntC Enzymes. [Thesis]. Wilfrid Laurier University; 2019. Available from: https://scholars.wlu.ca/etd/2163

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Florida

11. Ocampo, Charles. Long-Range Intramolecular S → N Acyl Migration via 15- and 16-Membered Cyclic Transition States: A Study of the Formation of Native Peptide Analogues.

Degree: 2012, University of Florida

URL: http://ufdc.ufl.edu/AA00059806

► The intramolecular long-range S to N acyl migration of S-acyl peptides containing cysteine residues via 15- and 16-membered cyclic transition states was studied. Unnatural amino… (more)

Subjects/Keywords: Acetates; Amino acids; Chemicals; Dimers; HIV 1; Lactones; Ligation; Microcrystals; Microwaves; Proteins; Peptides

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APA (6^th Edition):

Ocampo, C. (2012). Long-Range Intramolecular S → N Acyl Migration via 15- and 16-Membered Cyclic Transition States: A Study of the Formation of Native Peptide Analogues. (Thesis). University of Florida. Retrieved from http://ufdc.ufl.edu/AA00059806

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ocampo, Charles. “Long-Range Intramolecular S → N Acyl Migration via 15- and 16-Membered Cyclic Transition States: A Study of the Formation of Native Peptide Analogues.” 2012. Thesis, University of Florida. Accessed February 24, 2020. http://ufdc.ufl.edu/AA00059806.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ocampo, Charles. “Long-Range Intramolecular S → N Acyl Migration via 15- and 16-Membered Cyclic Transition States: A Study of the Formation of Native Peptide Analogues.” 2012. Web. 24 Feb 2020.

Vancouver:

Ocampo C. Long-Range Intramolecular S → N Acyl Migration via 15- and 16-Membered Cyclic Transition States: A Study of the Formation of Native Peptide Analogues. [Internet] [Thesis]. University of Florida; 2012. [cited 2020 Feb 24]. Available from: http://ufdc.ufl.edu/AA00059806.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ocampo C. Long-Range Intramolecular S → N Acyl Migration via 15- and 16-Membered Cyclic Transition States: A Study of the Formation of Native Peptide Analogues. [Thesis]. University of Florida; 2012. Available from: http://ufdc.ufl.edu/AA00059806

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Arkansas

12. Bullock, Cody. Dissecting the Mechanism of Action of a Novel Antifungal Peptide.

Degree: MS, 2018, University of Arkansas

URL: https://scholarworks.uark.edu/etd/2891

► There is an urgent need for novel treatments for Candida infections. The utility of antimicrobial peptides for antifungal therapy has garnered interest in recent… (more)

▼ There is an urgent need for novel treatments for Candida infections. The utility of antimicrobial peptides for antifungal therapy has garnered interest in recent years. One promising family of peptides is the Histatins, a family of naturally-occurring peptides secreted into the oral cavity that display antimicrobial activity. Histatin 5 is a twenty-four amino acid peptide with strong antifungal activity. Studies from our laboratory have identified a small histatin-derived peptide, KM29, that yields fungicidal activity 10-fold greater than Histatin 5 against multiple Candida species. Our laboratory has focused on understanding the mechanism of action of KM29 to further develop it as a therapeutic agent for oral and systemic candidiasis. To this end, a genetic screen was carried out using the available genome-wide deletion collection in S. cerevisiae. Our goal was to use this as a subrogates species to learn about the killing mechanism used by KM29 in Candida species. Analysis of the mutants revealed a significant presence of genes involved in mitochondrial function conferring increased resistance to KM29. We hypothesized that the S. cerevisiae mutants affected in different aspects of mitochondrial function will be more resistant to KM29 either because there is less ROS production due to their defective mitochondria, or less ATP production, which in turn may decrease peptide uptake and/or mitochondrial localization. We observed concentration dependent ROS production after exposure to KM29, however, this ROS production was loosely correlated with cell death. We also observed mitochondrial membrane potential depolarization and mitochondrial fission after exposure to KM29, indicating impairment of mitochondrial function. Additionally, we observed that the respiratory status of yeast cells inversely regulates KM29 fungicidal activity by influencing KM29 uptake. In conclusion, these studies provide valuable insights into the mechanism of action of KM29 and of cationic peptides in general. Advisors/Committee Members: Inés Pinto, Daniel Lessner, Yuchun Du.

Subjects/Keywords: Antifungal; Antimicrobials; Candida; Amino Acids, Peptides, and Proteins; Cell Biology; Microbial Physiology

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APA (6^th Edition):

Bullock, C. (2018). Dissecting the Mechanism of Action of a Novel Antifungal Peptide. (Masters Thesis). University of Arkansas. Retrieved from https://scholarworks.uark.edu/etd/2891

Chicago Manual of Style (16^th Edition):

Bullock, Cody. “Dissecting the Mechanism of Action of a Novel Antifungal Peptide.” 2018. Masters Thesis, University of Arkansas. Accessed February 24, 2020. https://scholarworks.uark.edu/etd/2891.

MLA Handbook (7^th Edition):

Bullock, Cody. “Dissecting the Mechanism of Action of a Novel Antifungal Peptide.” 2018. Web. 24 Feb 2020.

Vancouver:

Bullock C. Dissecting the Mechanism of Action of a Novel Antifungal Peptide. [Internet] [Masters thesis]. University of Arkansas; 2018. [cited 2020 Feb 24]. Available from: https://scholarworks.uark.edu/etd/2891.

Council of Science Editors:

Bullock C. Dissecting the Mechanism of Action of a Novel Antifungal Peptide. [Masters Thesis]. University of Arkansas; 2018. Available from: https://scholarworks.uark.edu/etd/2891

University of Arkansas

13. Hardman, Rebecca E. Global Acetylation Dynamics in the Heat Shock Response of Saccharomyces cerevisiae.

Degree: PhD, 2019, University of Arkansas

URL: https://scholarworks.uark.edu/etd/3489

► All organisms face a constant barrage of environmental stresses. Single-cell organisms such as Saccharomyces cerevisiae, or common Baker’s yeast, must rely solely on cellular… (more)

▼ All organisms face a constant barrage of environmental stresses. Single-cell organisms such as Saccharomyces cerevisiae, or common Baker’s yeast, must rely solely on cellular responses in order to survive. This response must occur in a rapid and highly coordinated manner to quickly inhibit all unnecessary processes and shuttle all available resources to those necessary for survival. One method that cells utilize for rapid protein regulation is the use of post-translational modifications. Enzymes within the cell add or remove a variety of chemical modifications, thus altering the local chemical environment of a protein. This creates a conformational change in the protein that can increase, decrease, or completely change the activity of the protein, as well as target them for relocation or degradation. Examples of common post-translational modifications include phosphorylation, ubiquitination, and the focus of this dissertation, acetylation. That protein acetylation occurs has been known for decades, but it is only recently that advances in technology such as high-resolution mass spectrometry and immunoprecipitation have led to the recognition of thousands of acetylated proteins across all domains of life. The roles and regulation of this modification, however, are still widely unknown. One approach to better understand possible roles for acetylation is to look at its dynamics in response to environmental stress. In this dissertation, I examine global changes in protein acetylation in the response of Saccharomyces cerevisiae to a mild heat shock and the potential mechanisms regulating these changes. Following an introductory literature review, this dissertation will cover the results of a large time-scale profiling of acetylome dynamics in response to heat shock. Proteins identified in this experiment are enriched for many cellular processes, suggesting that acetylation may play a much wider regulatory role than previously believed. These proteins are also enriched for interactions with many lysine acetyltransferases and deacetylases, suggesting that the regulation of this modification is complex. The next chapter will then discuss possible mechanisms regulating this response. This includes the investigation into concentrations of metabolites known to affect acetylation and deacetylation, lysine acetyltransferase and deacetylase complex remodeling, and localization changes for those complexes within the cell. Advisors/Committee Members: Jeffrey A. Lewis, Yuchun Du, Paul D. Adams.

