Showing 791 - 800 of 2040 Items
Design of a drug discovery course for non-science majors
Date: 2018-07-01
Creator: Danielle H. Dube
Access: Open access
- “Drug Discovery” is a 13-week lecture and laboratory-based course that was developed to introduce non-science majors to foundational chemistry and biochemistry concepts as they relate to the unifying theme of drug discovery. The first part of this course strives to build students' understanding of molecules, their properties, the differences that enable them to be separated from one another, and their abilities to bind to biological receptors and elicit physiological effects. After building students' molecular worldview, the course then focuses on four classes of drugs: antimicrobials, drugs that affect the mind, steroid-based drugs, and anti-cancer drugs. During each of these modules, an emphasis is placed on how understanding the basis of disease and molecular-level interactions empowers us to identify novel medicinal compounds. Periodic in class discussions based on articles pertinent to class topics ranging from the spread of antibiotic resistance, to the molecular basis of addiction, to rational drug design, are held to enable students to relate course material to pressing problems of national and daily concern. In addition to class time, weekly inquiry-based laboratories allow students to critically analyze data related to course concepts, and later in the semester give students an opportunity to design and implement their own experiments to screen for antimicrobial activity. This course provides students with an understanding of the importance of chemistry and biochemistry to human health while emphasizing the process, strategies, and challenges related to drug discovery. © 2018 by The International Union of Biochemistry and Molecular Biology, 46:327–335, 2018.
Partner choice in spontaneous mitotic recombination in wild type and homologous recombination mutants of Candida albicans
Date: 2019-11-01
Creator: Alberto Bellido
Toni Ciudad
Belén Hermosa
Encarnación Andaluz
Anja, Forche
Germán Larriba
Access: Open access
- Candida albicans, the most common fungal pathogen, is a diploid with a genome that is rich in repeats and has high levels of heterozygosity. To study the role of different recombination pathways on direct-repeat recombination, we replaced either allele of the RAD52 gene (Chr6) with the URA-blaster cassette (hisG-URA3-hisG), measured rates of URA3 loss as resistance to 5-fluoroorotic acid (5FOAR) and used CHEF Southern hybridization and SNP-RFLP analysis to identify recombination mechanisms and their frequency in wildtype and recombination mutants. FOAR rates varied little across different strain backgrounds. In contrast, the type and frequency of mechanisms underlying direct repeat recombination varied greatly. For example, wildtype, rad59 and lig4 strains all displayed a bias for URA3 loss via pop-out/deletion vs. inter-homolog recombination and this bias was reduced in rad51 mutants. In addition, in rad51-derived 5FOAR strains direct repeat recombination was associated with ectopic translocation (5%), chromosome loss/truncation (14%) and inter-homolog recombination (6%). In the absence of RAD52, URA3 loss was mostly due to chromosome loss and truncation (80–90%), and the bias of retained allele frequency points to the presence of a recessive lethal allele on Chr6B. However, a few single-strand annealing (SSA)-like events were identified and these were independent of either Rad59 or Lig4. Finally, the specific sizes of Chr6 truncations suggest that the inserted URA-blaster could represent a fragile site.
Development of Rare Bacterial Monosaccharide Analogs for Metabolic Glycan Labeling in Pathogenic Bacteria
Date: 2016-12-16
Creator: Emily L. Clark
Madhu Emmadi
Katharine L. Krupp
Ananda R. Podilapu
Jennifer D., Helble
Suvarn S. Kulkarni
Danielle H. Dube
Access: Open access
- Bacterial glycans contain rare, exclusively bacterial monosaccharides that are frequently linked to pathogenesis and essentially absent from human cells. Therefore, bacterial glycans are intriguing molecular targets. However, systematic discovery of bacterial glycoproteins is hampered by the presence of rare deoxy amino sugars, which are refractory to traditional glycan-binding reagents. Thus, the development of chemical tools that label bacterial glycans is a crucial step toward discovering and targeting these biomolecules. Here, we explore the extent to which metabolic glycan labeling facilitates the studying and targeting of glycoproteins in a range of pathogenic and symbiotic bacterial strains. We began with an azide-containing analog of the naturally abundant monosaccharide N-acetylglucosamine and discovered that it is not broadly incorporated into bacterial glycans, thus revealing a need for additional azidosugar substrates to broaden the utility of metabolic glycan labeling in bacteria. Therefore, we designed and synthesized analogs of the rare deoxy amino d-sugars N-acetylfucosamine, bacillosamine, and 2,4-diacetamido-2,4,6-trideoxygalactose and established that these analogs are differentially incorporated into glycan-containing structures in a range of pathogenic and symbiotic bacterial species. Further application of these analogs will refine our knowledge of the glycan repertoire in diverse bacteria and may find utility in treating a variety of infectious diseases with selectivity.
