gebhart/patrepeval huggingface dataset:
Estrogen Receptor-mediated Activation of the Serum Response Element in MCF-7 Cells through MAPK-dependent Phosphorylation of Elk-1 (2001)

17beta-Estradiol (E2) induces c-fos protooncogene expression in MCF-7 human breast cancer cells, and deletion analysis of the c-fos promoter showed that the serum response element (SRE) at -325 to -296 was E2-responsive. The mechanism of ligand-activated estrogen receptor alpha (ERalpha)-dependent activation of gene expression through the SRE was determined by mutational analysis of the promoter, analysis of mitogen-activated protein kinase (MAPK) pathway activation by E2, and transforming growth factor alpha (TGF-alpha) as a positive control. In addition, ERalpha-negative MDA-MB-231 breast cancer and Chinese hamster ovary cells were used as reference cell lines. The results showed that transcriptional activation of the SRE by E2 was due to ERalpha activation of the MAPK pathway and increased binding of the serum response factor and Elk-1 to the SRE. Subsequent studies with dominant negative Elk-1, wild type, and variant GAL4-Elk-1 fusion proteins confirmed that phosphorylation of Elk-1 at serines 383 and 389 in the C-terminal region of Elk-1 is an important downstream target associated with activation of an SRE by E2. Both E2 (ERalpha-dependent) and growth factors (ERalpha-independent) activated the SRE in breast cancer cells via the Ras/MAPK pathway; however, in ER-negative CHO cells that do not express a receptor for TGF-alpha, only hormone-induced activation was observed in cells transfected with ERalpha.
Drug metabolism and pharmacokinetics (2009)

In this article, aspects of absorption, distribution, metabolism, and excretion have been described bearing in mind the pathogenesis of allergic diseases and their possible therapeutic opportunities. The importance of the routes of administration of the different therapeutic groups has been emphasized. The classical aspects of drug metabolism and disposition related to oral administration have been reviewed, but special emphasis has been given to intranasal, cutaneous, transdermal, and ocular administration as well as to the absorption and the subsequent bioavailability of drugs. Drug-metabolizing enzymes and transporters present in extrahepatic tissues, such as nasal mucosa and the respiratory tract, have been particularly discussed. As marketed antiallergic drugs include both racemates and enantiomers, aspects of stereoselective absorption, distribution, metabolism, and excretion have been discussed. Finally, a new and promising methodology, microdosing, has been presented, although it has not yet been applied to drugs used in the treatment of allergic diseases.
Subspace (2007)

Combining data and code from third-party sources has enabled a new wave of web mashups that add creativity and functionality to web applications. However, browsers are poorly designed to pass data between domains, often forcing web developers to abandon security in the name of functionality. To address this deficiency, we developed Subspace, a cross-domain communication mechanism that allows efficient communication across domains without sacrificing security. Our prototype requires only a small JavaScript library, and works across all major browsers. We believe Subspace can serve as a new secure communication primitive for web mashups.
Mutant epidermal growth factor receptor signaling down-regulates p27 through activation of the phosphatidylinositol 3-kinase/Akt pathway in glioblastomas. (2002)

Alterations of the epidermal growth factor receptor (EGFR) gene are common in some forms of cancer and the most frequent is a deletion of exons 2-7. We have previously shown that this mutant receptor, called DeltaEGFR, confers enhanced tumorigenicity to glioblastoma cells through elevated proliferation and reduced apoptotic rates of the tumor cells in vivo. To understand the molecular mechanisms that underlie DeltaEGFR-enhanced proliferation, we examined the gene products that control cell cycle progression. We found that levels of the cyclin-dependent kinase (CDK) inhibitor, p27, were lower in U87MG.DeltaEGFR tumors than in parental U87MG or control U87MG.DK tumors. Consequently, CDK2-cyclin A activity was also elevated, concomitant with the RB protein hyperphosphorylation. In addition, activated phosphatidylinositol 3-kinase (PI3-K) and phosphorylated Akt levels were also elevated in the U87MG.DeltaEGFR tumors. U87MG.DeltaEGFR cells failed to arrest in G(1) in response to serum starvation in vitro and while maintaining high levels of PI3-K activity and hyperphosphorylated RB. Treatment of U87MG.DeltaEGFR cells with LY294002, a PI3-K inhibitor, caused reduced levels of phosphorylated Akt and concomitantly up-regulated levels of p27. Expression of a kinase dead dominant-negative Akt mutant in the U87MG.DeltaEGFR cells similarly resulted in up-regulation of p27 and down-regulation of tumorigenicity in vivo. These results suggest that the constitutively active DeltaEGFR can enhance cell proliferation in part by down-regulation of p27 through activation of the PI3-K/Akt pathway. This pathway may represent another therapeutic target for treatment of those aggressive glioblastomas expressing DeltaEGFR.
Light-Scattering Studies of a Polystyrene-Poly(methyl methacrylate) Two-Block Copolymer in Mixed Solvents (1974)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTLight-Scattering Studies of a Polystyrene-Poly(methyl methacrylate) Two-Block Copolymer in Mixed SolventsHiroyasu Utiyama, Kunihiro Takenaka, Motoo Mizumori, Mitsutoshi Fukuda, Yoshisuke Tsunashima, and Michio KurataCite this: Macromolecules 1974, 7, 4, 515–520Publication Date (Print):July 1, 1974Publication History Published online1 May 2002Published inissue 1 July 1974https://pubs.acs.org/doi/10.1021/ma60040a020https://doi.org/10.1021/ma60040a020research-articleACS PublicationsRequest reuse permissionsArticle Views199Altmetric-Citations53LEARN 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
Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium (2017)