Subjects/Keywords: acetylation; acetylome; global; heat shock; stress; yeast; Amino Acids, Peptides, and Proteins; Molecular Biology

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APA (6^th Edition):

Hardman, R. E. (2019). Global Acetylation Dynamics in the Heat Shock Response of Saccharomyces cerevisiae. (Doctoral Dissertation). University of Arkansas. Retrieved from https://scholarworks.uark.edu/etd/3489

Chicago Manual of Style (16^th Edition):

Hardman, Rebecca E. “Global Acetylation Dynamics in the Heat Shock Response of Saccharomyces cerevisiae.” 2019. Doctoral Dissertation, University of Arkansas. Accessed February 24, 2020. https://scholarworks.uark.edu/etd/3489.

MLA Handbook (7^th Edition):

Hardman, Rebecca E. “Global Acetylation Dynamics in the Heat Shock Response of Saccharomyces cerevisiae.” 2019. Web. 24 Feb 2020.

Vancouver:

Hardman RE. Global Acetylation Dynamics in the Heat Shock Response of Saccharomyces cerevisiae. [Internet] [Doctoral dissertation]. University of Arkansas; 2019. [cited 2020 Feb 24]. Available from: https://scholarworks.uark.edu/etd/3489.

Council of Science Editors:

Hardman RE. Global Acetylation Dynamics in the Heat Shock Response of Saccharomyces cerevisiae. [Doctoral Dissertation]. University of Arkansas; 2019. Available from: https://scholarworks.uark.edu/etd/3489

Texas Medical Center

14. Moore, John R. Phage Display Library Screening for PSA-/lo Prostate Cancer Cell-Binding Peptides.

Degree: MS, 2014, Texas Medical Center

URL: http://digitalcommons.library.tmc.edu/utgsbs_dissertations/453

► Prostate cancer (PCa) is one of the leading malignancies affecting men worldwide. Our lab focuses on understanding the molecular mechanisms underlying prostate carcinogenesis and… (more)

▼ Prostate cancer (PCa) is one of the leading malignancies affecting men worldwide. Our lab focuses on understanding the molecular mechanisms underlying prostate carcinogenesis and developing therapeutics that target the cells responsible for driving PCa and mediating therapy resistance. My master thesis research employs a phage display library screening technology aiming to identify peptides that preferentially home in to undifferentiated PCa cells, which our lab has previously demonstrated to be intrinsically resistant to castration. There is now evidence that a population of cells in PCa possesses characteristics associated with stem cells; these cells are referred to as cancer stem cells (CSCs). CSCs have been implicated in tumor propagation, progression and recurrence. In PCa, androgen deprivation therapy (ADT) is the mainstay treatment however, the majority of patients relapse after treatments, resulting in castration-resistant prostate cancer (CRPC). Our lab has provided evidence that the phenotypically undifferentiated PCa cell population expressing low levels or no prostate specific antigen (i.e., PSA^-/lo) is enriched in prostate cancer stem cells (PCSCs) that can long-term propagate tumors and also resist ADT. The PSA^-/lo PCa cell population represents the best characterized PCSCs and likely a cell-of-origin for CRPC. Consequently, it is important to find therapeutics that can preferentially target these cells. To this end, we employed highly purified PSA^-/lo LNCaP PCa cells to perform phage display library screening. Our preliminary efforts identified two peptides, JRM1 and JRM2 that displayed preferential binding to PSA^-/lo PCa cells. We first identified a potential peptide that may home in to the PSA^-/lo LNCaP cells by conducting a phage display library screening of LNCaP PSA-GFP utilizing a competitive assay technique. This peptide, TEWDYLTV, referred to as JRM1, showed slight but not statistically significant, preferential binding to the PSA^-/lo LNCaP cells. With this knowledge we carried out another phage display library screening using adherent LNCaP PSA-GFP cells and an indirect subtraction assay. The results led to the identification of peptide JRM2, GFYVGQR, which demonstrated preferential and statistically significant binding to the PSA^-/lo LNCaP cells. With this peptide we would like to attach either anti-cancer drugs or pro-apoptotic peptides to it and measure their effectiveness at killing undifferentiated and castration-resistant PCa cells. Advisors/Committee Members: Dr. Dean Tang, Dr. David Johnson, Dr. Mark McArthur.

Subjects/Keywords: Prostate cancer stem cells; PSA-; Phage Display; Peptides; Amino Acids, Peptides, and Proteins; Medicine and Health Sciences; Therapeutics

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APA (6^th Edition):

Moore, J. R. (2014). Phage Display Library Screening for PSA-/lo Prostate Cancer Cell-Binding Peptides. (Masters Thesis). Texas Medical Center. Retrieved from http://digitalcommons.library.tmc.edu/utgsbs_dissertations/453

Chicago Manual of Style (16^th Edition):

Moore, John R. “Phage Display Library Screening for PSA-/lo Prostate Cancer Cell-Binding Peptides.” 2014. Masters Thesis, Texas Medical Center. Accessed February 24, 2020. http://digitalcommons.library.tmc.edu/utgsbs_dissertations/453.

MLA Handbook (7^th Edition):

Moore, John R. “Phage Display Library Screening for PSA-/lo Prostate Cancer Cell-Binding Peptides.” 2014. Web. 24 Feb 2020.

Vancouver:

Moore JR. Phage Display Library Screening for PSA-/lo Prostate Cancer Cell-Binding Peptides. [Internet] [Masters thesis]. Texas Medical Center; 2014. [cited 2020 Feb 24]. Available from: http://digitalcommons.library.tmc.edu/utgsbs_dissertations/453.

Council of Science Editors:

Moore JR. Phage Display Library Screening for PSA-/lo Prostate Cancer Cell-Binding Peptides. [Masters Thesis]. Texas Medical Center; 2014. Available from: http://digitalcommons.library.tmc.edu/utgsbs_dissertations/453

15. Yang, Xiaoyan. Long-Range Side Chain-Main Chain Hydrogen Bonds: A Molecular Signature of the TIM Barrel Architecture: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, Program in Biochemistry and Molecular Pharmacology, 2009, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/430

► The hydrophobic effect and hydrogen bonding interactions have long been considered to be the dominant forces in protein folding. However, the contribution of hydrogen… (more)

