gebhart/patrepeval huggingface dataset:
Design, synthesis and biological evaluation of non-natural modulators of quorum sensing in Pseudomonas aeruginosa (2012)

Many species of bacteria employ a mechanism of intercellular communication known as quorum sensing which is mediated by small diffusible signalling molecules termed autoinducers. The most common class of autoinducer used by Gram-negative bacteria are N-acylated-L-homoserine lactones (AHLs). Pseudomonas aeruginosa is a clinically important bacterium which is known to use AHL-mediated quorum sensing systems to regulate a variety of processes associated with virulence. Thus the selective disruption of AHL-based quorum sensing represents a strategy to attenuate the pathogenicity of this bacterium. Herein we describe the design, synthesis and biological evaluation of a collection of structurally novel AHL mimics. A number of new compounds capable of modulating the LasR-dependent quorum sensing system of P. aeruginosa were identified, which could have value as molecular tools to study and manipulate this signalling pathway. Worthy of particular note, this research has delivered novel potent quorum sensing antagonists, which strongly inhibit the production of virulence factors in a wild type strain of this pathogenic bacterium.
A Phase I and Pharmacokinetic Study of TAS-108 in Postmenopausal Female Patients with Locally Advanced, Locally Recurrent Inoperable, or Progressive Metastatic Breast Cancer (2004)

TAS-108 was well tolerated in the doses studied with no maximum tolerated dose. The drug has linear pharmacokinetics, and in this heavily treated patient population, there was evidence of biological antitumor activity. A multi-institutional phase II study is planned.
Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice (1993)

To understand the role of TNF in the regulation of inflammation and the development of autoimmune diseases such as insulin-dependent diabetes mellitus, we produced transgenic mice in which the synthesis of murine TNF-alpha was directed by the rat insulin II promoter. The expression of the TNF-alpha transgene was restricted to the pancreas, in contrast to TNF-beta expression from the same promoter, in which the transgene was expressed in the pancreas, kidney, and skin. The expression of TNF-alpha in the pancreas of transgenic mice resulted in an overwhelming insulitis, composed of CD4+ and CD8+ T cells and B220+ B cells, considerably greater than that of TNF-beta transgenics. Moreover, in contrast to the predominant peri-insulitis observed in TNF-beta transgenic mice, the majority of the infiltrate in the TNF-alpha transgenic mice was within the islet itself. These unique patterns of infiltration were observed in the F1 progeny of crosses with C57BL/6 as well as NOD. Both TNF-alpha and TNF-beta transgenic mice show elevated expression of leukocyte adhesion molecules VCAM-1 and ICAM-1 in islet endothelia and increased expression of MHC class I on islet cells. This inflammation did not result in reduced insulin content of the islets, nor did it lead to diabetes. These data suggest that additional stimuli are necessary to initiate the process of islet destruction.
The Coupling of Neurotransmitter Receptors to Ion Channels in the Brain (1988)

Recent studies on the action of neurotransmitters on hippocampal pyramidal cells indicate that different neurotransmitter receptors that use either the same or different coupling mechanisms converge onto the same ion channel. Conversely, virtually all of the neurotransmitters act on at least two distinct receptor subtypes coupled to different ion channels on the same cell. The existence of both convergence and divergence in the action of neurotransmitters results in a remarkable diversity in neuronal signaling.
Observation of single-electron charging effects in small tunnel junctions (1987)

Unusual structure and large electric-field--induced oscillations have been observed in the current-voltage curves of small-area tunnel junctions arranged in a low-capacitance (\ensuremath{\lesssim}1 fF) multiple-junction configuration. This behavior arises from the tunneling of individual electrons charging and discharging the capacitance. The observations are in accord with what would be expected from a simple model of the charging energies and voltage fluctuations of e/C associated with such effects.
Characterization of bradyzoite-specific antigens of Toxoplasma gondii (1991)

Monoclonal antibodies that react specifically with bradyzoite antigens of Toxoplasma gondii were selected by differential immunofluorescence among hybridomas produced against these organisms. These antigens were further characterized by immunofluorescence on living bradyzoites and Western immunoblotting. Four pellicular antigens (36, 34, 21, and 18 kDa) were identified; three of these are exposed on the surface of the organism and accessible to either antibodies, trypsin cleavage, or both of these surface-probing procedures. These antigens were found on recent human isolates of T. gondii, as well as on laboratory strain bradyzoites obtained from either brain cysts or in vitro-grown parasites.
Books Online: Visions, Plans, and Perspectives for Electronic Text. (1991)

Vue d'ensemble sur les textes electroniques: definition du sujet traite, enjeux, technologie, normes et codage, copyright, acces, ergonomie, presentation de quelques projets
Current Production and Metal Oxide Reduction by <i>Shewanella oneidensis</i> MR-1 Wild Type and Mutants (2007)

