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1
Bornscheid, Jens. "Stapled Stock = (Verbundaktien) /". Frankfurt am Main [u.a.] : Lang, 2006. http://www.gbv.de/dms/spk/sbb/recht/toc/502180196.pdf.
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2
Chu, Qian. "I. Targeted β-catenin Ubiquitination and Degradation Using Bifunctional Stapled Peptides II. Studies on Cell Penetration by Stapled Peptides". Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11278.
Testo completoAbstract (sommario):
Hydrocarbon-stapled alpha-helical peptides represent a relatively new class of synthetic peptidomimetics capable of inhibiting protein-protein interactions. It has been shown that hydrocarbon "staples" spanning one or two helical turns in a peptide increase alpha-helical content and protease resistance, enhance target binding affinity, and promote cell penetration. This technology has been applied to the development of cell-permeable ligands targeting several intracellular targets. This dissertation describes efforts to further the development of stapled peptide technology.Chemistry and Chemical Biology
3
Thaha, Mohamed Adhnan. "Circular stapled anopexy in the treatment of haemorrhoidal disease". Thesis, University of Dundee, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521688.
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4
Lau, Nathan Yu Heng. "Double-click stapled peptides for inhibiting protein-protein interactions". Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708627.
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5
Sharma, Krishna. "Strain-promoted stapled peptides for inhibiting protein-protein interactions". Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/288602.
Testo completoAbstract (sommario):
Protein-protein interactions (PPIs) are responsible for the regulation of a variety of important functions within living organisms. Compounds which can selectively modulate aberrant PPIs are novel therapeutic candidates for treating human diseases. Whilst PPIs have traditionally been considered as "undruggable", research in this area has led to the emergence of several effective methodologies for targeting PPIs. One such methodology is peptide stapling, which involves constraining a short peptide into its native alpha-helical form by forming a covalent link between two of its amino acid side-chains. The Sondheimer dialkyne reagent has previously been used in strain-promoted double-click cycloadditions with diazidopeptides to generate stapled peptides that are capable of inhibiting PPIs. However, the Sondheimer dialkyne suffers from poor water-solubility; it decomposes rapidly in aqueous solutions which limits its application in biological systems. This dissertation describes the design and synthesis of new substituted variants of the Sondheimer dialkyne with increased solubility and stability, that are suitable for application in strain promoted double click peptide stapling. In total, ten different derivatives were generated; of these, a meta-trimethylammonium substituted variant was found to have particularly high water-solubility and aqueous stability, as well as high azide reactivity. The substituted Sondheimer dialkynes were applied to the strain promoted double click stapling of p53-based diazido peptides in an effort to generate stapled peptide-based inhibitors of the oncogenic p53 MDM2 PPI, a validated target for anticancer therapeutics. Three stapled peptides were found to have inhibitory activity, thus demonstrating the utility of the novel dialkynes in the preparation of PPI inhibitors. The functionalised stapled peptide formed from a meta-fluoro substituted Sondheimer dialkyne was found to be the most potent inhibitor. All ortho-substituted Sondheimer dialkynes were found to be unreactive, whereas those with a meta-trimethylammonium substituent were highly reactive when compared to other meta-substituted dialkynes. These patterns in azide reactivity could be explained through X-ray crystallographic studies and density functional theory calculations.
6
Saunders, Alexander William. "New approaches to stapled peptides targeting the p53-MDM2 interaction". Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25664.
Testo completoAbstract (sommario):
Recent approaches to constraining peptide sequences into more structurally-defined α- helical secondary structures, so-called peptide stapling, are discussed. Stapled peptides are a class of therapeutics that have been shown to more effectively target protein-protein interactions, which are harder to target using a classical small-molecule therapeutic approach. Stapling a peptide constrains it into a well-defined secondary structure. This more accurately mimics the protein-protein interaction making the peptide a more viable therapeutic. Starting from the p53-MDM2 interaction, a protein-protein interaction with important implications in cell health, a known peptidyl inhibitor of this interaction was stapled and analysed for increased α-helicity. This was achieved by using monomers that utilise the copper (I) alkyne azide cycloaddition as a cross-linking methodology, which has been less well researched in the context of peptide stapling. The viability of a novel stapled peptomer inhibitor approach, accomplished using a new, optimised monomer synthesis, is investigated. Additionally, the synthesis of a ligand series designed for use in the copper(I) alkyne azide cycloaddition is also discussed.
7
Liang, Rebecca Yue. "Probing Protein Interactions with Stapled Peptides: Myc Family and Insulin Receptor". Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11063.
Testo completoAbstract (sommario):
One of the most exciting frontiers of expanding pharmacopeia to combat currently untreatable diseases is achieving specifically and potently disruption of unwanted protein-protein interactions where traditional small molecule drugs tend to fall short. Our laboratory has developed the methodology of peptide stapling and pioneered successful applications in multiple disease models since its induction over a decade ago. One common feature of past applications is the use of a single stapled peptide in helical form, derived from the natural binding interface of target proteins. This dissertation ventures into protein interactions that involve multiple components and sites and explores the extended use of stapled peptides in these volatile settings.Chemistry and Chemical Biology
8
Ito, Eiji. "Synthetic Absorbable Film for Prevention of Air Leaks After Stapled Pulmonary Resection". Kyoto University, 2002. http://hdl.handle.net/2433/149729.
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9
Edwards, Amanda Lee. "Dissecting and Targeting the PUMA and OLIG2 Control Points of Tumors of Neuroectodermal Origin with Stapled Peptides". Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10886.
Testo completoAbstract (sommario):
Tumors of neuroectodermal origin are among the most aggressive and treatment-refractory forms of human cancer. While such tumors arise from a variety of defects, two key targets are the transcription factors p53 and OLIG2. We have developed stabilized peptides to study and target deregulated p53 and OLIG2 pathways in neuroectodermal cancers. PUMA (p53-upregulated modulator of apoptosis) is a BH3-only member of the BCL-2 protein family that regulates apoptosis in response to p53-dependent and p53-independent stress signals. The specific interactions that mediate the pro-apoptotic activity of PUMA remain controversial. We generated stabilized alpha-helices of BCL-2 domains (SAHB) peptides modeled after the BH3 effector domain of PUMA. Structural analyses determined that PUMA SAHB contacts BAX at both the N-terminal \(\alpha1/\alpha6\) trigger site and the canonical BH3 binding pocket, binding events that functionally activate BAX. Notably, both PUMA SAHB and PUMA protein pull-downs identified anti- and pro-apoptotic binding partners in a cellular context. As PUMA has been implicated in driving apoptosis in multiple neural cell types, we further demonstrated that treatment of neuroblastoma cell lines with a cell-permeable PUMA SAHB analog triggered dose-dependent apoptosis. Together, we find that the PUMA BH3 domain activates apoptosis through multimodal interactions with BCL-2 family proteins, and its mimetics may serve as prototype therapeutics in tumors of neural origin. Whereas suppression of p53 signaling and apoptosis are features of diverse tumor types, the basic helix-loop-helix (bHLH) transcription factor OLIG2 is selectively overexpressed in gliomas. Early in development, OLIG2 is responsible for maintaining progenitor cells in a replication-competent state. Tumor stem cells are believed to co-opt this OLIG2 functionality to continually repopulate glial tumors. To achieve its transcriptional function, OLIG2 must dimerize via its bHLH domain. Stabilized alpha-helices of OLIG2 (SAH-OLIG2) peptides of the OLIG2 bHLH domain were generated in an effort to disrupt this pathologic dimerization. While helical stabilization of several SAH-OLIG2 peptides was achieved, specific engagement and disruption of the native bHLH dimer did not occur, informing alternative design strategies for future targeting efforts. These studies underscored the importance of interrogating the OLIG2 dimeric structure and catalyzed the discovery of candidate OLIG2 interaction partners for therapeutic targeting.
10
Yeo, David James. "Development and evaluation of novel hydrocarbon stapled peptidomimetics with future application to bionic proteins". Thesis, University of Leeds, 2014. http://etheses.whiterose.ac.uk/7218/.
