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Title: The cerebral cortex of Albert Einstein: a description and preliminary analysis of unpublished photographs.
Creator: Falk, Dean, Lepore, Fredrick, Noe, Adrianne
Abstract/Description: Upon his death in 1955, Albert Einstein's brain was removed, fixed and photographed from multiple angles. It was then sectioned into 240 blocks, and histological slides were prepared. At the time, a roadmap was drawn that illustrates the location within the brain of each block and its associated slides. Here we describe the external gross neuroanatomy of Einstein's entire cerebral cortex from 14 recently discovered photographs, most of which were taken from unconventional angles. Two of the...
Show moreUpon his death in 1955, Albert Einstein's brain was removed, fixed and photographed from multiple angles. It was then sectioned into 240 blocks, and histological slides were prepared. At the time, a roadmap was drawn that illustrates the location within the brain of each block and its associated slides. Here we describe the external gross neuroanatomy of Einstein's entire cerebral cortex from 14 recently discovered photographs, most of which were taken from unconventional angles. Two of the photographs reveal sulcal patterns of the medial surfaces of the hemispheres, and another shows the neuroanatomy of the right (exposed) insula. Most of Einstein's sulci are identified, and sulcal patterns in various parts of the brain are compared with those of 85 human brains that have been described in the literature. To the extent currently possible, unusual features of Einstein's brain are tentatively interpreted in light of what is known about the evolution of higher cognitive processes in humans. As an aid to future investigators, these (and other) features are correlated with blocks on the roadmap (and therefore histological slides). Einstein's brain has an extraordinary prefrontal cortex, which may have contributed to the neurological substrates for some of his remarkable cognitive abilities. The primary somatosensory and motor cortices near the regions that typically represent face and tongue are greatly expanded in the left hemisphere. Einstein's parietal lobes are also unusual and may have provided some of the neurological underpinnings for his visuospatial and mathematical skills, as others have hypothesized. Einstein's brain has typical frontal and occipital shape asymmetries (petalias) and grossly asymmetrical inferior and superior parietal lobules. Contrary to the literature, Einstein's brain is not spherical, does not lack parietal opercula and has non-confluent Sylvian and inferior postcentral sulci.
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Date Issued: 2012
Identifier: FSU_migr_anthro_faculty_publications-0001, 10.1093/brain/aws295
Format: Citation

Title: The Illustrated American and the Lakota Ghost Dance.
Creator: Bearor, Karen
Abstract/Description: The ceremonial dance contemporary reporters dubbed the ghost dance has inspired shelves of books and hundreds of articles, both popular and scholarly. Called the spirit dance by the Lakota, it was part of a revivalist and millennialist movement sweeping through Native American tribes in the West in the late 1880s and early 1890s. As such, it remains cemented in the country's collective consciousness by its association with the Wounded Knee Massacre on December 29, 1890, that inglorious symbol...
Show moreThe ceremonial dance contemporary reporters dubbed the ghost dance has inspired shelves of books and hundreds of articles, both popular and scholarly. Called the spirit dance by the Lakota, it was part of a revivalist and millennialist movement sweeping through Native American tribes in the West in the late 1880s and early 1890s. As such, it remains cemented in the country's collective consciousness by its association with the Wounded Knee Massacre on December 29, 1890, that inglorious symbol for both the end of the Indian wars and the failure of governmental and reformist policies.
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Date Issued: 2011
Identifier: FSU_migr_arh_faculty_publications-0001, 10.1353/amp.2011.0009
Format: Citation

Title: Affirmative Action and Diversity: Implications for Arts Management.
Creator: Cuyler, Antonio C. (Antonio Christopher)
Abstract/Description: Affirmative action and diversity can serve as a powerful framework for helping arts management educators address the challenge of diversity in the arts. This article encourages arts management educators to use affirmative action and diversity to proactively recruit diverse students into academic degree programs.
Date Issued: 2013
Identifier: FSU_migr_arted_faculty_publications-0001, 10.1080/10632921.2013.786009
Format: Citation

Title: The Autolytic Regulation of Human Kallikrein-Related Peptidase 6.
Creator: Blaber, Sachiko, Yoon, Hyesook, Scarisbrick, Isobel, Juliano, Maria, Blaber, Michael
Abstract/Description: Human kallikrein-related peptidase 6 (KLK6) is a member of the kallikrein family of serine-type proteases, characterized as an arginine-specific digestive-type protease capable of degrading a wide-variety of extracellular matrix proteins. KLK6 has been proposed to be a useful biomarker for breast and ovarian cancer prognosis, is abundantly expressed in the CNS and cerebrospinal fluid, and is intimately associated with regions of active inflammatory demyelination in multiple sclerosis (MS)...
Show moreHuman kallikrein-related peptidase 6 (KLK6) is a member of the kallikrein family of serine-type proteases, characterized as an arginine-specific digestive-type protease capable of degrading a wide-variety of extracellular matrix proteins. KLK6 has been proposed to be a useful biomarker for breast and ovarian cancer prognosis, is abundantly expressed in the CNS and cerebrospinal fluid, and is intimately associated with regions of active inflammatory demyelination in multiple sclerosis (MS) lesions. Inhibition of KLK6 results in delayed onset and reduced severity of symptoms associated with experimental autoimmune encephalomyelitis, suggesting a key effector role for this protease in CNS inflammatory disease. KLK6 has been shown to autolytically cleave internally, leading to inactivation and suggesting a negative feedback inhibition control mechanism. Alternatively, the ability of KLK6 to self-activate has also been reported, suggesting a positive feedback activation loop control mechanism. Activation of pro-KLK6 requires hydrolysis after a Lys residue; however, KLK6 exhibits 2 order of magnitude reduced affinity for hydrolysis after Lys versus Arg residues; therefore, the ability to autolytically activate has been called into question. In the present study the catalytic activity of KLK6 toward its pro-sequence and internal autolytic sequence is characterized. The results show that the ability of KLK6 to activate pro-KLK6 is essentially negligible when compared to the rate of the internal autolytic inactivation or to the ability of other proteases to activate pro-KLK6. The results thus show that the primary autolytic regulatory mechanism of KLK6 is negative feedback inhibition, and activation is likely achieved through the action of a separate protease.
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Date Issued: 2007
Identifier: FSU_migr_biomed_faculty_publications-0002, 10.1021/bi6025006, PMC2517904
Format: Citation

Title: Substrate Specificity of Human Kallikreins 1 and 6 Determined by Phage Display.
Creator: Li, Hai-Xin, Hwang, Bum-Yeol, Laxmikanthan, Gurunathan, Blaber, Sachiko, Blaber, Michael, Golubkov, Pavel, Ren, Pengyu, Iverson, Brent, Georgiou, George
Abstract/Description: The human tissue kallikrein (KLK) family contains 15 secreted serine proteases that are expressed in a wide range of tissues and have been implicated in different physiological functions and disease states. Of these, KLK1 has been shown to be involved in the regulation of multiple physiological processes such as blood pressure, smooth muscle contraction, and vascular cell growth. KLK6 is overexpressed in breast and ovarian cancer tissues and has been shown to cleave peptide derived from human...
Show moreThe human tissue kallikrein (KLK) family contains 15 secreted serine proteases that are expressed in a wide range of tissues and have been implicated in different physiological functions and disease states. Of these, KLK1 has been shown to be involved in the regulation of multiple physiological processes such as blood pressure, smooth muscle contraction, and vascular cell growth. KLK6 is overexpressed in breast and ovarian cancer tissues and has been shown to cleave peptide derived from human myelin protein and Abeta amyloid peptide in vitro. Here we analyzed the substrate specificity of KLK1 and KLK6, by substrate phage display using a random octapeptide library. Consistent with earlier biochemical data, KLK1 was shown to exhibit both trypsin- and chymotrypsin-like selectivities with Tyr/Arg preferred at site P1, Ser/Arg strongly preferred at P1', and Phe/Leu at P2. KLK6 displayed trypsin-like activity, with the P1 position occupied only by Arg and a strong preference for Ser in P1'. Docking simulations of consensus peptide provide information on the identity of the enzyme residues that are responsible for substrate binding. Bioinformatic analysis suggested several putative KLK6 protein substrates, such as ionotropic glutamate receptor (GluR) and synphilin.
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Date Issued: 2008
Identifier: FSU_migr_biomed_faculty_publications-0006
Format: Citation

Title: Mutagenesis of the Crystal Contact of Acidic Fibroblast Growth Factor.
Creator: Honjo, Eijiro, Tamada, Taro, Adachi, Motoyasu, Kuroki, Ryota, Meher, Akshaya, Blaber, Michael
Abstract/Description: An attempt has been made to improve a crystal contact of human acidic fibroblast growth factor (haFGF; 140 amino acids) to control the crystal growth, because haFGF crystallizes only as a thin-plate form, yielding crystals suitable for X-ray but not neutron diffraction. X-ray crystal analysis of haFGF showed that the Glu81 side chain, located at a crystal contact between haFGF molecules, is in close proximity with an identical residue related by crystallographic symmetry, suggesting that...
Show moreAn attempt has been made to improve a crystal contact of human acidic fibroblast growth factor (haFGF; 140 amino acids) to control the crystal growth, because haFGF crystallizes only as a thin-plate form, yielding crystals suitable for X-ray but not neutron diffraction. X-ray crystal analysis of haFGF showed that the Glu81 side chain, located at a crystal contact between haFGF molecules, is in close proximity with an identical residue related by crystallographic symmetry, suggesting that charge repulsion may disrupt suitable crystal-packing interactions. To investigate whether the Glu residue affects the crystal-packing interactions, haFGF mutants in which Glu81 was replaced by Ala, Val, Leu, Ser and Thr were constructed. Although crystals of the Ala and Leu mutants were grown as a thin-plate form by the same precipitant (formate) as the wild type, crystals of the Ser and Thr mutants were grown with increased thickness, yielding a larger overall crystal volume. X-ray structural analysis of the Ser mutant determined at 1.35 A resolution revealed that the hydroxy groups of Ser are linked by hydrogen bonds mediated by the formate used as a precipitant. This approach to engineering crystal contacts may contribute to the development of large protein crystals for neutron crystallography.
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Date Issued: 2008
Identifier: FSU_migr_biomed_faculty_publications-0007
Format: Citation

