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Institution

Torrey Pines Institute for Molecular Studies

NonprofitSan Diego, California, United States
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.


Papers
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Journal ArticleDOI
TL;DR: Conformationally defined combinatorial libraries were generated based on an 18-mer antimicrobial peptide known to be induced into an alpha-helical conformation in a lipidic environment and not only were novel sequences readily identified with 10-fold increases in activity, but detailed information about the structure-activity relationships of the peptides studied was also obtained during the deconvolution process.
Abstract: We have combined the strength of our synthetic combinatorial library approach for the rapid identification of highly active compounds with prior knowledge of the relationship between the antimicrobial activities of individual peptides with specific induced conformations in order to identify new peptides with enhanced activity relative to a starting known antimicrobial sequence In the current study, conformationally defined combinatorial libraries were generated based on an 18-mer antimicrobial peptide known to be induced into an alpha-helical conformation in a lipidic environment Not only were novel sequences readily identified with 10-fold increases in activity, but detailed information about the structure-activity relationships of the peptides studied was also obtained during the deconvolution process By using circular dichroism spectroscopy it was found that the individual 18-mer peptides could be induced into alpha-helical conformations on interaction with the cell lipid layer and/or sialic acids, which could result in bacterial cell lysis due to perturbation of the lipid packing of the cell wall

59 citations

Journal ArticleDOI
TL;DR: A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a b-annulated 1,4-dihydropyridine that inhibited transforming growth factor β (TGFβ)/Smad signaling by clearing the type II TGFβ receptor from the cell surface.
Abstract: A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a b-annulated 1,4-dihydropyridine (1,4-DHP) that inhibited transforming growth factor β (TGFβ)/Smad signaling by clearing the type II TGFβ receptor from the cell surface Because this is an unprecedented mechanism of action, we explored the series' structure-activity relationship (SAR) based on TGFβ inhibition, and evaluated SAR aspects for cell-surface clearance of TGFβ receptor II (TGFBR2) and for biological activity in mESCs We determined a pharmacophore and generated 1,4-DHPs with IC(50)s for TGFβ inhibition in the nanomolar range (eg, compound 28, 170 nM) Stereochemical consequences of a chiral center at the 4-position was evaluated, revealing 10- to 15-fold more potent TGFβ inhibition for the (+)- than the (-) enantiomer This stereopreference was not observed for the low level inhibition against Activin A signaling and was reversed for effects on calcium handling in HL-1 cells

59 citations

Journal ArticleDOI
TL;DR: The NOP-eGFP receptor was present in brain of homozygous knock-in animals in concentrations somewhat higher than in wild-type mice and was functional when tested for stimulation of GTPγS binding in vitro and in patch-clamp electrophysiology in dorsal root ganglia (DRG) neurons and hippocampal slices as discussed by the authors.
Abstract: The nociceptin/orphanin FQ (NOP) receptor, the fourth member of the opioid receptor family, is involved in many processes common to the opioid receptors including pain and drug abuse. To better characterize receptor location and trafficking, knock-in mice were created by inserting the gene encoding enhanced green fluorescent protein (eGFP) into the NOP receptor gene ( Oprl1 ) and producing mice expressing a functional NOP-eGFP C-terminal fusion in place of the native NOP receptor. The NOP-eGFP receptor was present in brain of homozygous knock-in animals in concentrations somewhat higher than in wild-type mice and was functional when tested for stimulation of [ 35 S]GTPγS binding in vitro and in patch-clamp electrophysiology in dorsal root ganglia (DRG) neurons and hippocampal slices. Inhibition of morphine analgesia was equivalent when tested in knock-in and wild-type mice. Imaging revealed detailed neuroanatomy in brain, spinal cord, and DRG and was generally consistent with in vitro autoradiographic imaging of receptor location. Multicolor immunohistochemistry identified cells coexpressing various spinal cord and DRG cellular markers, as well as coexpression with μ-opioid receptors in DRG and brain regions. Both in tissue slices and primary cultures, the NOP-eGFP receptors appear throughout the cell body and in processes. These knock-in mice have NOP receptors that function both in vitro and in vivo and appear to be an exceptional tool to study receptor neuroanatomy and correlate with NOP receptor function. SIGNIFICANCE STATEMENT The NOP receptor, the fourth member of the opioid receptor family, is involved in pain, drug abuse, and a number of other CNS processes. The regional and cellular distribution has been difficult to determine due to lack of validated antibodies for immunohistochemical analysis. To provide a new tool for the investigation of receptor localization, we have produced knock-in mice with a fluorescent-tagged NOP receptor in place of the native NOP receptor. These knock-in mice have NOP receptors that function both in vitro and in vivo and have provided a detailed characterization of NOP receptors in brain, spinal cord, and DRG neurons. They appear to be an exceptional tool to study receptor neuroanatomy and correlate with NOP receptor function.

