gebhart/patrepeval huggingface dataset:
Memory systems in normal and pathological aging (1994)

Normal memory depends on a number of interdependent systems whose specialized contributions are dissociable at both cognitive and neurobiological levels of analysis. Guided by this multiple systems view of memory, this review provides a selective survey of recent studies on cognitive and neurobiological aging. Taken together, the results suggest that memory decline in human aging partly reflects a compromise of executive memory processes supported by frontal lobe regions of the brain, combined with a deterioration of explicit memory capacities supported by the hippocampal system. Defining how deficits in multiple memory systems interact to account for cognitive aging remains a significant challenge.
Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye (2012)

LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1/ICAM-1 antagonists could be an effective topical treatment for dry eye. In this letter, we describe the discovery of a potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonist (SAR 1118) and its development as an ophthalmic solution for treating dry eye.
Identification and Analysis of Mouse Erythroid Progenitors using the CD71/TER119 Flow-cytometric Assay (2011)

The study of erythropoiesis aims to understand how red cells are formed from earlier hematopoietic and erythroid progenitors. Specifically, the rate of red cell formation is regulated by the hormone erythropoietin (Epo), whose synthesis is triggered by tissue hypoxia. A threat to adequate tissue oxygenation results in a rapid increase in Epo, driving an increase in erythropoietic rate, a process known as the erythropoietic stress response. The resulting increase in the number of circulating red cells improves tissue oxygen delivery. An efficient erythropoietic stress response is therefore critical to the survival and recovery from physiological and pathological conditions such as high altitude, anemia, hemorrhage, chemotherapy or stem cell transplantation. The mouse is a key model for the study of erythropoiesis and its stress response. Mouse definitive (adult-type) erythropoiesis takes place in the fetal liver between embryonic days 12.5 and 15.5, in the neonatal spleen, and in adult spleen and bone marrow. Classical methods of identifying erythroid progenitors in tissue rely on the ability of these cells to give rise to red cell colonies when plated in Epo-containing semi-solid media. Their erythroid precursor progeny are identified based on morphological criteria. Neither of these classical methods allow access to large numbers of differentiation-stage-specific erythroid cells for molecular study. Here we present a flow-cytometric method of identifying and studying differentiation-stage-specific erythroid progenitors and precursors, directly in the context of freshly isolated mouse tissue. The assay relies on the cell-surface markers CD71, Ter119, and on the flow-cytometric 'forward-scatter' parameter, which is a function of cell size. The CD71/Ter119 assay can be used to study erythroid progenitors during their response to erythropoietic stress in vivo, for example, in anemic mice or mice housed in low oxygen conditions. It may also be used to study erythroid progenitors directly in the tissues of genetically modified adult mice or embryos, in order to assess the specific role of the modified molecular pathway in erythropoiesis.
The Enediyne Antibiotics (1996)

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTThe Enediyne AntibioticsAdrian L. Smith and K. C. NicolaouView Author Information Departments of Chemistry, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, California 92037, and University of California, San Diego, La Jolla, California 92093Cite this: J. Med. Chem. 1996, 39, 11, 2103–2117Publication Date (Web):May 24, 1996Publication History Received11 January 1996Published online24 May 1996Published inissue 1 January 1996https://pubs.acs.org/doi/10.1021/jm9600398https://doi.org/10.1021/jm9600398review-articleACS PublicationsCopyright © 1996 American Chemical SocietyRequest reuse permissionsArticle Views3897Altmetric-Citations324LEARN 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 SUBJECTS:Antimicrobial agents,Chromophores,Crystal cleavage,Genetics,Toxicity Get e-Alerts
Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85‐8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases (2015)

Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease-anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.
Identification, Cloning, and Characterization of Cystatin M, a Novel Cysteine Proteinase Inhibitor, Down-regulated in Breast Cancer (1997)

