480 results on '"Lewis, Benjamin A."'
Search Results
452. Intellectual Engagement and Other Principles of Mathematics Instruction.
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Peterson, Blake E., Corey, Douglas L., Lewis, Benjamin M., and Bukarau, Jared
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MATHEMATICS , *CURRICULUM , *EDUCATIONAL objectives , *STUDENTS , *PERFORMANCE - Abstract
The article presents information on several principles related to high-quality mathematics instructions which include the goal principle, the unit principle, and the preparation principle. It informs that an ideal lesson in mathematics consist of specific set of goals which include students' motivation, understanding, and performance. It also informs that the high-quality instruction requires a detailed plan which addresses and ties all the respective principles together in a coherent lesson.
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- 2013
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453. Effects of amino acid substitutions at positions 33 and 37 on UDP-glucuronosyltransferase 1A9 (UGT1A9) activity and substrate selectivity
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Korprasertthaworn, Porntipa, Rowland, Andrew, Lewis, Benjamin C., Mackenzie, Peter I., Yoovathaworn, Krongtong, and Miners, John O.
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GLUCURONOSYLTRANSFERASE , *GLUCURONIDATION , *AMINO acids , *XENOBIOTICS , *HISTIDINE , *MYCOPHENOLIC acid , *NAPROXEN , *SULFINPYRAZONE - Abstract
Abstract: UGT1A9 contributes to the glucuronidation of numerous drugs and xenobiotics. There is evidence to suggest that the Met33Thr substitution, as occurs in the polymorphic variant UGT1A9*3, variably affects xenobiotic glucuronidation. The equivalent position in UGT1A4 is also known to influence enzyme activity, whilst an N-terminal domain histidine (His37 in UGT1A9) is believed to function as the catalytic base in most UGT enzymes. To elucidate the roles of key amino acids and characterise structure–function relationships, we determined the effects of amino acid substitutions at positions 33 and 37 of UGT1A9 on the kinetics of 4-methylumbelliferone (4-MU), mycophenolic acid (MPA), propofol (PRO), sulfinpyrazone (SFZ), frusemide (FSM), (S)-naproxen (NAP) and retigabine (RTB) glucuronidation, compounds that undergo glucuronidation at either a phenolic (4-MU, MPA, PRO), carboxylate (FSM, NAP), acidic carbon (SFZ) or amine (RTB) function. Substitution of Met33 with Val, Ile, Thr, and Gln, as occur in UGT1A1, UGT1A3, UGT1A4 and UGT1A6 respectively, variably affected kinetics and catalytic efficiency. Whilst K m values were generally higher and V max and CLint values were generally lower than for wild-type UGT1A9 with most substrate-mutant pairs, the pattern and the magnitude of the changes in each parameter differed substantially. Moreover, exceptions occurred; CLint values for MPA and FSM glucuronidation by the position-33 mutants were the same as or higher than that of UGT1A9. Mutation of His37 abolished activity towards all substrates, except RTB N-glucuronidation. The data confirm the importance of single amino acids for UGT enzyme activity and substrate selectivity, and support a pivotal role for residue-33 in facilitating substrate binding to UGT1A9. [Copyright &y& Elsevier]
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- 2012
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454. The glycosidation of xenobiotics and endogenous compounds: Versatility and redundancy in the UDP glycosyltransferase superfamily
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Meech, Robyn, Miners, John O., Lewis, Benjamin C., and Mackenzie, Peter I.
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XENOBIOTICS , *GLYCOSYLTRANSFERASES , *GLYCOSIDES , *COENZYME A , *DRUG metabolism , *SUGARS , *CHROMOSOME duplication , *BACTERIA - Abstract
Abstract: The covalent addition of sugars to small organic molecules is mediated by a superfamily of UDP glycosyltransferases (UGTs) found in animals, plants and bacteria. This superfamily evolved by gene duplication and divergence to manage exposure to a changing environment of lipophilic chemicals. The recent characterization of the UGT3A family provides further insights into the origin and evolution of this superfamily in mammals and the role of individual UGTs in the formation of the various chemical glycosides found in body tissues and fluids. Furthermore, the unique UDP-sugar specificities of the two enzymes in this family inform our knowledge of UGT structure relating to catalysis and UDP-sugar specificity. In addition to the UGT3 gene family, three other gene families, UGTs1, 2, and 8, are found in mammalian genomes. The 19 members of the UGT1 and 2 families have a major role in processing lipophilic chemicals due to their capacity to glucuronidate a broad range of structurally-dissimilar substrates. In contrast, the UGT3 enzymes only have a minor role, as their activities are very low in the major drug-metabolic organs, and their N-acetylglucosaminide and glucoside products are only a minor component of circulating and excreted drug metabolites. Although the endogenous role of the UGT3 family is still unknown, participation in the processing of lipophilic chemicals in specific cell types or at specific times during ontogeny cannot be excluded. In contrast to the UGT 1, 2 and 3 families, the single member of the UGT8 family appears to have no role in drug metabolism. [Copyright &y& Elsevier]
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- 2012
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455. Protein-RNA interface residue prediction using machine learning: an assessment of the state of the art.
