CONSTRAINT BASED ANALYSIS OF DATABASE UPDATE PROPAGATION

Semantic and object-oriented data models provide convenient constructs for the specification of objects, relationships, and operations. The vehicle of representation is a collection of abstractions which parallel the means by which humans prefer to organize complex enterprises. These constructs inherently permit focus on one object, relationship, or operation at a time. Propagation, as a semantic construct, provides the extension of existing modeling capabilities by providing a mechanism for the specification of the update semantics between database objects. Through the analysis of constraints and the propagated actions necessary to maintain them, we attempt to do the following: 1) incorporate additional semantics into the database schema in the form of database propagation rules, 2) in the context of constraints and propagation rules, provide a model independent paradigm for determining if schemata are correct, and 3) provide a vehicle fur the explicit specification of update actions during database schema design

Redistribution of critical major histocompatibility complex and T cell receptor-binding functions of residues in an antigenic sequence after biterminal substitution

Residues critical for establishing a trimolecular interaction with a major histocompatibility complex (MHC)-encoded receptor and a T cell antigen receptor (TcR) were determined for an antigenic nonapeptide. The N-terminal residue proved to be involved in binding of the peptide to both receptors and the C-terminal residue was essential for MHC binding. While substitution of either of these critical terminal residues by alanine resulted in an almost complete loss of peptide antigenicity, simultaneous substitution of both created a new functional ligand for the same MHC molecule and the same TcR. Notably, in the biterminally substituted peptide, the core residues took on new roles in the trimolecular interaction in that a residue critical in the authentic nonapeptide for TcR binding became critical for MHC binding and former spacer residues became essential to various degrees for the interaction with either receptor or both. Thus, apparently, the loss of the terminal residues' contribution was at least partially compensated by a redistribution of the roles among the remaining residues. These results reflect a cooperative contribution of all residues of an antigenic peptide to its binding to both receptors and thus challenge a static definition of agretope and epitope as MHC and TcR binding sites

Memory TCR repertoires analyzed long-term reflect those selected during the primary response

Normal T cell repertoire selection and evolution in antigen-specific responses is poorly understood. We have recently described an MHC class I-restricted response characterized by an overwhelming expansion of CD8 cells expressing a Vβ10 TCR, thus allowing the identification of antigen-selected cells directly ex vivo. Our present strategy to follow the overall TCR repertoire selection was to monitor the expression of a particular TCR α chain (Vα8) on antigen-selected Vβ10+ cells by four-color flow cytometry. We demonstrate that while there is substantial variation among the responder mice in Vα8 usage, the repertoires of individual animals remain relatively stable over long periods of time (>1 year), with or without repeated antigenic challenge. Thus if any evolution of this response occurs upon re-exposure to antigen, it would appear not to skew the TCR repertoire established during the primary respons

Supporting Teaching with Primary Sources at Indiana University: An Ithaka S+R Summary Report

Beginning in early 2019, Indiana University joined 24 other institutions from the United States plus two from the United Kingdom to participate in the Ithaka S&R study “Supporting Teaching with Primary Sources”. Indiana University-Bloomington (IUB) includes a vast network of over 50 galleries, libraries, archives, and museums that utilize primary sources to support the educational mission of the University. For the project, a local team of one archivist and one special collections librarian conducted interviews focusing on teaching with primary sources at IUB with the goal of identifying and developing recommendations for supporting this work at the local level. This report covers four general themes that were identified by the project team during the course of the study: The Importance of Teaching with Primary Sources, Learning to Teach with Primary Sources, Discovery and Access, and Physical Primary Sources and Collaboration

The identification of tyrosine as a common key residue in unrelated H-2Kd restricted antigenic peptides

we have compared the activity of several Kd-or Ld-restricted antigenic peptides as competitors in a functional competition assay using cytolytic T lymphocyte (CTL) clones. All of four unrelated Kd-restricted peptides tested could compete with each other but not with the Ld-restricted peptide P91A-.12-24 (P91A). Moreover, the P91A peptide falled to compete with the four Kd-restricted peptides. In contrast, another Ld-restricted peptide[mouse cytomegalovirus (MCMV) pp89 167-176] could clearly compete with both Kd- and Ld-restricted peptides. The comparison of a series of modified MCMV pp89 peptides suggested that distinct structural features allow the Interaction of the peptide with the two different MHC class I molecules. We showed previously that the competitor activity of two different Kd-restricted antigenic peptides was reduced substantially upon Ala substitution of the single Tyr residues present in these peptides. We now show a similar effect for two additional Kd-restricted peptides. Our results thus suggest that Tyr may function as an ‘anchor' residue for many antigentic peptides that bind to the Kdmolecule. Molecular modeling of the presumed antigen-binding site of the Kdmolecule revealed the presence of two deep cavities that may be involved in binding peptide amino acid side chains. A model Illustrating one possible interaction of a Tyr-containing peptide with the Kdmolecule is presente

Classic wisdom about ways to happiness: How does it apply today?