Testo completoAbstract (sommario):
Hydrocarbon stapling is a method of constraining a short polypeptide through the incorporation of alkenyl alanine unnatural amino acids, which are metathesised during peptide synthesis to afford a covalent crosslink on one face of the peptide. The purpose of 'stapling' is to improve the therapeutic properties of a peptide by improving transport properties and resistance to proteolysis. Stapling also reduces the conformational plasticity of a peptide, which in turn, should improve the potency of the crosslinked peptide with its binding partner. Alkenyl glycine ('monosubstituted') derivatives of amino acids have been previously synthesised, but overlooked for peptide stapling experiments. This project investigated the utility of monosubstituted amino acids as surrogates for hydrocarbon stapling with a therapeutically relevant family of proteins, the apoptosis regulator Bcl-2 family and p53 proteins. This led onto an investigation of the foundations of hydrocarbon stapling, to assess the extent that hydrocarbon stapling modulates potency through various biophysical and structural experiments. Hydrocarbon stapled peptides are classified as peptidomimetics within the field of foldamers, which aims to construct scaffolds from synthetic oligomers which can replicate the three dimensional topography and functionality of native proteins. Since the de novo design of synthetic proteins is out of reach, regions of proteins with distinct architecture have been replaced with mimetics to afford semi-synthetic proteins in a technique described as 'protein prosthesis'. The project also aimed to chemically synthesise a protein with four distinct helical regions, colicin immunity protein Im7, with the view to replace one of the helical regions with a stapled peptide or an oligobenzamide helix mimetic to afford a semi-synthetic protein to add to the growing field of secondary and tertiary structure mimetics.
11
Medina, Daniel E. "Filtration Performance of a NIOSH-Approved N95 Filtering Facepiece Respirator With Stapled Head Straps". Scholar Commons, 2009. https://scholarcommons.usf.edu/etd/1709.
Testo completoAbstract (sommario):
Certain models of NIOSH-approved filtering facepiece air purifying respirators are manufactured with stapled head straps. Depending on the manufacturer, these head straps may be stapled to the filter media itself. This may cause leakage through the filter media of the respirator, potentially exposing the user to an unacceptable level of contaminant. In this study, monodisperse polystyrene latex (PSL) spheres were generated to challenge four replicates of a N95 single use respirator model made by the same manufacturer.
Nominal particle sizes of the PSL spheres used to challenge the respirators were 0.5, 1, and 2 micrometers in diameter. All respirators were sealed onto a custom built testing assembly and tested in a sealed chamber. Particle sizes of interest were generated using a nebulizer, and passed through a diffusion dryer and a Krypton-85 radioactive source prior to entering the test chamber. The dryer reduces the humidity of the aerosol generating by the nebulizer, while the radioactive source neutralizes the charge of the aerosol cloud. The test chamber was constructed using a glass aquarium measuring 32 x 53 x 122 centimeters. Three stainless steel air diffusers were placed above the testing compartment to evenly distribute the aerosol in the chamber. An exhaust manifold was placed at the lower part of the chamber beneath another stainless steel diffuser below the area where test respirators were placed.
The respirators were challenged as received from the manufacturer with 0.5, 1 and 2 micrometer-sized (PSL) spheres. The same procedure was repeated for each respirator after sealing the areas where the head straps were stapled with silicon rubber. Testing was conducted at a flow rate of 85 liters per minute, as specified in the NIOSH respirator testing protocol. A laser particle counter was used to measure the concentration inside and outside of the respirator.
The results showed unsealed efficiencies for particle sizes 0.5, 1, and 2 micrometers of 96.68%, 99.72%, 99.88% and sealed efficiencies of 97.35%, 99.82%, 99.93% respectively. There were no differences for particle size or sealing at 1.0 and 2.0 micrometers. A significant drop in efficiency was observed when testing with 0.5 micrometer PSL spheres. The drops in efficiency are not sufficient to reduce the integrity of the respirator for N95 certification. However, the leakages detected will have a cumulative effect when added to other sources of single use respirator leakage in the field.
12
Braun, Craig Ronald. "Structural Characterization of BCL-2 Family Protein Interactions Using Photoreactive Stapled Peptides and Mass Spectrometry". Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10139.
Testo completoAbstract (sommario):
Recent improvements in mass spectrometry instrumentation have stimulated the fusion of this technology with protein crosslinking to advance the structural proteomics field. However, analysis of complex datasets from crosslinking experiments remains a bottleneck. The majority of crosslinking studies for structural characterization of protein- protein interactions have been conducted with reagents specific for discrete amino acids. While this approach simplifies data analysis, the requirement for specific functionalities to be present at the interaction interface limits resolution. Herein, we report the application of stapled peptides for the development of photoaffinity reagents for mass spectrometric characterization of BCL-2 family protein interactions. To validate this approach, we synthesized photoreactive stabilized alpha-helices of BH3 domains (pSAHBs) incorporating a benzophenone containing amino acid, and demonstrated that the photo crosslinking specificity of these reagents paralleled the interaction specificity of the native proteins. We show that the standard SEQUEST algorithm is effective at identifying specific amino acids crosslinked by pSAHBs, and that this information can be used to create distance restraints for characterizing interaction interfaces by in silico docking. The pSAHB approach is applied to characterize previously elusive activating interactions between BH3 domains and the proapoptotic proteins BAX and BAK. We demonstrate that full-length BAK requires a direct activation stimulus, and that this involves interaction at a canonical surface groove at the C-terminal face of BAK. We confirmed that initiation of direct BAX activation occurs at a geographically distinct site at the N-terminal face of BAX, but further find that induced release of its C-terminus from the canonical groove exposes these residues for secondary BH3 interaction. These data suggest that BAX may be subject to a two-step activation mechanism within distinct cytosolic and mitochondrial compartments. Finally, we report the structural characterization of an interaction between BAD and glucokinase, the first description of a BH3 domain interaction with a non-BCL-2 family member. We identify the active site region of glucokinase as the BAD interaction site, establishing this region as a novel target for development of glucokinase activators. We conclude that the pSAHB approach represents a rapid and powerful approach to protein interaction site identification that complements conventional structural biology techniques.
13
McWhinnie, Fergus Stewart. "Alpha synuclein in Parkinson's disease : determining the role of helical alpha synuclein using stapled peptides". Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/29599.
Testo completoAbstract (sommario):
Neurodegeneration, the progressive and irrevocable loss of neuronal structure, is quickly becoming an imposing health concern in a globally ageing society. While specific neurodegenerative conditions exhibit specific clinical symptoms and progressions, a common neuropathological feature is the misfolding, oligomerisation and fibrillation of certain proteins causing neuronal stress and death. Parkinson’s disease, PD, has long been characterised by the death of nerve cells focused in the substantia nigra pars compacta region of the midbrain and deposition of large protein aggregates, called Lewy Bodies, throughout the central nervous system. More recently, the protein which forms these inclusion bodies was identified as alpha synuclein, αSyn, a ubiquitous neuroprotein with no known function. Furthermore, persons with mutations in the SNCA gene, which codes for αSyn, exhibit PD progression at a far younger age with a more severe phenotype, positively linking αSyn with PD. αSyn is an intrinsically disordered protein, IDP, and generally persists as such in solution and inside bacterial and mammalian cells. However, when in contact with a lipid bilayer the protein will embed upon the surface in an amphipathic alpha helical conformation and can also aggregate, forming toxic oligomeric and fibrillar species containing significant β-sheet identity. Its function as a helical apolipoprotein and subcellular localisation to both the nucleus and synapse has led researchers to suggest that αSyn has a role synaptic transmission and release. However, knocking out the protein does not reduce viability or produce pathological abnormalities in neuronal structure. The helical form of the protein may also persist as transient, metastable helical bundles which are non-toxic and resist aggregation. While a number of studies and tools have been reported and developed to investigate the toxic oligomeric/fibrillar forms of αSyn, very little attention has been accorded to the helical conformation. This thesis will redress this balance by producing tools which will allow us to mimic the helical form of αSyn, promote the active refolding of the full-length protein using a stable, helical peptide template and produce antibodies which recognise helical αSyn specifically for use in discovery and chaperone-like refolding. In Chapter 2 a region of αSyn (14 amino acids) was identified with a unique primary sequence located within a mutation prone section of the protein. Peptide ‘stapling’ technologies were then employed using a panel of monosubstituted ‘staple’ diastereomers, to produce a highly helical portion of αSyn. Using several other protein targets particular diastereomeric ‘staple’ combinations were analysed for obvious trends in helical content. Using solution NMR, backbone refined three dimensional structures of these helical peptides were produced which showed that they were faithful structural homologues of their parent helical proteins. In Chapter 3 the drug-like properties and therapeutic potential of stable, helical αSyn peptides were investigated. Using fluorescently labelled peptide substrates, ‘stapled’ peptides were shown to be far more cell penetrant than their wild type equivalents and demonstrated that the mechanism for cellular uptake appears to be specific. Furthermore, under harsh proteolytic conditions the ‘stapled’, helical peptides were far more resistant to hydrolysis than wild type or ‘stapled’, poorly helical peptides. The ‘stapled’ peptides were also highly soluble and did not appear to aggregate in a time-dependent manner. Using ion mobility mass spectrometry, it was shown that incubation of full-length protein with the ‘stapled’, helical peptides caused a contraction in the hydrodynamic radius of the protein. However, using solution NMR no active refolding of αSyn was observed when under the same conditions. Rather small perturbations in chemical shift were apparent which did not suggest that the αSyn protein folded into a discrete structural conformation, such as an alpha helix. In Chapter 4 the stable, helical αSyn peptide was employed as a conformational model and unique antigen in antibody discovery. Immunisation with the ‘stapled’, helical αSyn peptide initially produced a pool of polyclonal antibodies with a half log specificity for the helical peptide. After bespoke affinity chromatography this was increased to three log orders of specificity. Initial immunocytochemistry did not detect any helical αSyn protein in SH-SY5Y cells. To validate the helical epitope on the full-length protein in vitro an assay based around flow cytometry of synthetic vesicle structures was developed, with their synthesis, characterisation and binding of the αSyn protein described.