Shewanella oneidensis MR-1 is a gram-negative facultative anaerobe capable of utilizing a broad range of electron acceptors, including several solid substrates. S. oneidensis MR-1 can reduce Mn(IV) and Fe(III) oxides and can produce current in microbial fuel cells. The mechanisms that are employed by S. oneidensis MR-1 to execute these processes have not yet been fully elucidated. Several different S. oneidensis MR-1 deletion mutants were generated and tested for current production and metal oxide reduction. The results showed that a few key cytochromes play a role in all of the processes but that their degrees of participation in each process are very different. Overall, these data suggest a very complex picture of electron transfer to solid and soluble substrates by S. oneidensis MR-1.
Coupled Decomposition of Four-Dimensional NOESY Spectra (2009)

Four-dimensional (4D) NOESY spectra provide unambiguous distance information at a resolution that cannot be achieved in fewer dimensions and thus increase the quality of biomolecular structure determination substantially. Since the degree of chemical shift degeneracy increases with protein size, the use of 4D NOESY spectra is particularly important for large proteins. The potential high resolution in 4D spectra cannot be achieved in a reasonable time with conventional acquisition routines that sample the Nyquist grid uniformly. It can, however, be obtained with nonuniform sampling of the data grid, but optimal processing of such data has not yet been established. Here we describe a processing method for a pair of sparsely sampled 4D NOESY spectra, a methyl-methyl and an amide-methyl NOESY, recorded on a perdeuterated protein with protonated isoleucine, leucine, and valine methyl groups. The coupled multidimensional decomposition (Co-MDD) of these two spectra together with a 2D template spectrum results in a substantial increase in sensitivity, evidenced by 50-100% additional cross peaks, when compared to alternative processing schemes. At the same time, Co-MDD allows the use of low sparse levels of 10-15% of the full data grid for NOESY spectra. For the 283-residue integral human membrane protein VDAC-1, which has a rotational correlation time of about 70 ns in detergent micelles, the two 4D Co-MDD NOESYs yielded a total of 366 NOEs, resulting in 139 unambiguous upper limit distance constraints for the structure calculation.
Rebiopsy of Lung Cancer Patients with Acquired Resistance to EGFR Inhibitors and Enhanced Detection of the T790M Mutation Using a Locked Nucleic Acid-Based Assay (2011)

The re-biopsy of lung cancer patients with acquired resistance is feasible and provides sufficient material for mutation analysis in most patients. Using high sensitivity methods, the T790M is detected in up to 68% of these patients.
Template synthesis of metal microtubules (1991)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTemplate synthesis of metal microtubulesCharles J. Brumlik and Charles R. MartinCite this: J. Am. Chem. Soc. 1991, 113, 8, 3174–3175Publication Date (Print):April 1, 1991Publication History Published online1 May 2002Published inissue 1 April 1991https://pubs.acs.org/doi/10.1021/ja00008a057https://doi.org/10.1021/ja00008a057research-articleACS PublicationsRequest reuse permissionsArticle Views1228Altmetric-Citations228LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Chemical Reagents for Protein Modification (2014)

The use of the chemical modification of proteins has evolved over the past 80 years, benefiting from advances in analytical, physical, and organic chemistry. Over the past 30 years, the use of chemical reagents to modify proteins has been crucial in determining the function and structure of purified proteins. This groundbreaking work is part of the
Plasmacytoid dendritic cells efficiently cross-prime naive T cells in vivo after TLR activation (2008)

Cross-presentation is a crucial mechanism in tumoral and microbial immunity because it allows internalized cell associated or exogenous antigens (Ags) to be delivered into the major histocompatibility complex I pathway. This pathway is important for the development of CD8(+) T-cell responses and for the induction of tolerance. In mice, cross-presentation is considered to be a unique property of CD8alpha+ conventional dendritic cells (DCs). Here we show that splenic plasmacytoid DCs (pDCs) efficiently capture exogenous Ags in vivo but are not able to cross-present these Ags at steady state. However, in vitro and in vivo stimulation by Toll-like receptor-7, or -9 or viruses licenses pDCs to cross-present soluble or particulate Ags by a transporter associated with antigen processing-dependent mechanism. Induction of cross-presentation confers to pDCs the ability to generate efficient effector CD8+ T-cell responses against exogenous Ags in vivo, showing that pDCs may play a crucial role in induction of adaptive immune responses against pathogens that do not infect tissues of hemopoietic origin. This study provides the first evidence for an in vivo role of splenic pDCs in Ag cross-presentation and T-cell cross-priming and suggests that pDCs may constitute an attractive target to boost the efficacy of vaccines based on cytotoxic T lymphocyte induction.
Hydrolysis of Platelet Activating Factor and Its Methylated Analogs by Acetylhydrolases1 (1988)