__Abstract__ Since we humans have some choice in how we live our lives, there has always been ideas about what constitutes a good life. Written reflections on that subject focus typically on moral issues, but there have always been ideas about what constitutes a satisfying life. Interest in this classic wisdom is increasing today, as part of the rising concern about happiness. This begs the question of what we can learn from this ancient wisdom. Does it hold universal truth? Or are these views specific for the historical conditions from which they emerged? In this paper I consider some classic beliefs about happiness and inspect how well these apply in contemporary society. The following five beliefs are considered: 1) Happiness is found in fame and power: follow the path of the warrior. 2) Happiness is found in wealth and involvement: follow the path of the merchant. 3) Happiness is found in intellectual development: follow the path of the philosopher. 4) Happiness is found in simplicity: follow the path of the peasant. 5) Happiness is not of this world: follow the path of the monk. Each of these ways to happiness will manifest in specific behaviors and attitudes and I inspected to what extent these go together with happiness today. To do this. I selected relevant research findings from the World Database of Happiness. The classic beliefs 1 and 2 seem to apply fairly well today, but 3 and 4 not. The advice to seek happiness in other-worldly detachment (5) may have been more sensible in the brutish conditions of feudal society, in which it emerged

Molecular modeling of an antigenic complex between a viral peptide and a class I major histocompatibility glycoprotein

Computer simulation of the conformations of short antigenic peptides (&lo residues) either free or bound to their receptor, the major histocompatibility complex (MHC)- encoded glycoprotein H-2 Ld, was employed to explain experimentally determined differences in the antigenic activities within a set of related peptides. Starting for each sequence from the most probable conformations disclosed by a pattern-recognition technique, several energyminimized structures were subjected to molecular dynamics simulations (MD) either in vacuo or solvated by water molecules. Notably, antigenic potencies were found to correlate to the peptides propensity to form and maintain an overall a-helical conformation through regular i,i + 4 hydrogen bonds. Accordingly, less active or inactive peptides showed a strong tendency to form i,i+3 hydrogen bonds at their Nterminal end. Experimental data documented that the C-terminal residue is critical for interaction of the peptide with H-2 Ld. This finding could be satisfactorily explained by a 3-D Q.S.A.R. analysis postulating interactions between ligand and receptor by hydrophobic forces. A 3-D model is proposed for the complex between a high-affinity nonapeptide and the H- 2 Ld receptor. First, the H-2 Ld molecule was built from X-ray coordinates of two homologous proteins: HLA-A2 and HLA-Aw68, energyminimized and studied by MD simulations. With HLA-A2 as template, the only realistic simulation was achieved for a solvated model with minor deviations of the MD mean structure from the X-ray conformation. Water simulation of the H-2 Ld protein in complex with the antigenic nonapeptide was then achieved with the template- derived optimal parameters. The bound peptide retains mainly its a-helical conformation and binds to hydrophobic residues of H-2 Ld that correspond to highly polymorphic positions of MHC proteins. The orientation of the nonapeptide in the binding cleft is in accordance with the experimentally determined distribution of its MHC receptor-binding residues (agretope residues). Thus, computer simulation was successfully employed to explain functional data and predicts a-helical conformation for the bound peptid

Reconstructing 3D x-ray CT images of polymer gel dosimeters using the zero-scan method

In this study x-ray CT has been used to produce a 3D image of an irradiated PAGAT gel sample, with noise-reduction achieved using the ‘zero-scan’ method. The gel was repeatedly CT scanned and a linear fit to the varying Hounsfield unit of each pixel in the 3D volume was evaluated across the repeated scans, allowing a zero-scan extrapolation of the image to be obtained. To minimise heating of the CT scanner’s x-ray tube, this study used a large slice thickness (1 cm), to provide image slices across the irradiated region of the gel, and a relatively small number of CT scans (63), to extrapolate the zero-scan image. The resulting set of transverse images shows reduced noise compared to images from the initial CT scan of the gel, without being degraded by the additional radiation dose delivered to the gel during the repeated scanning. The full, 3D image of the gel has a low spatial resolution in the longitudinal direction, due to the selected scan parameters. Nonetheless, important features of the dose distribution are apparent in the 3D x-ray CT scan of the gel. The results of this study demonstrate that the zero-scan extrapolation method can be applied to the reconstruction of multiple x-ray CT slices, to provide useful 2D and 3D images of irradiated dosimetry gels

CD8+ cytolytic T cell clones derived against the Plasmodium yoelii circumsporozoite protein protect against malaria

Immunization of BALB/c mice with radiation-attenuated Plasmodium yoelli sporozoites induces cytotoxic T lymphocytes (CTL) specific for an epitope located within the amlno acid sequence 277-288 of the P. yoellicircumsporozoite (CS) protein. Several CD8 + CTL clones were derived from the spleen cells of sporozolte-immunlzed mice, all displaying an apparently identical epitope specificity. All the clones Induced high levels of cytotysls in vitro upon exposure to peptide-incubated MHC-compatlble target cells. The adoptive transfer of two of these clones conferred complete protection against sporozotte challenge to naive mice. This protection Is species and stage specific. Using P. yoelli specific ribosomal RNA probes to monitor the in vivo effects of the CTL clones, we found that their target was the intrahepatocytic stage of the parasite. The protective clones completely Inhibited the development of the liver stages of P. yoelli Some CTL clones were only partially Inhibitory in vivo, while others failed completely to alter liver stage development and to confer any detectable degree of protection. The elucidation of the effector mechanism of this CTL mediated protection against rodent malaria should facilitate the design of an effective malaria vaccine. From a broader perspective this model may provide further insight into the mechanlsm(s) of CTL mediated killing of intracellular non-viral pathogens in genera