14
Barclay, Lauren Anne. "Direct Inhibition of the Conformational Activation of Pro-Apoptotic BAX by the BH4 Domain Helix of BCL-2". Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070041.
Testo completoAbstract (sommario):
Programmed cell death by apoptosis is required for normal development and tissue homeostasis. Perturbations of the critical signaling pathways that regulate apoptosis drive a number of pathologic diseases; therefore, a deep understanding of the apoptotic regulatory networks and methods for therapeutically modulating them is highly warranted. As constituents of the intrinsic pathway of apoptosis, pro-apoptotic BCL-2 family proteins respond to internal signals of cell stress to activate cell death through permeabilization of the outer mitochondrial membrane to release cytochrome c and other apoptogenic factors. Anti-apoptotic BCL-2 proteins block apoptosis by forming stable heterodimers with pro-apoptotic BAX and BAK. Specifically, the C-terminal binding groove of BCL-2 sequesters the BCL-2 homology 3 (BH3) death domain of BAX to prevent BAX oligomerization. The N-terminal BH4 domain of BCL-2 is also believed to confer anti-apoptotic activity but the mechanism by which this occurs remains unknown. A direct, inhibitory interaction between the BCL-2 BH4 domain and BAX was established through application of a peptide stapling technology to preserve the α-helical character of the BH4 domain outside the context of full-length BCL-2. Photoaffinity labeling identified a new mode of BH4 domain interaction at the C-terminal face of BAX, revealing an additional layer of apoptotic regulation. Examination of the conformational activation of full-length BAX in a lipid membrane by hydrogen-deuterium exchange mass spectrometry revealed that the BCL-2 BH4 helix blocks the BAX conformational changes triggered by an activating BH3 peptide to preserve the inactive BAX fold. Thus, the mechanistic paradigm for BCL-2 inhibition of BAX has been expanded to allow future opportunities for modulation of apoptosis by mimicking or inhibiting the BH4 motif.
15
Pau, Daniel. "Investigation of Hydrocarbon Stapled Alpha-Helical Peptides as a Novel Method to Interrupt Protein-Target Interactions in Bacteria". Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34413.
Testo completoAbstract (sommario):
With the increasing threat of multidrug resistant bacteria, there is a growing need to invent new drug classes that combat untreatable infections. Small molecule antibiotics have been successful in the past, but humanity is now losing the arms race against previously treatable pathogens. However, the number of clinically approved drugs targeting traditionally undruggable targets in bacteria remains low. New targets of complex protein-target interactions must be targeted for future pharmacological development. In an effort to create clinically viable biologics, the Verdine lab has developed a class of therapeutics called hydrocarbon stapled α-helical peptides; these peptides are known to affect protein-protein interactions by retaining secondary structure in vivo. Although this class of molecules has been extensively researched in cancer and viral therapies, there has been little work in bacteria due to the proposed endocytic method of entry. Moreover, DNA-binding stapled peptides have not been extensively investigated due the complexities in designing a peptide with gene selectivity. In an attempt to study peptides in bacteria, two stapled peptides based on the RpoN domain of σ54 and the FtsZ C-terminus have been synthesized. σ 54 is a DNA-binding co-factor of RNA polymerase (RNAP) and has been shown to regulate virulence and nitrogen and carbon metabolism. FtsZ is the structural unit of the contractile Z-ring that induces cell division. By designing stapled α-helical peptides to target these untraditional PPIs, we anticipate that these molecules may be used for future antimicrobial pharmacological development that treat multidrug resistant bacteria.
16
Leshchiner, Elizaveta S. "Dissecting the Mechanisms of Direct Activation for Proapoptotic BAK and BAX". Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10778.
Testo completo
17
Guo, Zuojun. "Structural Stability of Nucleic Acids and Peptides: a Theoretical and Computational Study". Thesis, Boston College, 2012. http://hdl.handle.net/2345/3782.
Testo completoAbstract (sommario):
Thesis advisor: Udayan MohantyIn chapter one, two simple models are used to estimate the electrostatic contributions to the stiffness of short DNA fragments. The first model views DNA as two strands that are appropriately parameterized and are wrapped helically around a straight cylinder radius equal to the radius of the DNA molecule. The potential energy of the DNA due to phosphate-phosphate electrostatic interactions is evaluated assuming that the charges interact through Debye-Hückle potentials. This potential energy is compared with the potential energy as computed using our second model in which DNA is viewed as two helical strands wrapping around a curved tube whose cross-section is a disk of radius equal to the radius of the DNA. The results are compared with counterion condensation models and experimental data (Guo et al. J. Phys. Chem. B, 2008, 112, 16163-16169). In chapter two, the fidelity of translation selection begins with the base pairing of codon-anticodon complex between the mRNA and tRNAs. Binding of cognate and near-cognate tRNAs induces 30S subunit of the ribosome to wrap around the ternary complex, EF-Tu(GTP)aa-tRNA. We have proposed that large thermal fluctuations play a crucial role in the selection process. The binding energies of over a dozen unique site-bound magnesium structural motifs are investigated and provide insights into the nature of interaction of divalent metal ions with the ribosome (Guo et al. Proc. Nat. Acad. Sci. 2011, 108, 3947-3951). In chapter three, we use extensive molecular dynamics simulations to study a series of stapled alpha helical peptides over a range of temperatures in solution. The peptides are found to exhibit substantial variations in predicted helicities that are in good agreement with the experimental value. In addition, we find significant variation in local structural flexibility of the peptides with the position of the linker, which appears to be more closely related to the observed differences in activity than the absolute alpha helical stability (Guo et al. Chem. Biol. Drug. Des. 2010, 75, 348-359.). In chapter four, the alpha helical conformation and structural stability of single and double stapled all-hydrocarbon cross-linked p53 peptides in solution and when bound to MDM2 is investigated. We determined the effects of the peptide sequence, the stereochemistry of the cross-linker, the conformation of the double bond in the alkene bridge, the length of the bridge, on the relative stability of the alpha helix structure. The conformation population distribution indicates a fully helical state and several partially folded states. The distribution of dihedral pairs of the stapled peptides in the bound state indicates a significant population around the alpha helical region. Sequences over which the linker spans tend to have the highest helical occupancy. Significant helical content is observed for a double stapled p53 peptide at 575 K. The probability to form native contacts is increased when the stapled peptides are bound to MDM2. The distribution of the end-to-end distance of the peptides is bimodal
Thesis (PhD) — Boston College, 2012
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry
18
Filho, Francisco Leopoldo Albuquerque. "Compliance and retal sensitivity during pre and post-operative of pacients with haemorrhoidal disease treated by stapled anopexy". Universidade Federal do CearÃ, 2005. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=187.
Testo completoAbstract (sommario):
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicoO tratamento cirÃrgico da doenÃa hemorroidÃria pela Anopexia MecÃnica (AM), utilizando grampeador circular PPH de 33mm (Ethicon EndoSurgery) pode estar relacionado a lesÃo esfincteriana perianal, com repercussÃo no padrÃo evacuatÃrio. O objetivo deste estudo à avaliar a sensibilidade e complacÃncia retal em pacientes submetidos a esta tÃcnica operatÃria. Foram estudados 10 pacientes portadores de hemorrÃidas grau III ou IV sintomÃticas. Todos os pacientes foram avaliados prÃ-operatoriamante utilizando-se um barostato (Visceral Stimulator; Synetics Medical), com base em dois protocolos de pesquisa da sensibilidade retal: um contÃnuo (Ramp Test) e outro aleatÃrio (Random test), nos quais foram aferidas as diferentes reaÃÃes dos pacientes frente à distensÃo volumÃtrica de um balÃo retal sob controle de um "software" (Polygram for Windows; Medtronic), o que permitiu a reprodutibilidade do mÃtodo no pÃs-operatÃrio. Foram observadas a sensaÃÃo retal inicial (1a. sensaÃÃo), a sensibilidade evacuatÃria (2a. sensaÃÃo) e a sensibilidade a dor (3a. sensaÃÃo). ApÃs cirurgia os pacientes foram reavaliados ao final de 2, 4 e 6 meses. Utilizou-se um grupo controle de 10 pacientes portadores de doenÃa pilonidal sacro-coccÃgea, submetidos ao mesmo protocolo de avaliaÃÃo no prà e pÃs-operatÃrio, diferenciando-os do grupo cirÃrgico pela nÃo realizaÃÃo da anopexia mecÃnica. Foram aplicados os testes estatÃsticos de Pearson e t-student para a anÃlise dos estatÃstica dos resultados. Observou-se diminuiÃÃo dos valores de complacÃncia e sensibilidade retal ao final de 2 meses de pÃs-operatÃrio no grupo submetido a AM, para todas as sensaÃÃes pesquisadas, em ambos os protocolos de insuflaÃÃo do barostato. NÃo se observou diferenÃa entre a complacÃncia e sensibilidade retal observada nas avaliaÃÃes prÃ-operatÃria e aos quatro e seis meses no grupo submetido a AM, bem como em nenhuma das avaliaÃÃes realizadas no grupo controle. Conclui-se que a Anopexia MecÃnica causa uma diminuiÃÃo transitÃria da complacÃncia e sensibilidade retal aos dois meses de pÃs-operatÃrio, valores estes que se recuperam a partir do quarto mÃs pÃs-operatÃrio.