Title: Kallikreins are Associated with Secondary Progressive Multiple Sclerosis and Promote Neurodegeneration.
Creator: Scarisbrick, Isobel, Linbo, Rachel, Vandell, Alexander, Keegan, Mark, Blaber, Sachiko, Blaber, Michael, Sneve, Diane, Lucchinetti, Claudia F., Rodriguez, Moses, Diamandis,...
Show moreScarisbrick, Isobel, Linbo, Rachel, Vandell, Alexander, Keegan, Mark, Blaber, Sachiko, Blaber, Michael, Sneve, Diane, Lucchinetti, Claudia F., Rodriguez, Moses, Diamandis, Eleftherios P.
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Abstract/Description: Tissue kallikrein KLK1 and the kallikrein-related peptidases KLK2-15 are a subfamily of serine proteases that have defined or proposed roles in a range of central nervous system (CNS) and non-CNS pathologies. To further understand their potential activity in multiple sclerosis (MS), serum levels of KLK1, 6, 7, 8 and 10 were determined in 35 MS patients and 62 controls by quantitative fluorometric ELISA. Serum levels were then correlated with Expanded Disability Status Scale (EDSS) scores...
Show moreTissue kallikrein KLK1 and the kallikrein-related peptidases KLK2-15 are a subfamily of serine proteases that have defined or proposed roles in a range of central nervous system (CNS) and non-CNS pathologies. To further understand their potential activity in multiple sclerosis (MS), serum levels of KLK1, 6, 7, 8 and 10 were determined in 35 MS patients and 62 controls by quantitative fluorometric ELISA. Serum levels were then correlated with Expanded Disability Status Scale (EDSS) scores determined at the time of serological sampling or at last clinical follow-up. Serum levels of KLK1 and KLK6 were elevated in MS patients (p
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Date Issued: 2008
Identifier: FSU_migr_biomed_faculty_publications-0008
Format: Citation

Title: Activation Profiles of Human Kallikrein-Related Peptidases by Proteases of the Thrombostasis Axis.
Creator: Yoon, Hyesook, Blaber, Sachiko, Evans, D., Trim, Julie, Juliano, Maria, Scarisbrick, Isobel, Blaber, Michael
Abstract/Description: The human kallikrein-related peptidases (KLKs) comprise 15 members (KLK1-15) and are the single largest family of serine proteases. The KLKs are utilized, or proposed, as clinically important biomarkers and therapeutic targets of interest in cancer and neurodegenerative disease. All KLKs appear to be secreted as inactive pro-forms (pro-KLKs) that are activated extracellularly by specific proteolytic release of their N-terminal pro-peptide. This processing is a key step in the regulation of...
Show moreThe human kallikrein-related peptidases (KLKs) comprise 15 members (KLK1-15) and are the single largest family of serine proteases. The KLKs are utilized, or proposed, as clinically important biomarkers and therapeutic targets of interest in cancer and neurodegenerative disease. All KLKs appear to be secreted as inactive pro-forms (pro-KLKs) that are activated extracellularly by specific proteolytic release of their N-terminal pro-peptide. This processing is a key step in the regulation of KLK function. Much recent work has been devoted to elucidating the potential for activation cascades between members of the KLK family, with physiologically relevant KLK regulatory cascades now described in skin desquamation and semen liquefaction. Despite this expanding knowledge of KLK regulation, details regarding the potential for functional intersection of KLKs with other regulatory proteases are essentially unknown. To elucidate such interaction potential, we have characterized the ability of proteases associated with thrombostasis to hydrolyze the pro-peptide sequences of the KLK family using a previously described pro-KLK fusion protein system. A subset of positive hydrolysis results were subsequently quantified with proteolytic assays using intact recombinant pro-KLK proteins. Pro-KLK6 and 14 can be activated by both plasmin and uPA, with plasmin being the best activator of pro-KLK6 identified to date. Pro-KLK11 and 12 can be activated by a broad-spectrum of thrombostasis proteases, with thrombin exhibiting a high degree of selectivity for pro-KLK12. The results show that proteases of the thrombostasis family can efficiently activate specific pro-KLKs, demonstrating the potential for important regulatory interactions between these two major protease families.
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Date Issued: 2008
Identifier: FSU_migr_biomed_faculty_publications-0009
Format: Citation

Title: Protease-Activated Receptor Dependent and Independent Signaling by Kallikreins 1 and 6 in CNS Neuron and Astroglial Cell Lines.
Creator: Vandell, Alexander, Larson, Nadya, Laxmikanthan, Gurunathan, Panos, Michael, Blaber, Sachiko, Blaber, Michael, Scarisbrick, Isobel
Abstract/Description: While protease-activated receptors (PARs) are known to mediate signaling events in CNS, contributing both to normal function and pathogenesis, the endogenous activators of CNS PARs are poorly characterized. In this study, we test the hypothesis that kallikreins (KLKs) represent an important pool of endogenous activators of CNS PARs. Specifically, KLK1 and KLK6 were examined for their ability to evoke intracellular Ca(2+) flux in a PAR-dependent fashion in NSC34 neurons and Neu7 astrocytes....
Show moreWhile protease-activated receptors (PARs) are known to mediate signaling events in CNS, contributing both to normal function and pathogenesis, the endogenous activators of CNS PARs are poorly characterized. In this study, we test the hypothesis that kallikreins (KLKs) represent an important pool of endogenous activators of CNS PARs. Specifically, KLK1 and KLK6 were examined for their ability to evoke intracellular Ca(2+) flux in a PAR-dependent fashion in NSC34 neurons and Neu7 astrocytes. Both KLKs were also examined for their ability to activate mitogen-activated protein kinases (extracellular signal-regulated kinases, C-Jun N-terminal kinases, and p38) and protein kinase B (AKT) intracellular signaling cascades. Cumulatively, these studies show that KLK6, but not KLK1, signals through PARs. KLK6 evoked intracellular Ca(2+) flux was mediated by PAR1 in neurons and both PAR1 and PAR2 in astrocytes. Importantly, both KLK1 and KLK6 altered the activation state of mitogen-activated protein kinases and AKT, suggestive of important roles for each in CNS neuron and glial differentiation, and survival. The cellular specificity of CNS-KLK activity was underscored by observations that both proteases promoted AKT activation in astrocytes, but inhibited such signaling in neurons. PAR1 and bradykinin receptor inhibitors were used to demonstrate that KLK1-mediated activation of extracellular signal-regulated kinases in neurons occurred in a non-PAR, bradykinin 2 (B2) receptor-dependent fashion, while similar signaling by KLK6 was mediated by the combined activation of PAR1 and B2. Cumulatively results indicate KLK6, but not KLK1 is an activator of CNS PARs, and that both KLKs are poised to signal in a B2 receptor-dependent fashion to regulate multiple signal transduction pathways relevant to CNS physiologic function and dysfunction.
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Date Issued: 2008
Identifier: FSU_migr_biomed_faculty_publications-0010
Format: Citation

Title: S(1)' and S(2)' Subsite Specificities of Human Plasma Kallikrein and Tissue Kallikrein 1 for the Hydrolysis of Peptides Derived from the Bradykinin Domain of Human Kininogen.
Creator: Lima, Aurelio, Alves, Fabiana, Angelo, Pedro, Andrade, Douglas, Blaber, Sachiko, Blaber, Michael, Juliano, Luiz, Juliano, Maria
Abstract/Description: The S(1)' and S(2)' subsite specificities of human tissue kallikrein 1 (KLK1) and human plasma kallikrein (HPK) were examined with the peptide series Abz-GFSPFRXSRIQ-EDDnp and Abz-GFSPFRSXRIQ-EDDnp [X=natural amino acids or S(PO(3)H(2))]. KLK1 efficiently hydrolyzed most of the peptides except those containing negatively charged amino acids at P(1)' and P(2)' positions. Abz-GFSPFRSSRIQ-EDDnp, as in human kininogen, is the best substrate for KLK1 and exclusively cleaved the R-S bond. All other...
Show moreThe S(1)' and S(2)' subsite specificities of human tissue kallikrein 1 (KLK1) and human plasma kallikrein (HPK) were examined with the peptide series Abz-GFSPFRXSRIQ-EDDnp and Abz-GFSPFRSXRIQ-EDDnp [X=natural amino acids or S(PO(3)H(2))]. KLK1 efficiently hydrolyzed most of the peptides except those containing negatively charged amino acids at P(1)' and P(2)' positions. Abz-GFSPFRSSRIQ-EDDnp, as in human kininogen, is the best substrate for KLK1 and exclusively cleaved the R-S bond. All other peptides were cleaved also at the F-R bond. The synthetic human kininogen segment Abz-MISLMKRPPGFSPFRS(390)S(391)RI-NH(2) was hydrolyzed by KLK1 first at R-S and then at M-K bonds, releasing Lys-bradykinin. In the S(390) and S(391) phosphorylated analogs, this order of hydrolysis was inverted due to the higher resistance of the R-S bond. Abz-MISLMKRPPG-FSPFRSS(PO(3)H(2))(391)RI-NH(2) was hydrolyzed by KLK1 at M-K and mainly at the F-R bond, releasing des-(Arg(9))-Lys-Bk which is a B1 receptor agonist. HPK cleaved all the peptides at R and showed restricted specificity for S in the S(1)' subsite, with lower specificity for the S(2)' subsite. Abz-MISLMKRPPGFSPFRSSRI-NH(2) was efficiently hydrolyzed by HPK under bradykinin release, while the analogs containing S(PO(3)H(2)) were poorly hydrolyzed. In conclusion, S(1)' and S(2)' subsite specificities of KLK1 and HPK showed peculiarities that were observed with substrates containing the amino acid sequence of human kininogen.
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Date Issued: 2008
Identifier: FSU_migr_biomed_faculty_publications-0011
Format: Citation

Title: A Completed KLK Activome Profile: Investigation of Activation Profiles of KLK9, 10, and 15..
Creator: Yoon, Hyesook, Blaber, Sachiko, Debela, Mekdes, Goettig, Peter, Scarisbrick, Isobel, Blaber, Michael
Abstract/Description: We previously reported the activation profiles of the human kallikrein-related peptidases (KLKs) as determined from a KLK pro-peptide fusion-protein system. That report described the activity profiles of 12 of the 15 mature KLKs versus the 15 different pro-KLK sequences. The missing profiles in the prior report, involving KLK9, 10, and 15, are now described. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis, mass spectrometry, and N-terminal sequence analyses show that KLK9 and 10...
Show moreWe previously reported the activation profiles of the human kallikrein-related peptidases (KLKs) as determined from a KLK pro-peptide fusion-protein system. That report described the activity profiles of 12 of the 15 mature KLKs versus the 15 different pro-KLK sequences. The missing profiles in the prior report, involving KLK9, 10, and 15, are now described. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis, mass spectrometry, and N-terminal sequence analyses show that KLK9 and 10 exhibit low hydrolytic activities towards all of the 15 pro-KLK sequences, while KLK15 exhibits significant activity towards both Arg- and Lys-containing KLK pro-sequences. The ability of KLK15 to activate pro-KLK8, 12, and 14 is confirmed using recombinant pro-KLK proteins, and shown to be significant for activation of pro-KLK8 and 14, but not 12. These additional data for KLK9, 10, and 15 now permit a completed KLK activome profile, using a KLK pro-peptide fusion-protein system, to be described. The results suggest that KLK15, once activated, can potentially feed back into additional pro-KLK activation pathways. Conversely, KLK9 and 10, once activated, are unlikely to participate in further pro-KLK activation pathways, although similar to KLK1 they may activate other bioactive peptides.
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Date Issued: 2009
Identifier: FSU_migr_biomed_faculty_publications-0012
Format: Citation