A novel human cystatin gene was identified in a differential display comparison aimed at the isolation of transcriptionally regulated genes involved in invasion and metastasis of breast cancer. Messenger RNAs from primary and metastatic tumor cells isolated from the same patient were compared. A partial cDNA was isolated that was expressed in the primary tumor cell line but not in the metastatic line. The full-length cDNA was cloned and sequenced, and the inferred amino acid sequence was found to encode a novel protein, which we named cystatin M, with 40% homology to human family 2 cystatins and similar overall structure. Cystatin M is expressed by normal mammary cells and a variety of human tissues. The mature cystatin M protein was produced in Escherichia coli as a glutathione S-transferase fusion protein using the pGEX-2T expression system and purified by affinity chromatography. The cystatin M fusion protein displayed inhibitory activity against papain. Native cystatin M protein of approximately 14.5 kDa is secreted and was immunoprecipitated from supernatants of mammary cell cultures using affinity-purified antisera raised against recombinant cystatin M. An N-glycosylated form of cystatin M of 20-22 kDa was co-immunoprecipitated and accounted for about 30-40% of total cystatin M protein. Both forms of native cystatin M also occurred intracellularly. Consistent with the mRNA differential expression, no cystatin M protein was detected in metastatic mammary epithelial tumor cells. Loss of expression of cystatin M is likely associated with the progression of a primary tumor to a metastatic phenotype.
Platinum-Intercalator Conjugates: From DNA-Targeted Cisplatin Derivatives to Adenine Binding Complexes as Potential Modulators of Gene Regulation (2004)

Nuclear DNA is the cellular target for many cancer treatments, and DNA-directed chemotherapies continue to play an important role in drug discovery in the postgenomic era. The majority of DNA-targeted anticancer agents bind through covalent interactions, non-covalent intercalation or groove binding, or hybrid binding modes. The sequence and regiospecificity of these interactions and the resulting structural alterations within the biopolymer play an important role in the mechanism of action of these drugs. DNA-binding proteins and/or DNA-processing enzymes, which also interact with DNA in a sequence- and groove-specific manner, are mediators of the cytotoxic effect produced by these agents. Thus one major goal in the design of new clinical agents of this type is to produce new types of adducts on DNA, which may lead to unprecedented cell kill mechanisms. Platinum-intercalator conjugates are such a class of hybrid agents acting through a dual DNA binding mode. The platinum center (usually a cis-diaminedichloroPt(II) unit) dominates the DNA adduct profiles in the majority of these species-the result of the metal's tendency to form cross-links in runs of consecutive guanine bases in the major groove of DNA. This paradigm has been broken recently for the first time with the design of cytotoxic platinum-acridinylthiourea conjugates, a class of adenine-affinic minor-groove directed agents. This review summarizes major advancements in the chemistry and biology of platinum-intercalators from 1984 to 2004, with emphasis being placed on the interplay between chemical structure, mechanism of DNA binding, and biological properties.
Significance of Tyrosine Kinase Inhibitors in the Treatment of Metastatic Breast Cancer (2009)

Preclinical and clinical trials suggest that tyrosine kinase inhibitors (TKI) could supplement current therapies in metastatic breast cancer (MBC). HER-2 inhibition is still a main focus. Numerous agents targeting the epidermal growth factor receptors EGFR and HER-2 are currently tested after previous trastuzumab treatment. Lapatinib targets HER-2 and EGFR. As monotherapy, clinical activity was low. Combined with cytotoxic agents, lapatinib showed good activity (overall response rate (ORR) 24-27%) and moderate toxicity. Neratinib, a pan-ErbB TKI, showed an ORR of 26%. Neratinib combined with trastzumab was well tolerated and active (ORR = 27%). After bevacizumab's proof-of-concept studies, anti-angiogenesis remains of importance. Sunitinib inhibits the vascular endothelial growth factor receptor (VEGFR), the platelet-derived growth factor receptor (PDGFR), c-kit and the colony-stimulating factor 1 (CSF-1) receptor. Monotherapy is tolerated and moderately active in MBC. Combination trials are ongoing. Toxicities of docetaxel ± sunitinib were manageable (ORR 72.2%). Pazopanib targets VEGFR, PDGFR and c-kit. Pazopanib ± lapatinib was superior in combination (progression-free survival (PFS) = 27% vs. 19%). Axitinib has similar targets. Combined with docetaxel, it was superior compared to placebo (ORR 40% vs. 23%), with manageable toxicity. Imatinib inhibits PDGFR and c-kit. As monotherapy, it showed no clinical activity. Combination trials with chemotherapy are ongoing.
Design of New Chiral Phase-Transfer Catalysts with Dual Functions for Highly Enantioselective Epoxidation of α,β-Unsaturated Ketones (2004)