Post-graduation Course in Surgery (Strictu Sensu), Departament of Surgery, Medicine School, Federal University of Cearà (Master in Surgery Degree). 2005, September. Professor: Prof. Dr. Lusmar Veras Rodrigues Surgical treatment of haemorrhoids by Stapled Anopexy (SA), using a circular stapler PPH - 33mm (Ethicon EndoSurgery) may damage perianal muscle fibers, with changes In defecation pattern. The aim of this study was to evaluate rectal compliance and sensitivity in patients treated by SA. Ten patients with grade III or IV sintomatic haemorrhoids were elegible for this study. All patients were studied before surgery with a barostat (Visceral Stimulator; Synetics Medical), using two research protocols for rectal sensitivity: a continuous one (Ramp Test) and another one in steps (Random test), that could record patient's perception to volumetric distention of a rectal baloon, controled by a software (Polygram for Windows, Medtronic). This software made the method reproductible to all patients in the post-operative period. The barostat was able to record the first rectal sensation (1st. sensation), urge to defecate (2nd. sensation) and rectal pain (3rd. sensation). Patients were studied following the same protocol at two, four and six months after surgery. A control group of ten patients with pilonidal sinus disease was submitted to the same protocol, except for stapled anopexy. Statistical analysis was acomplished using Pearson and Student's t test. The study found a decrease in retal compliance and sensitivity of patients treated by stapled anopexy, during the second post-operative month evaluation, for all recorded sensations, to all distension protocols. There was no difference in rectal compliance and sensitivity between pre-operative and post-operative at four and six months evaluations for patients treated by stapled anopexy. There was no difference in rectal compliance and sensitivity for any patient in control group, for any sensation recordered, using any distension protocol. The conclusion was that stapled anopexy caused a transient decrease in rectal compliance and sensitivity at the second postoperative month, that returned to normal values at the fourth post-operative month.
19
Baek, Sohee [Verfasser], Robert [Akademischer Betreuer] Huber e Sevil [Akademischer Betreuer] Weinkauf. "Structural and Functional Analysis of the Natural JNK1 Inhibitor Quercetagetin : Structure of the Stapled p53 Peptide Bound to HDM2 / Sohee Baek. Gutachter: Sevil Weinkauf ; Robert Huber. Betreuer: Robert Huber". München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1050817494/34.
Testo completo
20
Kalistratova, Aleksandra. "Tuning bioactive peptides properties : new developments in the O-N acyl transfer reaction and dimerization of unprotected peptides". Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT229/document.
Testo completoAbstract (sommario):
L’intérêt des peptides comme des médicaments potentiels est en constante augmentation. Des stratégies ont été développées pour améliorer la sélectivité, l’activité, et la stabilité des peptides vis-à-vis de la protéolyse. Dans ce mémoire de thèse, deux nouvelles modifications de peptides sont proposées.Dans le premier chapitre, nous présentons une nouvelle application de la réaction de transfert O-N acylique pour la synthèse de peptides agrafés (ou ‘stapled peptides’). L’introduction d’une ‘agrafe’ dans un peptide est un moyen de stabiliser une structure secondaire hélicoïdale en établissant un pont entre les résidus appropriés des chaînes latérales. Dans notre cas, l'agrafe est formée par un O-acyl isodipeptide. La liaison ester peut être convertie en liaison amide par un transfert O-N acylique. Cette stratégie permet une amélioration de la solubilité d’un peptide hydrophobe agrafé, avant son réarrangement à pH neutre.Dans le dernier chapitre, nous avons développé une méthodologie nouvelle pour la dimérisation de peptides non protégés. Cette méthode repose sur la formation de liaisons siloxane entre des peptides hybrides portant chacun un groupement dimethylchlorosilane. Nous avons ainsi dimérisé une séquence dérivée de la protéine p53, impliquée dans l’apoptose. A titre de comparaison, cette même séquence a été dimérisée en utilisant la cycloaddition d’Huisgen entre deux peptides modifiés possédant un azoture ou un alcyne en position N-terminale. Enfin, plusieurs dimères de la séquence du GHRP-6 (growth hormone releasing peptide) ont été synthétisés, avec des bras dimethylhydroxysilane placés à différentes positions. L’homodimérisation a été effectuée dans l'eau à pH neutreThe interest in peptides as potential drug candidates was revived and is increasing constantly. Strategies have been developed to improve their selectivity and activity, and their stability toward proteolysis. In this thesis, two new peptide modifications are proposed.In the first chapter, we present a new application of the O-N acyl transfer reaction for the synthesis of stapled peptides. Peptide ‘stapling’ is a way of stabilizing secondary helical structure by establishment of a bridge between the side chains of suitable residues. In our case, the staple is formed by an O-acyl isopeptide which can be converted into amide bond by acyl migration. This strategy allows an improved solubility of the stapled hydrophobic peptide prior to rearrangement at neutral pH.In the last chapter, we developed also a new methodology for the dimerization of unprotected peptides. This method is based on siloxane bond formation between hybrid dimethylhydroxysilane peptides. A peptide derived from the tumor suppressor protein p53 was dimerized in water, at neutral pH using this methodology. The method was compared with the homodimerization carried out by Cu(I) azide-alkyne cycloaddition (CuAAC). For that purpose, p53 peptide derivative was synthesized with azide and alkyne linkers at the N-terminus. At last, several homodimers of growth hormone releasing hexapeptide (GHRP-6) were synthesized, with dimethylhydroxy silane linkers placed at various positions
21
Shim, So Youn. "A Step Toward Achieving Peptide Based Therapeutics I. Analysis of the Effect of Olefin Position and Linker Length in Hydrocarbon Stapled Peptides II. Development and Structural Studies of Direct Peptide Inhibitors of Ras". Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467494.
Testo completoAbstract (sommario):
Traditionally the two major classes of drugs, small molecules and biologics, have been extensively used in drug discovery. However, it is difficult to inhibit protein-protein interactions with small molecules, and targets of biologics are limited to extracellular proteins. Considering such limitations, there has been a call for a new therapeutic modality to target ‘undruggable’ proteins. Structurally-stabilized peptide therapeutics has emerged as a new class that could overcome the limitations of the previously established drug classes while retaining their benefits. Among several strategies that have been employed to constrain the conformation of peptides to enhance their pharmacological properties, the all-hydrocarbon stapling system has been particularly successful. This system combines the helix-stabilizing effects of alpha methylation with peptide macrocyclization, which confers improvement not only in helix stabilization but also in protease resistance and cell permeability. The first part of my dissertation focuses on exploring this system further by shortening the established hydrocarbon bridge length as well as moving the position of the olefin along the cross-link, and looking at the effects of these attributes on the helical propensity of the peptides by circular dichroism.
In cases where there is no structural information or obvious binding partner that has an alpha-helical component that could be used for rational design of a stapled peptide inhibitor, screening a naïve library of stabilized scaffolds using yeast cell-surface display would be an alternative starting point. Oncogenic K-Ras is one such case; the structures of Ras with its effectors have shown that they interact with Ras via beta-sheet complementation. The second part of my dissertation will describe efforts to develop peptide inhibitors that target Ras by using screening and directed evolution of libraries of an avian pancreatic polypeptide-based scaffold by yeast cell-surface display. We have identified lead peptides that disrupt the binding of effectors to Ras, and the structures of these peptides bound to Ras have been solved and analyzed, leading us to improve the lead peptides further by rational design.Chemistry and Chemical Biology
22
Gibson, Meghan E. "Examining the Role of Magnesium Ions in the Structural Stability of Ribosomal Subunits and An Investigation of a Novel Anticancer Therapeutic: Analyzing the Binding Affinity of a Stapled p53 Peptide Analog for Regulator MDM2". Thesis, Boston College, 2011. http://hdl.handle.net/2345/bc-ir:104431.