Title: X-ray Structure and Biophysical Properties of Rabbit Fibroblast Growth Factor 1.
Creator: Lee, Jihun, Blaber, Sachiko, Irsigler, Andre, Aspinwall, Eric, Blaber, Michael
Abstract/Description: The rabbit is an important and de facto animal model in the study of ischemic disease and angiogenic therapy. Additionally, fibroblast growth factor 1 (FGF-1) is emerging as one of the most important growth factors for novel proangiogenic and pro-arteriogenic therapy. However, despite its significance, the fundamental biophysical properties of rabbit FGF-1, including its X-ray structure, have never been reported. Here, the cloning, crystallization, X-ray structure and determination of the...
Show moreThe rabbit is an important and de facto animal model in the study of ischemic disease and angiogenic therapy. Additionally, fibroblast growth factor 1 (FGF-1) is emerging as one of the most important growth factors for novel proangiogenic and pro-arteriogenic therapy. However, despite its significance, the fundamental biophysical properties of rabbit FGF-1, including its X-ray structure, have never been reported. Here, the cloning, crystallization, X-ray structure and determination of the biophysical properties of rabbit FGF-1 are described. The X-ray structure shows that the amino-acid differences between human and rabbit FGF-1 are solvent-exposed and therefore potentially immunogenic, while the biophysical studies identify differences in thermostability and receptor-binding affinity that distinguish rabbit FGF-1 from human FGF-1.
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Date Issued: 2009
Identifier: FSU_migr_biomed_faculty_publications-0016, 10.1107/S1744309109040287, PMC2777034
Format: Citation

Title: Engineering an Improved Crystal Contact Across a Solvent-Mediated Interface of Human Fibroblast Growth Factor 1.
Creator: Meher, Akshaya, Blaber, Sachiko, Lee, Jihun, Honjo, Ejiro, Kuroki, Ryota, Blaber, Michael
Abstract/Description: Large-volume protein crystals are a prerequisite for neutron diffraction studies and their production represents a bottleneck in obtaining neutron structures. Many protein crystals that permit the collection of high-resolution X-ray diffraction data are inappropriate for neutron diffraction owing to a plate-type morphology that limits the crystal volume. Human fibroblast growth factor 1 crystallizes in a plate morphology that yields atomic resolution X-ray diffraction data but has...
Show moreLarge-volume protein crystals are a prerequisite for neutron diffraction studies and their production represents a bottleneck in obtaining neutron structures. Many protein crystals that permit the collection of high-resolution X-ray diffraction data are inappropriate for neutron diffraction owing to a plate-type morphology that limits the crystal volume. Human fibroblast growth factor 1 crystallizes in a plate morphology that yields atomic resolution X-ray diffraction data but has insufficient volume for neutron diffraction. The thin physical dimension has been identified as corresponding to the b cell edge and the X-ray structure identified a solvent-mediated crystal contact adjacent to position Glu81 that was hypothesized to limit efficient crystal growth in this dimension. In this report, a series of mutations at this crystal contact designed to both reduce side-chain entropy and replace the solvent-mediated interface with direct side-chain contacts are reported. The results suggest that improved crystal growth is achieved upon the introduction of direct crystal contacts, while little improvement is observed with side-chain entropy-reducing mutations alone.
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Date Issued: 2009
Identifier: FSU_migr_biomed_faculty_publications-0017, 10.1107/S1744309109036987, PMC2777043
Format: Citation

Title: Functional Intersection of the Kallikrein-Related Peptidases (KLKs) and Thrombostasis Axis.
Creator: Blaber, Michael, Yoon, Hyesook, Juliano, Maria, Scarisbrick, Isobel, Blaber, Sachiko
Abstract/Description: A large body of emerging evidence indicates a functional interaction between the kallikrein-related peptidases (KLKs) and proteases of the thrombostasis axis. These interactions appear relevant for both normal health as well as pathologies associated with inflammation, tissue injury, and remodeling. Regulatory interactions between the KLKs and thrombostasis proteases could impact several serious human diseases, including neurodegeneration and cancer. The emerging network of specific...
Show moreA large body of emerging evidence indicates a functional interaction between the kallikrein-related peptidases (KLKs) and proteases of the thrombostasis axis. These interactions appear relevant for both normal health as well as pathologies associated with inflammation, tissue injury, and remodeling. Regulatory interactions between the KLKs and thrombostasis proteases could impact several serious human diseases, including neurodegeneration and cancer. The emerging network of specific interactions between these two protease families appears to be complex, and much work remains to elucidate it. Complete understanding how this functional network resolves over time, given specific initial conditions, and how it might be controllably manipulated, will probably contribute to the emergence of novel diagnostics and therapeutic agents for major diseases.
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Date Issued: 2010
Identifier: FSU_migr_biomed_faculty_publications-0018, 10.1515/BC.2010.024, PMC3047482
Format: Citation

Title: Experimental Support for the Evolution of Symmetric Protein Architecture from a Simple Peptide Motif.
Creator: Lee, Jihun, Blaber, Michael
Abstract/Description: The majority of protein architectures exhibit elements of structural symmetry, and "gene duplication and fusion" is the evolutionary mechanism generally hypothesized to be responsible for their emergence from simple peptide motifs. Despite the central importance of the gene duplication and fusion hypothesis, experimental support for a plausible evolutionary pathway for a specific protein architecture has yet to be effectively demonstrated. To address this question, a unique "top-down...
Show moreThe majority of protein architectures exhibit elements of structural symmetry, and "gene duplication and fusion" is the evolutionary mechanism generally hypothesized to be responsible for their emergence from simple peptide motifs. Despite the central importance of the gene duplication and fusion hypothesis, experimental support for a plausible evolutionary pathway for a specific protein architecture has yet to be effectively demonstrated. To address this question, a unique "top-down symmetric deconstruction" strategy was utilized to successfully identify a simple peptide motif capable of recapitulating, via gene duplication and fusion processes, a symmetric protein architecture (the threefold symmetric β-trefoil fold). The folding properties of intermediary forms in this deconstruction agree precisely with a previously proposed "conserved architecture" model for symmetric protein evolution. Furthermore, a route through foldable sequence-space between the simple peptide motif and extant protein fold is demonstrated. These results provide compelling experimental support for a plausible evolutionary pathway of symmetric protein architecture via gene duplication and fusion processes.
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Date Issued: 2011
Identifier: FSU_migr_biomed_faculty_publications-0020, 10.1073/pnas.1015032108, PMC3017207
Format: Citation

Title: Expression and Function of the Kallikrein-Related Peptidase 6 in the Human Melanoma Microenvironment.
Creator: Krenzer, Stefanie, Peterziel, Heike, Mauch, Cornelia, Blaber, Sachiko, Blaber, Michael, Angel, Peter, Hess, Jochen
Abstract/Description: Cutaneous malignant melanoma is an aggressive disease of poor prognosis. Clinical and experimental studies have provided major insight into the pathogenesis of the disease, including the functional interaction between melanoma cells and surrounding keratinocytes, fibroblasts, and immune cells. Nevertheless, patients with metastasized melanoma have a very poor prognosis and are largely refractory to clinical therapies. Hence, diagnostic tools to monitor melanoma development, as well as...
Show moreCutaneous malignant melanoma is an aggressive disease of poor prognosis. Clinical and experimental studies have provided major insight into the pathogenesis of the disease, including the functional interaction between melanoma cells and surrounding keratinocytes, fibroblasts, and immune cells. Nevertheless, patients with metastasized melanoma have a very poor prognosis and are largely refractory to clinical therapies. Hence, diagnostic tools to monitor melanoma development, as well as therapeutic targets, are urgently needed. We investigated the expression pattern of the kallikrein-related peptidase 6 (KLK6) in human melanoma tissue sections throughout tumor development. Although KLK6 was not detectable in tumor cells, we found strong KLK6 protein expression in keratinocytes and stromal cells located adjacent to benign nevi, primary melanomas, and cutaneous metastatic lesions, suggesting a paracrine function of extracellular KLK6 during neoplastic transformation and malignant progression. Accordingly, recombinant Klk6 protein significantly induced melanoma cell migration and invasion accompanied by an accelerated intracellular Ca(2+) flux. We could further demonstrate that KLK6-induced intracellular Ca(2+) flux and tumor cell invasion critically depends on the protease-activated receptor 1 (PAR1). Our data provide experimental evidence that specific inhibition of the KLK6-PAR1 axis may interfere with the deleterious effect of tumor-microenvironment interaction and represent a potential option for translational melanoma research.
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Date Issued: 2011
Identifier: FSU_migr_biomed_faculty_publications-0024, 10.1038/jid.2011.190
Format: Citation

Title: Kallikrein 6 is a Novel Molecular Trigger of Reactive Astrogliosis.
Creator: Scarisbrick, Isobel, Radulovic, Maja, Burda, Joshua, Larson, Nadya, Blaber, Sachiko, Giannini, Caterina, Blaber, Michael, Vandell, Alexander
Abstract/Description: Kallikrein-related peptidase 6 (KLK6) is a trypsin-like serine protease upregulated at sites of central nervous system (CNS) injury, including de novo expression by reactive astrocytes, yet its physiological actions are largely undefined. Taken with recent evidence that KLK6 activates G-protein-coupled protease-activated receptors (PARs), we hypothesized that injury-induced elevations in KLK6 contribute to the development of astrogliosis and that this occurs in a PAR-dependent fashion. Using...
Show moreKallikrein-related peptidase 6 (KLK6) is a trypsin-like serine protease upregulated at sites of central nervous system (CNS) injury, including de novo expression by reactive astrocytes, yet its physiological actions are largely undefined. Taken with recent evidence that KLK6 activates G-protein-coupled protease-activated receptors (PARs), we hypothesized that injury-induced elevations in KLK6 contribute to the development of astrogliosis and that this occurs in a PAR-dependent fashion. Using primary murine astrocytes and the Neu7 astrocyte cell line, we show that KLK6 causes astrocytes to transform from an epitheliod to a stellate morphology and to secrete interleukin 6 (IL-6). By contrast, KLK6 reduced expression of glial fibrillary acidic protein (GFAP). The stellation-promoting activities of KLK6 were shown to be dependent on activation of the thrombin receptor, PAR1, as a PAR1-specific inhibitor, SCH79797, blocked KLK6-induced morphological changes. The ability of KLK6 to promote astrocyte stellation was also shown to be linked to activation of protein kinase C (PKC). These studies indicate that KLK6 is positioned to serve as a molecular trigger of select physiological processes involved in the development of astrogliosis and that this is likely to occur at least in part by activation of the G-protein-coupled receptor, PAR1.
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Date Issued: 2012
Identifier: FSU_migr_biomed_faculty_publications-0030, 10.1515/hsz-2011-0241
Format: Citation