A new chiral ammonium bromide, 1-Br, possessing diarylmethanol functionality as a substrate recognition site has been designed as a promising, dual-functioning catalyst for the highly enantioselective epoxidation of alpha,beta-unsaturated ketones under mild phase-transfer conditions. For instance, vigorous stirring of a mixture of chalcone, 1-Br (3 mol %), and 13% NaOCl in toluene at 0 degrees C for 24 h gave rise to epoxy chalcone quantitatively with 96% ee. A variety of alpha,beta-unsaturated ketones can also be epoxidized with rigorous stereochemical control, clearly demonstrating the effectiveness and utility of the present system. Further, a successful single-crystal X-ray diffraction analysis of 1-PF6 uncovered its distinctive three-dimensional molecular architecture and provided useful information for postulating the transition state.
Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. (2003)

SU11248 is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities through targeting platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and FLT3, the first three of which are expressed in human breast cancer and/or its supporting tissues. The purpose of the present studies was to demonstrate the potent anticancer activity of SU11248 alone or in combination with conventional cytotoxic agents against several distinct preclinical models of breast cancer. SU11248 was administered as a monotherapy to (1) mouse mammary tumor virus-v-Ha-ras mice and 7,12-dimethylbenz(a)anthracene-treated rats bearing mammary tumors and (2) mice bearing human breast cancer xenografts of s.c. MX-1 tumors and osseous metastasis of a MDA-MB-435-derived cell line (435/HAL-Luc). SU11248 was also administered in combination with docetaxel both in xenograft models and in combination with 5-fluorouracil and doxorubicin in the MX-1 model. SU11248 treatment potently regressed growth of mammary cancers in mouse mammary tumor virus-v-Ha-ras transgenic mice (82% regression) and 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats (99% regression at the highest dose; P < 0.05 for both). This agent also inhibited MX-1 tumor growth by 52%, with markedly enhanced anticancer effects when administered in combination with docetaxel, 5-fluorouracil, or doxorubicin compared with either agent alone (P < 0.05). SU11248 treatment in combination with docetaxel effectively prolonged survival of mice, with 435/HAL-Luc cancer xenografts established in bone compared with either agent alone (P < 0.05). These results demonstrate that SU11248 is effective in preclinical breast cancer models and suggest that it may be useful in the treatment of breast cancer in the clinic.
E-Cadherin Regulates Neural Stem Cell Self-Renewal (2009)

E-Cadherin, a cell adhesion protein, has been shown to take part in the compartmentalization, proliferation, survival, and differentiation of cells. E-Cadherin is expressed in the adult and embryonic forebrain germinal zones in vivo, and in clonal colonies of cells derived from these regions and grown in vitro. Mice carrying E-Cadherin floxed genes crossed to mice expressing Cre under the Nestin promoter demonstrate defects in the self-renewal of neural stem cells both in vivo and in vitro. The functional role of E-Cadherin is further demonstrated using adhesion-blocking antibodies in vitro, which specifically target cadherin extracellular adhesive domains. Adult neural stem cell colonies decrease in the presence of E-Cadherin antibodies in a dosage-dependent manner, in contrast to P-Cadherin antibody. On overexpression of normal E-Cadherin and a mutated E-Cadherin, containing no intracellular binding domain, an increased number of clonal adult neural stem cell colonies are observed. These data suggest it is specifically E-Cadherin adhesion that is responsible for these self-renewal effects. These data show the importance of E-Cadherin in the neural stem cell niche and suggest E-Cadherin regulates the number of these cells.
Functional and Molecular Characterization of a Monoclonal Antibody against the 165–186 Peptide of Human 1β (1989)

