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Search Results: 1 - 10 of 2516 matches for " Amy Milsted "
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Differential Mechanisms of Activation of the Ang Peptide Receptors AT1, AT2, and MAS: Using In Silico Techniques to Differentiate the Three Receptors
Jeremy W. Prokop, Robson A. S. Santos, Amy Milsted
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065307
Abstract: The renin-angiotensin system is involved in multiple conditions ranging from cardiovascular disorders to cancer. Components of the pathway, including ACE, renin and angiotensin receptors are targets for disease treatment. This study addresses three receptors of the pathway: AT1, AT2, and MAS and how the receptors are similar and differ in activation by angiotensin peptides. Combining biochemical and amino acid variation data with multiple species sequence alignments, structural models, and docking site predictions allows for visualization of how angiotensin peptides may bind and activate the receptors; allowing identification of conserved and variant mechanisms in the receptors. MAS differs from AT1 favoring Ang-(1–7) and not Ang II binding, while AT2 recently has been suggested to preferentially bind Ang III. A new model of Ang peptide binding to AT1 and AT2 is proposed that correlates data from site directed mutagenesis and photolabled experiments that were previously considered conflicting. Ang II binds AT1 and AT2 through a conserved initial binding mode involving amino acids 111 (consensus 325) of AT1 (Asn) interacting with Tyr (4) of Ang II and 199 and 256 (consensus 512 and 621, a Lys and His respectively) interacting with Phe (8) of Ang II. In MAS these sites are not conserved, leading to differential binding and activation by Ang-(1–7). In both AT1 and AT2, the Ang II peptide may internalize through Phe (8) of Ang II propagating through the receptors’ conserved aromatic amino acids to the final photolabled positioning relative to either AT1 (amino acid 294, Asn, consensus 725) or AT2 (138, Leu, consensus 336). Understanding receptor activation provides valuable information for drug design and identification of other receptors that can potentially bind Ang peptides.
Testosterone influences renal electrolyte excretion in SHR/y and WKY males
Jonathan Toot, Cathy Jenkins, Gail Dunphy, Shannon Boehme, Mike Hart, Amy Milsted, Monte Turner, Daniel Ely
BMC Physiology , 2008, DOI: 10.1186/1472-6793-8-5
Abstract: To investigate the role of the Yc and T, consomic borderline hypertensive (SHR/y) and normotensive Wistar-Kyoto (WKY) rat strains were used (15 weeks) in three T treatment groups: castrate, castrate with T implant and gonadally intact males. Urine was collected (24 hrs at 15 weeks of age) for Na and K measurements by flame photometry. RT-PCR was used to demonstrate the presence of renal androgen receptor (AR) transcripts. Plasma T and aldosterone were measured by RIA. In another experiment the androgen receptor was blocked using flutamide in the diet.Na and K excretion were decreased by T in SHR/y and WKY. AR transcripts were identified in SHR/y and WKY kidneys. Plasma aldosterone was decreased in the presence of T. Blockade of the AR resulted in a significant increase in Na excretion but not in K excretion in both SHR/y and WKY males.T influences electrolyte excretion through an androgen receptor dependent mechanism. There was not a differential Yc involvement in electrolyte excretion between WKY and SHR/y males.Human [1,2] and animal studies [3] have implicated Y-chromosome (Yc) loci as influencing the onset of male hypertension. In the Spontaneously Hypertensive Rat strain (SHR), the SHR Yc contains a locus which increases blood pressure (BP) approximately 20 mmHg compared to the normotensive Wistar Kyoto (WKY) Y chromosome. The Yc is only one genetic component of the total SHR hypertension. In SHR males, the presences of testosterone and androgen receptors through puberty are required for development of the hypertension and associated sympathetic nervous system potentiation, including the Yc component [4,5]. In examining phenotypes that mapped to the Yc and differed between SHR and WKY, our laboratory demonstrated an earlier rise of testosterone (T) levels in SHR males leading into puberty [4] and this phenotype mapped to the SHR Yc. Because of the unique biology of the mammalian Yc the blood pressure phenotype and the T timing phenotype cannot be separated usin
Sry delivery to the adrenal medulla increases blood pressure and adrenal medullary tyrosine hydroxylase of normotensive WKY rats
Daniel Ely, Amy Milsted, Jason Bertram, Mat Ciotti, Gail Dunphy, Monte E Turner
BMC Cardiovascular Disorders , 2007, DOI: 10.1186/1471-2261-7-6