Testo completoAbstract (sommario):
Thesis advisor: Udayan MohantyComputational research can play a crucial component in the discovery of unique biochemical phenomena, from answering fundamental questions about molecular function and structure to the modeling of designed pharmaceuticals to cure many debilitating illnesses. Here computational methods are employed to examine the exquisite role that magnesium ions play in stabilizing ribosomal subunits responsible for protein translation and to analyze the potential of a proposed anticancer drug for a pathway that is impaired in the majority of human cancer cases
Thesis (BS) — Boston College, 2011
Submitted to: Boston College. College of Arts and Sciences
Discipline: College Honors Program
Discipline: Chemistry
23
Perdriau, Camille. "Stabilisation et mimes de structures secondaires peptidiques : applications aux hélices alpha et feuillets beta". Thesis, Bordeaux, 2019. http://www.theses.fr/2019BORD0308.
Testo completoAbstract (sommario):
Des avancées en biologie moléculaire ont permis de voir émerger des molécules biologiques (anticorps, hormones) comme agents thérapeutiques. Les peptides qui peuvent adopter les structures secondaires (hélices α et feuillets β) rencontrées dans les protéines et qui possèdent des caractéristiques intermédiaires entre les petites molécules et les protéines, représentent donc un enjeu thérapeutique intéressant. Leurs principaux inconvénients résident dans leur faible stabilité plasmatique, leur faible pénétration cellulaire et leur flexibilité conformationnelle qui limitent leur développement thérapeutique. Stabiliser la structure secondaire de peptides dans leur conformation bioactive ou développer des squelettes non naturels comme peptidomimes sont devenus des moyens de contourner ces difficultés. A ce jour, diverses approches chimiques ont été proposées pour stabiliser le repliement en hélice α comme la macrocyclisation entre deux chaînes latérales d’un peptide. Une première partie de cette thèse a consisté à développer une stratégie de macrocyclisation menant à des agrafes peptidiques originales, comportant une fonction guanidine polaire. Différentes séquences peptidiques ont ainsi pu être macrocyclisées en (i, i+4) ou (i, i+7), et des études structurales ont été amorcées. L’introduction d’une guanidine pourrait apporter de nouvelles propriétés aux peptides macrocyclisés dont l’amélioration de leur perméabilité cellulaire. Le feuillet β multi-brins, l’autre structure secondaire d'intérêt, s'avère être moins étudié par les chimistes malgré son importance biologique, en raison probablement d'une tendance excessive à l’agrégation et la précipitation. Pour réussir à obtenir des peptidomimes stables de ces feuillets β, il est possible d’avoir recours à des squelettes non naturels comme les foldamères. Dans ce contexte, nous nous sommes intéressés à la conception d'une nouvelle classe de molécules programmées pour se replier en feuillets β, par formation de liaisons hydrogène intramoléculaires. Des foldamères alternant des motifs coudes et brins artificiels comportant des dérivés de diamine et diacide ont alors été synthétisés. Des études en solution et à l’état solide sur ces molécules ont attesté leur repliement en feuillet β multi-brinsRecent advances in molecular biology gave rise to the emergence of biologics (antibodies, hormones) as therapeutic agents. Peptides which are able to adopt secondary structures encountered in proteins and presenting intermediates features between small molecules and biologics are seen as potent therapeutics. The disadvantages of peptides lie in poor plasma stability and their poor cell membrane permeability as well as conformational flexibility, thus limiting their therapeutic potential. Stabilizing peptide secondary structures in their bioactive conformations and the development of non natural peptidomimetics became important tools to counteract those difficulties. Nowadays, several chemical approaches have been considered to stabilize α-helix folding such as the macrocyclization between two side chains of a peptide. The first project of this PhD thesis has focused on the design and the synthesis of new stapled peptides containing a guanidine motif. Several macrocyclized peptides with a guanidine bridge in (i, i+4) or in (i, i+7) positions have thus been obtained and some structural studies performed. Introduction the guanidine moiety could provide new properties to peptides such as improvement of their cell permeability. Notwithstanding their importance in biology, multi-stranded β-sheets, another protein secondary structure of interest, have comparatively been less studied by chemists probably because of their tendencies towards agregation and precipitation. To obtain stable peptidomimetics folded into βsheets it is possible to use non natural moieties such as foldamers. In this context, we have been interested in the design of a novel class of molecules programmed to fold into β-sheet structures through the formation of intramolecular hydrogen bonds. Foldamers alternating artificial strands and turns composed of diamine and diacid have been synthesized. Studies were performed in solution and in the solid state to confirm their folding into multi-stranded β-sheets architectures
24
Armstrong, Jim. "Short Staple Variety Comparison". College of Agriculture, University of Arizona (Tucson, AZ), 1985. http://hdl.handle.net/10150/203925.
Testo completo
25
Layton, Dennis, Ron Cluff, Claude Evans, Sam Stedman, Bruce Church e Billy Moore. "Short Staple Variety Demonstrations". College of Agriculture, University of Arizona (Tucson, AZ), 1985. http://hdl.handle.net/10150/204046.
Testo completo
26
Clapp, Carl, e Sam Stedman. "Short Staple Variety Demonstration". College of Agriculture, University of Arizona (Tucson, AZ), 1987. http://hdl.handle.net/10150/204479.
Testo completo
27
Thacker, Gary. "Short Staple Variety Demonstration". College of Agriculture, University of Arizona (Tucson, AZ), 1987. http://hdl.handle.net/10150/204482.
Testo completo
28
Benedict, Bret, Sam Stedman e Jim Armstrong. "Short Staple Variety Demonstrations". College of Agriculture, University of Arizona (Tucson, AZ), 1986. http://hdl.handle.net/10150/219758.
Testo completo
29
Leal, Vilmar Moura. "AvaliaÃÃo clÃnica e funcional no prà e pÃs-operatÃrio de pacientes portadoras de defecaÃÃo obstruÃda por retocele e prolapso mucoso retal, submetidas ao procedimento âtrremsâ". Universidade Federal do CearÃ, 2009. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=4686.