▼ The hydrophobic effect and hydrogen bonding interactions have long been considered to be the dominant forces in protein folding. However, the contribution of hydrogen bonds to stabilizing proteins has been difficult to clarify. As the intramolecular hydrogen bonds are formed in place of hydrogen bonds with solvent during folding, measures of stability fail to give a significant change in free energy. Previous studies on hydrogen bonding interactions have shown that they are only marginally important. Three long-range side chain-main chain hydrogen bonds have been found in the alpha subunit of tryptophan synthase (αTS), a (βα)₈TIM barrel protein. These long-range noncovalent interactions connect either the N-terminus of one β-strand with the C-terminus of the succeeding and anti-parallel α-helix (F19-D46 and I97-D124) or the N-terminus of an α-helix with the C-terminus of the succeeding β-strand (A103-D130). By analogy, these interactions are designated as βα- or αβ-hairpin clamps. Surprisingly, the removal of any one of these clamp interactions, by replacement of the aspartic acid with alanine, results in significantly decreased thermodynamic stability for the native state and a substantial loss of secondary structure. When compared to several other side chain-side chain and short-range side chain-main chain interactions in αTS, these hairpin clamps clearly play a unique role in the structure and stability of αTS. The generality of these observations for βα-hairpin clamps in TIM barrel proteins was tested by experimental analysis of the clamps in a pair of homologous indole-3-glycerol phosphate synthase (IGPS) TIM barrels of low sequence identity. The results suggest that only the subset of conserved βα-hairpin clamps with hydrogen bond length less than 2.80 Å make substantive contributions to stability and/or structure. Those clamps with longer hydrogen bonds make modest contributions to stability and structure, similar to other types of side chain-main chain or side chain-side chain hydrogen bonds. The role of these clamps in defining the structures of the super-family of TIM barrel proteins was examined by a survey of 71 TIM barrel proteins from the structural database. Conserved features of βα-hairpin clamps are consistent with a 4-fold symmetry, with a predominance of main chain amide hydrogen bond donors near the N-terminus of the odd-number β-strands and side chain hydrogen bond acceptors in the loops between the subsequent α-helices and even-numbered β-strands. In this configuration, the clamps provide an N-terminal cap to odd-number β- strands in the β-barrel. Taken together, these findings suggest that βα-hairpin clamps are a vestigial signature of the fundamental βαβ building block for the (βα)8 motif and an integral part of the basic TIM barrel architecture. The relative paucity of βα-hairpin clamps remaining in TIM barrel structures and their variable contributions to stability imply that other determinants for structure and stability of the barrel have evolved to… Advisors/Committee Members: C. Robert Matthews, Ph.D..

Subjects/Keywords: Hydrogen Bonding; Protein Folding; Amino Acid Motifs; Tryptophan Synthase; Amino Acids, Peptides, and Proteins; Enzymes and Coenzymes; Inorganic Chemicals

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APA (6^th Edition):

Yang, X. (2009). Long-Range Side Chain-Main Chain Hydrogen Bonds: A Molecular Signature of the TIM Barrel Architecture: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/430

Chicago Manual of Style (16^th Edition):

Yang, Xiaoyan. “Long-Range Side Chain-Main Chain Hydrogen Bonds: A Molecular Signature of the TIM Barrel Architecture: A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/430.

MLA Handbook (7^th Edition):

Yang, Xiaoyan. “Long-Range Side Chain-Main Chain Hydrogen Bonds: A Molecular Signature of the TIM Barrel Architecture: A Dissertation.” 2009. Web. 24 Feb 2020.

Vancouver:

Yang X. Long-Range Side Chain-Main Chain Hydrogen Bonds: A Molecular Signature of the TIM Barrel Architecture: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/430.

Council of Science Editors:

Yang X. Long-Range Side Chain-Main Chain Hydrogen Bonds: A Molecular Signature of the TIM Barrel Architecture: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/430

16. Kathuria, Sagar V. Sequence Determinants of the Folding Free-Energy Landscape of beta alpha-Repeat Proteins: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, Biochemistry and Molecular Pharmacology Program, 2010, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/480

► The most common structural platform in biology, the βα-repeat classes of proteins, are represented by the (βα)₈TIM barrel topology and the α/β/α sandwich, CheY-like… (more)

▼ The most common structural platform in biology, the βα-repeat classes of proteins, are represented by the (βα)₈TIM barrel topology and the α/β/α sandwich, CheY-like topology. Previous studies on the folding mechanisms of several members of these proteins have suggested that the initial event during refolding involves the formation of a kinetically trapped species that at least partially unfolds before the native conformation can be accessed. The simple topologies of these proteins are thought to permit access to locally folded regions that may coalesce in non-native ways to form stable interactions leading to misfolded intermediates. In a pair of TIM barrel proteins, αTS and sIGPS, it has been shown that the core of the off-pathway folding intermediates is comprised of locally connected clusters of isoleucine, leucine and valine (ILV) residues. These clusters of Branched Aliphatic Side Chains (BASiC) have the unique ability to very effectively prevent the penetration of water to the underlying hydrogen bond networks. This property retards hydrogen exchange with solvent, strengthening main chain hydrogen bonds and linking tertiary and secondary structure in a cooperative network of interactions. This property would also promote the rapid formation of collapsed species during refolding. From this viewpoint, the locally connected topology and the appropriate distribution of ILV residues in the sequence can modulate the energy landscapes of TIM barrel proteins. Another sequence determinant of protein stability that can significantly alter the structure and stability of TIM barrels is the long-range main chain-side chain hydrogen bond. Three of these interactions have been shown to form the molecular underpinnings for the cooperative access to the native state in αTS. Global analysis results presented in Chapter II and Chapter III, suggest that the off-pathway mechanism is common to three proteins of the CheY-like topology, namely CheY, NT-NtrC and Spo0F. These results are corroborated by Gō-simulations that are able to identify the minimal structure of kinetically trapped species during the refolding of CheY and Spo0F. The extent of transient, premature structure appears to correlate with the number of ILV side chains involved in a large sequence-local cluster that is formed between the central β-sheet and helices α2, α3 and α4. The failure of Gō-simulations to detect off-pathway species during the refolding of NT-NtrC may reflect the smaller number of ILV side chains in its corresponding hydrophobic cluster. In Chapter IV, comparison of the location of large ILV clusters with the hydrogen exchange protected regions in 19 proteins, suggest that clusters of BASiC residues are the primarily determinants of the stability cores of globular proteins. Although the location of the ILV clusters is sufficient to determine a majority of the protected amides in a protein structure, the extent of protection is over predicted by the ILV cluster method. The survey of 71 TIM barrel proteins presented in… Advisors/Committee Members: C. Robert Matthews, Ph.D..

Subjects/Keywords: Protein Folding; Protein Structure; Secondary; Repetitive Sequences; Amino Acid; Amino Acids, Peptides, and Proteins; Biochemistry, Biophysics, and Structural Biology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kathuria, S. V. (2010). Sequence Determinants of the Folding Free-Energy Landscape of beta alpha-Repeat Proteins: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/480

Chicago Manual of Style (16^th Edition):

Kathuria, Sagar V. “Sequence Determinants of the Folding Free-Energy Landscape of beta alpha-Repeat Proteins: A Dissertation.” 2010. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/480.

MLA Handbook (7^th Edition):

Kathuria, Sagar V. “Sequence Determinants of the Folding Free-Energy Landscape of beta alpha-Repeat Proteins: A Dissertation.” 2010. Web. 24 Feb 2020.

Vancouver:

Kathuria SV. Sequence Determinants of the Folding Free-Energy Landscape of beta alpha-Repeat Proteins: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2010. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/480.