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Walia, Rasna R., Caragea, Cornelia, Lewis, Benjamin A., Towfic, Fadi, Terribilini, Michael, El-Manzalawy, Yasser, Dobbs, Drena, and Honavar, Vasant
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RNA-protein interactions , *CATALYTIC RNA , *GENE expression , *SUPPORT vector machines , *MACHINE learning - Abstract
Background: RNA molecules play diverse functional and structural roles in cells. They function as messengers for transferring genetic information from DNA to proteins, as the primary genetic material in many viruses, as catalysts (ribozymes) important for protein synthesis and RNA processing, and as essential and ubiquitous regulators of gene expression in living organisms. Many of these functions depend on precisely orchestrated interactions between RNA molecules and specific proteins in cells. Understanding the molecular mechanisms by which proteins recognize and bind RNA is essential for comprehending the functional implications of these interactions, but the recognition ‘code’ that mediates interactions between proteins and RNA is not yet understood. Success in deciphering this code would dramatically impact the development of new therapeutic strategies for intervening in devastating diseases such as AIDS and cancer. Because of the high cost of experimental determination of protein-RNA interfaces, there is an increasing reliance on statistical machine learning methods for training predictors of RNA-binding residues in proteins. However, because of differences in the choice of datasets, performance measures, and data representations used, it has been difficult to obtain an accurate assessment of the current state of the art in protein-RNA interface prediction. Results: We provide a review of published approaches for predicting RNA-binding residues in proteins and a systematic comparison and critical assessment of protein-RNA interface residue predictors trained using these approaches on three carefully curated non-redundant datasets. We directly compare two widely used machine learning algorithms (Naïve Bayes (NB) and Support Vector Machine (SVM)) using three different data representations in which features are encoded using either sequence- or structure-based windows. Our results show that (i) Sequenced-based classifiers that use a position-specific scoring matrix (PSSM)-based representation (PSSM Seq) outperform those that use an amino acid identity based representation (IDSeq) or a smoothed PSSM (SmoPSSMSeq); (ii) Structure-based classifiers that use smoothed PSSM representation (SmoPSSMStr) outperform those that use PSSM (PSSMStr) as well as sequence identity based representation (IDStr). PSSMSeq classifiers, when tested on an independent test set of 44 proteins, achieve performance that is comparable to that of three state-of-the-art structure-based predictors (including those that exploit geometric features) in terms of Matthews Correlation Coefficient (MCC), although the structure-based methods achieve substantially higher Specificity (albeit at the expense of Sensitivity) compared to sequence-based methods. We also find that the expected performance of the classifiers on a residue level can be markedly different from that on a protein level. Our experiments show that the classifiers trained on three different non-redundant protein-RNA interface datasets achieve comparable cross-validation performance. However, we find that the results are significantly affected by differences in the distance threshold used to define interface residues. Conclusions: Our results demonstrate that protein-RNA interface residue predictors that use a PSSM based encoding of sequence windows outperform classifiers that use other encodings of sequence windows. While structure-based methods that exploit geometric features can yield significant increases in the Specificity of protein-RNA interface residue predictions, such increases are offset by decreases in Sensitivity. These results underscore the importance of comparing alternative methods using rigorous statistical procedures, multiple performance measures, and datasets that are constructed based on several alternative definitions of interface residues and redundancy cutoffs as well as including evaluations on independent test sets into the comparisons. [ABSTRACT FROM AUTHOR]
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- 2012
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456. Are There Any Places That Students Use Their Heads? Principles of High-Quality Japanese Mathematics Instruction.
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Corey, Douglas L., Peterson, Blake E., Lewis, Benjamin Merrill, and Bukarau, Jared
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MATHEMATICS education , *MATHEMATICS teachers , *JAPANESE people , *STUDENT teachers - Abstract
Previous research gives evidence that Japanese mathematics teachers "may have a more detailed and widely shared theory about how to teach effectively" when compared to their U.S. counterparts (Jacobs & Morita, 2002). This study explores the conceptions and cultural scripts of a group of Japanese mathematics teachers by analyzing the conversations between cooperating teachers and student teachers. It describes 6 principles of high-quality instruction that arose in at least half the conversations we analyzed. Each of these principles is examined in detail. Finally, some advantages of having a strong, shared conception of high-quality instruction and focusing on widely applicable instructional principles are presented. [ABSTRACT FROM AUTHOR]
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- 2010
457. Isotope Program Report September FY2016
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Lewis, Benjamin [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)]
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- 2016
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458. Isotope Program Report August FY2016
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Lewis, Benjamin [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)]
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- 2016
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459. Demographic Characteristics, Risk Behaviors, and HIV Seroprevalence Among Intravenous Drug Users by Site on Contact: Results from a Community-wide HIV Surveillence Project.
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McCusker, Jane, Koblin, Beryl, Lewis, Benjamin F., and John, Sullivan
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HIV , *DRUG abuse , *SUBSTANCE abuse , *IMMUNOGLOBULINS , *AIDS prevention , *PREVENTIVE medicine , *PREVENTION - Abstract
We investigated differences in behaviors important for human immunodeficiency virus (HIV) transmission and HIV antibody status among 927 recent needle users enrolled in a multi-site HIV surveillance project in Worcester, Massachusetts, Subjects were enrolled at drug abuse treatment centers, other clinical sites, and a men's jail. Subjects at drug treatment centers reported less risky injection practices unexplained by demographic variables. Risky sexual practices were in general reported more frequently by men at the jail than men at other sites. However, HIV status showed little relation to enrollment site. These results have implications both for targeting of acquired immunodeficiency syndrome (AIDS) prevention programs to needle users not in drug abuse treatment and for potential selection bias in studies of intravenous drug users. [ABSTRACT FROM AUTHOR]
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- 1990
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460. LONGEVITY OF CHEMISTS.