Title: Pharmacokinetic Properties of 2(nd)-Generation Fibroblast Growth Factor-1 Mutants for Therapeutic Application.
Creator: Xia, Xue, Babcock, Joseph, Blaber, Sachiko, Harper, Kathleen, Blaber, Michael
Abstract/Description: Fibroblast growth factor-1 (FGF-1) is an angiogenic factor with therapeutic potential for the treatment of ischemic disease. FGF-1 has low intrinsic thermostability and is characteristically formulated with heparin as a stabilizing agent. Heparin, however, adds a number of undesirable properties that negatively impact safety and cost. Mutations that increase the thermostability of FGF-1 may obviate the need for heparin in formulation and may prove to be useful "2nd-generation" forms for...
Show moreFibroblast growth factor-1 (FGF-1) is an angiogenic factor with therapeutic potential for the treatment of ischemic disease. FGF-1 has low intrinsic thermostability and is characteristically formulated with heparin as a stabilizing agent. Heparin, however, adds a number of undesirable properties that negatively impact safety and cost. Mutations that increase the thermostability of FGF-1 may obviate the need for heparin in formulation and may prove to be useful "2nd-generation" forms for therapeutic use. We report a pharmacokinetic (PK) study in rabbits of human FGF-1 in the presence and absence of heparin, as well as three mutant forms having differential effects upon thermostability, buried reactive thiols, and heparin affinity. The results support the hypothesis that heparan sulfate proteoglycan (HSPG) in the vasculature of liver, kidney and spleen serves as the principle peripheral compartment in the distribution kinetics. The addition of heparin to FGF-1 is shown to increase endocrine-like properties of distribution. Mutant forms of FGF-1 that enhance thermostability or eliminate buried reactive thiols demonstrate a shorter distribution half-life, a longer elimination half-life, and a longer mean residence time (MRT) in comparison to wild-type FGF-1. The results show how such mutations can produce useful 2nd-generation forms with tailored PK profiles for specific therapeutic application.
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Date Issued: 2012
Identifier: FSU_migr_biomed_faculty_publications-0041, 10.1371/journal.pone.0048210
Format: Citation

Title: Activation Profiles of Human Kallikrein-Related Peptidases by Matrix Metalloproteinases.
Creator: Yoon, Hyesook, Blaber, Sachiko, Li, Wu, Scarisbrick, Isobel, Blaber, Michael
Abstract/Description: Abstract The 15 human kallikrein-related peptidases (KLKs) are clinically important biomarkers and therapeutic targets of interest in inflammation, cancer, and neurodegenerative disease. KLKs are secreted as inactive pro-forms (pro-KLKs) that are activated extracellularly by specific proteolytic release of their amino-terminal pro-peptide, and this is a key step in their functional regulation. Physiologically relevant KLK regulatory cascades of activation have been described in skin...
Show moreAbstract The 15 human kallikrein-related peptidases (KLKs) are clinically important biomarkers and therapeutic targets of interest in inflammation, cancer, and neurodegenerative disease. KLKs are secreted as inactive pro-forms (pro-KLKs) that are activated extracellularly by specific proteolytic release of their amino-terminal pro-peptide, and this is a key step in their functional regulation. Physiologically relevant KLK regulatory cascades of activation have been described in skin desquamation and semen liquefaction, and work by a large number of investigators has elucidated pairwise and autolytic activation relationships among the KLKs with the potential for more extensive activation cascades. More recent work has asked whether functional intersection of KLKs with other types of regulatory proteases exists. Such studies show a capacity for members of the thrombostasis axis to act as broad activators of pro-KLKs. In the present report, we ask whether such functional intersection is possible between the KLKs and the members of the matrix metalloproteinase (MMP) family by evaluating the ability of the MMPs to activate pro-KLKs. The results identify MMP-20 as a broad activator of pro-KLKs, suggesting the potential for intersection of the KLK and MMP axes under pathological dysregulation of MMP-20 expression.
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Date Issued: 2013
Identifier: FSU_migr_biomed_faculty_publications-0042, 10.1515/hsz-2012-0249, PMC3709557
Format: Citation

Title: Spermitin: A Novel Mitochondrial Protein in Drosophila Spermatids.
Creator: Chen, Jieyan, Megraw, Timothy
Abstract/Description: Mitochondria, important energy centers in the cell, also control sperm cell morphogenesis.Drosophila spermatids have a remarkably large mitochondrial formation called the nebenkern. Immediately following meiosis during sperm development, the mitochondria in the spermatid fuse together into two large aggregates which then wrap around one another to produce the spherical nebenkern: a giant mitochondrion about 6 micrometers in diameter. The fused mitochondria play an important role in sperm tail...
Show moreMitochondria, important energy centers in the cell, also control sperm cell morphogenesis.Drosophila spermatids have a remarkably large mitochondrial formation called the nebenkern. Immediately following meiosis during sperm development, the mitochondria in the spermatid fuse together into two large aggregates which then wrap around one another to produce the spherical nebenkern: a giant mitochondrion about 6 micrometers in diameter. The fused mitochondria play an important role in sperm tail elongation by providing a structural platform to support the elongation of sperm cells. We have identified a novel testis-specific protein, Spermitin (Sprn), a protein with a Pleckstrin homology-like (PH) domain related to Ran-binding protein 1 at its C-terminus. Fluorescence microscopy showed that Sprn localizes at mitochondria in transfected Kc167 cells, and in the nebenkern throughout spermatid morphogenesis. The role of Sprn is unclear, as sprn mutant males are fertile, and have sperm tail length comparable to the wild-type.
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Date Issued: 2014
Identifier: FSU_migr_biomed_faculty_publications-0049, 10.1371/journal.pone.0108802
Format: Citation

Title: Myofilament Ca2+ Sensitization Causes Susceptibility to Cardiac Arrhythmia in Mice.
Creator: Baudenbacher, Franz, Schober, Tilmann, Pinto, Jose, Sidorov, Veniamin, Hilliard, Fredrick, Solaro, R. John, Potter, James, Knollmann, Björn C.
Abstract/Description: In human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias and sudden death. Here we have shown that increased myofilament Ca2+ sensitivity, also a common feature in both inherited and acquired human cardiomyopathies, created arrhythmia susceptibility in mice, even in the absence of anatomical abnormalities. In mice expressing troponin T mutants that cause hypertrophic cardiomyopathy in humans, the risk of developing...
Show moreIn human cardiomyopathy, anatomical abnormalities such as hypertrophy and fibrosis contribute to the risk of ventricular arrhythmias and sudden death. Here we have shown that increased myofilament Ca2+ sensitivity, also a common feature in both inherited and acquired human cardiomyopathies, created arrhythmia susceptibility in mice, even in the absence of anatomical abnormalities. In mice expressing troponin T mutants that cause hypertrophic cardiomyopathy in humans, the risk of developing ventricular tachycardia was directly proportional to the degree of Ca2+ sensitization caused by the troponin T mutation. Arrhythmia susceptibility was reproduced with the Ca2+-sensitizing agent EMD 57033 and prevented by myofilament Ca2+ desensitization with blebbistatin. Ca2+ sensitization markedly changed the shape of ventricular action potentials, resulting in shorter effective refractory periods, greater beat-to-beat variability of action potential durations, and increased dispersion of ventricular conduction velocities at fast heart rates. Together these effects created an arrhythmogenic substrate. Thus, myofilament Ca2+ sensitization represents a heretofore unrecognized arrhythmia mechanism. The protective effect of blebbistatin provides what we believe to be the first direct evidence that reduction of Ca2+ sensitivity in myofilaments is antiarrhythmic and might be beneficial to individuals with hypertrophic cardiomyopathy.
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Date Issued: 2008
Identifier: FSU_migr_biomed_faculty_publications-0050, 10.1172/JCI36642
Format: Citation

Title: Cardiac Troponin Mutations and Restrictive Cardiomyopathy.
Creator: Parvatiyar, Michelle, Pinto, Jose, Dweck, David, Potter, James
Abstract/Description: Mutations in sarcomeric proteins have recently been established as heritable causes of Restrictive Cardiomyopathy (RCM). RCM is clinically characterized as a defect in cardiac diastolic function, such as, impaired ventricular relaxation, reduced diastolic volume and increased end-diastolic pressure. To date, mutations have been identified in the cardiac genes for desmin, alpha-actin, troponin I and troponin T. Functional studies in skinned muscle fibers reconstituted with troponin mutants...
Show moreMutations in sarcomeric proteins have recently been established as heritable causes of Restrictive Cardiomyopathy (RCM). RCM is clinically characterized as a defect in cardiac diastolic function, such as, impaired ventricular relaxation, reduced diastolic volume and increased end-diastolic pressure. To date, mutations have been identified in the cardiac genes for desmin, alpha-actin, troponin I and troponin T. Functional studies in skinned muscle fibers reconstituted with troponin mutants have established phenotypes consistent with the clinical findings which include an increase in myofilament Ca(2+) sensitivity and basal force. Moreover, when RCM mutants are incorporated into reconstituted myofilaments, the ability to inhibit the ATPase activity is reduced. A majority of the mutations cluster in specific regions of cardiac troponin and appear to be mutational "hot spots". This paper highlights the functional and clinical characteristics of RCM linked mutations within the troponin complex.
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Date Issued: 2010
Identifier: FSU_migr_biomed_faculty_publications-0053, 10.1155/2010/350706
Format: Citation

Title: Late Onset Sporadic Dilated Cardiomyopathy Caused by a Cardiac Troponin T Mutation.
Creator: Morales, Ana, Pinto, Jose, Siegfried, Jill, Li, Duanxiang, Norton, Nadine, Hofmeyer, Mark, Vallin, Marta, Morales, Azorides R., Potter, James, Hershberger, Ray
Abstract/Description: Mutations in TNNT2, encoding cardiac troponin T, commonly shows early onset, aggressive dilated cardiomyopathy (DCM). This observation may influence the decision of whether to undertake clinical genetic testing for TNNT2 in later onset DCM. Further, the trigger for late onset DCM remains enigmatic. A 70-year-old woman, previously healthy with a left ventricular ejection fraction of 50%-55% at age 69, presented with DCM of unknown cause and a 4-month history progressive heart failure requiring...
Show moreMutations in TNNT2, encoding cardiac troponin T, commonly shows early onset, aggressive dilated cardiomyopathy (DCM). This observation may influence the decision of whether to undertake clinical genetic testing for TNNT2 in later onset DCM. Further, the trigger for late onset DCM remains enigmatic. A 70-year-old woman, previously healthy with a left ventricular ejection fraction of 50%-55% at age 69, presented with DCM of unknown cause and a 4-month history progressive heart failure requiring cardiac transplantation. Clinical genetic testing revealed a novel TNNT2 R139H mutation but no relevant variants in 18 other DCM genes. Her explanted heart showed partial fatty replacement in the right ventricle. Sequencing for five arrhythmogenic right ventricular dysplasia genes was negative. Functional studies in porcine cardiac skinned fibers reconstituted with the mutant R139H troponin T protein showed decreased Ca(2+) sensitivity at pH 7, characteristic of DCM. Because fatty infiltration may acidify the myocellular environment, maximal force development examined at pH 6.5 was diminished, suggesting a possible environmental trigger. We conclude that the TNNT2 R139H mutation was likely to be disease causing. Further, later age of onset may not be relevant to exclude genetic testing for TNNT2 mutations.
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Date Issued: 2010
Identifier: FSU_migr_biomed_faculty_publications-0054, 10.1111/j.1752-8062.2010.00228.x
Format: Citation

