Torrey Pines Institute for Molecular Studies

About: Torrey Pines Institute for Molecular Studies is a nonprofit organization based out in San Diego, California, United States. It is known for research contribution in the topics: T cell & Antigen. The organization has 2323 authors who have published 2217 publications receiving 112618 citations.

The Response to Forced Decompression in Six Species of Pacific Rockfish

Abstract: Pacific rockfish experience high discard mortality when captured owing to a condition called barotrauma, which is caused by the change in pressure during capture This condition appears to be species specific at the macroscopic level; however, little is known about the microscopic tissue-level effects of barotrauma Determining whether tissue-level injuries are also species specific or influenced by factors such as life history and phylogenetic relatedness can improve our management of discard mortality We evaluated the responses of six species of Pacific rockfish (black rockfish Sebastes melanops, blue rockfish S mystinus, yellowtail rockfish S flavidus, quillback rockfish S maliger, canary rockfish S pinniger, and yelloweye rockfish S ruberrimus) captured from varying depths to forced decompression at the histological level (heart ventricle, rete mirabile, head kidney, liver, gill, and eye) as well as the macroscopic level At the macroscopic level we focused on injuries caused by barotra

Inhibitors of DNA Methyltransferases: Insights from Computational Studies

Abstract: DNA methyltransferases (DNMTs) are a family of epigenetic enzymes for which inhibition is an attractive strategy for the treatment of cancer and other diseases. In synergy with experimental approaches, computational methods are increasingly being used to identify and optimize the activity of inhibitors of DNMTs as well as to rationalize at the molecular level of the mechanism of established inhibitors. Recently, a crystallographic structure of the methyltransferase domain of human DNMT1 bound to unmethylated DNA was published encouraging the application of structure-based approaches to design and optimize the activity of currently known inhibitors. Herein, we review the progress in the discovery and optimization of inhibitors of DNMTs using computational approaches including homology modeling, docking, pharmacophore modeling, molecular dynamics, and virtual screening.

Modeling of peptides containing D-amino acids: implications on cyclization

Abstract: Cyclic peptides are therapeutically attractive due to their high bioavailability, potential selectivity, and scaffold novelty. Furthermore, the presence of D-residues induces conformational preferences not followed by peptides consisting of naturally abundant L-residues. Therefore, comprehending how amino acids induce turns in peptides, subsequently facilitating cyclization, is significant in peptide design. Here, we performed 20-ns explicit-solvent molecular dynamics simulations for three diastereomeric peptides with stereochemistries: LLLLL, LLLDL, and LDLDL. Experimentally LLLLL and LDLDL readily cyclize, whereas LLLDL cyclizes in low yield. Simulations at 310 K produced conformations with inter-terminal hydrogen bonds that correlated qualitatively with the experimental cyclization trend. Energies obtained for representative structures from quantum chemical (B3LYP/PCM/cc-pVTZ//HF/6-31G*) calculations predicted pseudo-cyclic and extended conformations as the most stable for LLLLL and LLLDL, respectively, in agreement with the experimental data. In contrast, the most stable conformer predicted for peptide LDLDL was not a pseudo-cyclic structure. Moreover, D-residues preferred the experimentally less populated αL rotamers even when simulations were performed at a higher temperature and with strategically selected starting conformations. Energies calculated with molecular mechanics were consistent only with peptide LLLLL. Thus, the conformational preferences obtained for the all L-amino acid peptide were in agreement with the experimental observations. Moreover, refinement of the force field is expected to provide far-reaching conformational sampling of peptides containing D-residues to further develop force field-based conformational-searching methods.

Dendritic Cells Use Endocytic Pathway for Cross-Priming Class Ib MHC-Restricted CD8αα+TCRαβ+ T Cells with Regulatory Properties

Abstract: Understanding the mechanisms leading to effective priming of lymphocytes with regulatory properties is crucial for the manipulation of immune responses. CD8αα + TCRαβ + T cells are a special subset of innate-like lymphocytes that have been shown to be involved in immune regulation. These cells can recognize self-peptides in the context of a class Ib molecule, Qa-1. How self-Ags are processed in the Qa-1 pathway and presented to CD8αα + TCRαβ + T cells is not understood. In this study we demonstrate a cross-presentation pathway by which bone marrow-derived dendritic cells (DCs) capture apoptotic CD4 + T cells and process and present TCR-derived peptides in the context of Qa-1 to prime CD8αα + TCRαβ + T cells. The priming ability of the DCs is enhanced following TLR signaling using TLR3, TLR4, and TLR9 agonists. DC-mediated cross-presentation is inhibited in the presence of endosomal and proteasomal Ag-processing antagonists. Importantly, DCs loaded with apoptotic T cells prime CD8αα + TCRαβ + T cells in vivo, which in turn provides protection from CD4 + T cell-mediated autoimmune disease. These data provide a key insight related to processing and presentation of self-Ags in the Qa-1 pathway for priming of CD8αα + TCRαβ + T cells and have implications for a DC-based immunotherapeutic approach to inflammatory diseases.

National Athletic Trainers' Association Position Statement: Management of Individuals With Patellofemoral Pain.

Abstract: Objective: To present recommendations for athletic trainers and other health care providers regarding the identification of risk factors for and management of individuals with patellofemoral pain ...