Council of Science Editors:

Kathuria SV. Sequence Determinants of the Folding Free-Energy Landscape of beta alpha-Repeat Proteins: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2010. Available from: https://escholarship.umassmed.edu/gsbs_diss/480

17. Ghosh, Shubhendu. Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation.

Degree: Molecular Genetics and Microbiology, Microbiology and Physiological Systems, 2010, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/454

► The proper workings of an organism rely on the accurate expression of genes throughout its lifetime. An important determinant for protein production is the… (more)

▼ The proper workings of an organism rely on the accurate expression of genes throughout its lifetime. An important determinant for protein production is the availability of template mRNA molecules, the net effect of which is governed by their rates of synthesis vs. their rates of degradation. Normal mRNAs are proposed to be relatively stable in the cytoplasm while present in a protective, circularized conformation – the closed loop – through eIF4G-bridged interactions with 3’-bound poly(A) binding protein (Pab1p) and 5’-bound eIF4E. Introduction of a premature nonsense codon into an otherwise normal mRNA results in its rapid destabilization in cells, suggesting that not all stop codons behave the same, and events at premature termination events that lead to accelerated degradation of nonsense-containing mRNAs likely differ from those at normal termination, in which normal decay rates are maintained. The enhanced degradation observed for nonsense-containing mRNAs occurs through an evolutionarily conserved pathway involving the products of the UPF1, UPF2/NMD2, and UPF3 genes, the precise biochemical roles of which have remained elusive. We have developed a yeast cell-free translation system that allows us to assay biochemical events occurring at premature termination codons, compare them to those occurring at normal terminators, and study the role of Upf1p in these events. We find that premature termination is an inefficient process compared to normal termination and that one outcome of termination at a premature termination codon (PTC) is reinitiation at a nearby start codon. This in vitro post-termination reinitiation phenotype is dependent on the presence of Upf1p, a finding we have recapitulated in vivo. We also developed biochemical assays to define a role for Upf1p in translation following premature termination in vitro and find that Upf1p is involved in post-termination ribosome dissociation and reutilization. Supporting this idea are our findings that Upf1p predominantly cosediments with purified 40S ribosomal subunits. Finally, using our in vitro translation/toeprinting system, we have further characterized events leading to the formation of the mRNA closed loop structure and find that two states of the closed loop exist. The first requires the preinitiation 48S complex and includes Pab1p, eIF4G, eIF4E, and eIF3, whereas the second is formed after 60S joining and additionally requires the translation termination factors eRF1 and eRF3. Advisors/Committee Members: Dr. Allan Jacobson.

Subjects/Keywords: RNA; Messenger; RNA Stability; Protein Biosynthesis; Amino Acids, Peptides, and Proteins; Cells; Genetic Phenomena; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ghosh, S. (2010). Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/454

Chicago Manual of Style (16^th Edition):

Ghosh, Shubhendu. “Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation.” 2010. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/454.

MLA Handbook (7^th Edition):

Ghosh, Shubhendu. “Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation.” 2010. Web. 24 Feb 2020.

Vancouver:

Ghosh S. Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2010. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/454.

Council of Science Editors:

Ghosh S. Cross-Talk Between Factors Involved in mRNA Translation and Decay: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2010. Available from: https://escholarship.umassmed.edu/gsbs_diss/454

18. Duffy, Caroline M. Structural Mechanisms of the Sliding Clamp and Sliding Clamp Loader: Insights into Disease and Function: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, Biochemistry and Molecular Pharmacology, 2016, U of Massachusetts : Med

URL: http://escholarship.umassmed.edu/gsbs_diss/844

► Chromosomal replication is an essential process in all life. This dissertation highlights regulatory roles for two critical protein complexes at the heart of the… (more)

Subjects/Keywords: DNA Replication; DNA-Binding Proteins; DNA Primers; Amino Acids, Peptides, and Proteins; Biochemistry; Molecular Biology; Structural Biology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Duffy, C. M. (2016). Structural Mechanisms of the Sliding Clamp and Sliding Clamp Loader: Insights into Disease and Function: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from http://escholarship.umassmed.edu/gsbs_diss/844

Chicago Manual of Style (16^th Edition):

Duffy, Caroline M. “Structural Mechanisms of the Sliding Clamp and Sliding Clamp Loader: Insights into Disease and Function: A Dissertation.” 2016. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. http://escholarship.umassmed.edu/gsbs_diss/844.

MLA Handbook (7^th Edition):

Duffy, Caroline M. “Structural Mechanisms of the Sliding Clamp and Sliding Clamp Loader: Insights into Disease and Function: A Dissertation.” 2016. Web. 24 Feb 2020.

Vancouver:

Duffy CM. Structural Mechanisms of the Sliding Clamp and Sliding Clamp Loader: Insights into Disease and Function: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2016. [cited 2020 Feb 24]. Available from: http://escholarship.umassmed.edu/gsbs_diss/844.

Council of Science Editors:

Duffy CM. Structural Mechanisms of the Sliding Clamp and Sliding Clamp Loader: Insights into Disease and Function: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2016. Available from: http://escholarship.umassmed.edu/gsbs_diss/844

19. Yuan, Quan. The Circadian Clock in Monarch Butterfly: A Tale of Two CRYs: A Dissertation.

Degree: Neuroscience, Department of Neurobiology; Reppert Lab, 2009, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/429

► Every fall, Northeastern America monarch butterflies (Danaus plexippus) undergo an extraordinary migration to their overwintering site in Central Mexico. During their long migration, monarch… (more)

▼ Every fall, Northeastern America monarch butterflies (Danaus plexippus) undergo an extraordinary migration to their overwintering site in Central Mexico. During their long migration, monarch migrants use sun compass to navigate. To maintain a southward flying direction, monarch migrants compensate for the continuously changing position of the sun by providing timing information to the compass using their circadian clock. Animal circadian clocks depend primarily on a negative transcriptional feedback loop to track time. I started my work to re-construct the monarch butterfly circadian clock negative feedback loop in cell culture, focusing on homologs of Drosophila clock genes. It turned out that in addition to a Drosophila-like cryptochrome (cry1) gene, a second mammalian-like cry2 gene exists in monarch butterflies and many other insects, except in Drosophila. The two CRYs showed distinct functions in our initial assays in cultured Drosophila Schneider 2 (S2) cells. CRY2 functions as a potent transcriptional repressor, while CRY1 is light sensitive but shows no obvious transcriptional activity. The existence of two cry genes in insects changed the Drosophila-centric view of insect circadian clock. During the course of my study, our lab obtained a monarch cell line called DpN1 cells. These cells possess a light-driven clock and contributed tremendously to the research on monarch circadian clock. Using this cell line, I provided strong evidence supporting monarch CRY2’s role as a major circadian clock repressor and identified a protein-protein protective interaction cascade underlying the CRY1-mediated resetting of the molecular oscillator in DpN1 cells. I continued my work trying to understand how insect CRY2 inhibits transcription. I provided evidence suggesting the involvement of monarch PER in promoting CRY2 nuclear entry in both S2 cells and DpN1 cells. Finally, I mapped CRY2’s transcriptional inhibitory activity onto its N-terminal domain. Collectively, my research helped to change our view of insect clocks from a Drosophila-centric standpoint to a much more diverse picture. My studies also advanced the understanding of monarch circadian clock mechanism, and provides a foundation for further studies. Advisors/Committee Members: Steven M. Reppert.