Title: Myosin Cross-Bridges Do Not Form Precise Rigor Bonds in Hypertrophic Heart Muscle Carrying Troponin T Mutations.
Creator: Midde, K., Dumka, V., Pinto, Jose, Muthu, P., Marandos, P., Gryczynski, I., Gryczynski, Z., Potter, James, Borejdo, J.
Abstract/Description: Distribution of orientations of myosin was examined in ex-vivo myofibrils from hearts of transgenic (Tg) mice expressing Familial Hypertrophic Cardiomyopathy (FHC) troponin T (TnT) mutations I79N, F110I and R278C. Humans are heterozygous for sarcomeric FHC mutations and so hypertrophic myocardium contains a mixture of the wild-type (WT) and mutated (MUT) TnT. If mutations are expressed at a low level there may not be a significant change in the global properties of heart muscle. In contrast,...
Show moreDistribution of orientations of myosin was examined in ex-vivo myofibrils from hearts of transgenic (Tg) mice expressing Familial Hypertrophic Cardiomyopathy (FHC) troponin T (TnT) mutations I79N, F110I and R278C. Humans are heterozygous for sarcomeric FHC mutations and so hypertrophic myocardium contains a mixture of the wild-type (WT) and mutated (MUT) TnT. If mutations are expressed at a low level there may not be a significant change in the global properties of heart muscle. In contrast, measurements from a few molecules avoid averaging inherent in the global measurements. It is thus important to examine the properties of only a few molecules of muscle. To this end, the lever arm of one out of every 60,000 myosin molecules was labeled with a fluorescent dye and a small volume within the A-band (~1 fL) was observed by confocal microscopy. This volume contained on average 5 fluorescent myosin molecules. The lever arm assumes different orientations reflecting different stages of acto-myosin enzymatic cycle. We measured the distribution of these orientations by recording polarization of fluorescent light emitted by myosin-bound fluorophore during rigor and contraction. The distribution of orientations of rigor WT and MUT myofibrils was significantly different. There was a large difference in the width and of skewness and kurtosis of rigor distributions. These findings suggest that the hypertrophic phenotype associated with the TnT mutations can be characterized by a significant increase in disorder of rigor cross-bridges.
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Date Issued: 2011
Identifier: FSU_migr_biomed_faculty_publications-0055, 10.1016/j.yjmcc.2011.06.001
Format: Citation

Title: Collagen XIV Is Important for Growth and Structural Integrity of the Myocardium.
Creator: Tao, Ge, Levay, Agata, Peacock, Jacqueline, Huk, Danielle, Both, Sarah, Purcell, Nicole, Pinto, Jose, Galantowicz, Maarten, Koch, Manuel, Lucchesi, Pamela, Birk, David E.,...
Show moreTao, Ge, Levay, Agata, Peacock, Jacqueline, Huk, Danielle, Both, Sarah, Purcell, Nicole, Pinto, Jose, Galantowicz, Maarten, Koch, Manuel, Lucchesi, Pamela, Birk, David E., Lincoln, Joy
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Abstract/Description: Collagen XIV is a fibril-associated collagen with an interrupted triple helix (FACIT). Previous studies have shown that this collagen type regulates early stages of fibrillogenesis in connective tissues of high mechanical demand. Mice null for Collagen XIV are viable, however formation of the interstitial collagen network is defective in tendons and skin leading to reduced biomechanical function. The assembly of a tightly regulated collagen network is also required in the heart, not only for...
Show moreCollagen XIV is a fibril-associated collagen with an interrupted triple helix (FACIT). Previous studies have shown that this collagen type regulates early stages of fibrillogenesis in connective tissues of high mechanical demand. Mice null for Collagen XIV are viable, however formation of the interstitial collagen network is defective in tendons and skin leading to reduced biomechanical function. The assembly of a tightly regulated collagen network is also required in the heart, not only for structural support but also for controlling cellular processes. Collagen XIV is highly expressed in the embryonic heart, notably within the cardiac interstitium of the developing myocardium, however its role has not been elucidated. To test this, we examined cardiac phenotypes in embryonic and adult mice devoid of Collagen XIV. From as early as E11.5, Col14a1(-/-) mice exhibit significant perturbations in mRNA levels of many other collagen types and remodeling enzymes (MMPs, TIMPs) within the ventricular myocardium. By post natal stages, collagen fibril organization is in disarray and the adult heart displays defects in ventricular morphogenesis. In addition to the extracellular matrix, Col14a1(-/-) mice exhibit increased cardiomyocyte proliferation at post natal, but not E11.5 stages, leading to increased cell number, yet cell size is decreased by 3 months of age. In contrast to myocytes, the number of cardiac fibroblasts is reduced after birth associated with increased apoptosis. As a result of these molecular and cellular changes during embryonic development and post natal maturation, cardiac function is diminished in Col14a1(-/-) mice from 3 months of age; associated with dilation in the absence of hypertrophy, and reduced ejection fraction. Further, Col14a1 deficiency leads to a greater increase in left ventricular wall thickening in response to pathological pressure overload compared to wild type animals. Collectively, these studies identify a new role for type XIV collagen in the formation of the cardiac interstitium during embryonic development, and highlight the importance of the collagen network for myocardial cell survival, and function of the working myocardium after birth.
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Date Issued: 2012
Identifier: FSU_migr_biomed_faculty_publications-0056, 10.1016/j.yjmcc.2012.08.002
Format: Citation

Title: Molecular and Functional Characterization of Novel Hypertrophic Cardiomyopathy Susceptibility Mutations in TNNC1-encoded Troponin C.
Creator: Landstrom, Andrew, Parvatiyar, Michelle, Pinto, Jose, Marquardt, Michelle, Bos, J., Tester, David, Ommen, Steve, Potter, James, Ackerman, Michael
Abstract/Description: Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined by a hypertrophied left ventricle, is one of the main causes of sudden death in young athletes, and has been associated with mutations in most sarcomeric proteins (tropomyosin, troponin T and I, and actin, etc.). Many of these mutations appear to affect the functional properties of cardiac troponin C (cTnC), i.e., by increasing the Ca(2+)-sensitivity of contraction, a hallmark of HCM, yet surprisingly, prior to...
Show moreHypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined by a hypertrophied left ventricle, is one of the main causes of sudden death in young athletes, and has been associated with mutations in most sarcomeric proteins (tropomyosin, troponin T and I, and actin, etc.). Many of these mutations appear to affect the functional properties of cardiac troponin C (cTnC), i.e., by increasing the Ca(2+)-sensitivity of contraction, a hallmark of HCM, yet surprisingly, prior to this report, cTnC had not been classified as a HCM-susceptibility gene. In this study, we show that mutations occurring in the human cTnC (HcTnC) gene (TNNC1) have the same prevalence (~0.4%) as well established HCM-susceptibility genes that encode other sarcomeric proteins. Comprehensive open reading frame/splice site mutation analysis of TNNC1 performed on 1025 unrelated HCM patients enrolled over the last 10 years revealed novel missense mutations in TNNC1: A8V, C84Y, E134D, and D145E. Functional studies with these recombinant HcTnC HCM mutations showed increased Ca(2+) sensitivity of force development (A8V, C84Y and D145E) and force recovery (A8V and D145E). These results are consistent with the HCM functional phenotypes seen with other sarcomeric-HCM mutations (E134D showed no changes in these parameters). This is the largest cohort analysis of TNNC1 in HCM that details the discovery of at least three novel HCM-associated mutations and more strongly links TNNC1 to HCM along with functional evidence that supports a central role for its involvement in the disease. This study may help to further define TNNC1 as an HCM-susceptibility gene, a classification that has already been established for the other members of the troponin complex.
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Date Issued: 2008
Identifier: FSU_migr_biomed_faculty_publications-0058, 10.1016/j.yjmcc.2008.05.003
Format: Citation

Title: Clinical and Functional Characterization of TNNT2 Mutations Identified in Patients with Dilated Cardiomyopathy.
Creator: Hershberger, Ray, Pinto, Jose, Parks, Sharie, Kushner, Jessica, Li, Duanxiang, Ludwigsen, Susan, Cowan, Jason, Morales, Ana, Parvatiyar, Michelle, Potter, James
Abstract/Description: BACKGROUND: A key issue for cardiovascular genetic medicine is ascertaining if a putative mutation indeed causes dilated cardiomyopathy (DCM). This is critically important as genetic DCM, usually presenting with advanced, life-threatening disease, may be preventable with early intervention in relatives known to carry the mutation. METHODS AND RESULTS: We recently undertook bidirectional resequencing of TNNT2, the cardiac troponin T gene, in 313 probands with DCM. We identified 6 TNNT2 protein...
Show moreBACKGROUND: A key issue for cardiovascular genetic medicine is ascertaining if a putative mutation indeed causes dilated cardiomyopathy (DCM). This is critically important as genetic DCM, usually presenting with advanced, life-threatening disease, may be preventable with early intervention in relatives known to carry the mutation. METHODS AND RESULTS: We recently undertook bidirectional resequencing of TNNT2, the cardiac troponin T gene, in 313 probands with DCM. We identified 6 TNNT2 protein-altering variants in 9 probands, all who had early onset, aggressive disease. Additional family members of mutation carriers were then studied when available. Four of the 9 probands had DCM without a family history, and 5 probands had familial DCM. Only 1 mutation (Lys210del) could be attributed as definitively causative from previous reports. Four of the 5 missense mutations were novel (Arg134Gly, Arg151Cys, Arg159Gln, and Arg205Trp), and one was previously reported with hypertrophic cardiomyopathy (Glu244Asp). Based on the clinical, pedigree, and molecular genetic data, these 5 mutations were considered possibly or likely disease causing. To further clarify their potential pathophysiologic impact, we undertook functional studies of these mutations in cardiac myocytes reconstituted with mutant troponin T proteins. We observed decreased Ca(2+) sensitivity of force development, a hallmark of DCM, in support of the conclusion that these mutations are disease causing. CONCLUSIONS: We conclude that the combination of clinical, pedigree, molecular genetic, and functional data strengthen the interpretation of TNNT2 mutations in DCM.
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Date Issued: 2009
Identifier: FSU_migr_biomed_faculty_publications-0059, 10.1161/CIRCGENETICS.108.846733
Format: Citation