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Lewis, Benjamin Arthur
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LETTERS to the editor , *OBITUARY writing , *CHEMISTS - Abstract
A letter to the editor is presented in response to obituaries of accomplished chemists in the November 29, 2010 issue.
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- 2011
461. A retrospective 4D-MRI based on 2D diaphragm profiles for lung cancer patients.
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Lee, Danny, Kim, Siyong, Palta, Jatinder, Lewis, Benjamin, Keall, Paul, and Kim, Taeho
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LUNG cancer patients , *MAGNETIC resonance imaging , *RADIOTHERAPY , *DIAPHRAGM (Anatomy) , *DIAGNOSTIC imaging - Abstract
Introduction: 4D-MRI, compared to 4D-CT, provides better soft-tissue contrast for target delineation. However, motion artefacts are often observed due to residual breathing variations. This study is to present a retrospective 4D-MRI reconstruction method based on 2D diaphragm profiles to improve the quality of 4D-MR images in the presence of significant breathing variations.Methods: The proposed 4D-MRI reconstruction method utilized diaphragm profiles (2D cine images on a single sagittal plan at the peak diaphragm) in conjunction with 4D-MR scans (2D-cine images on multiple pre-determined coronal planes along the anterior-posterior direction over a volume of interest). The diaphragm profile images were exploited to sort the 4D-MR scans by matching respiratory amplitude of diaphragm on the 4D-MR scans to the diaphragm profiles. To evaluate reconstructed 4D-MR images (ten 3D-MR images), sagittal images on ten 3D-MR images under free breathing (FB) and respiratory guidance (GB) were compared with diaphragm profile images (reference) from 13 healthy volunteers.Results: Forty-four 4D-MR scan datasets were successfully reconstructed without distinct respiratory-related motion artefacts even with the presence of breathing variation. The differences in diaphragm profiles between the reference and corresponding reconstructed images in the mean of root mean square were similar between FB (3.5 mm) and GB (3.0 mm), confirming that the 4D-MRI reconstruction method was effective even with significant breathing variation.Conclusions: The diaphragm profiles were utilized to reconstruct 4D-MR images with spatial reliability and a fixed scan time under FB and GB. Our method can provide reliable 4D information of thoracic and abdominal regions for MRI-guided radiotherapy. [ABSTRACT FROM AUTHOR]- Published
- 2019
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462. 88 - Effect of Acute Voluntary Exercise on Expression and Oxidative Modification of Low Density Lipoprotein Receptor-Related Protein 1 in Brain of Wild Type Mice as a Function of Age.
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Boyd-Kimball, Debra, Gonczy, Katelyn, Lewis, Benjamin, and Mason, Thomas
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CENTRAL nervous system , *VASCULAR smooth muscle , *BRAIN proteins , *AMYLOID beta-protein , *MUSCLE cells , *MEMBRANE proteins - Abstract
Low density lipoprotein receptor-related protein 1 (LRP1) is a type I membrane protein expressed in multiple cell types in the central nervous system including endothelial cells, vascular smooth muscle cells, pericytes, astrocytes, and neurons. LRP1 acts as an important efflux transporter of amyloid β-peptide 1-42 (Aβ42) across the blood-brain barrier from brain to blood. Expression of LRP1 and efflux of Aβ42 are both significantly decreased in Alzheimer’s Disease (AD) brain. LRP1 is oxidatively modified by the lipid peroxidation product 4-hydroxy-2-trans-nonenal (HNE) in AD hippocampus suggesting that Aβ42-mediated oxidative stress may result in oxidative modification of its own transporter decreasing the clearance of Aβ42 in AD brain. Exercise has been shown to increase the capacity of the brain to tolerate oxidation damage. In this study, the effect of acute voluntary exercise on expression and oxidative modification of LRP1 in brain of 5, 10, and 22 month old wild type mice was examined. [ABSTRACT FROM AUTHOR]
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- 2017
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463. Syntheses, crystal structure, and electronic properties of the five ABaMQ4 compounds RbBaPS4, CsBaPS4, CsBaVS4, RbBaVSe4, and CsBaVSe4.
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Mesbah, Adel, Prakash, Jai, Rocca, Dario, Lebègue, Sébastien, Beard, Jessica C., Lewis, Benjamin A., and Ibers, James A.
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ELECTRONIC structure , *CRYSTAL structure , *CRYSTALLOGRAPHY , *DENSITY functional theory , *SEMICONDUCTORS - Abstract
Five new compounds belonging to the ABaMQ 4 family were synthesized by solid-state chemistry at 1123 K. The compounds RbBaPS 4 , CsBaPS 4 , CsBaVS 4 , RbBaVSe 4 , and CsBaVSe 4 are isostructural and have the TlEuPS 4 structure type. They crystallize in space group D 16 2 h – Pnma of the orthorhombic system. Their structure consists isolated MQ 4 tetrahedra separated by A and Ba atoms to form a salt-like structure. Density Functional Theory (DFT) calculations of the electronic structures with the use of the HSE functional suggest that the compounds are semiconductors with calculated band gaps of 3.3 eV (RbBaPS 4 ), 3.4 eV (CsBaPS 4 ), 2.3 eV (CsBaVS 4 ), and 1.6 eV (RbBaVSe 4 ). [ABSTRACT FROM AUTHOR]
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- 2016
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464. A meta-analysis of American black duck winter habitat use along the Atlantic Coast.