We examined the substrate specificity of PAF-degrading enzymes from various sources using platelet activating factor (PAF) and its synthetic analogs. The results were as follows: 1) Tissue-originated acetylhydrolases, such as rat kidney soluble enzyme, deacetylated 1S-methyl-1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (1S-Me-PAF) slightly more rapidly than PAF, whereas plasma acetylhydrolase hydrolyzed PAF more effectively than 1S-Me-PAF. 2) Rat polymorphonuclear leukocytes, monocytes, and lymphocytes homogenates showed an appreciable acetylhydrolase activity, the substrate specificity of which resembled that of the plasma enzyme. 3) Pleural exudates in an experimental pleurisy induced in rats by carrageenan contained an acetylhydrolase activity, the properties of which were similar to those of the plasma enzyme. 4) An extracellular phospholipase A2 activity, which was also observed in the pleural exudate and required Ca2+ ion for maximum activity, seemed not to participate in the deacetylation of PAF, since addition of EDTA did not affect the PAF deacetylation catalyzed by the pleural exudate. These findings indicate that the inactivation reaction of PAF present in the extracellular space is mainly catalyzed by plasma acetylhydrolase, which yields lysoPAF.
HIV Nef is Secreted in Exosomes and Triggers Apoptosis in Bystander CD4<sup>+</sup> T Cells (2009)

The HIV accessory protein negative factor (Nef) is one of the earliest and most abundantly expressed viral proteins. It is also found in the serum of infected individuals (Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C. Exosomal-like vesicles are present in human blood plasma. Int Immunol 2005;17:879-887). Extracellular Nef protein has deleterious effects on CD4(+) T cells (James CO, Huang MB, Khan M, Garcia-Barrio M, Powell MD, Bond VC. Extracellular Nef protein targets CD4(+) T cells for apoptosis by interacting with CXCR4 surface receptors. J Virol 2004;78:3099-3109), the primary targets of HIV, and can suppress immunoglobulin class switching in bystander B cells (Qiao X, He B, Chiu A, Knowles DM, Chadburn A, Cerutti A. Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nat Immunol 2006;7:302-310). Nevertheless, the mode of exit of Nef from infected cells remains a conundrum. We found that Nef stimulates its own export via the release of exosomes from all cells examined. Depending on its intracellular location, these Nef exosomes form at the plasma membrane, late endosomes or both compartments in Jurkat, SupT1 and primary T cells, respectively. Nef release through exosomes is conserved also during HIV-1 infection of peripheral blood lymphocytes (PBLs). Released Nef exosomes cause activation-induced cell death of resting PBLs in vitro. Thus, HIV-infected cells export Nef in bioactive vesicles, which facilitate the depletion of CD4(+) T cells that is a hallmark of acquired immunodeficiency syndrome (AIDS).
Evidence for Seed-Mediated Nucleation in the Chemical Reduction of Gold Salts to Gold Nanoparticles (2001)

Central to the concept of seed-mediated growth of nanoparticles is that small nanoparticle seeds serve as nucleation centers to grow nanoparticles to a desired size. We have examined this common assumption in a model system, the wet chemical synthesis of gold nanoparticles via reduction of a gold salt, by transmission electron microscopy and electronic absorption spectroscopy. We find that changing the seed concentration does affect the size of the product nanoparticles, but the method of reagent addition drastically affects the outcome even more. For fast addition of reducing agent, the presence of seeds appears to promote the formation of more seeds instead of growth. The observed nucleations are drastically enhanced (99%) compared to particle growth. For slow addition of reducing agent, the seeds do grow, but the product nanoparticle's degree of homogeneity in shape is compromised. For higher concentrations of seeds, nanoparticle growth is better controlled for slow addition of reducing agent compared to fast addition of reducing agent. We propose a mechanistic step to explain the commonly observed size distribution.
Clinical Overview of MDM2/X-Targeted Therapies (2016)

MDM2 and MDMX are the primary negative regulators of p53, which under normal conditions maintain low intracellular levels of p53 by targeting it to the proteasome for rapid degradation and inhibiting its transcriptional activity. Both MDM2 and MDMX function as powerful oncogenes and are commonly over-expressed in some cancers, including sarcoma (~20%) and breast cancer (~15%). In contrast to tumors that are p53 mutant, whereby the current therapeutic strategy restores the normal active conformation of p53, MDM2 and MDMX represent logical therapeutic targets in cancer for increasing wild-type (WT) p53 expression and activities. Recent preclinical studies suggest that there may also be situations that MDM2/X inhibitors could be used in p53 mutant tumors. Since the discovery of nutlin-3a, the first in a class of small molecule MDM2 inhibitors that binds to the hydrophobic cleft in the N-terminus of MDM2, preventing its association with p53, there is now an extensive list of related compounds. In addition, a new class of stapled peptides that can target both MDM2 and MDMX have also been developed. Importantly, preclinical modeling, which has demonstrated effective in vitro and in vivo killing of WT p53 cancer cells, has now been translated into early clinical trials allowing better assessment of their biological effects and toxicities in patients. In this overview, we will review the current MDM2- and MDMX-targeted therapies in development, focusing particularly on compounds that have entered into early phase clinical trials. We will highlight the challenges pertaining to predictive biomarkers for and toxicities associated with these compounds, as well as identify potential combinatorial strategies to enhance its anti-cancer efficacy.
Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants (2000)

