gebhart/patrepeval huggingface dataset:
Acceleration of Age-Related Hearing Loss by Early Noise Exposure: Evidence of a Misspent Youth (2006)

Age-related and noise-induced hearing losses in humans are multifactorial, with contributions from, and potential interactions among, numerous variables that can shape final outcome. A recent retrospective clinical study suggests an age-noise interaction that exacerbates age-related hearing loss in previously noise-damaged ears (Gates et al., 2000). Here, we address the issue in an animal model by comparing noise-induced and age-related hearing loss (NIHL; AHL) in groups of CBA/CaJ mice exposed identically (8-16 kHz noise band at 100 dB sound pressure level for 2 h) but at different ages (4-124 weeks) and held with unexposed cohorts for different postexposure times (2-96 weeks). When evaluated 2 weeks after exposure, maximum threshold shifts in young-exposed animals (4-8 weeks) were 40-50 dB; older-exposed animals (> or =16 weeks) showed essentially no shift at the same postexposure time. However, when held for long postexposure times, animals with previous exposure demonstrated AHL and histopathology fundamentally unlike unexposed, aging animals or old-exposed animals held for 2 weeks only. Specifically, they showed substantial, ongoing deterioration of cochlear neural responses, without additional change in preneural responses, and corresponding histologic evidence of primary neural degeneration throughout the cochlea. This was true particularly for young-exposed animals; however, delayed neuropathy was observed in all noise-exposed animals held 96 weeks after exposure, even those that showed no NIHL 2 weeks after exposure. Data suggest that pathologic but sublethal changes initiated by early noise exposure render the inner ears significantly more vulnerable to aging.
GSK3β Activity Modifies the Localization and Function of Presenilin 1 (2007)

Presenilin 1, a causative gene product of familial Alzheimer disease, has been reported to be localized mainly in the endoplasmic reticulum and Golgi membranes. However, endogenous Presenilin 1 also localizes at the plasma membrane as a biologically active molecule. Presenilin 1 interacts with N-cadherin/beta-catenin to form a trimeric complex at the synaptic site through its loop domain, whose serine residues (serine 353 and 357) can be phosphorylated by glycogen synthase kinase 3beta. Here, we demonstrate that cell-surface expression of Presenilin 1/gamma-secretase is enhanced by N-cadherin-based cell-cell contact. Physical interaction between Presenilin 1 and N-cadherin/beta-catenin plays an important role in this process. Glycogen synthase kinase 3beta-mediated phosphorylation of Presenilin 1 reduces its binding to N-cadherin, thereby down-regulating its cell-surface expression. Moreover, reduction of the Presenilin 1.N-cadherin.beta-catenin complex formation leads to an impaired activation of contact-mediated phosphatidylinositol 3-kinase/Akt cell survival signaling. Furthermore, phosphorylation of Presenilin 1 hinders epsilon-cleavage of N-cadherin, whereas epsilon-cleavage of APP remained unchanged. This is the first report that clarifies the regulatory mechanism of Presenilin 1/gamma-secretase with respect to its subcellular distribution and its differential substrate cleavage. Because the cleavage of various membrane proteins by Presenilin 1/gamma-cleavage is involved in cellular signaling, glycogen synthase kinase 3beta-mediated phosphorylation of Presenilin 1 should be deeply associated with signaling functions. Our findings indicate that the abnormal activation of glycogen synthase kinase 3beta can reduce neuronal viability and synaptic plasticity via modulating Presenilin 1/N-cadherin/beta-catenin interaction and thus have important implications in the pathophysiology of Alzheimer disease.
Thy1-Expressing Neurons in the Basolateral Amygdala May Mediate Fear Inhibition (2013)

Research has identified distinct neuronal circuits within the basolateral amygdala (BLA) that differentially mediate fear expression versus inhibition; however, molecular markers of these populations remain unknown. Here we examine whether optogenetic activation of a cellular subpopulation, which may correlate with the physiologically identified extinction neurons in the BLA, would differentially support fear conditioning versus fear inhibition/extinction. We first molecularly characterized Thy1-channelrhodopsin-2 (Thy1-ChR2-EYFP)-expressing neurons as a subpopulation of glutamatergic pyramidal neurons within the BLA. Optogenetic stimulation of these neurons inhibited a subpopulation of medial central amygdala neurons and shunted excitation from the lateral amygdala. Brief activation of these neurons during fear training disrupted later fear memory in male mice. Optogenetic activation during unreinforced stimulus exposure enhanced extinction retention, but had no effect on fear expression, locomotion, or open-field behavior. Together, these data suggest that the Thy1-expressing subpopulation of BLA pyramidal neurons provide an important molecular and pharmacological target for inhibiting fear and enhancing extinction and for furthering our understanding of the molecular mechanisms of fear processing.
p185c-erbB-2 signal enhances cisplatin-induced cytotoxicity in human breast carcinoma cells: association between an oncogenic receptor tyrosine kinase and drug-induced DNA repair. (1994)