Title: Functional Effects of a Restrictive-Cardiomyopathy-Linked Cardiac Troponin I Mutation (R145W) in Transgenic Mice.
Creator: Wen, Yuhui, Xu, Yuanyuan, Wang, Yingcai, Pinto, Jose, Potter, James, Kerrick, W.
Abstract/Description: The human cardiac troponin I (hcTnI) mutation R145W has been associated with restrictive cardiomyopathy. In this study, simultaneous measurements of ATPase activity and force in skinned papillary fibers from hcTnI R145W transgenic mice (Tg-R145W) were explored. Tg-R145W fibers showed an approximately 13-16% increase in maximal Ca(2+)-activated force and ATPase activity compared to hcTnI wild-type transgenic mice. The force-generating cross-bridge turnover rate (g) and the energy cost (ATPase...
Show moreThe human cardiac troponin I (hcTnI) mutation R145W has been associated with restrictive cardiomyopathy. In this study, simultaneous measurements of ATPase activity and force in skinned papillary fibers from hcTnI R145W transgenic mice (Tg-R145W) were explored. Tg-R145W fibers showed an approximately 13-16% increase in maximal Ca(2+)-activated force and ATPase activity compared to hcTnI wild-type transgenic mice. The force-generating cross-bridge turnover rate (g) and the energy cost (ATPase/force) were the same in all groups of fibers. Also, the Tg-R145W fibers showed a large increase in the Ca(2+) sensitivity of both force development and ATPase. In intact fibers, the mutation caused prolonged force and intracellular [Ca(2+)] transients and increased time to peak force. Analysis of force and Ca(2+) transients showed that there was a 40% increase in peak force in Tg-R145W muscles, which was likely due to the increased Ca(2+) transient duration. The above cited results suggest that: (1) there would be an increase in resistance to ventricular filling during diastole resulting from the prolonged force and Ca(2+) transients that would result in a decrease in ventricular filling (diastolic dysfunction); and (2) there would be a large (approximately 53%) increase in force during systole, which may help to partly compensate for diastolic dysfunction. These functional results help to explain the mechanisms by which these mutations give rise to a restrictive phenotype.
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Date Issued: 2009
Identifier: FSU_migr_biomed_faculty_publications-0060, 10.1016/j.jmb.2009.07.080
Format: Citation

Title: Calibration and Evaluation of Link Congestion Functions: Applying Intrinsic Sensitivity of Link Speed as a Practical Consideration to Heterogeneous Facility Types within Urban Network.
Creator: Mtoi, Enock T., Moses, Ren
Abstract/Description: This paper explores the use of archived data to calibrate volume delay functions (VDFs) and updates their input parameters (capacity and free-flow speed) for planning applications. The sensitivity analysis of speed to change in congestion level is performed to capture functional characteristics of VDFs in modeling specific facility types. Different sensitivity characteristics shown by the VDFs indicate that each function is suitable to a particular facility type. The results of sensitivity...
Show moreThis paper explores the use of archived data to calibrate volume delay functions (VDFs) and updates their input parameters (capacity and free-flow speed) for planning applications. The sensitivity analysis of speed to change in congestion level is performed to capture functional characteristics of VDFs in modeling specific facility types. Different sensitivity characteristics shown by the VDFs indicate that each function is suitable to a particular facility type. The results of sensitivity analysis are confirmed by the root mean square percent error (RMSPE) values calculated using the Orlando Urban Area Transportation Study (OUATS) model results and observed data. The modified Davidson's function exhibits remarkable performance in nearly all facility types. The strength of the modified Davidson's function across a broad range of facilities can be attributed to the flexibility of its tuning parameter, μ. Fitted Bureau of Public Road (BPR) and conical delay functions show lower RMSPE for uninterrupted flow facilities (freeways/expressways, managed lanes) and higher values for toll roads (which might have partial interruptions due to toll booths) and signalized arterials. Akcelik function underperforms on freeways/expressways and managed lanes but shows some improvements for toll roads and superior results for the signalized arterials. This was a desired strength of Akcelik function when modeling link travel speed on facilities where stopped delays were encountered.
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Date Issued: 2014
Identifier: FSU_migr_cee_faculty_publications-0001, 10.4236/jtts.2014.42014
Format: Citation

Title: Correlation of Seebeck Coefficient and Electric Conductivity in Polyaniline and Polypyrrole.
Creator: Mateeva, N., Niculescu, H., Schlenoff, Joseph B., Testardi, L.
Abstract/Description: We have measured the Seebeck coefficient and electric conductivity in the air-stable conducting polymers polyaniline and polypyrrole at different doping levels. We find, at 300 K, the general correlation that the logarithm of the electrical conductivity varies linearly with the Seebeck coefficient on doping, but with a proportionality substantially in excess of a prediction from simple theory for a single type of mobile carrier. The correlation is unexpected in its universality and...
Show moreWe have measured the Seebeck coefficient and electric conductivity in the air-stable conducting polymers polyaniline and polypyrrole at different doping levels. We find, at 300 K, the general correlation that the logarithm of the electrical conductivity varies linearly with the Seebeck coefficient on doping, but with a proportionality substantially in excess of a prediction from simple theory for a single type of mobile carrier. The correlation is unexpected in its universality and unfavorable in its consequences for thermoelectric applications. A standard model suggests that conduction by carriers of both signs may occur in these doped polymers, which thus leads to reduced thermoelectric efficiency. We also show that polyacetylene ~which is not air stable!, does exhibit the correlation with the expected proportionality, and, thus, its properties could be more favorable for thermoelectricity. © 1998 American Institute of Physics. [S0021-8979(98)05906-4]
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Date Issued: 1998
Identifier: FSU_migr_chm_faculty_publications-0001, 10.1063/1.367119
Format: Citation

Title: Electrochromism and Electrocatalysis in Viologen Polyelectrolyte Multilayers.
Creator: Stepp, Jason, Schlenoff, Joseph B.
Abstract/Description: Polyelectrolyte multilayers were constructed from a polyviologen and poly(styrene sulfonate) using an alternating polyion solution deposition technique. In situ absorption spectroscopy showed multilayers to be strongly electrochromic. Oxygen reduction at multilayercoated conducting glass electrodes was also shown to be facilitated.
Date Issued: 1997
Identifier: FSU_migr_chm_faculty_publications-0002, 10.1149/1.1837709
Format: Citation

Title: Numerical Simulation of the Cyclic Voltammogram of Polyacetylene.
Creator: Diess, E., Haas, O., Schlenoff, Joseph B.
Abstract/Description: The measured cyclic voltammogram of a polyacety]ene-coated electrode bathed in an electrolyte solution was simulated numerically for various scan rates. The model used accounts for a modified Butler-Vo]mer-type heterogeneous kinetics at the electrode surface including a lateral interaction term which effects the observed hysteresis behavior. Within the polymer an electron flux obeying Ohm's law as well as electrolyte diffusion and migration is considered and Poisson's equation holds for...
Show moreThe measured cyclic voltammogram of a polyacety]ene-coated electrode bathed in an electrolyte solution was simulated numerically for various scan rates. The model used accounts for a modified Butler-Vo]mer-type heterogeneous kinetics at the electrode surface including a lateral interaction term which effects the observed hysteresis behavior. Within the polymer an electron flux obeying Ohm's law as well as electrolyte diffusion and migration is considered and Poisson's equation holds for electroneutrality. Donnan partition kinetics describes the flux and potential at the interface between the polymer and diffusion layer. Electrolyte diffusion is considered in the diffusion layer.
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Date Issued: 1995
Identifier: FSU_migr_chm_faculty_publications-0003, 10.1149/1.2049971
Format: Citation

Title: Evolution of Physical and Electrochemical Properties of Polypyrrole during Extended Oxidation.
Creator: Schlenoff, Joseph B., Xu, Hong
Abstract/Description: The charge storage capacity and electrical conductivity of polypyrrole are followed through regimes of chemically reversible and irreversible electroactivity. Overoxidation of polypyrrole occurs at potentials in excess of 0.7 V vs. a saturated calomel electrode (SCE), as demonstrated by cyclic voltammetry of thin films. Material loss from polymer films as they are overoxidized is determined by in situ quartz microbalance experiments. The potential window for reversible electrochemistry in...
Show moreThe charge storage capacity and electrical conductivity of polypyrrole are followed through regimes of chemically reversible and irreversible electroactivity. Overoxidation of polypyrrole occurs at potentials in excess of 0.7 V vs. a saturated calomel electrode (SCE), as demonstrated by cyclic voltammetry of thin films. Material loss from polymer films as they are overoxidized is determined by in situ quartz microbalance experiments. The potential window for reversible electrochemistry in polypyrrole is compared to that for other conducting polymers. Reflectance FTIR of thick films reveals that hydroxyl groups, followed by carbonyls, result from overoxidation.
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Date Issued: 1992
Identifier: FSU_migr_chm_faculty_publications-0004, 10.1149/1.2221238
Format: Citation

Title: Prospects for Using C60 and C70 in Lithium Batteries.
Creator: Seger, L., Wen, L., Schlenoff, Joseph B.
Abstract/Description: Solid films of C60 and C70 fullerenes are evaluated in propylene carbonate/lithium perchlorate, an electrolyte commonly used in lithium batteries. Cyclic voltammetry, chronopotentiometry, and an effusion test, show that reduced C60 and C70 are soluble in the electrolyte tested, which, coupled with poor stability of the highly reduced material and poor electrochemical reversibility, would compromise the performance of secondary batteries based on these fullerenes.
Date Issued: 1991
Identifier: FSU_migr_chm_faculty_publications-0005, 10.1149/1.2085516
Format: Citation

Title: Transport, magnetic, and optical properties of electrochemically doped poly(1, 4-dimethoxy phenylene vinylene).
Creator: Schlenoff, Joseph B., Obrzut, Jan, Karasz, F.
Abstract/Description: A coordinated study on electrochemical, magnetic, optical, and transport properties of poly(1, 4- dimethoxy phenylene vinylene) (PDMPV) using in situ electrochemical doping techniques is presented. Properties are correlated through a common axis of applied voltage. Electrochemical doping shows approx. 100% Coulombic efficiency up to an applied potential of 3.8 V versus lithium in propylene carbonate electrolyte. Conductivity increases in a reversible manner to a maximum of 250 0 ' cm ' and an...
Show moreA coordinated study on electrochemical, magnetic, optical, and transport properties of poly(1, 4- dimethoxy phenylene vinylene) (PDMPV) using in situ electrochemical doping techniques is presented. Properties are correlated through a common axis of applied voltage. Electrochemical doping shows approx. 100% Coulombic efficiency up to an applied potential of 3.8 V versus lithium in propylene carbonate electrolyte. Conductivity increases in a reversible manner to a maximum of 250 0 ' cm ' and an applied potential of 3.9 V. Potentials in excess of 3.9 V cause an irreversible decrease in conductivity. Spin and charge show a 1:1 relation on/y to very low doping levels. Two paramagnetic species are produced on doping. A maximum spin concentration is observed at =3.7 V. The ultraviolet —visible —near-infrared spectra of doped PDMPV show at least five absorption bands, at 4.8, 3.7, 2.5, 1.7, and 0.6 eV. The first three bands decrease with doping and the latter two increase. When analyzed by the polaron or bipolaron model, the optical data imply significant symmetry breaking, Contributions to the optical activity from polarons and bipolarons are determined from the EPR results and are found to be di6'erent for both peaks, implying greater symmetrybreaking eA'ects for polarons. An electrochemical analysis of EPR results suggests that polaron interaction energies are =0.4S eV greater than those for bipolarons.
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Date Issued: 1989
Identifier: FSU_migr_chm_faculty_publications-0006
Format: Citation