In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit and differentiation into decidual cells that control embryo implantation. Here we show that FOXO1 also causes acute senescence of a subpopulation of decidualizing EnSCs in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives the transient inflammatory response associated with endometrial receptivity. Further, senescent cells prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. Our findings reveal that acute decidual senescence governs endometrial rejuvenation and remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining homeostasis in cycling endometrium.
Cortical Spreading Depression Reduces Dural Blood Flow a Possible Mechanism for Migraine Pain? (1994)

These experiments were designed to investigate a possible mechanism linking the phenomenon of cortical spreading depression with activation of the trigeminal sensory system in migraine. Blood flow in the cortex and middle meningeal artery was measured in cats before and during propagation of a wave of cortical spreading depression, initiated by cortical pin-prick. This caused a transient propagated increase in cortical blood flow. Cortical spreading depression was accompanied by a decrease in blood flow in the middle meningeal artery, sometimes to very low levels. The results suggest that the pain of migraine could arise from dural ischemia induced by cortical spreading depression.
Experimental demonstration of an OpenFlow based software-defined optical network employing packet, fixed and flexible DWDM grid technologies on an international multi-domain testbed (2013)

Software defined networking (SDN) and flexible grid optical transport technology are two key technologies that allow network operators to customize their infrastructure based on application requirements and therefore minimizing the extra capital and operational costs required for hosting new applications. In this paper, for the first time we report on design, implementation & demonstration of a novel OpenFlow based SDN unified control plane allowing seamless operation across heterogeneous state-of-the-art optical and packet transport domains. We verify and experimentally evaluate OpenFlow protocol extensions for flexible DWDM grid transport technology along with its integration with fixed DWDM grid and layer-2 packet switching.
CD133 marks a myogenically primitive subpopulation in rhabdomyosarcoma cell lines that are relatively chemoresistant but sensitive to mutant HSV (2012)

Our findings demonstrate that CD133+ cells from A-RMS and E-RMS cell lines are characterized by a myogenically primitive phenotype. These cells have the capacity to form colonies in vitro and are more resistant to chemotherapy than CD133- cells. CD133 expression may denote a subset of RMS cells with an important role in tumorigenesis and treatment failure. These resistant cells may be effectively targeted by oHSV therapy.
Effect of Structural Modification of the Hydantoin Ring on Anticonvulsant Activity (1985)

Selectively substituted hydantoins 1 (15 examples), 4-hydroxy-2-imidazolidinones 2 (13 examples), 2-imidazolones 3 (10 examples), 2-imidazolidinones 4 (four examples), vicinal diamines 5 (two examples), and simple amino acid derivatives 6 (four examples) have been prepared and evaluated in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole seizure threshold (sc Met), and rotorod (Tox) tests. The medium effective doses (ED50) and the medium toxic dose (TD50) for the most active compounds are reported. In general, the most pronounced activity was observed for hydantoins 1 and protected amino acids 6. Within each series of compounds, enhanced anticonvulsant activity was often noted for compounds containing an aromatic group one carbon removed from a nitrogen atom. Among the most active compounds observed were the amino acid derivative N-acetyl-D,L-alanine benzylamide (6d) and the two 2-imidazolones 4-methyl-1-(phenylmethyl)-1,3-dihydro-2H-imidazol-2-one (3e) and 1-phenyl-1,3-dihydro-2H-imidazol-2-one (3g). Compound 6d proved to be slightly more potent in the MES test than phenacemide.
The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth (2008)

Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD(+)-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a beta-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates beta-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of beta-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in beta-catenin-driven malignancies.
Recognizing Problem Sleepiness in Your Patient (1999)