The c-erbB-2 (HER-2/neu) protooncogene encodes an M(r) 185,000 transmembrane glycoprotein with intrinsic tyrosine kinase activity. Agonistic antibodies against p185c-erbB-2 enhance the cytotoxic effect of the DNA alkylator, cisplatin, against c-erbB-2-overexpressing human carcinoma cells (Hancock et al., Cancer Res., 51:4575-4580, 1991). We have studied the possible association between receptor signal transduction and cisplatin-mediated cytotoxicity utilizing the SKBR-3 human breast cancer cell line and the anti-p185 TAb 250 IgG1. TAb 250 induced tyrosine phosphorylation of p185 and the receptor substrate phospholipase C-gamma 1, as well as rapid association of these molecules in vivo. Simultaneously with phosphorylation, phospholipase C-gamma 1 catalytic activity measured in a [3H]phosphatidylinositol-4,5-bisphosphate hydrolysis assay was increased 61 +/- 12% above control. Preincubation of SKBR-3 cells with the tyrosine kinase inhibitor tyrphostin 50864-2 abrogated the enhancement of drug-mediated cell kill induced by TAb 250. The supraadditive drug/antibody effect was not seen in SKBR-3 cells with TAb 263, an anti-p185 IgG1 that does not induce receptor signaling or with TAb 250 in MDA-468 breast cancer cells which do not overexpress c-erbB-2. In addition, transforming growth factor-alpha increased cisplatin-induced cytotoxicity against NIH 3T3 cells overexpressing an epidermal growth factor receptor/c-erbB-2 chimera. Cellular uptake or efflux of [195mPt]cisplatin by SKBR-3 cells was not altered by TAb 250. Finally, simultaneous treatment of SKBR-3 cells with TAb 250 and cisplatin increased cisplatin/DNA intrastrand adduct formation and delayed the rate of adduct decay. Taken together these data support a direct association between p185c-erbB-2 signal transduction and inhibition of cisplatin-induced DNA repair.
A Liquid Chromatography−Tandem Mass Spectrometry Multiresidue Method for Quantification of Specific Metabolites of Organophosphorus Pesticides, Synthetic Pyrethroids, Selected Herbicides, and DEET in Human Urine (2004)

The ability to estimate low-dose human exposure to commonly used pesticides often is requested in epidemiologic studies. Therefore, fast and robust methods are necessary that can measure many analytes in the same sample. We have developed a method for high-throughput analysis of 19 markers of commonly used pesticides in human urine. The analytes were seven specific metabolites of organophosphorus pesticides, five metabolites of synthetic pyrethroids, six herbicides or their metabolites, and one insect repellant. Human urine (2 mL) was spiked with stable isotopically labeled analogues of the analytes, enzymatically hydrolyzed, extracted using solid-phase extraction, concentrated, and analyzed using high-performance liquid chromatography-tandem mass spectrometry. The sample was divided into two portions and analyzed on two different mass spectrometers, one using atmospheric pressure chemical ionization (APCI) and the other using turbo ion spray atmospheric pressure ionization (TIS). All analytes except the pyrethroid metabolites were analyzed using APCI. The detection limits for all analytes ranged from 0.1 to 1.5 ng/mL of urine, with the majority (17) below 0.5 ng/mL. The analytical precision for the different analytes, estimated as both the within-day and between-day variation, was 3-14 and 4-19%, respectively. The extraction recoveries of the analytes ranged from 68 to 114%. The throughput, including calibration standards and quality control samples, is approximately 50 samples a day. However, the analysis time with the TIS application is much shorter, and if only pyrethroid metabolite data are of interest, the throughput can be increased to 100-150 samples/day.
Optical Frequency Domain Reflectometry for Single- and Multi-Mode Avionics Fiber-Optics Applications (2006)

In this talk, we will introduce a commercially available optical frequency domain reflectometry (OFDR) technique and its applications in avionics fiber-optics. We will provide multiple measurement examples within the avionics field not currently supported by conventional test tools or methods including high-resolution fault detection and distributed fiber sensing
Sorting Out Breast-Cancer Gene Signatures (2007)

The advent of technology for the analysis of human tissue samples for the activity of the entire genome initiated a quest for the molecular profiling of tumors. The aim of this quest was a better system for classifying cancers, a clarification of the origin of these diseases, a more accurate prognostic capacity than was previously available, and an improved ability to choose among possible therapies. Progress in the molecular profiling of solid tumors began with the identification of sets of genes whose expression can be used to classify breast cancers into five so-called intrinsic subtypes.1 Soon thereafter, two independent comparisons . . .
An acoustic metafluid: realizing a broadband acoustic cloak (2008)