Subjects/Keywords: circadian clock; monarch butterfly; Circadian Rhythm; Butterflies; Biological Clocks; Drosophila Proteins; Flavoproteins; Amino Acids, Peptides, and Proteins; Animal Experimentation and Research

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Yuan, Q. (2009). The Circadian Clock in Monarch Butterfly: A Tale of Two CRYs: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/429

Chicago Manual of Style (16^th Edition):

Yuan, Quan. “The Circadian Clock in Monarch Butterfly: A Tale of Two CRYs: A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/429.

MLA Handbook (7^th Edition):

Yuan, Quan. “The Circadian Clock in Monarch Butterfly: A Tale of Two CRYs: A Dissertation.” 2009. Web. 24 Feb 2020.

Vancouver:

Yuan Q. The Circadian Clock in Monarch Butterfly: A Tale of Two CRYs: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/429.

Council of Science Editors:

Yuan Q. The Circadian Clock in Monarch Butterfly: A Tale of Two CRYs: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/429

20. Mehrotra, Swarna. IAP Regulation of Tumor Metastasis: A Dissertation.

Degree: Cancer Biology, Department of Cancer Biology, 2009, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/437

► The dissemination of tumor cells to distant organs i.e. metastasis is an exceedingly complex process leading to 90% of all cancer deaths. Despite being… (more)

▼ The dissemination of tumor cells to distant organs i.e. metastasis is an exceedingly complex process leading to 90% of all cancer deaths. Despite being so clinically important, little is known about this process that requires tumor cells to leave the primary tumor site, intravasate and transport through the blood stream, extravasate and colonize at secondary sites leading to distant metastases. Survivin, a member of the IAP (Inhibitor of Apoptosis) family with known functions in apoptosis and mitosis, is highly expressed in aggressive tumors and is associated with poor prognosis and adverse clinical outcome. But the mechanistic role of survivin in metastatic dissemination has not been investigated. In this study, we demonstrate an important and novel role of survivin in activating a broad gene expression program in tumor cells. Of particular importance is the upregulation of a distinct class of cell adhesion molecules, particularly fibronectin. This IAP mediated gene regulation requires synergistic intermolecular cooperation between survivin and its related cofactor molecule, XIAP that results in activation of NF-κB dependent fibronectin gene expression. The binding of fibronectin with its cognate cell surface receptors initiates outside–in signaling leading to the autocrine and paracrine activation of cell motility kinases, FAK and Src, in turn leading to enhanced tumor invasion and metastasis. The importance of survivin and XIAP in the process of metastasis has also been demonstrated in vivousing intrasplenic injections in mouse models. Overall this study is the first to place survivin upstream of transcriptional activation of gene expression particularly fibronectin. In addition, it also demonstrates the importance of survivin-XIAP complex in mediating NF-κB activation which in turn switches on the expression of various target genes involved in tumor metastasis. Hence this study dissects the upstream and downstream requirements of survivin- XIAP complex mediated tumor dissemination and metastasis. Significance of this Study The hallmark of end-stage cancer is metastasis, an incurable condition almost invariably associated with death from disease. Despite a better understanding of the metastatic process, and the identification of key gene expression requirements of this pathway, the development of anti-metastatic therapies has lagged behind, with no viable options being currently offered in the clinical setting. Our findings that Inhibitor of Apoptosis (IAP) proteins functions as metastasis-promoting genes independently of cell survival, but through activation of cell motility could have important ramifications for the broader application of IAP antagonists currently in early clinical trials, as novel anti-metastatic therapies. Advisors/Committee Members: Dario C. Altieri, M.D..

Subjects/Keywords: Neoplasm Metastasis; Inhibitor of Apoptosis Proteins; Fibronectins; Transcriptional Activation; X-Linked Inhibitor of Apoptosis Protein; Amino Acids, Peptides, and Proteins; Neoplasms

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Mehrotra, S. (2009). IAP Regulation of Tumor Metastasis: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/437

Chicago Manual of Style (16^th Edition):

Mehrotra, Swarna. “IAP Regulation of Tumor Metastasis: A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/437.

MLA Handbook (7^th Edition):

Mehrotra, Swarna. “IAP Regulation of Tumor Metastasis: A Dissertation.” 2009. Web. 24 Feb 2020.

Vancouver:

Mehrotra S. IAP Regulation of Tumor Metastasis: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/437.

Council of Science Editors:

Mehrotra S. IAP Regulation of Tumor Metastasis: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/437

21. Ramachandran, Preethi. Cytoskeletal Regulation and Morphogen Signaling During Synaptic Outgrowth at the Drosophila Larval Neuromuscular Junction : A Dissertation.

Degree: Neuroscience, Department of Neurobiology; Budnik Lab, 2009, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/442

► Synaptic plasticity, in its broadest sense, can be defined as the ability of synapses to be modified structurally and functionally in response to various… (more)

▼ Synaptic plasticity, in its broadest sense, can be defined as the ability of synapses to be modified structurally and functionally in response to various internal and external factors. Growing evidence has established that at the very core of these modifications are alterations in the cytoskeletal architecture. This discovery has led to the unearthing of a number of signaling pathways that might be involved in cytoskeletal regulation and also in the regulation of other aspects of synapse development and plasticity. In this regard, polarity proteins and secreted morphogens such as the Wnt proteins, typically involved in embryonic development, are emerging as critical determinants of synaptic growth and plasticity. However, their mechanism of action at synapses needs further investigation. Additionally, not much is known about how these morphogens are secreted or transported across synapses. Using the Drosophila larval NMJ as a model system, I have addressed aspects related to the issues mentioned above in the subsequent body of work. In the first half of my thesis, I have uncovered a role for the aPKC/Baz/Par-6 polarity protein complex in the regulation of the postsynaptic actin cytoskeleton in conjunction with the lipid and protein phosphatase PTEN. In the second half of my thesis, I have contributed to the elucidation of mechanisms underlying the secretion of Wg, the Drosophila Wnt homolog. Our findings suggest that Wnts might be secreted via a previously unidentified mechanism involving the release of exosome like vesicles from the presynapse and this process requires Evi/Wntless (Evi), a protein dedicated to Wnt secretion. Alterations in signaling pathways and aberrant cytoskeletal regulation lead to a variety of neurological disorders. The body of work in this thesis will provide a deeper understanding of the mechanisms involved in synaptic plasticity and provide a basis for uncovering similar pathways in the context of vertebrate synapses. Advisors/Committee Members: Vivian Budnik.

Subjects/Keywords: Synapses; Actins; Cytoskeleton; Protein Kinase; Wnt Proteins; Amino Acids, Peptides, and Proteins; Animal Experimentation and Research; Enzymes and Coenzymes; Macromolecular Substances

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ramachandran, P. (2009). Cytoskeletal Regulation and Morphogen Signaling During Synaptic Outgrowth at the Drosophila Larval Neuromuscular Junction : A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/442

Chicago Manual of Style (16^th Edition):

Ramachandran, Preethi. “Cytoskeletal Regulation and Morphogen Signaling During Synaptic Outgrowth at the Drosophila Larval Neuromuscular Junction : A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/442.

MLA Handbook (7^th Edition):

Ramachandran, Preethi. “Cytoskeletal Regulation and Morphogen Signaling During Synaptic Outgrowth at the Drosophila Larval Neuromuscular Junction : A Dissertation.” 2009. Web. 24 Feb 2020.

Vancouver:

Ramachandran P. Cytoskeletal Regulation and Morphogen Signaling During Synaptic Outgrowth at the Drosophila Larval Neuromuscular Junction : A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/442.