Testo completoAbstract (sommario):
CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorSÃndrome de DefecaÃÃo ObstruÃda (SDO) pode ser produzida por alteraÃÃo funcional (anismus) ou por alteraÃÃes anatÃmicas, especialmente retocele e prolapso mucoso retal. VÃrias tÃcnicas cirÃrgicas vÃm sendo utilizadas no tratamento da retocele, com vias de acesso transvaginal, perineal ou transanal, aquelas mais utilizadas por ginecologistas e a transanal por coloproctologistas, isto em funÃÃo das pacientes recorrerem a especialistas diferentes, dependendo da predominÃncia dos sintomas, sendo apresentados resultados semelhantes. O objetivo deste estudo foi avaliar os resultados do tratamento cirÃrgico de pacientes portadoras de SDO por retocele e prolapso mucoso retal, submetidas à ressecÃÃo transanal da retocele e mucosectomia com um grampeador (procedimento âTRREMSâ. Foram avaliadas 35 pacientes, sendo uma nulÃpara e as demais multÃparas, com idade mÃdia de 47,5 Â10,83 anos (31 â 67), portadoras de retocele e prolapso mucoso retal interno, sendo 13 (37,10%) com grau II e 22 (62,90%) com grau III. Os parÃmetros avaliados foram os escores de defecaÃÃo obstruÃda e de constipaÃÃo, o Ãndice funcional para continÃncia assim como a avaliaÃÃo da dor, satisfaÃÃo com o resultado e com a funÃÃo sexual e realizaÃÃo de defecografia no prà e no pÃs-operatÃrio. O escore mÃdio de SDO de 10,63 no prÃ-operatÃrio reduziu significativamente para 2,91 no pÃs-operatÃrio (p = 0,000). O escore mÃdio de constipaÃÃo de 15,23 no prÃ-operatÃrio reduziu significativamente para 4,46 no pÃs-operatÃrio (p = 0,000). O Ãndice funcional mÃdio para continÃncia, de 2,77 no prÃ-operatÃrio reduziu significativamente para 1,71 no pÃs-operatÃrio (p = 0,000). A dor no primeiro dia pÃs-operatÃrio, avaliada atravÃs da escala visual analÃgica (EVA) apresentou valor mÃdio de 5,23 reduzindo para 1,20 no oitavo dia (p = 0,000). A satisfaÃÃo com o resultado do tratamento, avaliada tambÃm atravÃs da EVA, ao final do primeiro mÃs foi 79,97, no terceiro 86,54, no sexto 87,65 e no dÃcimo segundo 88,06. TambÃm se obteve elevaÃÃo significativa, entre os valores mÃdios de 42,91 no prÃ-operatÃrio e 70,41 no sexto mÃs de pÃs-operatÃrio, para a satisfaÃÃo sexual avaliada atravÃs da EVA (p = 0,000). A defecografia demonstrou reduÃÃo significativa do tamanho mÃdio da retocele de 19,23 mm  8,84 (3 â 42) para 6,68 mm  3,65 (0 â 17) na fase de repouso e de 34,89 mm  12,30 (20 â 70) para 10,94 mm  5,97 (0 â 25) na fase evacuatÃria quando comparado o prà com o pÃs-operatÃrio (p = 0,000) (P=0,000) respectivamente. Procedimento âTRREMSâ à uma tÃcnica segura, eficiente e produziu resultados anatÃmicos e funcionais satisfatÃrios e nÃveis reduzidos de complicaÃÃes pÃs-operatÃrias
Obstructed defecation syndrome (ODS) can be induced by functional changes (anismus) or anatomical abnormalities, especially rectocele and rectal mucosal prolapse (RMP). Several surgical techniques with transvaginal, perineal or transanal access have been used in the treatment of rectocele. The first two are more commonly used by gynecologists, the last one is favored by proctologists. Depending on the prevalence of symptoms, patients may go to either specialist with the same result. The objective of the present study was to make a clinical and functional evaluation of patients submitted to the TRREMS procedure (transanal repair of rectocele and rectal mucosectomy with a single circular stapler) as treatment for ODS caused by rectocele and RMP. The study included 35 female patients (34 of whom multiparous) aged 47.5Â10.83 years (31â67) diagnosed with ODS caused by RMP-associated rectocele grade II (n=13; 37.1%) or grade III (n=22; 62.9%). The study parameters included SDO and constipation scores, functional continence index, sexual function and treatment outcome satisfaction and pre- and postoperative defecographic measures. The average preoperative ODS score (10.63) was significantly reduced after surgery (2.91) (p=0.000). The average constipation score fell from 15.23 to 4.46 (p=0.000). The average functional continence score decreased from 2.77 to 1.71 (p=0.000). Between the first and the eighth postoperative day, the average visual analog scale pain score fell from 5.23 to 1.20 (p=0.000). Using the same scale, satisfaction with the treatment outcome was 79.97, 86.54, 87.65 and 88.06 at 1, 3, 6 and 12 months, respectively, and the average sexual function satisfaction was 42.91 (19â70) and 70.41 (39â97) before and after surgery, respectively (p=0.000). On defecography, average reductions in rectocele size were from 19.23Â8.84 mm (3â42) to 6.68Â3.65 mm (0â17) at rest and from 34.89Â12.30 mm (20â70) to 10.94Â5.97 mm (0â25) during evacuation (both p=0.000). The TRREMS procedure is a safe, efficient technique associated with satisfactory anatomical and functional results and reduced levels of postoperative pain and complications.
30
Clark, Lee J., e E. W. Carpenter. "Date of Planting by Long Staple and Short Staple Variety Trial, Safford Agricultural Center, 1998". College of Agriculture, University of Arizona (Tucson, AZ), 1999. http://hdl.handle.net/10150/197037.
Testo completoAbstract (sommario):
Four varieties each of Long Staple and Short Staple cotton were tested over four dates of planting in this study. The first date of planting for the Long Staple cotton was delayed to the 3rd of April because of poor weather earlier. The latest planting was May 13th. Cultivars of differing maturities were tested for both long and short staple cotton to determine their optimal planting time. Many agronomic and hvi values were evaluated to determine the effect of different planting dates.
31
Clark, L. J., e E. W. Carpenter. "Date of Planting by Long Staple and Short Staple Variety Trial, Stafford Agricultural Center, 1999". College of Agriculture, University of Arizona (Tucson, AZ), 2000. http://hdl.handle.net/10150/197457.
Testo completoAbstract (sommario):
Four varieties each of Long Staple and Short Staple cotton were tested over five and four dates of planting, respectively, in this study. The first date of planting for the Long Staple cotton was the 18th of March and for Short Staple cotton the 1st of April. The latest planting was May 13th. Cultivars of differing maturities were tested for both long and short staple cotton to determine their optimal planting time. Many agronomic parameters were evaluated to determine the effect of different planting dates
32
Clark, L. J., e E. W. Carpenter. "Date of Planting by Long Staple and Short Staple Variety Trial, Safford Agricultural Center, 1997". College of Agriculture, University of Arizona (Tucson, AZ), 1998. http://hdl.handle.net/10150/210301.
Testo completoAbstract (sommario):
Four varieties each of Long Staple and Short Staple cotton were tested over five and four dates of planting, respectively, in this study. The first date of planting for the Long Staple cotton was pushed up to the 18th of March because planting is now legal in Graham county as early as March 15th. The latest planting was May 13th. Cultivars of differing maturities were tested for both long and short staple cotton to determine their optimal planting time. Many agronomic and hvi values were evaluated to determine the effect of different planting dates
33
Silvestre, Mónica Antunes. "Recrutamento e seleção na Staples Portugal". Master's thesis, Instituto Superior de Economia e Gestão, 2017. http://hdl.handle.net/10400.5/14317.
Testo completoAbstract (sommario):
Mestrado em Gestão de Recursos HumanosO presente relatório resulta de um estágio curricular realizado na Staples Portugal, no departamento de Recrutamento e Seleção. O estágio consistiu na envolvência ativa em todas as fases do processo de R&S, com o intuito de pôr em prática os conhecimentos desenvolvidos ao longo do mestrado. Inicialmente, são enquadrados teoricamente os conceitos inerentes ao recrutamento, dando especial ênfase ao recrutamento externo e às técnicas que o caracterizam. Em seguida, procede-se à contextualização da empresa e à descrição das tarefas realizadas ao longo do estágio. Por fim, é exposto um balanço crítico do estágio, na qual são confrontadas as atividades desenvolvidas ao longo do estágio com o enquadramento teórico.
The present report is the final result of an internship carried at Staples Portugal, in the Recruitment and Selection department. The internship consisted in active involvement in all stages of the R&S process, with the objective of practically apply the knowledge attained during the Master's degree. Initially, the concepts inherent to recruitment are theoretically framed, giving special emphasis on external recruiting and the techniques that characterize it. Afterwards, the company is contextualized and the tasks carried out during the internship are described. To conclude, a critical assessment of the internship is presented, in which the activities developed during the internship and the theoretical framework are compared.
info:eu-repo/semantics/publishedVersion
34
Dodd, Erin Linnea. "U.S. Trends in Short Staple Spinning". NCSU, 2000. http://www.lib.ncsu.edu/theses/available/etd-20001116-124455.
Testo completoAbstract (sommario):
The purpose of this research has been to examine possible factors which effect yarn production and prices in the U.S.The research approach first involved gathering the data from different sources about yarn production and prices. Second, data was gathered about the different factors which could have an effect on these. These factors included enduse demand, cotton consumption, the effect of spinning systems, labor cost and demand, machinery hours and shipments, and the level of imports and exports. Third, the data was compared and conclusions were made based solely on the obvious trends in the data. Fourth, current situations in the textile market were examined in order to conclude if any have had an effect on yarn production and price. The main issues which are facing the textile industry and were included in this analysis were NAFTA, CBI, Asia and the WTO. The effect that these have had and will have on the spinning industry was examined in detail. Fifth, a statistical analysis was conducted. The analysis included the use of a correlation matrix for both yarn production levels and yarn prices in order to see which factors statistically had the strongest impact on these. Overall, this research offers a view into the inside of the U.S. spinning industry, including the dynamics which effect final yarn production levels and yarn prices, as well as situations which will have an impact on the future of the spinning industry.
35
Clark, Lee J., e Ronald E. Cluff. "Short Staple Variety Demonstration, Graham County". College of Agriculture, University of Arizona (Tucson, AZ), 1988. http://hdl.handle.net/10150/204540.
Testo completoAbstract (sommario):
Two short staple variety trials were held in Graham county, one toward the west end of the valley (Eden), and one in the center of the valley (Thatcher), both with 15 varieties. Delta Pine 90 was the highest yielding variety at both locations, with yields of 1,386 pounds of lint per acre at Thatcher and 1,123 pounds at Eden. Two new varieties, Northrup King 111 and BR 110, show some promise in the area, with yields close to that of Delta Pine 90. Lint quality and grade are listed for each variety.
36
Malcuit, J., S. Stedman e J. Silvertooth. "Short Staple Variety Demonstrations, Pinal County". College of Agriculture, University of Arizona (Tucson, AZ), 1989. http://hdl.handle.net/10150/204838.