Abstract: The following study examined if exogenous Sry would elevate adrenal Th, adrenal catecholamines, plasma catecholamines and blood pressure. We delivered 10 μg of either the expression construct, Sry1/pcDNA 3.1, or control vector into the adrenal medulla of WKY rats by electroporation. Blood pressure was measured by the tail cuff technique and Th and catecholamines by HPLC with electrochemical detection.In the animals receiving Sry there were significant increases after 3 weeks in resting plasma NE (57%) and adrenal Th content (49%) compared to vector controls. BP was 30 mmHg higher in Sry injected animals (160 mmHg, p < .05) compared to vector controls (130 mmHg) after 2–3 weeks. Histological analysis showed that the electroporation procedure did not produce morphological damage.These results provide continued support that Sry is a candidate gene for hypertension. Also, these results are consistent with a role for Sry in increasing BP by directly or indirectly activating sympathetic nervous system activity.We have shown previously that there is a locus on the SHR Y chromosome that increases blood pressure (BP) about 20–25 mmHg [1,2]. Backcrosses of the SHR Y chromosome into WKY rats show a significant Y chromosome BP increase of 20 mmHg [3]. Further studies showed that the SHR Y chromosome increased several indices of SNS activity [4]. We demonstrated that renal norepinephrine (NE) turnover rate is higher by 100% [5] and renal NE content is 44% higher in males with the Y chromosome from an SHR [5]. Our recent studies indicate that a candidate gene for this SNS and BP effect is Sry, a transcription factor on the Y chromosome that is the testis determining factor [6]. Sry expression has been reported in testis, the brain and in additional tissues that have BP relevance in adult humans and rodents [7-9]. Recently, we demonstrated that Sry increased tyrosine hydroxylase (Th) promoter activity in transfected PC12 cells [6] although much of the effect was indirect. Th catal
A cell culture model using rat coronary artery adventitial fibroblasts to measure collagen production
Cathleen Jenkins, Amy Milsted, Kathleen Doane, Gary Meszaros, Jonathan Toot, Daniel Ely
BMC Cardiovascular Disorders , 2007, DOI: 10.1186/1471-2261-7-13
Abstract: Hearts (10–12 weeks) were harvested and the left anterior descending coronary artery (LAD) was isolated and removed. Tissue explants were cultured and cells (passages 2–4) were confirmed as fibroblasts using immunohistochemistry. Optimal conditions were determined for cell tissue harvest, timing, proliferation and culture conditions. Fibroblasts were exposed to 10-7 M testosterone or 10-7 M estrogen for 24 hours and either immunostained for collagen type I or subjected to ELISA.Results showed increased collagen staining in fibroblasts treated with testosterone compared to control and decreased staining with estrogen. ELISA results showed that testosterone increased collagen I by 20% whereas estrogen decreased collagen I by 15%.Data demonstrates the usefulness of our cell model in studying the specific role of the adventitia apart from other blood vessel tissue in rat coronary arteries. Results suggest opposite effects of testosterone and estrogen on collagen synthesis in the rat coronary artery adventitial fibroblasts.Cardiovascular disease is the number one cause of death in the United States. Diseases such as hypertension and coronary artery disease develop through multiple mechanisms; of significance are the structural changes that take place within blood vessels. In vivo data has shown that coronary artery fibrosis can result as a consequence of high blood pressure (BP). In addition to elevated BP, testosterone has been shown to increase the amount of collagen measured around coronary blood vessels contributing to fibrosis. For example, Seachrist found that testosterone increased coronary adventitial collagen in male hypertensive rats independent of the renin-angiotensin system [1]. Studies have provided further evidence for the role of testosterone in coronary artery fibrosis in male borderline hypertensive rats. Sympathectomy reduced systolic BP, but more interestingly reduced plasma testosterone levels correlated with decreased coronary artery collagen deposi
Matrix product states and the nonabelian rotor model
Ashley Milsted
Physics , 2015,
Abstract: We use uniform matrix product states (MPS) to study the (1+1)D $O(2)$ and $O(4)$ rotor models, which are equivalent to the Kogut-Susskind formulation of matter-free nonabelian lattice gauge theory on a "hawaiian earring" graph for $U(1)$ and $SU(2)$, respectively. Applying tangent space methods to obtain ground states and determine the mass gap and the $\beta$-function, we find excellent agreement with known strong results, locating the BKT transition for $O(2)$ and successfully entering the asymptotic weak-coupling regime for $O(4)$. To obtain a finite local Hilbert space, we truncate in the space of irreducible representations (irreps) of the gauge group, comparing the effects of different cutoff values. We find that higher irreps become important in the crossover and weak-coupling regimes of the nonabelian theory, where entanglement also suddenly increases. This could have important consequences for TNS studies of Yang-Mills on higher dimensional graphs.