Recent theory shows that sound can be controlled and directed almost at will provided that suitable materials can be found. Here, we propose a structure permeated by a fluid and designed so that the composite medium, the metafluid, has an anisotropic density tensor, and a compressibility of choice.
Activin signaling as an emerging target for therapeutic interventions (2009)

After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-beta (TGF-beta) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-beta, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-beta ligands, and control the signaling and availability of ligands.The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases. Accordingly, activin signaling may be a target for therapeutic interventions. In this review, we summarize the current knowledge on activin signaling and discuss the potential roles of this pathway as a molecular target of therapy for metabolic diseases, musculoskeletal disorders, cancers and neural damages.
Solution structure of a trefoil-motif-containing cell growth factor, porcine spasmolytic protein. (1994)

The porcine spasmolytic protein (pSP) is a 106-residue cell growth factor that typifies a family of eukaryotic proteins that contain at least one copy of an approximately 40-amino acid protein domain known as the trefoil motif. In fact, pSP contains two highly homologous trefoil domains. We have determined the complete three-dimensional solution structure of pSP by using a combination of two- and three-dimensional 1H NMR spectroscopy and distance geometry calculations. pSP is a relatively elongated molecule, consisting of two compact globular domains joined via a small interface. The protein's two trefoil domains adopt the same tertiary structure and contain a core C-terminal two-stranded antiparallel beta-sheet, preceded by a 6-residue helix that packs against the N-terminal beta-strand. The remainder of the protein backbone is taken up by two short loops that lie on either side of the beta-hairpin and are linked by an extended region that wraps around the C-terminal beta-strand. The topology of the protein backbone observed for the trefoil domains in pSP represents an unusual polypeptide fold. A striking feature of both trefoil domains is a surface patch formed from five conserved residues that have no obvious structural role. The two patches are located at the far ends of the protein molecule, and we propose that these residues form at least part of the receptor binding site, or sites, on pSP.
Prognostic value of cyclin B1 in patients with esophageal squamous cell carcinoma (2002)

These findings suggest that cyclin B1 is involved in the pathogenesis of carcinoma of the esophagus and that elevated levels of cyclin B1 expression, but not p53 expression, may indicate a poor prognosis for patients with ESCC.
Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. (1994)

Mice that are homozygous for a targeted disruption of the LDL receptor gene (LDLR-/- mice) were fed a diet that contained 1.25% cholesterol, 7.5% cocoa butter, 7.5% casein, and 0.5% cholic acid. The total plasma cholesterol rose from 246 to > 1,500 mg/dl, associated with a marked increase in VLDL, intermediate density lipoproteins (IDL), and LDL cholesterol, and a decrease in HDL cholesterol. In wild type littermates fed the same diet, the total plasma cholesterol remained < 160 mg/dl. After 7 mo, the LDLR-/- mice developed massive xanthomatous infiltration of the skin and subcutaneous tissue. The aorta and coronary ostia exhibited gross atheromata, and the aortic valve leaflets were thickened by cholesterol-laden macrophages. No such changes were seen in the LDLR-/- mice on a normal chow diet, nor in wild type mice that were fed either a chow diet or the high-fat diet. We conclude that LDL receptors are largely responsible for the resistance of wild type mice to atherosclerosis. The cholesterol-fed LDLR-/- mice offer a new model for the study of environmental and genetic factors that modify the processes of atherosclerosis and xanthomatosis.
Clinical and pharmacodynamic (PD) results of a phase I trial with AMP-224 (B7-DC Fc) that binds to the PD-1 receptor. (2013)

3044 Background: PD-1/B7-H1 (PD-L1) axis blockade can reinvigorate T cells, and overcome tumor immune evasion of multiple tumor types. AMP-224 is the first recombinant B7-DC-Fc fusion protein tested in patients that binds to and modulates the PD-1 axis through a unique MOA. The MoA hypothesis for AMP-224 is depletion of PD-1high expressing T-cells representing exhausted effector cells. Subsequent replenishment of the T-cell pool with functional T-cells may restore immune function. Methods: Patients with advanced solid tumors received low dose CTX on Day 0, followed by AMP-224 (IV infusion) on Days 1 and 15 of each 28-day cycle in doses ranging from 0.3 to 30 mg/kg. Blood samples were assessed serially for changes in lymphocyte subsets, PD-1 HI T cells and T cell effector function. IHC staining of paired biopsies for B7-H1, CD8, PD-1, CD4 and FoxP3 was performed to assess immunological status of the tumor at baseline and following treatment and then relative to peripheral readouts. Results: 42 patients (83% melanoma) were treated with varying doses of AMP-224 [0.3 mg/kg (n = 6); 1 mg/kg (n=4); 3 mg/kg (n = 4); 10 mg/kg (n = 22); 30 mg/kg (n = 6)]. Infusion reactions were common (69% across dose cohorts) and occurred mostly at higher doses (86% at the 10 mg/kg dose). No drug-related inflammatory adverse events were identified contrary to PD-1 blocking antibodies. Fresh pre-treatment biopsies were collected from 33/42 (78.5%) patients and paired biopsies have been collected thus far from 19/36 (52.7%) patients on study. 31% of baseline tumors were B7-H1+. Several PD readouts in the periphery showed reductions in PD-1 HI cells and emergence of a functional T cell response (increases in IFNg+, TNFa+, IL-2+ CD4 and CD8 T cells) in individual patients where partial response, stable disease, and mixed responses were seen. Conclusions: Data from peripheral readouts is consistent with hypothesized AMP-224 MoA. B7-H1+ was not always predictive of functional response to AMP-224 immunotherapy. Comprehensive PD readouts and evaluation of PK/PD relationships will be presented and may ultimately predict restoration of immune competence even in the presence of initial disease progression. Clinical trial information: NCT01352884.
Selective inhibition of DNA methyltransferase enzymes as a novel strategy for cancer treatment. (2002)