Council of Science Editors:

Ramachandran P. Cytoskeletal Regulation and Morphogen Signaling During Synaptic Outgrowth at the Drosophila Larval Neuromuscular Junction : A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/442

22. Alexa, Kristen M. Endoderm Patterning in Zebrafish: Pancreas Development: A Dissertation.

Degree: Interdisciplinary Graduate Program, Biochemistry and Molecular Pharmacology, 2009, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/450

► The pancreas is located below the liver and adjacent to the small intestine where it connects to the duodenum. It consists of exocrine and… (more)

Subjects/Keywords: Zebrafish; Zebrafish Proteins; Pancreas; Endoderm; SOX Transcription Factors; Amino Acids, Peptides, and Proteins; Animal Experimentation and Research; Digestive System; Embryonic Structures

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Alexa, K. M. (2009). Endoderm Patterning in Zebrafish: Pancreas Development: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/450

Chicago Manual of Style (16^th Edition):

Alexa, Kristen M. “Endoderm Patterning in Zebrafish: Pancreas Development: A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/450.

MLA Handbook (7^th Edition):

Alexa, Kristen M. “Endoderm Patterning in Zebrafish: Pancreas Development: A Dissertation.” 2009. Web. 24 Feb 2020.

Vancouver:

Alexa KM. Endoderm Patterning in Zebrafish: Pancreas Development: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/450.

Council of Science Editors:

Alexa KM. Endoderm Patterning in Zebrafish: Pancreas Development: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/450

23. Ray, Samriddha. Elucidation of the Multi-Faceted Roles of the SIN (Septation Initiation Network); Understanding How the SIN Promotes Cytokinesis and Inhibits Interphase Growth in the Fission Yeast Schizosaccharomyces pombe: A Dissertation.

Degree: Interdisciplinary Graduate Program, Biochemistry and Molecular Pharmacology, 2010, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/482

► Cytokinesis is the cytoplasmic division of one cell into two independent daughter cells. Precise regulation of cytokinesis during cell cycle is essential for healthy… (more)

▼ Cytokinesis is the cytoplasmic division of one cell into two independent daughter cells. Precise regulation of cytokinesis during cell cycle is essential for healthy and rapid multiplication of any organism. Schizosaccharomyces pombe has emerged as an excellent model system to study eukaryotic cell division regulation. This rod shaped organism grows by bipolar elongation in interphase when its actin cytoskeleton is concentrated at the cell ends (poles). However, growth stops in mitosis and the actin cytoskeleton is rearranged to facilitate assembly of the contractile actomyosin ring at the cell middle. Although several studies have focused on the separate processes of growth and division, it was unclear how cells regulate the cytoskeletal remodeling during the transition between the different stages of the cell cycle. The Septation Initiation Network (SIN) is a signaling cascade essential for fission yeast cytokinesis (Balasubramanian et al., 1998; Mishra et al., 2004) and the MOR (morphogenesis) signaling pathway is essential for interphase bipolar growth (Kanai et al, 2005). Interestingly, inactivation of the SIN not only failed to maintain the cytokinetic apparatus at the cell middle but also caused the redistribution of the cytoskeletal elements like actin to the cell ends that led to bipolar cell elongation similar to cells in interphase (Mishra et al., 2004). These results suggested that SIN signaling inhibits interphase bipolar growth, but it was not clear if the SIN had a direct role in inhibition of interphase growth during mitosis and this question was the major focus of this thesis. The results presented in Chapter II show a novel cross-pathway interaction between the SIN and the MOR in the fission yeast. Our results in Chapter III suggest that some of the MOR pathway components might be important for coordination between nuclear and cytoplasmic divisions in mitosis, revealing novel roles of the pathway. In a separate study (Chapter IV) we sought to identify additional regulators of the SIN and cytokinesis through a suppressor screen and found that the nucleolar rDNA transcription machinery inhibits cytokinesis in fission yeast. Advisors/Committee Members: Dannel McCollum, Ph.D..

Subjects/Keywords: Cytokinesis; Schizosaccharomyces pombe Proteins; Signal Transduction; Amino Acids, Peptides, and Proteins; Cell and Developmental Biology; Cells; Fungi; Genetic Phenomena

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ray, S. (2010). Elucidation of the Multi-Faceted Roles of the SIN (Septation Initiation Network); Understanding How the SIN Promotes Cytokinesis and Inhibits Interphase Growth in the Fission Yeast Schizosaccharomyces pombe: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/482

Chicago Manual of Style (16^th Edition):

Ray, Samriddha. “Elucidation of the Multi-Faceted Roles of the SIN (Septation Initiation Network); Understanding How the SIN Promotes Cytokinesis and Inhibits Interphase Growth in the Fission Yeast Schizosaccharomyces pombe: A Dissertation.” 2010. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/482.

MLA Handbook (7^th Edition):

Ray, Samriddha. “Elucidation of the Multi-Faceted Roles of the SIN (Septation Initiation Network); Understanding How the SIN Promotes Cytokinesis and Inhibits Interphase Growth in the Fission Yeast Schizosaccharomyces pombe: A Dissertation.” 2010. Web. 24 Feb 2020.

Vancouver:

Ray S. Elucidation of the Multi-Faceted Roles of the SIN (Septation Initiation Network); Understanding How the SIN Promotes Cytokinesis and Inhibits Interphase Growth in the Fission Yeast Schizosaccharomyces pombe: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2010. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/482.

Council of Science Editors:

Ray S. Elucidation of the Multi-Faceted Roles of the SIN (Septation Initiation Network); Understanding How the SIN Promotes Cytokinesis and Inhibits Interphase Growth in the Fission Yeast Schizosaccharomyces pombe: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2010. Available from: https://escholarship.umassmed.edu/gsbs_diss/482

24. Chen, Yuanyuan. Generating Nucleosomal Asymmetry in Saccharomyces cerevisiae: A Masters Thesis.

Degree: Interdisciplinary Graduate Program, Program in Molecular Medicine, 2010, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/500

► There are two copies of each core histone in a nucleosome, however, it is unclear whether post-translational modifications on each molecule function redundantly or… (more)

Subjects/Keywords: Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Gene Expression; Nucleosomes; Histones; Amino Acids, Peptides, and Proteins; Cells; Fungi; Genetic Phenomena; Genetics and Genomics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Chen, Y. (2010). Generating Nucleosomal Asymmetry in Saccharomyces cerevisiae: A Masters Thesis. (Masters Thesis). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/500

Chicago Manual of Style (16^th Edition):

Chen, Yuanyuan. “Generating Nucleosomal Asymmetry in Saccharomyces cerevisiae: A Masters Thesis.” 2010. Masters Thesis, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/500.

MLA Handbook (7^th Edition):

Chen, Yuanyuan. “Generating Nucleosomal Asymmetry in Saccharomyces cerevisiae: A Masters Thesis.” 2010. Web. 24 Feb 2020.

Vancouver:

Chen Y. Generating Nucleosomal Asymmetry in Saccharomyces cerevisiae: A Masters Thesis. [Internet] [Masters thesis]. U of Massachusetts : Med; 2010. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/500.