Normal sleep is required for optimal functioning. Normal wakefulness should be effortless and free of unintended sleep episodes. Problem sleepiness is common and occurs when the quantity of sleep is inadequate because of primary sleep disorders, other medical conditions or lifestyle factors. Medications and substances that disturb sleep, such as caffeine and nicotine, or those that have sedating side effects, may also cause problem sleepiness. This condition can lead to impairment in attention, performance problems at work and school, and potentially dangerous situations when the patient is driving or undertaking other safety-sensitive tasks. However, problem sleepiness is generally correctable when it is recognized. Asking a patient and his or her bed partner about the likelihood of drowsiness or of falling asleep during specific activities, as well as questions that uncover factors contributing to the sleepiness, helps the physician to recognize the disorder. Accurate diagnosis of specific sleep disorders may require evaluation by a specialist. The primary care physician is in an ideal position to identify signs and symptoms of problem sleepiness and initiate appropriate care of the patient, including educating the patient about the dangers of functioning while impaired by sleepiness.
Fox Plaza [Los Angeles] (1987)

General view; Completed in 1987, the architects behind its design were Scott Johnson, Bill Fain and William L. Pereira. Owned by Orange County-based The Irvine Company, Fox Plaza is 20th Century Fox's headquarters. This was the last project that architect William L. Pereira worked on before his death in 1985. Source: Emporis [website]; http://www.emporis.com/ (accessed 6/21/2009)
The Competitive Innovator (1995)

The study reported here is of an engineer who has established a long and distinguished record as a highly successful and highly innovative designer in a highly competitive environment ‐ Formula One racing car design. Gordon Murray joined the Brabham racing car team as a designer‐draughtsman in 1971, and was appointed chief designer in 1973. Brabham cars designed by him were driven by Nelson Piquet to win the World Championship in 1981 and 1983. In 1987, he moved to the McLaren Formula One team as technical director, and again his car designs, driven by Alain Prost and Ayrton Senna, won the World Championship in 1989 and 1990. In some 20 years as a Formula One designer, he established an outstanding reputation not only as a successful designer (over 50 race wins) but also as a consistently radical innovator. Gordon Murray then became technical director of McLaren Cars Limited, and became responsible for the design and development of a completely new, road‐going ‘super car’ ‐ the McLaren F1, which has attracted immense attention as the ‘ultimate’ motor car.
Serine Proteases: Structure and Mechanism of Catalysis (1977)

PERSPECTIVES AND SUMMARY .... 331 THE REACTION SEQUENCE AND INTERMEDIATES .... . .. . ..... 333 TRANSITION-STATE STABILIZATION .... .. . . . ... .. . 338 STRUCTURAL FEATURES PARTICIPATING IN CATALYSIS ........ 341 Polypeptide Binding on the Acyl-Group Side 342 Side-Chain Specificity Sites 344 Polypeptide Binding on the Leaving-Group Side 346 Tetrahedral Binding and the Oxyanion Binding Site 348 The Reactive Serine and the Charge Relay System . . . . . . . . . . . . . . . . . . . . . . 351
Etanercept reduces hyperalgesia in experimental painful neuropathy (2001)

Etanercept, a recombinant tumor necrosis factor receptor (p75)-Fc fusion protein competitively inhibits tumor necrosis factor-alpha (TNF). Etanercept has been successfully used in patients with rheumatoid arthritis, where it reduces pain and inflammation. Because locally produced proinflammatory cytokines play a role in pain after nerve injury, we investigated whether etanercept can reduce pain and hyperalgesia in an animal model of painful neuropathy, the chronic constriction injury of the sciatic nerve. C57BL/6 mice received etanercept or sham treatment by local near-nerve injection to the injured nerve or by systemic application. Treatment with etanercept reduced thermal hyperalgesia and mechanical allodynia significantly in both modes of application. The effect of etanercept was present in animals that were treated from the time of surgery and in those that were treated from day 6, when hyperalgesia was already present. These results suggest the potential of etanercept as a treatment option for patients with neuropathic pain.
Pathophysiology of depression: the concept of synaptic plasticity (2002)

Neuronal plasticity or remodeling is most often discussed with regard to cellular and behavioral models of learning and memory. However, neuronal plasticity is a fundamental process by which the brain acquires information and makes the appropriate adaptive responses in future-related settings. Dysfunction of these fundamental processes could thereby contribute to the pathophysiology of mood disorders, and recovery could occur by induction of the appropriate plasticity or remodeling. These possibilities are supported by preclinical and clinical studies demonstrating that there are structural alterations that occur in response to stress and in patients with mood disorders. Moreover, antidepressant treatment may oppose these effects by regulation of signal transduction and gene expression pathways linked to neuronal plasticity. These findings comprise a novel conceptual framework for future studies of the etiology of mood disorders and for the development of novel therapeutic interventions.
Group I allergens of grass pollen as cell wall-loosening agents (1997)