From Rat to Human: Regulation of Renin-Angiotensin System Genes by Sry
Jeremy W. Prokop,Ingrid Kazue Mizuno Watanabe,Monte E. Turner,Adam C. Underwood,Almir S. Martins,Amy Milsted
International Journal of Hypertension , 2012, DOI: 10.1155/2012/724240
Abstract: The testis determining protein, Sry, has functions outside of testis determination. Multiple Sry loci are found on the Y-chromosome. Proteins from these loci have differential activity on promoters of renin-angiotensin system genes, possibly contributing to elevation of blood pressure. Variation at amino acid 76 accounts for the majority of differential effects by rat proteins Sry1 and Sry3. Human SRY regulated rat promoters in the same manner as rat Sry, elevating Agt, Ren, and Ace promoter activity while downregulating Ace 2. Human SRY significantly regulated human promoters of AGT, REN, ACE2, AT2, and MAS compared to control levels, elevating AGT and REN promoter activity while decreasing ACE2, AT2, and MAS. While the effect of human SRY on individual genes is often modest, we show that many different genes participating in the renin-angiotensin system can be affected by SRY, apparently in coordinated fashion, to produce more Ang II and less Ang-(1–7).
Delivery of sry1, but not sry2, to the kidney increases blood pressure and sns indices in normotensive wky rats
Daniel Ely, Amy Milsted, Gail Dunphy, Shannon Boehme, Jeff Dunmire, Mike Hart, Jonathon Toot, Almir Martins, Monte Turner
BMC Physiology , 2009, DOI: 10.1186/1472-6793-9-10
Abstract: In the animals receiving the Sry1 plasmid there were significant increases after 21 days in resting plasma norepinephrine (NE, 27%) and renal tyrosine hydroxylase content (41%, p < .05) compared to controls. BP was higher in animals electroporated with Sry1 (143 mmHg, p < .05) compared to controls (125 mmHg) between 2–4 weeks. Also the pressor response to air stress was significantly elevated in males electroporated with Sry1 (41 mmHg) compared to controls (28 mmHg, p < .001). Sry2 did not elevate BP or SNS indices and further tests were not done. The hormone profiles for plasma renin, aldosterone, and corticosterone between electroporated Sry1 and control vector males showed no significant differences over the 28 day period. Alpha adrenergic receptor blockade prevented the air stress pressor response in both strains. Urinary dopamine significantly increased after 7 days post Sry electroporation.These results are consistent with a role for Sry1 in increasing BP by directly or indirectly activating renal sympathetic nervous system activity.We have shown previously that there is a locus on the SHR Y chromosome that increased blood pressure (BP) in an additive manner by 20–25 mmHg and that The Y chromosome Sry locus increased tyrosine hydroxylase promoter activity [1-4] and increased several indices of sympathetic nervous system (SNS) activity [5]. We demonstrated that renal norepinephrine (NE) turnover rate is higher by 100% and renal NE content is 44% higher in males with the SHR Y chromosome [6]. Studies in our lab indicate that a candidate gene for this SNS and BP effect is the Sry gene complex on the rat Y chromosome. The Sry protein is a transcription factor that has been shown to be the testis determining factor in mice and humans [7], although Sry expression has been reported in adult testis, brain, adrenal gland and in additional tissues that have BP relevance in humans and rodents [8-11]. The Sry protein has potential target loci not involved in testis determ
Genomic and expression analysis of multiple Sry loci from a single Rattus norvegicus Y chromosome
Monte E Turner, Carey Martin, Almir S Martins, Jeffrey Dunmire, Joel Farkas, Daniel L Ely, Amy Milsted
BMC Genetics , 2007, DOI: 10.1186/1471-2156-8-11
Abstract: Y chromosome fragments were amplified and sequenced using primers that included the entire Sry coding region and flanking sequences. The analysis of these sequences identified six Sry loci on the Y chromosome. These are paralogous copies consistent with a single phylogeny and the divergence between any two copies is less than 2%. All copies have a conserved reading frame and amino acid sequence consistent with function. Fragment analysis of genomic DNA showed close approximations of experimental with predicted values, validating the use of this method to identify proportions of each copy. Using the fragment analysis procedure with cDNA samples showed the Sry copies expressed were significantly different from the genomic distribution (testis p < 0.001, adrenal gland p < 0.001), and the testis and adrenal copy distribution in the transcripts were also significantly different from each other (p < 0.001). Total Sry transcript expression, analyzed by real-time PCR, showed significantly higher levels of Sry in testis than adrenal gland (p, 0.001).The SHR Y chromosome contains at least 6 full length copies of the Sry gene. These copies have a conserved coding region and conserved amino acid sequence. The pattern of divergence is not consistent with gene conversion as the mechanism for this conservation. Expression studies show multiple copies expressed in the adult male testis and adrenal glands, with tissue specific differences in expression patterns. Both the DNA sequence analysis and RNA transcript expression analysis are consistent with more than one copy having function and selection preventing divergence although we have no functional evidence.The recent analysis of the DNA sequence of the human Y chromosome has required a change from the classical view of the mammalian Y chromosome as a passive, genetic graveyard to one of an active, self correcting entity [1,2]. In reality, the mammalian Y chromosome is a combination of both the classical and modern views, since di