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Ringelman, Kevin M., Williams, Christopher K., Devers, Patrick K., Coluccy, John M., Castelli, Paul M., Anderson, Kurt A., Bowman, Jacob L., Costanzo, Gary R., Cramer, Dane M., Dibona, Matt T., Eichholz, Michael W., Huang, Min, Lewis, Benjamin, Plattner, Dawn M., and Yerkes, Tina
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BLACK duck behavior , *WINTERING of birds , *BIRD habitats , *EFFECT of environment on birds , *WETLANDS - Abstract
ABSTRACT American black duck ( Anas rubripes) populations declined by more than 50% between the 1950s and 1990s, and the species serves as a flagship for conserving salt marsh habitats along the Atlantic Coast. Black ducks have generally been well studied throughout the annual cycle, but surprisingly, we lack a synthetic, quantitative understanding of their space use during the winter. This limits our ability to prioritize habitat acquisition and restoration efforts. We used >17,000 telemetry locations from 235 black ducks ranging from Connecticut to Virginia to study home range composition and space use during winter in relation to habitat quality, urbanization, and severe weather. Despite substantial environmental variation, home range sizes were similar among regions and years. Smaller home and core ranges contained a greater proportion of salt marsh habitat, and ducks experiencing more 4-day freeze events had larger home and core ranges. Ducks exposed to prolonged periods of cold weather had smaller core ranges when those areas comprised more energy-rich freshwater habitats. When we examined individual telemetry locations, we found that ducks used irregularly inundated high marsh more at night, presumably for foraging, and urban habitats more during the day and evening crepuscular periods. We found that black ducks used regularly inundated low marsh less on days where the temperature never rose above freezing, and instead used subtidal areas and forested wetlands more. Finally, we found ducks were marginally more likely to use freshwater habitats during high tides. Our study confirms that black ducks depend on salt marsh for wintering habitat, and points to an unexpectedly important role for forested wetlands during periods of cold weather. We found no evidence that black ducks avoided urban areas or roads, which supports the inclusion of all available habitats in carrying capacity modeling. We emphasize that new hypothesis-driven, local telemetry studies are needed to further elucidate the relationships between black duck movements and environmental variation, especially cold weather. Further, given that most remaining coastal wetlands are currently protected via state and federal lands, we suggest black duck habitat management should strive to acquire and restore brackish and forested wetlands in close proximity to coastal marshes. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. [ABSTRACT FROM AUTHOR]
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- 2015
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465. Diseases, patients and the epistemology of practice: mapping the borders of health, medicine and care.
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Loughlin, Michael, Bluhm, Robyn, Fuller, Jonathan, Buetow, Stephen, Borgerson, Kirstin, Lewis, Benjamin R., and Kious, Brent M.
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THERAPEUTICS , *CONFERENCES & conventions , *HEALTH , *THEORY of knowledge , *MEDICAL care , *MEDICAL ethics , *MEDICAL practice , *PATIENTS , *PHILOSOPHY , *SERIAL publications - Abstract
Last year saw the 20th anniversary edition of JECP, and in the introduction to the philosophy section of that landmark edition, we posed the question: apart from ethics, what is the role of philosophy 'at the bedside'? The purpose of this question was not to downplay the significance of ethics to clinical practice. Rather, we raised it as part of a broader argument to the effect that ethical questions - about what we should do in any given situation - are embedded within whole understandings of the situation, inseparable from our beliefs about what is the case (metaphysics), what it is that we feel we can claim to know (epistemology), as well as the meaning we ascribe to different aspects of the situation or to our perception of it. Philosophy concerns fundamental questions: it is a discipline requiring us to examine the underlying assumptions we bring with us to our thinking about practical problems. Traditional academic philosophers divide their discipline into distinct areas that typically include logic: questions about meaning, truth and validity; ontology: questions about the nature of reality, what exists; epistemology: concerning knowledge; and ethics: how we should live and practice, the nature of value. Any credible attempt to analyse clinical reasoning will require us to think carefully about these types of question and the relationships between them, as they influence our thinking about specific situations and problems. So, the answers to the question we posed, about the role of philosophy at the bedside, are numerous and diverse, and that diversity is illustrated in the contributions to this thematic edition. [ABSTRACT FROM AUTHOR]
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- 2015
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466. The Drosophila BTB Domain Protein Jim Lovell Has Roles in Multiple Larval and Adult Behaviors.
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Bjorum, Sonia M., Simonette, Rebecca A., Alanis Jr., Raul, Wang, Jennifer E., Lewis, Benjamin M., Trejo, Michael H., Hanson, Keith A., and Beckingham, Kathleen M.