Council of Science Editors:

Chen Y. Generating Nucleosomal Asymmetry in Saccharomyces cerevisiae: A Masters Thesis. [Masters Thesis]. U of Massachusetts : Med; 2010. Available from: https://escholarship.umassmed.edu/gsbs_diss/500

25. Rosadini, Charles V. Roles of Secreted Virulence Factors in Pathogenicity of Haemophilus Influenzae: A Dissertation.

Degree: Molecular Genetics and Microbiology, Molecular Genetics and Microbiology, 2011, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/541

► Haemophilus influenzae is a pathogenic Gram-negative bacterium that colonizes the upper respiratory tract of humans and can cause otitis media, upper and lower respiratory… (more)

Subjects/Keywords: Haemophilus influenzae; Periplasmic Binding Proteins; Protein Disulfide-Isomerases; Virulence Factors; Amino Acids, Peptides, and Proteins; Bacteria; Biological Factors; Microbiology; Respiratory System

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APA (6^th Edition):

Rosadini, C. V. (2011). Roles of Secreted Virulence Factors in Pathogenicity of Haemophilus Influenzae: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/541

Chicago Manual of Style (16^th Edition):

Rosadini, Charles V. “Roles of Secreted Virulence Factors in Pathogenicity of Haemophilus Influenzae: A Dissertation.” 2011. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/541.

MLA Handbook (7^th Edition):

Rosadini, Charles V. “Roles of Secreted Virulence Factors in Pathogenicity of Haemophilus Influenzae: A Dissertation.” 2011. Web. 24 Feb 2020.

Vancouver:

Rosadini CV. Roles of Secreted Virulence Factors in Pathogenicity of Haemophilus Influenzae: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2011. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/541.

Council of Science Editors:

Rosadini CV. Roles of Secreted Virulence Factors in Pathogenicity of Haemophilus Influenzae: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2011. Available from: https://escholarship.umassmed.edu/gsbs_diss/541

26. Harwood, Katryn R. Using Light to Observe and Control Cellular Function: Improving Bioluminescence Imaging and Photocontrol of Rho GTPase Activation States: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, Program in Biochemistry and Molecular Pharmacology, 2011, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/569

► The dynamic processes that occur at specific times and locations in cells and/or whole organisms during cellular division, migration, morphogenesis and development are critical.… (more)

▼ The dynamic processes that occur at specific times and locations in cells and/or whole organisms during cellular division, migration, morphogenesis and development are critical. When these molecular events are not properly regulated, disease states can develop. Tools that can allow us to better understand the specific events that, when misregulated, result in disease development can also allow us to determine better ways to combat such misregulation. Specifically, tools that could allow us to better visualize cellular processes or those that allow us to control cellular functioning in a spatiotemporal manner could present great insight into the detailed inner workings of cells and/or whole organisms. Where chemistry and biology intersect presents a powerful starting point for the development of such tools. The first half of this thesis addresses tools to allow the better visualization of cellular events, in particular the intriguing process of bioluminescence and the work that has been done to better understand and optimize its utilization, particularly in living organisms. The novel work presented here details a parallel approach to improve our ability to observe cellular functioning specifically by improving bioluminescence imaging through the generation and characterization of mutant luciferase proteins that can better utilize novel small molecule luciferin substrates. The second half of this thesis discusses methods that have been developed to better control cellular events through the control of protein activity, specifically a family of proteins called the Rho GTPases. This family’s activation at specific times and locations is essential to proper cellular function and exemplifies the need for spatiotemporal control. Described are methods to control the activation states of the Rho GTPases to probe their cellular roles in a temporal and spatial manner using photosensitive small molecules. Taken together, the findings described herein demonstrate the application of chemistry to allow for the better observation and control of cellular processes, toward the ultimate goal of improving our understanding of the regulatory processes involved in the control of key factors leading to disease states. Advisors/Committee Members: Stephen C. Miller, Ph.D..

Subjects/Keywords: Cell Physiological Processes; rho GTP-Binding Proteins; Luminescent Measurements; Amino Acids, Peptides, and Proteins; Cells; Cellular and Molecular Physiology

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APA (6^th Edition):

Harwood, K. R. (2011). Using Light to Observe and Control Cellular Function: Improving Bioluminescence Imaging and Photocontrol of Rho GTPase Activation States: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/569

Chicago Manual of Style (16^th Edition):

Harwood, Katryn R. “Using Light to Observe and Control Cellular Function: Improving Bioluminescence Imaging and Photocontrol of Rho GTPase Activation States: A Dissertation.” 2011. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/569.

MLA Handbook (7^th Edition):

Harwood, Katryn R. “Using Light to Observe and Control Cellular Function: Improving Bioluminescence Imaging and Photocontrol of Rho GTPase Activation States: A Dissertation.” 2011. Web. 24 Feb 2020.

Vancouver:

Harwood KR. Using Light to Observe and Control Cellular Function: Improving Bioluminescence Imaging and Photocontrol of Rho GTPase Activation States: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2011. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/569.

Council of Science Editors:

Harwood KR. Using Light to Observe and Control Cellular Function: Improving Bioluminescence Imaging and Photocontrol of Rho GTPase Activation States: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2011. Available from: https://escholarship.umassmed.edu/gsbs_diss/569

27. Porter-Goff, Mary Elizabeth. The Role of the MRN Complex in the S-Phase DNA Damage Checkpoint: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, Department of Biochemistry and Molecular Pharmacology, 2009, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/405

► The main focus of my work has been the role of the MRN in the S-phase DNA damage checkpoint. The MRN plays many roles… (more)

▼ The main focus of my work has been the role of the MRN in the S-phase DNA damage checkpoint. The MRN plays many roles in cellular metabolism; some are checkpoint dependent and some are checkpoint independent. The multiple roles in cellular metabolism complicate study of the role of the MRN in the checkpoint. MRN mutations in budding yeast and mammals may display separation of function. Mechanistically, MRN, along with its cofactor Ctp1, is involved in 5’ resection to create single stranded DNA that is required for both signaling and homologous recombination. However, it is unclear if resection is essential for all of the cellular functions of MRN. Therefore I have made mutations to mimic those in budding yeast and mammals. I found that several alleles of rad32, as well as ctp1Δ, are defective in double-strand break repair and most other functions of the complex but maintain an intact S-phase DNA damage checkpoint. Thus, the MRN S-phase checkpoint role is separate from its Ctp1- and resection-dependent role in double-strand break repair. This observation leads me to conclude that other functions of MRN, possibly its role in replication fork metabolism, are required for S-phase DNA damage checkpoint function. One of the potential roles of Rad32 and the rest of the MRN complex is in sister chromatid exchange. The genetic requirements of sister chromatid exchange have been examined using unequal sister chromatid assays which only are able to assay exchanges that are illegitimate and produce changes in the genome. Most sister chromatid exchange must be equal to maintain genomic integrity and thus far there is no good assay for equal sister chromatid exchange. Yeast cells expressing the human equilibrative nucleoside transporter 1 (hENT1) and the herpes simplex virus thymidine kinase (tk) are able to incorporate exogenous thymidine into their DNA. This strain makes it possible for the fission yeast DNA to be labeled with halogenated thymidine analogs. This strain is being used to design an assay that will label one sister with BrdU and then DNA combing will be used to see equal sister chromatid exchange. Advisors/Committee Members: Nicholas Rhind, PhD..