A synthetic peptide of human recombinant interleukin 1 beta (hrIL-1 beta) 165-186, which exhibits biological activity in the human fibroblast assay, was used as an immunizing antigen to obtain a murine monoclonal antibody (MoAb) termed FIB 1. This MoAb, an IgG1, reacts specifically with hrIL-1 beta, but not with hrIL-1 alpha, as measured in enzyme-linked immunosorbent assays (ELISA). The MoAb FIB 1 detects the characteristic 17 kDa IL-1 protein in Western blots. Binding to the antigen is specific, as deduced also from the close correlation of ELISA immunoreactivity with IL-1 biological activity. The anti-IL-1 beta 165-186 Ab specifically neutralizes the biological activity of hrIL-1 beta and native IL-1, as measured by the IL-1-induced proliferation of murine thymocytes and human fibroblasts and the IL-1-dependent IL-2 production by murine T cells (EL4-6.1). Fifty per cent of hrIL-1 beta activity (25 U/ml, or 0.25 ng/ml) has neutralized by less than 30 micrograms/ml of MoAb. Furthermore, FIB 1 recognizes intracellular IL-1 in lipopolysaccharide-stimulated human peripheral blood mononuclear cells. The anti-IL-1 beta 165-186 Ab does not react with the shorter IL-1 beta fragment 161-173 in solid-phase ELISA, therefore the binding region seems to be localized in the amino acid sequence VALGLKEKNLYLS. A sandwich-ELISA, using a polyclonal sheep anti-IL-1 beta 251-269 Ab as the capture antibody and an anti-IL-1 beta 165-186 MoAb as the detecting probe, allowed the determination of IL-1 beta from crude culture supernatants.
Nucleotide sequence of the lipoamide dehydrogenase gene of Escherichia coli K12 (1983)

The nucleotide sequence of a 1980-base-pair segment of DNA, containing the lpd gene encoding the lipoamide dehydrogenase component (E3) of the pyruvate dehydrogenase complex of Escherichia coli K12, has been determined by the dideoxy chain-termination method. The lpd structural gene comprises 1419 base pairs (473 codons, excluding the initiating AUG codon). It is preceded by a good promoter and an excellent ribosome binding site and it ends with a typical rho-independent terminator sequence. The results confirm that the lpd gene is an independent gene linked to, but not part of, the ace operon that encodes the E1 and E2 components of the pyruvate dehydrogenase complex. The location and transcriptional polarity of the lpd gene relative to the restriction map of the corresponding region of DNA, are completely consistent with previous genetic and post-infection labelling studies. The composition, Mr (50554 or 51274 if the FAD cofactor is included), amino-terminal sequence and carboxy-terminal sequence predicted from the nucleotide sequence are in excellent agreement with previous studies on the purified enzyme. The enzyme also exhibits a remarkable degree of sequence homology with peptides of the pig heart enzyme and with other pyridine nucleotide disulphide oxidoreductases whose sequences have been defined: human erythrocyte glutathione reductase and plasmid-encoded mercuric reductase.
Supramolecular Coordination: Self-Assembly of Finite Two- and Three-Dimensional Ensembles (2011)

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTSupramolecular Coordination: Self-Assembly of Finite Two- and Three-Dimensional EnsemblesRajesh Chakrabarty*†, Partha Sarathi Mukherjee*‡, and Peter J. Stang*†View Author Information† Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States‡ Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, IndiaE-mail: [email protected] (R.C.); [email protected] (P.J.S.); and [email protected] (P.S.M.)Cite this: Chem. Rev. 2011, 111, 11, 6810–6918Publication Date (Web):August 24, 2011Publication History Received12 March 2011Published online24 August 2011Published inissue 9 November 2011https://pubs.acs.org/doi/10.1021/cr200077mhttps://doi.org/10.1021/cr200077mreview-articleACS PublicationsCopyright © 2011 American Chemical SocietyRequest reuse permissionsArticle Views47089Altmetric-Citations2581LEARN 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 SUBJECTS:Cavities,Ligands,Metals,Self organization,Supramolecular structures and assemblies Get e-Alerts
Non‐invasive probing of pharmaceutical capsules using transmission Raman spectroscopy (2007)

Abstract We demonstrate how transmission Raman geometry can be effectively used for non‐invasive probing of the content of pharmaceutical capsules. This approach is particularly beneficial in situations where the conventional Raman backscattering method is hampered or fails because of excessive surface Raman or fluorescence signals emanating from the capsule shell material, which pollute the much weaker subsurface Raman signals with undesired noise. It is demonstrated that such interfering signals can be effectively suppressed by the transmission geometry. The ability to avoid surface fluorescence and Raman signals in conjunction with the superior, bulk‐probing properties of the transmission Raman geometry provides an analytical technique ideally suited for fast on‐line process control monitoring applications in pharmaceutical industry where rapid, chemically specific bulk analysis is required. Copyright © 2007 John Wiley &amp; Sons, Ltd.