Group I allergens are the major allergens of grass pollen, but their biological function is unknown. These proteins are shown here to be structurally related to expansins, which are able to induce extension (creep) of plant cell walls. Extracts of maize pollen possess potent expansin-like activity, as measured in wall extension and wall stress-relaxation assays. This activity is selective for grass cell walls and is, at least partly, due to the action of maize group I allergens. We propose that group I allergens facilitate invasion of the pollen tube into the maternal tissues by loosening the cell walls of the grass stigma and style. Additionally, the presence of related mRNAs in vegetative tissues of rice, Arabidopsis, and soybean implies that allergen homologs may function to loosen walls in growing vegetative tissues as well.
The Xanthomonas citri effector protein PthA interacts with citrus proteins involved in nuclear transport, protein folding and ubiquitination associated with DNA repair (2010)

Xanthomonas axonopodis pv. citri utilizes the type III effector protein PthA to modulate host transcription to promote citrus canker. PthA proteins belong to the AvrBs3/PthA family and carry a domain comprising tandem repeats of 34 amino acids that mediates protein-protein and protein-DNA interactions. We show here that variants of PthAs from a single bacterial strain localize to the nucleus of plant cells and form homo- and heterodimers through the association of their repeat regions. We hypothesize that the PthA variants might also interact with distinct host targets. Here, in addition to the interaction with alpha-importin, known to mediate the nuclear import of AvrBs3, we describe new interactions of PthAs with citrus proteins involved in protein folding and K63-linked ubiquitination. PthAs 2 and 3 preferentially interact with a citrus cyclophilin (Cyp) and with TDX, a tetratricopeptide domain-containing thioredoxin. In addition, PthAs 2 and 3, but not 1 and 4, interact with the ubiquitin-conjugating enzyme complex formed by Ubc13 and ubiquitin-conjugating enzyme variant (Uev), required for K63-linked ubiquitination and DNA repair. We show that Cyp, TDX and Uev interact with each other, and that Cyp and Uev localize to the nucleus of plant cells. Furthermore, the citrus Ubc13 and Uev proteins complement the DNA repair phenotype of the yeast Deltaubc13 and Deltamms2/uev1a mutants, strongly indicating that they are also involved in K63-linked ubiquitination and DNA repair. Notably, PthA 2 affects the growth of yeast cells in the presence of a DNA damage agent, suggesting that it inhibits K63-linked ubiquitination required for DNA repair.
Two independent mutations in a family with neurofibromatosis type 1 (NF1) (1999)

We report on two independent alterations of the NF1 gene in a three-generation kindred with neurofibromatosis type 1 (NF1). Using temperature gradient gel electrophoresis (TGGE) in a mutation analysis of exon 31 of the NF1 gene we detected the previously reported nonsense mutation R1947X. This C-to-T transition at codon 1947 in exon 31 is considered to represent a mutation “ot spot” of the NF1 gene due to 5mCpG deamination. All living family members together with their genomic DNA were included in this investigation. However, the mutation R1947X was absent from two undoubtedly affected siblings of the propositus. Another NF1 mutation (889-2A→G) was identified in the two sibs by the protein truncation test (PTT). The novel splice site mutation 889-2A→G results in a skip of NF1 exon 7 during splicing and protein truncation due to frameshift. The two NF1 alterations are linked to different paternal haplotypes. In our study of a three-generation kindred, R1947X represents a de novo mutation whereas 889-2A→G is an inherited splice mutation. Implications for phenotype variation are discussed. Am. J. Med. Genet. 83:6–12, 1999. © 1999 Wiley-Liss, Inc.
Antimelanoma Activity of Chloroquine, an Antimalarial Agent With High Affinity for Melanin (1993)

The antimalarial agent chloroquine is known for high affinity for melanin. This 4-aminoquinoline derivative was examined for anti-melanoma activity and uptake into melanoma cells. Chloroquine inhibited growth of cultured melanoma cells; the effect was much greater to a moderately pigmented cell line HMV-II than to a nonpigmented HMV-I. Treatment with chloroquine at a dose of 62 mg/kg i.p. for 12 days prolonged by 71% the life span of mice bearing B16 melanoma, while 24-day treatment at 31 mg/kg resulted in a 81% increase in life span. HMV-II cells showed a two-fold increase in uptake of chloroquine as compared with HMV-I cells. Chloroquine, 24 hr after administration to mice implanted s.c. with B16 melanoma, was selectively accumulated in the pigmented tissues, melanoma and eyes. Other nonpigmented tissues such as the liver, lung, and kidney showed rapid uptake (within 1 hr) and release. These results suggest that chloroquine is toxic to pigmented melanoma cells, the process being partly mediated by binding to melanin.