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BLUETONGUE virus , *DROSOPHILA , *LARVAL ecology , *PROTEINS , *GENE expression , *PHENOTYPES , *EMBRYOLOGY , *CELL differentiation , *DEVELOPMENTAL neurobiology - Abstract
Innate behaviors have their origins in the specification of neural fates during development. Within Drosophila, BTB (Bric-a-brac,Tramtrack, Broad) domain proteins such as Fruitless are known to play key roles in the neural differentiation underlying such responses. We previously identified a gene, which we have termed jim lovell (lov), encoding a BTB protein with a role in gravity responses. To understand more fully the behavioral roles of this gene we have investigated its function through several approaches. Transcript and protein expression patterns have been examined and behavioral phenotypes of new lov mutations have been characterized. Lov is a nuclear protein, suggesting a role as a transcriptional regulator, as for other BTB proteins. In late embryogenesis, Lov is expressed in many CNS and PNS neurons. An examination of the PNS expression indicates that lov functions in the late specification of several classes of sensory neurons. In particular, only two of the five abdominal lateral chordotonal neurons express Lov, predicting functional variation within this highly similar group. Surprisingly, Lov is also expressed very early in embryogenesis in ways that suggests roles in morphogenetic movements, amnioserosa function and head neurogenesis. The phenotypes of two new lov mutations that delete adjacent non-coding DNA regions are strikingly different suggesting removal of different regulatory elements. In lov47, Lov expression is lost in many embryonic neurons including the two lateral chordotonal neurons. lov47 mutant larvae show feeding and locomotor defects including spontaneous backward movement. Adult lov47 males perform aberrant courtship behavior distinguished by courtship displays that are not directed at the female. lov47 adults also show more defective negative gravitaxis than the previously isolated lov91Y mutant. In contrast, lov66 produces largely normal behavior but severe female sterility associated with ectopic lov expression in the ovary. We propose a negative regulatory role for the DNA deleted in lov66. [ABSTRACT FROM AUTHOR]
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- 2013
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467. Identification of Residues That Confer Sugar Selectivity to UDP-Glycosyltransferase 3A (UGT3A) Enzymes.
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Meech, Robyn, Rogers, Anne, Lizhe Zhuang, Lewis, Benjamin C., Miners, John O., and Mackenzie, Peter I.
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GLUCURONOSYLTRANSFERASE , *GLUCURONIC acid , *ASPARTIC acid , *STRUCTURAL frame models , *PHENYLALANINE - Abstract
Recent studies in this laboratory characterized the UGT3A family enzymes, UGT3A1 and UGT3A2, and showed that neither uses the traditional UDP-glycosyltransferase UGT co-substrate UDP-glucuronic acid. Rather, UGT3A1 uses GlcNAc as preferred sugar donor and UGT3A2 uses UDP-Glc. The enzymatic characterization ofUGT3Amutants, structural modeling, and multispecies gene analysis have now been employed to identify a residue within the active site of these enzymes that confers their unique sugar preferences. An asparagine (Asn-391) in the UGT signature sequence of UGT3A1 is necessary for utilization of UDP-GlcNAc. Conversely, a phenylalanine (Phe-391) in UGT3A2 favors UDP-Glc use. Mutation of Asn-391 to Phe in UGT3A1 enhances its ability to utilize UDP-Glc and completely inhibits its ability to use UDP-GlcNAc. An analysis of homology models docked with UDP-sugar donors indicates that Asn-391 in UGT3A1 is able to accommodate the N-acetyl group on C2 of UDP-GlcNAc so that the anomeric carbon atom (C1) is optimally situated for catalysis involving His-35. Replacement of Asn with Phe at position 391 disrupts this catalytically productive orientation of UDP-GlcNAc but allows a more optimal alignment of UDP-Glc for sugar donation. Multispecies sequence analysis reveals that only primates possess UGT3A sequences containing Asn-391, suggesting that other mammals may not have the capacity to N-acetylglucosaminidate small molecules. In support of this hypothesis, Asn-391-containing UGT3A forms from two non-human primates were found to use UDP-GlcNAc, whereas UGT3A isoforms from non-primates could not use this sugar donor. This work gives new insight into the residues that confer sugar specificity to UGT family members and suggests a primate-specific innovation in glycosidation of small molecules. [ABSTRACT FROM AUTHOR]
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- 2012
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468. Human telomerase model shows the role of the TEN domain in advancing the double helix for the next polymerization step.
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Steczkiewicz, Kamil, Zimmermann, Michael T., Kurcinski, Mateusz, Lewis, Benjamin A., Dobbs, Drena, Kloczkowski, Andrzej, Jernigan, Robert L., Kolinski, Andrzej, and Ginalski, Krzysztof
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TELOMERASE , *POLYMERIZATION , *NUCLEOPROTEINS , *HOMOLOGY (Biology) , *NUCLEOTIDE sequence , *DRUG design - Abstract
Telomerases constitute a group of specialized ribonucleoprotein enzymes that remediate chromosomal shrinkage resulting from the "end-replication" problem. Defects in telomere length regulation are associated with several diseases as well as with aging and cancer. Despite significant progress in understanding the roles of telomerase, the complete structure of the human telomerase enzyme bound to telomeric DNA remains elusive, with the detailed molecular mechanism of telomere elongation still unknown. By application of computational methods for distant homology detection, comparative modeling, and molecular docking, guided by available experimental data, we have generated a three-dimensional structural model of a partial telomerase elongation complex composed of three essential protein domains bound to a single-stranded telomeric DNA sequence in the form of a heteroduplex with the template region of the human RNA subunit, TER. This model provides a structural mechanism for the processivity of telomerase and offers new insights into elongation. We conclude that the RNA:DNA heteroduplex is constrained by the telomerase TEN domain through repeated extension cycles and that the TEN domain controls the process by moving the template ahead one base at a time by translation and rotation of the double helix. The RNA region directly following the template can bind complementarily to the newly synthesized telomeric DNA, while the template itself is reused in the telomerase active site during the next reaction cycle. This first structural model of the human telomerase enzyme provides many details of the molecular mechanism of telomerase and immediately provides an important target for rational drug design. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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469. AFM study of the interaction of cytochrome P450 2C9 with phospholipid bilayers
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Nussio, Matthew R., Voelcker, Nicolas H., Miners, John O., Lewis, Benjamin C., Sykes, Matthew J., and Shapter, Joseph G.