Metabolic Glycan Labeling-Based Screen to Identify Bacterial Glycosylation Genes
Date: 2020-12-11
Creator: Karen D. Moulton
Adedunmola P. Adewale
Hallie A. Carol
Sage A. Mikami
Danielle H., Dube
Access: Open access
- Bacterial cell surface glycans are quintessential drug targets due to their critical role in colonization of the host, pathogen survival, and immune evasion. The dense cell envelope glycocalyx contains distinctive monosaccharides that are stitched together into higher order glycans to yield exclusively bacterial structures that are critical for strain fitness and pathogenesis. However, the systematic study and inhibition of bacterial glycosylation enzymes remains challenging. Bacteria produce glycans containing rare sugars refractory to traditional glycan analysis, complicating the study of bacterial glycans and the identification of their biosynthesis machinery. To ease the study of bacterial glycans in the absence of detailed structural information, we used metabolic glycan labeling to detect changes in glycan biosynthesis. Here, we screened wild-type versus mutant strains of the gastric pathogen Helicobacter pylori, ultimately permitting the identification of genes involved in glycoprotein and lipopolysaccharide biosynthesis. Our findings provide the first evidence that H. pylori protein glycosylation proceeds via a lipid carrier-mediated pathway that overlaps with lipopolysaccharide biosynthesis. Protein glycosylation mutants displayed fitness defects consistent with those induced by small molecule glycosylation inhibitors. Broadly, our results suggest a facile approach to screen for bacterial glycosylation genes and gain insight into their biosynthesis and functional importance, even in the absence of glycan structural information.
Polar oceanography: Engendering students with a sense of place and a sense of time
Date: 2016-06-01
Creator: Collin S. Roesler
Access: Open access
The Art Gallery Theorem for Polyominoes
Date: 2012-10-01
Creator: Therese Biedl
Mohammad T. Irfan
Justin Iwerks
Joondong Kim
Joseph S.B., Mitchell
Access: Open access
- We explore the art gallery problem for the special case that the domain (gallery) P is an m-polyomino, a polyform whose cells are m unit squares. We study the combinatorics of guarding polyominoes in terms of the parameter m, in contrast with the traditional parameter n, the number of vertices of P. In particular, we show that ⌊m+1/3⌋ point guards are always sufficient and sometimes necessary to cover an m-polyomino, possibly with holes. When m < 3n/4-4, the sufficiency condition yields a strictly lower guard number than ⌊ n/4⌋, given by the art gallery theorem for orthogonal polygons. © 2012 Springer Science+Business Media, LLC.
The citizens united election? or same as it ever was?
Date: 2010-12-01
Creator: Michael M. Franz
Access: Open access
- In January 2010, the Supreme Court in Citizens United v. FEC overturned long-standing regulations governing the role of unions and corporations in sponsoring pro-candidate advocacy. Many predicted a deleterious effect on the electoral process. In the aftermath of the midterm elections, a number of questions deserve consideration. Was the observed level of outside spending abnormally high in 2010? What can we say about the potential effect of outside spending on the outcomes of House and Senate races? Moreover, what has the decision done to the power of parties and, most especially, their ability to compete with special interests in backing federal candidates? This paper investigates these questions using data from the Wesleyan Media Project, which tracked political ads in 2010. The initial evidence suggests that while interest groups were aggressive players in the air war, their impact may not have been as negative or as large as initially predicted. © 2011 Berkeley Electronic Press.
The H.C. Carey School of U.S. Currency Doctors: A "Subtle Principle" and its Progeny
Date: 2024-02-20
Creator: Stephen Meardon
Access: Open access
- Henry C. Carey led a school of post-Civil War U.S. currency doctors prescribing an “elastic currency,” expanding and contracting according to commercial needs. The problem for the Careyites was reconciling elasticity, which implied inconvertibility with gold, with the related aim of decentralized financial power. Careyite currency doctors included, among others, Wallace P. Groom, editor of the New York Mercantile Journal, and Henry Carey Baird, Carey’s own nephew and inheritor of his mantle. Their prescribed reform of the banking system featured a financial innovation that would remove superfluous currency from circulation while supplying what was needed. The innovation was an “interconvertible bond,” a debt instrument of the U.S. Treasury that was to be issued upon demand and redeemable for currency at the option of the holder. Its function was supposed to be like the mechanical governor of a steam engine, operating by a “subtle principle” that obviated human governing power and discretion. The Carey school’s prescription and its rationale remained salient up to the advent of the Federal Reserve System.
Hedgehog signaling regulates dental papilla formation and tooth size during zebrafish odontogenesis
Date: 2015-04-01
Creator: Jeffrey C. Yu
Zachary D. Fox
James L. Crimp
Hana E. Littleford
Andrea L., Jowdry
William R. Jackman
Access: Open access
- Intercellular communication by the hedgehog cell signaling pathway is necessary for tooth development throughout the vertebrates, but it remains unclear which specific developmental signals control cell behavior at different stages of odontogenesis. To address this issue, we have manipulated hedgehog activity during zebrafish tooth development and visualized the results using confocal microscopy. Results: We first established that reporter lines for dlx2b, fli1, NF-κB, and prdm1a are markers for specific subsets of tooth germ tissues. We then blocked hedgehog signaling with cyclopamine and observed a reduction or elimination of the cranial neural crest derived dental papilla, which normally contains the cells that later give rise to dentin-producing odontoblasts. Upon further investigation, we observed that the dental papilla begins to form and then regresses in the absence of hedgehog signaling, through a mechanism unrelated to cell proliferation or apoptosis. We also found evidence of an isometric reduction in tooth size that correlates with the time of earliest hedgehog inhibition. Conclusions: We hypothesize that these results reveal a previously uncharacterized function of hedgehog signaling during tooth morphogenesis, regulating the number of cells in the dental papilla and thereby controlling tooth size.
Statement by Melinda (Mindy) Kane collected by Rachel George on September 11, 2014
Date: 2014-09-11
Creator: Melinda Kane
Access: Open access