Subjects/Keywords: Methyl Methane sulfonate; DNA Damage; Cell Cycle Proteins; Intracellular Signaling Peptides and Proteins; Genes; cdc; S Phase; Amino Acids, Peptides, and Proteins; Cells; Enzymes and Coenzymes; Fungi; Genetic Phenomena; Viruses

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Porter-Goff, M. E. (2009). The Role of the MRN Complex in the S-Phase DNA Damage Checkpoint: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/405

Chicago Manual of Style (16^th Edition):

Porter-Goff, Mary Elizabeth. “The Role of the MRN Complex in the S-Phase DNA Damage Checkpoint: A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/405.

MLA Handbook (7^th Edition):

Porter-Goff, Mary Elizabeth. “The Role of the MRN Complex in the S-Phase DNA Damage Checkpoint: A Dissertation.” 2009. Web. 24 Feb 2020.

Vancouver:

Porter-Goff ME. The Role of the MRN Complex in the S-Phase DNA Damage Checkpoint: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/405.

Council of Science Editors:

Porter-Goff ME. The Role of the MRN Complex in the S-Phase DNA Damage Checkpoint: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/405

28. Guo, Daorong. Dissecting Signaling Pathways that Regulate Axonal Guidance Effects of Sonic Hedgehog: A Dissertation.

Degree: Interdisciplinary Graduate Program, Medicine; Cell Biology, 2011, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/531

► During development, axons respond to a variety of guidance cues in the environment to navigate to the proper targets. Sonic hedgehog (Shh), a classical… (more)

Subjects/Keywords: Hedgehog Proteins; Axons; Intracellular Signaling Peptides and Proteins; Retinal Ganglion Cells; Amino Acids, Peptides, and Proteins; Cell and Developmental Biology; Cells; Enzymes and Coenzymes; Sense Organs

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Guo, D. (2011). Dissecting Signaling Pathways that Regulate Axonal Guidance Effects of Sonic Hedgehog: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/531

Chicago Manual of Style (16^th Edition):

Guo, Daorong. “Dissecting Signaling Pathways that Regulate Axonal Guidance Effects of Sonic Hedgehog: A Dissertation.” 2011. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/531.

MLA Handbook (7^th Edition):

Guo, Daorong. “Dissecting Signaling Pathways that Regulate Axonal Guidance Effects of Sonic Hedgehog: A Dissertation.” 2011. Web. 24 Feb 2020.

Vancouver:

Guo D. Dissecting Signaling Pathways that Regulate Axonal Guidance Effects of Sonic Hedgehog: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2011. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/531.

Council of Science Editors:

Guo D. Dissecting Signaling Pathways that Regulate Axonal Guidance Effects of Sonic Hedgehog: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2011. Available from: https://escholarship.umassmed.edu/gsbs_diss/531

29. Pagano, John M., Jr. RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation.

Degree: Biochemistry and Molecular Pharmacology, Biochemistry and Molecular Pharmacology Program, 2010, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/486

► Post-transcriptional regulation of gene expression is a mechanism that governs developmental and cellular events in metazoans. In early embryogenesis, transcriptionally quiescent cells depend upon… (more)

▼ Post-transcriptional regulation of gene expression is a mechanism that governs developmental and cellular events in metazoans. In early embryogenesis, transcriptionally quiescent cells depend upon maternally supplied factors such as RNA binding proteins and RNA that control key decisions. Morphogen gradients form and in turn pattern the early embryo generating different cell types and spatial order. In the nematode Caenorhabditis elegans, the early embryo relies upon several RNA binding proteins that control mRNA stability, translation efficiency, and/or mRNA localization of cell fate determinants essential for proper development. MEX-5 and MEX-3 are two conserved RNA-binding proteins required to pattern the anterior/posterior axis and early embryo. Mutation of either gene results in a maternal effect lethal phenotype with proliferating posterior muscle into the anterior blastomeres (Muscle EXcess). Several cell-fate determinants are aberrantly expressed in mex-5 and mex-3 embryos. Both proteins are thought to interact with cis-regulatory elements present in 3’-UTRs of target RNAs controlling their metabolism. However, previous studies failed to demonstrate that these proteins regulate maternal transcripts directly. This dissertation presents a thorough assessment of the RNA binding properties of MEX-5 and MEX-3. Quantitative biochemical approaches were used to determine the RNA binding specificity of both proteins. MEX-5 has a relaxed specificity, binding with high affinity to linear RNA containing a tract of six or more uridines within an eight-nucleotide window. This is very different from its mammalian homologs Tristetraprolin (TTP) and ERF-2. I was able to identify two amino acids present within the MEX-5 RNA binding domain that are required for the differential RNA recognition observed between MEX-5 and TTP. MEX-3 on the other hand is a specific RNA binding protein, recognizing a bipartite element with flexible spacing between two four-nucleotide half-sites. I demonstrate that this element is required for MEX-3 dependent regulation in vivo. Previous studies only identify a small number of candidate regulatory targets of MEX-5 and MEX-3. The defined sequence specificity of both proteins is used to predict new putative targets that may be regulated by either protein. Collectively, this study examines the RNA binding properties of MEX-5 and MEX-3 to clarify their role as post-transcriptional regulators in nematode development. Advisors/Committee Members: Sean Ryder, PhD.

Subjects/Keywords: Caenorhabditis elegans Proteins; RNA-Binding Proteins; Amino Acids, Peptides, and Proteins; Animal Experimentation and Research; Biochemistry, Biophysics, and Structural Biology; Cells; Embryonic Structures; Genetic Phenomena; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pagano, John M., J. (2010). RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/486

Chicago Manual of Style (16^th Edition):

Pagano, John M., Jr. “RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation.” 2010. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/486.

MLA Handbook (7^th Edition):

Pagano, John M., Jr. “RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation.” 2010. Web. 24 Feb 2020.

Vancouver:

Pagano, John M. J. RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2010. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/486.

Council of Science Editors:

Pagano, John M. J. RNA Recognition by the Caenorhabditis elegans Embryonic Determinants MEX-5 and MEX-3: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2010. Available from: https://escholarship.umassmed.edu/gsbs_diss/486

30. Lin, Chien-Ling. Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation.

Degree: Interdisciplinary Graduate Program, Program in Molecular Medicine, 2012, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/583

► Post-transcriptional regulation of gene expression sits at the core of proteomic complexity; trans-acting factors that regulate RNA localization and translation capacity are thus indispensible.… (more)

Subjects/Keywords: RNA-Binding Proteins; Poly(A)-Binding Proteins; Polyadenylation; Amino Acids, Peptides, and Proteins; Biochemical Phenomena, Metabolism, and Nutrition; Biochemistry, Biophysics, and Structural Biology; Genetic Phenomena; Nucleic Acids, Nucleotides, and Nucleosides

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Lin, C. (2012). Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/583

Chicago Manual of Style (16^th Edition):

Lin, Chien-Ling. “Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation.” 2012. Doctoral Dissertation, U of Massachusetts : Med. Accessed February 24, 2020. https://escholarship.umassmed.edu/gsbs_diss/583.

MLA Handbook (7^th Edition):

Lin, Chien-Ling. “Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation.” 2012. Web. 24 Feb 2020.

Vancouver:

Lin C. Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2012. [cited 2020 Feb 24]. Available from: https://escholarship.umassmed.edu/gsbs_diss/583.

Council of Science Editors:

Lin C. Studies on the Regulation of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2012. Available from: https://escholarship.umassmed.edu/gsbs_diss/583

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