Testo completo
37
Clark, Lee J., e Ronald E. Cluff. "Short Staple Demonstrations, Graham County, 1989". College of Agriculture, University of Arizona (Tucson, AZ), 1990. http://hdl.handle.net/10150/208298.
Testo completoAbstract (sommario):
Short- staple variety trials were grown in two locations in Graham County in 1989. Exceptional weather conditions, coupled with good management practices, provided record cotton yields in the Safford valley. Delta Pine 77 was the highest yielding variety in the Thatcher location with a yield of 1740 pounds of lint per acre. An experimental acala from New Mexico came in second in this triad ahead of Delta Pine 90. Delta Pine 90 was the highest yielding variety in the Eden area with a yield of 1196 pounds per acre. Data on percent first pick plant height and plant populations are presented for each variety in each location. Graphs of heat units received each day throughout the growing season at the AZMET station on the Safford Agricultural Center are presented for 1988 and 1989.
38
Layton, Dennis, Ron Cluff e Lee J. Clark. "Short Staple Variety Demonstration, Graham County". College of Agriculture, University of Arizona (Tucson, AZ), 1986. http://hdl.handle.net/10150/219745.
Testo completo
39
Selander, David. "Stapla". Thesis, KTH, Arkitektur, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-188410.
Testo completoAbstract (sommario):
En pedagogisk institution, en förskola. Hur kan en förskolas pedagogik reflekteras i byggnaden. Hur kan rummen skapas för att återspegla de pedagogiska grundstenar som lärarna undervisar. Pedagogiken i det här fallet är Reggio Emilia. En pedagogik vars huvudintresse är att tillåta barnen utforska kreativt. Pedagogiken kretsar kring detta men hur kan det gestaltas? Kan byggnaden i sig tillåta kreativitet? Reggio Emilia-pedagogiken arbetar likt oss arkitekter i projekt. Barnen utforskar sin omgivning i projekt av olika slag. Genom att skapa ett system för barnen och lärarna att bygga rum med kan byggnaden i sig bli en del av deras projekt. En kub och ett rätblock blir receptet för detta system. Mellan flyttbara korspelare som stabiliserar kan byggstenarna användas för att skapa rum genom utforskning. För att programmera byggnaden har jag läst litteratur kring Reggio Emilia och låtit arkitekturen präglas av pedagogiken. Vissa av de formgivande besluten är direkt hämtade ur den litteratur jag läst medan vissa är tolkningar av litteraturens idéer och tankar. Bland andra följande punkter har bidragit till byggnadens gestaltning: Ateljén har jag i mitt läsande identifierat som det absolut viktigaste rummet. Ateljén anläggs på pelare ovanför det gemensamma rum som skapas i mitten av leklandskapet. Förvaring är viktigt då dokumentation ses som en viktig del i samspel med lärandet vilket krävs för projektbaserad undervisning Barnen ska kunna röra sig fritt över förskolan för att främja utbytet mellan årskullar vilket talar för en öppen plan Mottagandet ska vara välkomnande, avskedet skall ej stressas – därför anordnas ett särskilt avskedsrum i entréplan för att möjliggöra detta samt låta föräldrar gå igenom barnens tidigare aktiviteter som en del av avskedet Barnet välkomnas av de vuxna och andra barn – vilket leder till att trappan och hissen möter det gemensamma lekrummet Utrymmet organiseras efter interaktion mellan barn i olika åldrar – vilket talar för stora gemensamma och små intima rum Bandet mellan hem och skolmiljö är viktigt för att möjliggöra för barnen att ta saker till och från skolan – vilket tillsammans med dokumentationspunkten talar för individuell förvaring.An educational institution, a pre-school. How can a pre-schools pedagogy be reflected in the architecture? How can the rooms be created to mirror the educational foundation that the teachers teach to the children. The pedagogy in this case is Reggio Emilia. A pedagogy whose main interest is letting the children explore through creativity. The pedagogy revolves around this but how can it be translated into architecture? Can the building itself allow creativity? Reggio Emilia educators work, like us architects, through projects. The childrenexplore their surroundings in different kinds of projects. By creating a system for the children and the teachers to build their own rooms with the building can become part of their project. A cube and a rectangular parallelpiped is the main recipe for this system. Between movable cross pillars which stabilize the building blocks rooms can be created as a part of the exploration. I have read literature around Reggio Emilia to program the building and I have as such let the architecture be imprinted by the pedagogy. Some of the design decisions are directly borrowed from the literature and some are interpretations of the ideas that I have found while reading. Among other things the following points have contributed to the design of the project: The most important room for the pedagogy is the atelier. The atelier is built upon pillars above a common room created in the middle of the play area. Individual storage is important because documentation is valued by the pedagogy. And as we as architecture students know, storage is valuable in project based education. The children should be able to move freely around the school to further the exchange between years, which speak for an open plan. The greeting should be welcoming and the morning farewell should not be stressed - a special farewell room is because of this built in the entrance level. The child is welcomed by the adults and the other children - which leads to the stair and elevator leadnig into the common play area under the atelier. The space is organized after interaction between ages - which speaks for large common rooms and small intimate rooms. The connection between home and school is important to enable the children to bring their things to and from school - this also speaks for individual storage.
40
Bourbiaux, Kévin. "Développement de peptides structurés pour l’inhibition de l’interaction PCSK9/LDLR et le rétablissement de l’absorption cellulaire du LDL-c". Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTS009.
Testo completoAbstract (sommario):
La proprotéine convertase subtilisine/kexine de type 9 (PCSK9) régule la concentration des récepteurs des lipoprotéines de basse densité (LDLR) au niveau de la membrane cellulaire et par conséquent le taux de LDL-cholestérol dans le système vasculaire. PCSK9 est donc une cible essentielle dans le traitement des maladies cardiovasculaires (MCV). A ce jour, les anticorps monoclonaux anti-PCSK9 associés aux statines est la seule thérapie disponible ciblant PCSK9 en dépit des risques d’immunogénicité, une administration sous-cutanée contraignante et un coût élevé. Néanmoins, de petits peptides possédant des structures tridimensionnelles très stables se sont avérés être des inhibiteurs prometteurs de l’interaction entre PCSK9 et le LDLR induisant une augmentation significative de l’absorption du LDL dans les cellules. A partir de ces séquences, nous avons synthétisé des peptides stabilisés par des agrafes, avec un patch poly-lysine (technologie SIP) à l’extrémité C-terminale mais également des séquences chimériques afin de développer des analogues très actifs et résistants à la protéolyse. Nous avons obtenu des composés mille fois plus affins pour PCSK9 que le peptide de référence Pep2-8, capables de rétablir l’absorption du LDL dans les cellules pour de très faibles concentrations (IC50 = 175 nM). Les structures tridimensionnelles des composés clés ont été étudiées par dichroïsme circulaire (CD) et résonance magnétique nucléaire (RMN) afin d’étudier leurs relations structure-activitéProprotein convertase subtilisin/kexin type 9 (PCSK9) has been identified as a regulator of low density lipoprotein receptor (LDLR) on the cell membrane and therefore plays a major role in cardiovascular diseases (CVD). To date, only monoclonal antibodies (mAbs) to PCSK9 are used associated with statins in therapies, despite a potential immunogenicity, a restrictive mode of administration and a high cost. Beside, small peptides with discrete three-dimensional structures were found to inhibit the interaction between PCSK9 and the LDLR, increasing the LDL-uptake. Starting from these sequences, we used various strategies incorporating staples and/or C-terminal lysine patches (SIP technology), synthesizing chimeric sequences to develop highly potent compounds resistant to enzymatic degradation. We obtained derivatives that have a 1000-fold stronger affinity than the parent peptide with high biological activities (IC50 = 175 nM). The three-dimensional structures of key compounds were extensively studied by circular dichroim (CD) and nuclear magnetic resonance (NMR) to investigate their structure-activity relationship
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Staples, David Franklin. "Viable population monitoring risk-based population monitoring for threatened and endangered species with application to bull trout, Salvelinus confluentus /". Diss., Montana State University, 2006. http://etd.lib.montana.edu/etd/2006/staples/StaplesD0506.pdf.
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Staples, James Mark. "Slope scale modeling of snow surface temperature in topographically complex terrain". Thesis, Montana State University, 2008. http://etd.lib.montana.edu/etd/2008/staples/StaplesJ1208.pdf.