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ATOMIC force microscopy , *CYTOCHROME P-450 , *BILAYER lipid membranes , *PROTEIN-protein interactions , *ENZYMES , *DRUG metabolism , *XENOBIOTICS , *CELL membranes - Abstract
Abstract: Cytochromes P450 (CYP) are key enzymes involved in the metabolism of drugs and other lipophilic xenobiotics and endogenous compounds. In this study, atomic force microscopy was applied to characterise the association of CYP2C9 to dimyristoylphosphatidylcholine (DMPC) supported phospholipid bilayers. CYP2C9 was found to exclusively localise in the gel domains of partially melted DMPC bilayers. Despite lacking the N-terminus transmembrane spanning domain, the CYP2C9 protein appeared to partially embed into the membrane bilayer, as evidenced by an increase in melting temperature of surrounding phospholipids. Reversible binding of CYP2C9 via an engineered His tag to a phospholipid bilayer was facilitated using nickel-chelating lipids, presenting potential applications for biosensor technologies. [Copyright &y& Elsevier]
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- 2010
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470. An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid.
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Polasek, Thomas M., Elliot, David J., Somogyi, Andrew A., Gillam, Elizabeth M. J., Lewis, Benjamin C., and Miners, John O.
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CLINICAL pharmacology , *CYTOCHROME P-450 , *MONOAMINE oxidase inhibitors , *ISONIAZID , *ENZYMES , *ANTITUBERCULAR agents - Abstract
Aims To characterize potential mechanism-based inactivation (MBI) of major human drug-metabolizing cytochromes P450 (CYP) by monoamine oxidase (MAO) inhibitors, including the antitubercular drug isoniazid. Methods Human liver microsomal CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities were investigated following co- and preincubation with MAO inhibitors. Inactivation kinetic constants ( KI and kinact) were determined where a significant preincubation effect was observed. Spectral studies were conducted to elucidate the mechanisms of inactivation. Results Hydrazine MAO inhibitors generally exhibited greater inhibition of CYP following preincubation, whereas this was less frequent for the propargylamines, and tranylcypromine and moclobemide. Phenelzine and isoniazid inactivated all CYP but were most potent toward CYP3A and CYP2C19. Respective inactivation kinetic constants ( KI and kinact) for isoniazid were 48.6 µm and 0.042 min−1 and 79.3 µm and 0.039 min−1. Clorgyline was a selective inactivator of CYP1A2 (6.8 µm and 0.15 min−1). Inactivation of CYP was irreversible, consistent with metabolite-intermediate complexation for isoniazid and clorgyline, and haeme destruction for phenelzine. With the exception of phenelzine-mediated CYP3A inactivation, glutathione and superoxide dismutase failed to protect CYP from inactivation by isoniazid and phenelzine. Glutathione partially slowed (17%) the inactivation of CYP1A2 by clorgyline. Alternate substrates or inhibitors generally protected against CYP inactivation. Conclusions These data are consistent with mechanism-based inactivation of human drug-metabolizing CYP enzymes and suggest that impaired metabolic clearance may contribute to clinical drug–drug interactions with some MAO inhibitors. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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471. HIV-related services for persons with severe mental illness: policy and practice in New Hampshire community mental health.
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Brunette, Mary F., Mercer, Carolyn C., Carlson, Catherine L., Rosenberg, Stanley D., Lewis, Benjamin F., Brunette, M F, Mercer, C C, Carlson, C L, Rosenberg, S D, and Lewis, B F
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HIV-positive persons , *PEOPLE with mental illness , *CARE of people , *MENTAL health policy , *HIV infections , *THERAPEUTICS , *PSYCHOSES , *BEHAVIOR therapy , *HEALTH care teams , *HEALTH services accessibility , *COMORBIDITY - Abstract
Rates of HIV and HIV risk behaviors are elevated among people with severe mental illnesses (SMI). Little is known about the extent to which community mental health (CMH) centers screen, refer, and educate their clients regarding HIV and sexually transmitted diseases (STDs). The authors surveyed CMH administrators and clinicians in New Hampshire regarding HIV/STD policy, practices, knowledge, and attitudes. HIV/STD service availability varied, and the amount of services provided was unrelated to the prevalence of HIV and AIDS in that region. Clinicians were knowledgeable about general HIV information but lacked specific knowledge about HIV related to persons with SMI. CMH staff had positive attitudes about helping clients with HIV issues. Administrators were interested in receiving training. Policy leadership, CMH practice guidelines, and training are warranted in light of the pressing public health implications of HIV/STDs among people with SMI. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
472. Guidable pipe plug
- Author
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Lewis, Benjamin [Farragut, TN]