Title: The Cyclic Voltammetry of Pristine, Isomerized, Deuterated, and Partially Hydrogenated "P-Type" Polyacetylene.
Creator: Schlenoff, Joseph B., Chien, James C. W.
Abstract/Description: The cyclic voltammetry of ultrathin fihns of polyacetylene comprised of 2-3 nm micro fibrils and their aggregate 20 nm fibrils in methylene chloride, acetonitrile, propylene carbonate, and sulfo]ane shows many similarities, including a background oxidation of electrolyte that leads to serious coulombic inefficiency in rechargeable polyacetylene battery applications. Reversible charging in neutral aqueous solution is limited by the poor separation between the reversible and irreversible...
Show moreThe cyclic voltammetry of ultrathin fihns of polyacetylene comprised of 2-3 nm micro fibrils and their aggregate 20 nm fibrils in methylene chloride, acetonitrile, propylene carbonate, and sulfo]ane shows many similarities, including a background oxidation of electrolyte that leads to serious coulombic inefficiency in rechargeable polyacetylene battery applications. Reversible charging in neutral aqueous solution is limited by the poor separation between the reversible and irreversible oxidations. Comparison of ultrathin and free-standing 100 ~m thick films showed they have the same maximum reversible doping level and thus energy density of 280 Wh/kg. Pristine, isomerized, deuterated, and hydrogenated [CH].,. show similar electrochemistry. Both n and p-type chemical doping caused isomerization of cis-[CHL to trans-[CH]~.
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Date Issued: 1987
Identifier: FSU_migr_chm_faculty_publications-0007, 10.1149/1.2100848
Format: Citation

Title: Magnetic and Transport Properties of Electrochemically Oxidized Polyacetylene.
Creator: Reynolds, John, Schlenoff, Joseph B., Chien, James C. W.
Abstract/Description: The magnetic and transport properties of polyacetylene electrochemically oxidized in the presence of perchlorate ion have been determined. Room temperature dc conductivity is unaffected by doping between 10 -6
Show moreThe magnetic and transport properties of polyacetylene electrochemically oxidized in the presence of perchlorate ion have been determined. Room temperature dc conductivity is unaffected by doping between 10 -6 < y -< 10 -3~. A rapid conductivity increase occurs with increasing dopant level having a midpoint of transition at ca. y - 8 x 10-3 By comparison, the change in thermopower vs. y is sharper taking place within a tenfold increase in y with a midpoint at ca. y - 3 x 10 -3. The unparied spin concentrations remain constant as dopant concentration increases before the onset of a Dysonian lineshape at ca. y -= 10 -2. The results are interpreted as the melting of a glassy carrier state causing the sharp change of transport properties. A phase separation into metallic domains occurs at y = ca. 10 -~. Side reactions involving the electrolyte complicate the electrochemistry of po]yacetylene.
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Date Issued: 1985
Identifier: FSU_migr_chm_faculty_publications-0008, 10.1149/1.2114027
Format: Citation

Title: Rectified Ion Currents Through Ultrathin Polyelectrolyte Complex: Toward Chemical Transistors.
Creator: Salloum, David, Schlenoff, Joseph B.
Abstract/Description: We report an ion-conducting device comprising an ultrathin polyelectrolyte multilayer membrane assembled in a simple manner with water soluble polymers. Under the influence of external solution ionic strength ~salt concentration!, sites for ion transport are reversibly doped into the membrane. The device exhibits rectifying properties, preferring ions of lower charge, with a saturation ion current limited by diffusion. This system allows for the transduction of chemical potential into ion...
Show moreWe report an ion-conducting device comprising an ultrathin polyelectrolyte multilayer membrane assembled in a simple manner with water soluble polymers. Under the influence of external solution ionic strength ~salt concentration!, sites for ion transport are reversibly doped into the membrane. The device exhibits rectifying properties, preferring ions of lower charge, with a saturation ion current limited by diffusion. This system allows for the transduction of chemical potential into ion currents. Current/voltage curves spanning forward and reversed biased regimes are presented, together with linear and hyperlinear salt gating of ion currents.
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Date Issued: 2004
Identifier: FSU_migr_chm_faculty_publications-0009, 10.1149/1.1799954
Format: Citation

Title: Corrosion Control Using Polyelectrolyte Multilayers.
Creator: Farhat, Tarek, Schlenoff, Joseph B.
Abstract/Description: The corrosion of stainless steel under anodic conditions in salt solutions was strongly suppressed by an ultrathin layer of polyelectrolyte complex, applied using the layer-by-layer deposition method. Voltammetric scans over a wide potential region, as well as constant potential measurements in the metastable pitting regime, reveal the surprising effectiveness of polyelectrolyte multilayers, both hydrophilic and hydrophobic, at corrosion control, despite the significant water content and ion...
Show moreThe corrosion of stainless steel under anodic conditions in salt solutions was strongly suppressed by an ultrathin layer of polyelectrolyte complex, applied using the layer-by-layer deposition method. Voltammetric scans over a wide potential region, as well as constant potential measurements in the metastable pitting regime, reveal the surprising effectiveness of polyelectrolyte multilayers, both hydrophilic and hydrophobic, at corrosion control, despite the significant water content and ion permeability of the thin film.
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Date Issued: 2002
Identifier: FSU_migr_chm_faculty_publications-0010, 10.1149/1.1452484
Format: Citation

Title: Human Coronary Artery Smooth Muscle Cell Responses to Bioactive Polyelectrolyte Multilayer Interfaces.
Creator: Newcomer, Robert, Moussallem, Maroun, Keller, Thomas C. S., Schlenoff, Joseph B., Sang, Qing-Xiang
Abstract/Description: Under normal physiological conditions, mature human coronary artery smooth muscle cells (hCASMCs) exhibit a "contractile" phenotype marked by low rates of proliferation and protein synthesis, but these cells possess the remarkable ability to dedifferentiate into a "synthetic" phenotype when stimulated by conditions of pathologic stress. A variety of polyelectrolyte multilayer (PEMU) films are shown here to exhibit bioactive properties that induce distinct responses from cultured hCASMCs....
Show moreUnder normal physiological conditions, mature human coronary artery smooth muscle cells (hCASMCs) exhibit a "contractile" phenotype marked by low rates of proliferation and protein synthesis, but these cells possess the remarkable ability to dedifferentiate into a "synthetic" phenotype when stimulated by conditions of pathologic stress. A variety of polyelectrolyte multilayer (PEMU) films are shown here to exhibit bioactive properties that induce distinct responses from cultured hCASMCs. Surfaces terminated with Nafion or poly(styrenesulfonic acid) (PSS) induce changes in the expression and organization of intracellular proteins, while a hydrophilic, zwitterionic copolymer of acrylic acid and 3-[2-(acrylamido)-ethyl dimethylammonio] propane sulfonate (PAA-co-PAEDAPS) is resistant to cell attachment and suppresses the formation of key cytoskeletal components. Differential expression of heat shock protein 90 and actin is observed, in terms of both their magnitude and cellular localization, and distinct cytoplasmic patterns of vimentin are seen. The ionophore A23187 induces contraction in confluent hCASMC cultures on Nafion-terminated surfaces. These results demonstrate that PEMU coatings exert direct effects on the cytoskeletal organization of attaching hCASMCs, impeding growth in some cases, inducing changes consistent with phenotypic modulation in others, and suggesting potential utility for PEMU surfaces as a coating for coronary artery stents and other implantable medical devices.
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Date Issued: 2011
Identifier: FSU_migr_chm_faculty_publications-0011, 10.4061/2011/854068
Format: Citation

$Hermetic Sample Housing for X-ray Diffraction Studies$

Title: Hermetic Sample Housing for X-ray Diffraction Studies.
Creator: Schlenoff, Joseph B., Rink, W. Jack, Mathias, H.
Abstract/Description: A portable sample housing has been constructed for room-temperature powder geometry X-ray diffraction analysis of samples that are air or moisture sensitive. The housing can be easily handled in a glovebox, providing a means for direct loading and X-ray measurements on samples that should not be exposed to air or moisture after preparation. Its design allows adaptation to various makes of diffractometer that are limited to flat sample geometry. The design offers several improvements over...
Show moreA portable sample housing has been constructed for room-temperature powder geometry X-ray diffraction analysis of samples that are air or moisture sensitive. The housing can be easily handled in a glovebox, providing a means for direct loading and X-ray measurements on samples that should not be exposed to air or moisture after preparation. Its design allows adaptation to various makes of diffractometer that are limited to flat sample geometry. The design offers several improvements over existing technology, including the accommodation of large-area thin films and single crystals. Sample preparation and alignment in the X-ray beam have been found to be easy and efficient. The two-layer X-ray window of the device reduces the diffracted intensity by 40%, without any change in the relative intensities of the peaks in the spectrum.
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Date Issued: 1993
Identifier: FSU_migr_chm_faculty_publications-0012, 10.1107/S0021889893013822
Format: Citation

Title: Bis[N-alkyl-NN-di(2-pyridylmethyl)amine]zinc(II) perchlorates display cis-facial stereochemistry in solid state and solution.
Creator: Zhu, Lei, Simmons, J., Yuan, Zhao, Daykin, Kirsten, Nguyen, Brian, Clark, Ronald, Shatruk, Michael
Abstract/Description: N-Alkyl-N,N-di(2-pyridylmethyl)amines are ligands commonly used by supramolecular chemists in molecular recognition and sensing applications. The metal coordination complexes of these ligands, in particular those with 2:1 (ligand:metal) molar ratio, have not been sufficiently characterised in solution. In this work, bis[N-alkyl-N,N-di(2-pyridylmethyl)amine]zinc(II) perchlorates are characterised in both solid and solution phases, using X-ray crystallography and NMR spectroscopy, respectively....
Show moreN-Alkyl-N,N-di(2-pyridylmethyl)amines are ligands commonly used by supramolecular chemists in molecular recognition and sensing applications. The metal coordination complexes of these ligands, in particular those with 2:1 (ligand:metal) molar ratio, have not been sufficiently characterised in solution. In this work, bis[N-alkyl-N,N-di(2-pyridylmethyl)amine]zinc(II) perchlorates are characterised in both solid and solution phases, using X-ray crystallography and NMR spectroscopy, respectively. Only the cis-facial stereoisomer is observed. Density functional theory calculations support the thermodynamic preference for this stereochemistry, as in one representative case the gas phase energy of the cis-facial configuration is lower than those of the trans-facial and meridional configurations by 4.0 and 4.5 kcal/mol, respectively.
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Date Issued: 2013
Identifier: FSU_migr_chm_faculty_publications-0013, 10.1080/10610278.2013.844816
Format: Citation