From Rat to Human: Regulation of Renin-Angiotensin System Genes by Sry
Jeremy W. Prokop,Ingrid Kazue Mizuno Watanabe,Monte E. Turner,Adam C. Underwood,Almir S. Martins,Amy Milsted
International Journal of Hypertension , 2012, DOI: 10.1155/2012/724240
Abstract: The testis determining protein, Sry, has functions outside of testis determination. Multiple Sry loci are found on the Y-chromosome. Proteins from these loci have differential activity on promoters of renin-angiotensin system genes, possibly contributing to elevation of blood pressure. Variation at amino acid 76 accounts for the majority of differential effects by rat proteins Sry1 and Sry3. Human SRY regulated rat promoters in the same manner as rat Sry, elevating Agt, Ren, and Ace promoter activity while downregulating Ace 2. Human SRY significantly regulated human promoters of AGT, REN, ACE2, AT2, and MAS compared to control levels, elevating AGT and REN promoter activity while decreasing ACE2, AT2, and MAS. While the effect of human SRY on individual genes is often modest, we show that many different genes participating in the renin-angiotensin system can be affected by SRY, apparently in coordinated fashion, to produce more Ang II and less Ang-(1–7). 1. Introduction Many genes on the Y chromosome that are expressed in tissues not involved in testis formation could contribute to sex differences in blood pressure and other disease phenotypes. Sry is believed to have evolved from the X chromosome gene Sox3 during the process of Y-chromosome formation in therian mammals [1]. Since Sox3 has functions other than testis determination [2], Sry may also have additional functions outside testis determination. Sry and other Sox proteins are architectural transcription factors that bind to the minor groove of DNA, changing gene regulation through inducing a bend in the DNA [3]. The spontaneously hypertensive rat (SHR) has at least seven expressed Sry loci whereas the normotensive Wistar Kyoto (WKY) rat has at least six [4], lacking Sry3. Sry transcripts have been observed in adult rat tissues consistent with blood pressure regulation [5], and one or more of the Sry loci play a role in the development of hypertension in SHR [6]. Many rodent species have multiple Sry loci, while human and mouse have only one known locus. Sry proteins in human, rat, and other placental mammals have a homologous HMG box, hinge region, and bridge domain, with little homology in the N and C terminal ends (Figure 1(a)). The role of Sry regulation of blood pressure in humans has not been studied directly. However, with the high degree of conservation in the DNA-binding domain between human and rat, functions of Sry seen in rat are likely to translate into clinical relevance for human male blood pressure regulation. Figure 1: Modeling Sry variations of Sry1, Sry3, and hSRY. (a)
Canine distemper virus induces apoptosis in cervical tumor derived cell lines
Helen L Del Puerto, Almir S Martins, Amy Milsted, Elaine M Souza-Fagundes, Gissandra F Braz, Barbara Hissa, Luciana O Andrade, Fabiana Alves, Daniela S Raj?o, R?mulo C Leite, Anilton C Vasconcelos
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-334
Abstract: Apoptosis is a regulated form of cell death which occurs during physiological conditions. It plays a critical role in the homeostasis of multicelular organisms, and constitutes a common pathway for cell replacement, tissue remodeling, damaged cell removal and elimination of cancer cells [1]. It is a complex process which involves the participation of caspases, activation of proapoptotic genes, and inhibition of antiapoptotic proteins. Cells undergoing apoptosis present typical morphological characteristics, including membrane blebbing, chromatin condensation, cell shrinkage and apoptotic body formation [2].Apoptosis is triggered by sequential activation of caspases, a group of cysteine proteases, and proceeds primarily through two pathways. The extrinsic pathway involves activation of caspase-8 and is initiated by ligand interaction with death receptors, while the intrinsic pathway is activated by an imbalance between proapoptotic and antiapoptotic proteins from Bcl-2 family in mitochondria and cytosol, resulting in release of cytochrome c from mitochondria, which in turn activates caspase-9 [3]. Both caspase-8 and caspase-9 activate caspase-3, which along with other effectors caspases cleave critical cellular proteins, resulting in apoptosis [3].Many viral proteins can influence the cellular pathways that control cell proliferation and apoptosis. Some viral proteins trigger apoptotic cell death, and this may be important in host defense and viral spread. In other cases, viral proteins inhibit apoptosis [4].HeLa cells, derived from a cervical tumor, encode apoptosis inhibitor proteins E6 and E7, oncoproteins expressed by high-risk human papillomavirus (HPV), among them the HPV18 type [5,6]. HPV E6 protein target p53, a tumor suppressor protein that regulates the cell cycle. The E6 protein binding to p53 causes p53 inactivation by its degradation, turning off its function [6,7]. On the other hand, the HPV E7 protein acts by binding to members of the Rb (retinoblastom
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