- Published
- 2001
473. The Effectiveness of Alternative Planned Durations of Residential Drug Abuse Treatment.
- Author
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McCusker, Jane, Vickers-Lahti, Maureen, Stoddard, Anne, Hindin, Rita, Bigelow, Carol, Zorn, Martha, Garfield, Frances, Frost, Ray, Love, Craig, and Lewis, Benjamin
- Subjects
- *
CLINICAL trials , *REHABILITATION , *MEDICAL rehabilitation , *THERAPEUTICS , *REHABILITATION centers - Abstract
Randomized controlled trails were conducted at two trials were conducted at two residential drug abuse treatment facilities to compare programs that differed in planned duration. One trial compared a 6-month and a 12-month therapeutic community program (n = 184). And the second compared a 3-month and a 6-moth replace prevention program (n = 445). Retention rates over comparable time periods differed minimally by planned treatment duration, and the longer programs had lower completion rates. There was no effect in either trail of planned treatment duration on changes in psychosocial variables between admission and exit or on rates or patterns of drug use at follow-up between 2 and 6 months after exit. [ABSTRACT FROM AUTHOR]
- Published
- 1995
- Full Text
- View/download PDF
474. Behavioral Outcomes of AIDS Educational Interventions for Drug Users in Short-Term Treatment.
- Author
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McCusker, Jane, Stoddard, Anne M., Zapka, Jane G., and Lewis, Benjamin F.
- Subjects
- *
BEHAVIOR , *DRUG abusers , *THERAPEUTICS , *LOGISTIC regression analysis , *SEX customs - Abstract
This paper reports the behavioral outcomes of informational vs enhanced small-group educational interventions fro drug users among 407 subjects in a short-term drug treatment program. Logistic regression was used to analyze drug use and sexual behaviors at the final follow-up visit. Among lower risk subjects, the enhanced intervention was more effective in reducing injection practices that produced risks in terms of human immunodeficiency virus infection; among those at highest risk, the informational interventions were more effective. The enhanced intervention was more effective than the informational interventions in reducing cocaine use at follow-up. No differential intervention effect on sexual risk behaviors was found. [ABSTRACT FROM AUTHOR]
- Published
- 1993
- Full Text
- View/download PDF
475. AIDS Education for Drug Abusers: Evaluation of Short-Term Effectiveness.
- Author
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McCusker, Jane, Stoddard, Anne M., Zapka, Jane G., Morrison, Charles S., Zorn, Martha, and Lewis, Benjamin F.
- Subjects
- *
AIDS prevention , *HEALTH education , *HEALTH promotion , *DRUG abusers , *SELF-efficacy , *APPLIED psychology - Abstract
Background. Interventions are needed to assist drug abusers in reducing risky drug and sexual behavior. Methods. A randomized controlled trial compared three small group AIDS educational interventions among 567 clients of a 21-day inpatient drug detoxification program: a two-session informational intervention, given either during the first (early) or second (late) week of treatment; and a six-session enhanced intervention. Changes in knowledge, attitudes, and psychomotor skills were assessed before and after each intervention, and behavioral outcomes were assessed at follow-up 10 to 18 weeks after admission. Results. Immediately after the interventions, enhanced group members reported significantly greater self-efficacy to talk themselves out of AIDS-risky behavior, other knowledge and attitude scales did not differ by intervention. At follow-up, significant reductions in risky drug use were reported by all groups. Enhanced group members reported significantly greater reduction in injection frequency than did late informational subjects. Conclusions. No beneficial effect was detected of delaying Aids education for clients entering detoxification. At this early stage of follow-up, there is only weak evidence that an enhanced intervention improved outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 1992
- Full Text
- View/download PDF
476. Outcomes of a 21-Day Drug Detoxification Program: Retention, Transfer to Further Treatment, and HIV Risk Reduction.
- Author
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McCusker, Jane, Bigelow, Carol, Luippold, Rose, Zorn, Martha, and Lewis, Benjamin F.