A common event in the development of human neoplasia is the loss of growth regulatory tumor suppressor functions. Methylation of 5'-CpG islands of tumor suppressor genes and elevated levels of the DNA-(cytosine-5)-methyltransferase enzymes (DNMT1, 3A and 3B) are also prevalent features of human neoplasia. However, direct evidence that elevated DNMT enzyme levels alter gene expression and influence oncogenesis has been difficult to obtain due to the lack of specific DNMT inhibitors. We have developed potent and selective antisense inhibitors of the known DNA methyltransferases. MG-98, a second-generation DNMT1-specific antisense inhibitor currently in phase II clinical trials, reactivates silenced tumor suppressor genes and inhibits the growth of cancer cells in vitro and in preclinical in vivo models. Here, we will review the discovery and development of MG-98 as a cancer therapeutic.
Effects of calcitonin gene-related peptide and BIBN4096BS on myocardial ischemia in anesthetized rats. (2001)

The present study demonstrates that CGRP is a potent myocardial protective substance.
ENZYMATIC SYNTHESIS OF FOLIC ACID BY THE ACTION OF CARP THIAMINASE (1951)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTENZYMATIC SYNTHESIS OF FOLIC ACID BY THE ACTION OF CARP THIAMINASED. W. WoolleyCite this: J. Am. Chem. Soc. 1951, 73, 4, 1898Publication Date (Print):April 1, 1951Publication History Published online1 May 2002Published inissue 1 April 1951https://pubs.acs.org/doi/10.1021/ja01148a564https://doi.org/10.1021/ja01148a564research-articleACS PublicationsRequest reuse permissionsArticle Views67Altmetric-Citations9LEARN 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
Identification of refractory-metal-free C40 TiSi2 for low temperature C54 TiSi2 formation (2001)

A refractory-metal-free C40 TiSi2 phase formed by pulsed-laser annealing is identified experimentally by combined convergent beam electron diffraction (CBED) study and CBED pattern simulation. The simulation shows that the C40 TiSi2 has a hexagonal structure with the space group P6222 (180) and lattice parameters a=0.471 nm and c=0.653 nm. Upon further furnace annealing or rapid thermal annealing, C54 TiSi2 can be directly achieved from C40 TiSi2 at low temperatures (600–700 °C). This observation suggests that pulsed-laser annealing is promising for extension of TiSi2 into the subquarter micron region in semiconductor device fabrication.
Tumor necrosis factor expression in human epithelial tumor cell lines. (1988)

Tumor necrosis factor (TNF) is a monokine with in vitro cytotoxicity for some but not all tumor cells. The basis for sensitivity and resistance to the antitumor effects of this agent remains unclear. The present studies have monitored the effects of TNF on 14 epithelial tumor cell lines. Eleven of these cell lines were resistant to the growth inhibitory effects of TNF (50% inhibitory concentration greater than 1,000 U/ml). 12 of the 14 tumor cell lines has detectable levels of high affinity cell surface TNF binding sites, thus suggesting that resistance was not often due to the absence of cell surface TNF receptors. Northern blot analysis demonstrated that three of the eleven resistant cell lines expressed detectable levels of TNF mRNA. Furthermore, both sensitive and resistant epithelial tumor cells had the capacity to express TNF transcripts in the presence of the protein synthesis inhibitor, cycloheximide. Finally, the presence of TNF expression at the RNA level is shown to be associated with the production of a TNF-like protein in the resistant Ov-D ovarian carcinoma cells. These findings suggest that certain human epithelial tumor cell lines inherently resistant to TNF also express this cytokine.
Conceptual Foundations of Professional Nursing Practice (1992)

NP Reviewers Choose 1991's Outstanding Health Care Books: Book Reviews: Early/Middle Adult Health Care Issues: PDF Only