Over 150 mutations within the coding sequence of the V2 vasopressin receptor (V2R) gene are known to cause nephrogenic diabetes insipidus (NDI). A large number of these mutant receptors fail to fold properly and therefore are not routed to the cell surface. Here we show that selective, nonpeptidic V2R antagonists dramatically increase cell-surface expression and rescue the function of 8 mutant NDI-V2Rs by promoting their proper folding and maturation. A cell-impermeant V2R antagonist could not mimic these effects and was unable to block the rescue mediated by a permeant agent, indicating that the nonpeptidic antagonists act intracellularly, presumably by binding to and stabilizing partially folded mutants. In addition to opening new therapeutic avenues for NDI patients, these data demonstrate that by binding to newly synthesized mutant receptors, small ligands can act as pharmacological chaperones, promoting the proper folding and maturation of receptors and their targeting to the cell surface.
Electron and Photon Beams from a 50 MeV Racetrack Microtron (1980)

The quality of broad high energy photon and electron beams can be improved considerably by the scanning of elementary narrow beams. Dose distributions produced in this way have advantages with respect to improved dose gradients and therapeutic ranges for electrons and lower surface doses, increased depth doses and half value depths for photons. The possibility of giving the whole therapeutic dose in a single local pulse of short duration is discussed as a new method to protect superficial tissues.
Targeting CD22 as a strategy for treating systemic autoimmune diseases. (2007)

B-cells play an important role in the diagnosis and to some extent the pathogenesis of many autoimmune diseases. Specific B-cell directed antibodies are now gaining an increasing role in the management of these diseases. The first antibody target in this regard was CD20, with the development and introduction of rituximab in the management of B-cell malignancies as well as rheumatoid arthritis. A second candidate target is CD22, and the first antagonistic antibody to this B-cell marker is epratuzumab, which appears to function, in contrast to CD20 antibodies, more by modulation of B-cells than by their depletion capacity. Originally developed for the treatment of non-Hodgkin lymphoma, epratuzumab has now been reported to be effective, with a very good safety profile, in two prototype autoimmune diseases, systemic lupus erythematosus and primary Sjögren's syndrome. As such, this new investigational antibody may provide distinct therapeutic effects and may be complementary to the known effects and role of CD20 antibodies.
A generic system for the <i>Escherichia coli</i> cell‐surface display of lipolytic enzymes (2005)

EstA is an outer membrane-anchored esterase from Pseudomonas aeruginosa. An inactive EstA variant was used as an anchoring motif for the Escherichia coli cell-surface display of lipolytic enzymes. Flow cytometry analysis and measurement of lipase activity revealed that Bacillus subtilis lipase LipA, Fusarium solani pisi cutinase and one of the largest lipases presently known, namely Serratia marcescens lipase were all efficiently exported by the EstA autotransporter and also retained their lipolytic activities upon cell surface exposition. EstA provides a useful tool for surface display of lipases including variant libraries generated by directed evolution thereby enabling the identification of novel enzymes with interesting biological and biotechnological ramifications.
Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma (2018)

These results suggest that a switchable CAR-T system is efficacious against aggressive and disseminated tumours derived from patients with advanced PDAC while affording the potential safety of a control switch.
Integrated microfluidic tmRNA purification and real-time NASBA device for molecular diagnostics (2008)

We demonstrate the first integrated microfluidic tmRNA purification and nucleic acid sequence-based amplification (NASBA) device incorporating real-time detection. The real-time amplification and detection step produces pathogen-specific response in < 3 min from the chip-purified RNA from 100 lysed bacteria. On-chip RNA purification uses a new silica bead immobilization method. On-chip amplification uses custom-designed high-selectivity primers and real-time detection uses molecular beacon fluorescent probe technology; both are integrated on-chip with NASBA. Present in all bacteria, tmRNA (10Sa RNA) includes organism-specific identification sequences, exhibits unusually high stability relative to mRNA, and has high copy number per organism; the latter two factors improve the limit of detection, accelerate time-to-positive response, and suit this approach ideally to the detection of small numbers of bacteria. Device efficacy was demonstrated by integrated on-chip purification, amplification, and real-time detection of 100 E. coli bacteria in 100 microL of crude lysate in under 30 min for the entire process.