Title: Synthesis of 5-Iodo-1,2,3-triazoles from Organic Azides and Terminal Alkynes: Ligand Acceleration Effect, Substrate Scope, and Mechanistic Insights.
Creator: Zhu, Lei, Barsoum, David, Brassard, Christopher, Deeb, Jason, Okashah, Najeah, Sreenath, Kesavapillai, Simmons, J.
Abstract/Description: An improved method has been developed for the preparation of 5-iodo-1,2,3-triazoles directly from organic azides and terminal alkynes by a reaction mediated by copper(I) and iodinating agents generated in situ. The major methodological advance of the current procedure is that it provides a high conversion and good iodo/proto selectivity with a broad range of substrates without using an excess of the alkyne, which was required in the previous method. The use of an accelerating ligand is...
Show moreAn improved method has been developed for the preparation of 5-iodo-1,2,3-triazoles directly from organic azides and terminal alkynes by a reaction mediated by copper(I) and iodinating agents generated in situ. The major methodological advance of the current procedure is that it provides a high conversion and good iodo/proto selectivity with a broad range of substrates without using an excess of the alkyne, which was required in the previous method. The use of an accelerating ligand is essential to the success of reactions involving unreactive azides or alkynes. New mechanistic insights are provided, including the confirmation that a 1-iodoalkyne is formed as a key intermediate under the established conditions for the reaction.
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Date Issued: 2013
Identifier: FSU_migr_chm_faculty_publications-0014, 10.1055/s-0033-1339312
Format: Citation

Title: Distinguishing Förster resonance energy transfer and solvent-mediated charge-transfer relaxation dynamics in a zinc(II) indicator: a femtosecond time-resolved transient absorption spectroscopic study.
Creator: Zhu, Lei, Sreenath, Kesavapillai, Yi, Chongyue, Knappenberger, Kenneth
Abstract/Description: A bifluorophoric molecule (1) capable of intramolecular Förster Resonance Energy Transfer (FRET) is reported. The emission intensity of the FRET acceptor in 1 depends on the molar absorptivity of the donor, which is a function of zinc(II) complexation. The FRET dynamics of [Zn(1)](ClO4)2 is characterized by femtosecond time-resolved transient absorption spectroscopy. The solvent-mediated relaxation of the charge-transfer (CT) state of the isolated donor and the FRET process of the donor...
Show moreA bifluorophoric molecule (1) capable of intramolecular Förster Resonance Energy Transfer (FRET) is reported. The emission intensity of the FRET acceptor in 1 depends on the molar absorptivity of the donor, which is a function of zinc(II) complexation. The FRET dynamics of [Zn(1)](ClO4)2 is characterized by femtosecond time-resolved transient absorption spectroscopy. The solvent-mediated relaxation of the charge-transfer (CT) state of the isolated donor and the FRET process of the donor–acceptor conjugate are on similar time scales (40–50 ps in CH3CN), but distinguishable by the opposite solvent polarity dependency. As the solvent polarity increases, the efficiency of Columbic-based FRET is reduced, whereas CT relaxation is accelerated. In addition to revealing a method to distinguish CT and FRET dynamics, this work provides a photophysical foundation for developing indicators based on the FRET strategy.
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Date Issued: 2014
Identifier: FSU_migr_chm_faculty_publications-0015, 10.1039/C3CP55382E
Format: Citation

Title: Zn(II)-coordination modulated ligand photophysical processes – the development of fluorescent indicators for imaging biological Zn(II) ions.
Creator: Zhu, Lei, Yuan, Zhao, Simmons, J., Sreenath, Kesavapillai
Abstract/Description: Molecular photophysics and metal coordination chemistry are the two fundamental pillars that support the development of fluorescent cation indicators. In this article, we describe how Zn(II)-coordination alters various ligand-centered photophysical processes that are pertinent to developing Zn(II) indicators. The main aim is to show how small organic Zn(II) indicators work under the constraints of specific requirements, including Zn(II) detection range, photophysical requirements such as...
Show moreMolecular photophysics and metal coordination chemistry are the two fundamental pillars that support the development of fluorescent cation indicators. In this article, we describe how Zn(II)-coordination alters various ligand-centered photophysical processes that are pertinent to developing Zn(II) indicators. The main aim is to show how small organic Zn(II) indicators work under the constraints of specific requirements, including Zn(II) detection range, photophysical requirements such as excitation energy and emission color, temporal and spatial resolutions in a heterogeneous intracellular environment, and fluorescence response selectivity between similar cations such as Zn(II) and Cd(II). In the last section, the biological questions that fluorescent Zn(II) indicators help to answer are described, which have been motivating and challenging this field of research.
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Date Issued: 2014
Identifier: FSU_migr_chm_faculty_publications-0016, 10.1039/C4RA00354C
Format: Citation

Title: Classics and Digital Humanities.
Creator: Romano, Allen
Date Issued: 2011
Identifier: FSU_migr_clas_faculty_publications-0001
Format: Citation

Title: Medical Concerns in HIV-Positive Aging.
Creator: Simone, Mark, Appelbaum, Jonathan
Abstract/Description: The management and prognosis of HIV disease has changed dramatically since the introduction of combination HIV antiretroviral therapy in 1996. Thus, the number of older adults with HIV is increasing partly because people with HIV are living longer. At the same time, the rates of new HIV cases in older adults (usually defined as people over the age of 50) are also increasing. Currently, about 25 percent of all patients living with HIV are older than 50, and by 2015 adults older than 50 will...
Show moreThe management and prognosis of HIV disease has changed dramatically since the introduction of combination HIV antiretroviral therapy in 1996. Thus, the number of older adults with HIV is increasing partly because people with HIV are living longer. At the same time, the rates of new HIV cases in older adults (usually defined as people over the age of 50) are also increasing. Currently, about 25 percent of all patients living with HIV are older than 50, and by 2015 adults older than 50 will account for 50 percent of the population living with HIV.1 These trends make understanding the medical challenges of HIV in older adults more important than ever. This article reviews the special issues associated with HIV and AIDS in an older population.
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Date Issued: 2009
Identifier: FSU_migr_clinicalsciences_faculty_publications-0001
Format: Citation

Title: Determinants of Chicago Neighborhood Homicide Trajectories: 1965-1995.
Creator: Stults, Brian
Abstract/Description: The homicide rate in Chicago nearly tripled between 1965 and 1992, and subsequently declined by more than 50% through 2005. But is this trend representative of all areas in the city? Drawing on the social disorganization and concentrated disadvantage perspectives, this paper uses semi-parametric group-based trajectory modeling to examine homicide trajectories in Chicago neighborhoods from 1965-1995. Significant variability is found in homicide trajectories across neighborhoods. Multivariate...
Show moreThe homicide rate in Chicago nearly tripled between 1965 and 1992, and subsequently declined by more than 50% through 2005. But is this trend representative of all areas in the city? Drawing on the social disorganization and concentrated disadvantage perspectives, this paper uses semi-parametric group-based trajectory modeling to examine homicide trajectories in Chicago neighborhoods from 1965-1995. Significant variability is found in homicide trajectories across neighborhoods. Multivariate results show that disadvantage increases the likelihood of having an increasing or persistently high homicide trajectory. Social disorganization and family disruption are also predictive of variation in homicide trajectories, but only in communities with already low levels of homicide. Other theoretically relevant predictors are evaluated, and suggestions for theoretical refinement and future research are discussed.
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Date Issued: 2010
Identifier: FSU_migr_crim_faculty_publications-0001, 10.1177/1088767910371173
Format: Citation

Title: Child Maltreatment Reporting Patterns and Predictors of Substantiation: Comparing Adolescents and Younger Children.
Creator: Raissian, Kerri, Dierkhising, Carly, Mullins Geiger, Jennifer, Schelbe, Lisa
Abstract/Description: Adolescents, and especially male adolescents, make up a disproportionately smaller portion of maltreatment reports compared to younger children. This study used the National Child Abuse and Neglect Data System (NCANDS) to better understand the characteristics of adolescents reported to Child Protective Services (CPS), to examine if these characteristics changed over time, and to determine if certain child or CPS report characteristics predicted CPS involvement. Whereas adolescents were the...
Show moreAdolescents, and especially male adolescents, make up a disproportionately smaller portion of maltreatment reports compared to younger children. This study used the National Child Abuse and Neglect Data System (NCANDS) to better understand the characteristics of adolescents reported to Child Protective Services (CPS), to examine if these characteristics changed over time, and to determine if certain child or CPS report characteristics predicted CPS involvement. Whereas adolescents were the focal group, younger children were also analyzed for comparison. Between 2005 and 2010, reports of neglect and the proportion of children of Hispanic and unknown racial/ethnic origins increased. Concurrently, the proportion of cases resulting in CPS involvement declined. Although race/ethnicity predicted CPS involvement, this pattern was not consistent across all age groups or races/ethnicities. The type of alleged maltreatment did not typically predict CPS involvement; however, allegations of sexual abuse among school-age children and adolescents, particularly among girls, were more likely to result in CPS involvement. These findings can assist child welfare professionals in determining appropriate services tailored to families and developing prevention programs targeting adolescents.
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Date Issued: 2014
Identifier: FSU_migr_csw_faculty_publications-0001, 10.1177/1077559513518096
Format: Citation

Title: Why Youth Leave Care: Understandings of Adulthood and Transition Successes and Challenge Among Youth Aging Out of Child Welfare.
Creator: Goodkind, Sarah, Schelbe, Lisa, Shook, Jeffrey J.
Abstract/Description: Child welfare policies and practices are changing to allow more youth to remain in care beyond age 18. Yet, the majority of youth do not stay. Given recent evidence suggesting that remaining in care may be beneficial, there is a need to understand why youth leave. Using data gathered from in-depth interviews with young people aging out of care, this paper explores this question, relating it to youths' understandings of adulthood and the successes and challenges they face during their...
Show moreChild welfare policies and practices are changing to allow more youth to remain in care beyond age 18. Yet, the majority of youth do not stay. Given recent evidence suggesting that remaining in care may be beneficial, there is a need to understand why youth leave. Using data gathered from in-depth interviews with young people aging out of care, this paper explores this question, relating it to youths' understandings of adulthood and the successes and challenges they face during their transitions. We find that youth leave care because of misunderstanding and misinformation about the requirements for remaining in care, as well as because of a desire for autonomy and independence. Specifically, many youth equated adulthood with independence, and thus felt that they needed to leave care to achieve adulthood. Unfortunately, these efforts to be independent often hinder youths' development of supportive relationships, which they reported to be one of the greatest challenges in their transitions. Based on these findings, we conclude by challenging the conflation of adulthood and independence, as well as of childhood and dependence, calling for connected autonomy as a goal for child welfare involved young people of all ages.
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Date Issued: 2011
Identifier: FSU_migr_csw_faculty_publications-0002, 10.1016/j.childyouth.2011.01.010
Format: Citation

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