59 citations

Journal ArticleDOI
TL;DR: Two new products containing living cells, Dermagraft and Apligraf, are expected to be approved shortly for diabetic foot ulcers and venous stasis ulcers, respectively, expected to revolutionise wound care and provide a platform for gene therapy applications.
Abstract: Biologically-based skin substitutes have developed as commercial products over the last 5 years. The first generation includes the collagen-based synthetic device, Integra, and Alloderm, which is based on devitalised and cross-linked human dermis. These are used as dermal replacements for third degree burns. Within the last year, the tissue-engineered product, Dermagraft-TC, has become available. While originally intended as a temporary covering for severe burns, Dermagraft-TC has proved to markedly improve the healing of deep second degree burns. The earliest living skin substitutes used autologous keratinocytes expanded in vitro. Two new products containing living cells, Dermagraft and Apligraf, are expected to be approved shortly for diabetic foot ulcers and venous stasis ulcers, respectively. Dermagraft is produced by growing human fibroblasts on a three-dimensional scaffold. The cells actively proliferate and lay down extracellular matrix to generate a papillary dermis-like device that shows a combination of angiogenic, growth factor and cell adhesion properties that enhance healing in diabetic foot ulcers. The production of Apligraf includes casting human fibroblasts in collagen, in order to generate a dermal equivalent on which is grown an epidermis. The structure is akin to a skin graft and is so applied. Despite Dermagraft and Apligraf being of allogeneic origin, rejection has not been an issue in clinical trials and possible contamination by pathogens has been eliminated as a concern through extensive testing. These developments represent a new concept and are expected to revolutionise wound care. They may also provide a platform for gene therapy applications.

59 citations

Journal ArticleDOI
TL;DR: It is concluded that the in vitro assay suggested that certain food dyes were carcinogens and that in vivo studies in hamsters supported this interpretation.
Abstract: Eight food dyes or commercial color mixtures certified for use in the United States were tested for their ability to transform in vitro a serial line of Fischer rat embryo cells previously reported to be a sensitive indicator of chemicals having carcinogenic potential. Malignant cell transformation was induced by a commercial mixture (G2024) of two of these dyes (Blue 1 and Yellow 5) and by Blue 2, Green 3 (one of two experiments) and Red 4. Food dyes Blue 1, Red 3, Yellow 5 and Yellow 6 did not induce cell transformation. One to 1.5 mg of each dye was injected into suckling LVG or Graffi hamsters which were monitored for tumor induction and/or death over a 330-day period. None of the non-transforming dyes (Blue 1, Red 3, Yellow 5, Yellow 6) or Green 3 induced a significant increase in tumor (mostly lymphoma) incidence or animal mortality. Three of the transforming dyes (Blue 2, Green 2024, Red 4) did increase tumor incidence and/or mortality in at least one strain of hamster. We conclude the the in vitro assay suggested that certain food dyes were carcinogens and that in vivo studies in hamsters supported this interpretation.

58 citations


Authors

Showing all 2327 results

NameH-indexPapersCitations
Eric J. Topol1931373151025
John R. Yates1771036129029
George F. Koob171935112521
Ian A. Wilson15897198221
Peter G. Schultz15689389716
Gerald M. Edelman14754569091
Floyd E. Bloom13961672641
Stuart A. Lipton13448871297
Benjamin F. Cravatt13166661932
Chi-Huey Wong129122066349
Klaus Ley12949557964
Nicholas J. Schork12558762131
Michael Andreeff11795954734
Susan L. McElroy11757044992
Peter E. Wright11544455388
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
20235
202210
202153
202060
201950
201842