Testo completoAbstract (sommario):
In mountainous terrain, landscape can influences the thermal state of snow. Snow temperature and mass flux have been calculated using an energy balance model, Radtherm/RT, to account for the effects of topography and meteorological conditions. For a specific location, a terrain model is defined and contains a connected assemblage of elements or facets. Each element has a specified terrain type with assigned thermal properties. Meteorological data are applied, and a one dimensional energy balance is calculated for each element. This energy balance includes conduction, convection, radiation, and latent heat; however, the calculation of radiation is unique. Taking into account topography, global position, and time, the model is used to calculate incoming solar radiation for each element as well as reflected short wave radiation and the exchange of long wave radiation between terrain surfaces. Light detection and ranging topographic data with a one meter resolution were used to create separate models (on the order of 10 4 m2) for two slopes in southwest Montana. Meteorological data were collected at these two slopes as well as a third location having a relatively unobstructed view of the sky. The results for elements in different locations and under different meteorological conditions were compared. Readily available USGS topographic data with a 30 meter resolution were used to create a model (on the order of 10 6 m2) containing both slopes. For this model of a much larger scale, surface temperatures and mass flux were again calculated and compared with results for the slope scale models. Incoming long wave radiation from the atmosphere only was found to be critical input data for accurate temperature calculations. The set value for albedo also had a major effect. When suitable long wave data and good estimations of albedo were used, snow surface temperature was calculated with accuracies on the order of several degrees. Additionally, when surface hoar deposition and growth was observed and reasonable temperature results were achieved, calculated values of mass flux were consistently positive. In one instance, observed variations in surface hoar growth across a slope matched calculated variations in mass flux across the same slope.
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Modin, Svedberg Lina, e Charlotte Törnkvist. "Belöningssystem och motivation : En fallstudie på Staples". Thesis, Linnéuniversitetet, Institutionen för ekonomistyrning och logistik (ELO), 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-76254.
Testo completoAbstract (sommario):
Bakgrund och problem: Ett styrmedel företag kan använda för att nå sina mål är belöningssystem. Utformningen av belöningssystemet samt att det tydligt motiverar de anställda är två viktiga aspekter. Tillsammans är belöningssystem samt motivation två välstuderade ämnen inom vissa branscher. För mer monotona arbeten som lagerverksamhet saknas dock detta arbete. Av denna anledning är det av intresse att studera hur lagerpersonal upplever att de motiveras av belöningssystemet. Syfte: Syftet med studien är att beskriva fallföretagets belöningssystem samt utreda hur de anställda upplever belöningssystemet och huruvida det motiverar dem. Om det empiriska materialet visar på svagheter i belöningssystemet presenteras förslag på förändringar. Metod: Studien har genomförts i form av en fallstudie på fallföretaget. Flertalet respondenter har intervjuats genom semi-strukturerade intervjuer. För att stärka studiens kvalitet har flertalet teoretiska källor använts. Slutsats: Fallföretaget har idag uppsatta mål som de anställda arbetar mot samt ett utvecklat belöningssystem. Det som saknas för att belöningssystemet ska vara en motivationsfaktor är kopplingen mellan uppnådda mål och belöningen för detta.Det empiriska resultatet visar att gemenskapen är det som gjort att de anställda stannat kvar på företaget. Gemenskapen och grundlönen är även de största motivationsfaktorerna.Background: One of the control mechanisms the companies can use to reach their objectives is a reward system. The parts included in the reward system and that it motivates the employees are two important aspects. The two subjects, reward system and motivation, are very well studied for certain branches. For more monotonous works such as warehouse operations, that is not the case. Therefore,it is interesting to study how warehouse employees experience if and in what way they are motivated by the reward system. Purpose: The purpose of this study is to describe the case company’s reward system but also examine how the employees are experiencing the system and to find out how it motives them. If the empirical data shows that there are weaknesses in the reward system, suggestions for improvements will be given. Method: The paper has been conducted in a case study form. More than one respondent has been interviewed, by semi-structured interviews. To increase the quality of the study different theoretical sources have been used. Conclusions: The employees at the case company are working towards achieving objectives conducted by the company and the company has a well-developed reward system. However, what is missing is the connection between the objectives and the reward to make the reward system a factor of motivation. The empirical data shows that the feeling kinship among the employees is the reason why they have stayed at the company. The kinship and the salary is also the most important factors of motivation.
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Clark, Lee J., E. W. Carpenter e R. H. Walser. "Short Staple Variety Trials, Graham County, 1998". College of Agriculture, University of Arizona (Tucson, AZ), 1999. http://hdl.handle.net/10150/197245.
Testo completoAbstract (sommario):
Two replicated on-farm short staple variety trials were planted in 1998. Fifteen varieties were evaluated on both the Carpenter farm in Thatcher and the Colvin farm near Ft. Thomas. Several new varieties were planted in both studies, including 4 transgenic varieties: DP 90B, BXN 47, DP 90RR and Paymaster 1560BG, 2 varieties from Australia: FiberMax 989 and FiberMax 832, and seven other varieties seen for the first time. Two of the new varieties produced the highest yields; AgriPro 6101 and Phytogen 952 on the Carpenter and Colvin farms, respectively. Other agronomic data from the varieties and HVI values from the lint are also included in this report.
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Clark, Lee J. "Short Staple Variety Trial, Greenlee County, 1998". College of Agriculture, University of Arizona (Tucson, AZ), 1999. http://hdl.handle.net/10150/197247.
Testo completoAbstract (sommario):
Six short staple cotton varieties including two New Mexico acalas varieties and one advanced strain, an Australian varieties and two SureGrow varieties with higher yield potential were tested in this study. New Mexico Acala 1517-95 had the highest lint yield with a yield of 419 pounds of lint per acre. The average yield was about 400 pounds per acre lower than the 6 year average due to a cold spring and a four inch rain that fell in one hour in the middle of July. In addition to lint yields; percent lint, plant heights, plant populations and lint hvi values are shown. A lint yield comparison for 1993 through 1998 is included in this paper.
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J, Clark L., e E. W. Carpenter. "Short Staple Variety Trials, Graham County, 1999". College of Agriculture, University of Arizona (Tucson, AZ), 2000. http://hdl.handle.net/10150/197465.
Testo completoAbstract (sommario):
Two replicated on-farm short staple variety trials were planted in 1999. Twenty-two varieties were evaluated on the Claridge farm in Solomon and fifteen varieties on the Colvin farm near Ft. Thomas. Several new varieties were planted in these studies, including 2 transgenic varieties: DP 5690RR, BXN 16; 4 Israeli inter-specific hybrids and six other varieties seen for the first time. DP 35B was the highest yielding variety in the Claridge trial with BXN 47 a close second. Both varieties yielded over 1300 pounds of lint per acre. PM 1440 was the highest yielding variety in the Colvin trial with SG 747 and DP 5690RR following closely behind. These varieties yielded between 700 and 800 pounds of lint per acre. Other agronomic data from the varieties and HVI values from the lint are also included in this report.
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Clark, Lee J., e Ronald E. Cluff. "Short Staple Variety Demonstration, Graham County, 1986". College of Agriculture, University of Arizona (Tucson, AZ), 1987. http://hdl.handle.net/10150/204468.
Testo completo
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Clark, Lee J., e Deborah Young. "Short Staple Variety Trial, Cochise County, 1986". College of Agriculture, University of Arizona (Tucson, AZ), 1987. http://hdl.handle.net/10150/204480.
Testo completo
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Clark, Lee J., e Eric Schwennesen. "Short Staple Variety Trial, Cochise County, 1987". College of Agriculture, University of Arizona (Tucson, AZ), 1988. http://hdl.handle.net/10150/204541.
Testo completoAbstract (sommario):
Eleven varieties of short staple cotton, containing four varieties of Acala 1517 (including two new releases from New Mexico State University) were grown near the town of Cochise, which is at an elevation of 4,180 feet and has an average growing season of 232 days. Northrup King's KC 380 (the same as the experimental variety 2019) was the high yielder for the second year in a row, with 954.6 pounds of lint per acre. One of the new Acala' s, 1517-77BR was second in yield, with 936.5 pounds per acre. With the current premium structure, 1517-77BR would produce about $50 more gross farm income per acre than KC 380.
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Clark, L. J., e R. E. Cluff. "Short Staple Variety Demonstration, Graham County, 1988". College of Agriculture, University of Arizona (Tucson, AZ), 1989. http://hdl.handle.net/10150/204852.
Testo completoAbstract (sommario):
Cotton lint yields in the variety trials in Graham county were higher than the 1987 yields by close to 200 pounds per acre. Two varieties, BR 110 and NK KNX 111 (now KC 311) yielded more than DP 90 at the Thatcher site, the highest yield being 1,569 pounds of lint per acre. In Eden, DP 90 was the highest yielding variety with 1,237 pounds of lint per acre. The New Mexico acalas didn't yield as much lint per acre as the top yielding varieties, but with 1988's premium, produced substantial income per acre. In Thatcher the highest yielding acala produced $861 per acre compared with BR 110's $910, whereas in Eden the highest yielding acala produced $736 per acre against DP 90's $717.