- Subjects
- *
DETOXIFICATION (Substance abuse treatment) , *HIV infection transmission , *TOXINS , *SUBSTANCE abuse treatment , *SEXUALLY transmitted diseases , *STANDARD deviations - Abstract
We investigated the outcomes of a 21-day inpatient drug detoxification and rehabilitation program including length of stay, transfer to further treatment, and HIV risky behavior. Clients (n = 567) were predominantly White, male, currently unemployed, and their treatment was not covered by third party payment, 78% were detoxified with methadone. The median length of stay was 18 days. Higher education, not living with spouse or children, English as primary language, admission during fall or winter months, and greater knowledge of HIV transmission were independent predictors of greater length of stay. Among those with follow-up (n = 450), 19% were transferred to residential drug-free programs and 7% to outpatient programs. Taking into account loss to followup, the overall rate of treatment transfer could be as low as 21%, Greater length of stay was associated with higher rates of transfer to residential treatment. Relapse rates to either any drug use or injection drug use were lower among subjects transferred to residential treatment than either clients transferred to outpatient programs or those with no further treatment. Among subjects who continued to inject drugs at follow-up, no reduction in HIV risky behaviors was found regardless of further treatment. We conclude that detoxification programs have the potential for reducing relapse to drug use when followed by residential drug-free treatment. [ABSTRACT FROM AUTHOR]
- Published
- 1995
- Full Text
- View/download PDF
477. Identifying COX independent pathways involved in the anti-proliferative effects of R-flurbiprofen
- Author
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Lewis, Benjamin
- Subjects
Antineoplastic agents ,lipids (amino acids, peptides, and proteins) ,musculoskeletal system ,Skin - Abstract
Thesis (PhDPharmacy)--University of South Australia, 2011. Includes bibliographic references. Previous work has identified R-flurbiprofen as a candidate chemopreventive agent against skin cancer; however the mechanism of its anti-cancer properties remains unclear. The anti-proliferative effects of R-flurbiprofen and stereoisomer S-flurbiprofen against HaCaT cells was found to be equal at 1mM and resulted through a G1 phase growth arrest and an induction of apoptosis. Microarray studies identified altered gene expression of several genes involved in the G1 to S phase transition, as well as apoptosis regulators and growth factors, changes confirmed by RT-PCR and western blotting. Neither R-flurbiprofen nor S-flurbiprofen had any effects on AP-1 or NF-κB transcription factor activity, nor on the MAPK signalling kinases or the PI3K signalling pathway. Computational studies suggest the flurbiprofen enantiomers may interact with the IL-8 receptor, an avenue for future study.
- Published
- 2011
478. Chemoprevention of nonmelanoma skin cancer
- Author
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Lewis,Benjamin, Wigley, Peter Lance, and McKinnon, Ross Allan
- Subjects
skin cancer ,herbal medicine ,chemoprevention - Published
- 2010
479. ChemInform Abstract: Syntheses, Crystal Structure, and Electronic Properties of the Five ABaMQ4 Compounds RbBaPS4, CsBaPS4, CsBaVS4, RbBaVSe4, and CsBaVSe4.
- Author
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Mesbah, Adel, Prakash, Jai, Rocca, Dario, Lebegue, Sebastien, Beard, Jessica C., Lewis, Benjamin A., and Ibers, James A.
- Subjects
- *
SEMICONDUCTOR research , *CRYSTAL structure , *SOLID state chemistry , *ELECTRONIC structure , *CRYSTALLIZATION - Abstract
As an example for the title compounds, RbBaPS4 is prepared by solid state reaction of a 1:1:1:4 molar mixture of Ba, P2S5, S, and RbCl (C-coated evacuated silica tube, 1123 K, 4 d; cooling to 673 K at a rate of 2.5 K/h). [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
480. A MOTIF-BASED METHOD FOR PREDICTING INTERFACIAL RESIDUES IN BOTH THE RNA AND PROTEIN COMPONENTS OF PROTEIN-RNA COMPLEXES.
- Author
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Muppirala U, Lewis BA, Mann CM, and Dobbs D
- Subjects
- Amino Acid Motifs, Amino Acid Sequence, Base Sequence, Binding Sites genetics, Computational Biology methods, Computational Biology statistics & numerical data, Databases, Nucleic Acid statistics & numerical data, Databases, Protein statistics & numerical data, Escherichia coli Proteins chemistry, Escherichia coli Proteins genetics, Escherichia coli Proteins metabolism, Models, Molecular, Protein Binding, RNA genetics, RNA, Bacterial chemistry, RNA, Bacterial genetics, RNA, Bacterial metabolism, RNA, Ribosomal, 16S chemistry, RNA, Ribosomal, 16S genetics, RNA, Ribosomal, 16S metabolism, RNA-Binding Proteins genetics, Ribosomal Proteins chemistry, Ribosomal Proteins genetics, Ribosomal Proteins metabolism, Software, RNA chemistry, RNA metabolism, RNA-Binding Proteins chemistry, RNA-Binding Proteins metabolism
- Abstract
Efforts to predict interfacial residues in protein-RNA complexes have largely focused on predicting RNA-binding residues in proteins. Computational methods for predicting protein-binding residues in RNA sequences, however, are a problem that has received relatively little attention to date. Although the value of sequence motifs for classifying and annotating protein sequences is well established, sequence motifs have not been widely applied to predicting interfacial residues in macromolecular complexes. Here, we propose a novel sequence motif-based method for "partner-specific" interfacial residue prediction. Given a specific protein-RNA pair, the goal is to simultaneously predict RNA binding residues in the protein sequence and protein-binding residues in the RNA sequence. In 5-fold cross validation experiments, our method, PS-PRIP, achieved 92% Specificity and 61% Sensitivity, with a Matthews correlation coefficient (MCC) of 0.58 in predicting RNA-binding sites in proteins. The method achieved 69% Specificity and 75% Sensitivity, but with a low MCC of 0.13 in predicting protein binding sites in RNAs. Similar performance results were obtained when PS-PRIP was tested on two independent "blind" datasets of experimentally validated protein- RNA interactions, suggesting the method should be widely applicable and valuable for identifying potential interfacial residues in protein-RNA complexes for which structural information is not available. The PS-PRIP webserver and datasets are available at: http://pridb.gdcb.iastate.edu/PSPRIP/.
- Published
- 2016
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