gebhart/patrepeval huggingface dataset:
6'-Sulfated Sialyl Lewis x Is a Major Capping Group of GlyCAM-1 (1994)

The binding of L-selectin to the HEV-derived ligand GlyCAM-1 bears a strict requirement for oligosaccharide sulfation. In the companion study [Hemmerich, S., Bertozzi, C.R., Leffler, H., & Rosen, S. D. (1994) Biochemistry 33, 4820-4829], we identified the major sulfated mono- and disaccharides of GlyCAM-1 as Gal-6-SO4, GlcNAc-6-SO4, (SO4-6)Gal beta 1-->4GlcNAc, and Gal beta 1-->4(SO4-6)GlcNAc. Sialic acid and fucose are also critical to the recognition determinants on GlyCAM-1. However, the hydrolysis conditions employed in the previous study resulted in cleavage of these moieties, precluding their positional assignment. Here, we employ lectins of defined specificity in conjunction with specific exoglycosidases to identify a major GlyCAM-1 capping structure that includes all three critical elements. The complementary reactivity of Maackia amurensis agglutinin with fully sialylated, undersulfated GlyCAM-1 and Sambucus nigra agglutinin/Trichosanthes japonica agglutinin with desialylated but normally sulfated GlyCAM-1 indicates the presence of terminal 6'-sulfated sialyllactosamine. alpha (1-->3/4)Fucosidase removes fucose almost quantitatively from asialo-GlyCAM-1 while substantially enhancing its binding to Lycopersican esculentum agglutinin (specific for beta 1-->4-linked GlcNAc), indicating the presence of Fuc in an alpha 1-->3 linkage to GlcNAc. The strict requirement for desialylation to achieve defucosylation indicates a proximal location of Fuc with respect to terminal sialic acid. The nature of the capping group was further defined by studying the effects of sulfation, sialylation, and fucosylation on the ability of exo-beta(1-->4)galactosidase to release [3H]Gal from GlyCAM-1.(ABSTRACT TRUNCATED AT 250 WORDS)
Aromatase Inhibitors in the Treatment of Breast Cancer (2005)

Estradiol, the most potent endogenous estrogen, is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is present in breast tissue, and intratumoral aromatase is the source of local estrogen production in breast cancer tissues. Inhibition of aromatase is an important approach for reducing growth-stimulatory effects of estrogens in estrogen-dependent breast cancer. Steroidal inhibitors that have been developed to date build upon the basic androstenedione nucleus and incorporate chemical substituents at varying positions on the steroid. Nonsteroidal aromatase inhibitors can be divided into three classes: aminoglutethimide-like molecules, imidazole/triazole derivatives, and flavonoid analogs. Mechanism-based aromatase inhibitors are steroidal inhibitors that mimic the substrate, are converted by the enzyme to a reactive intermediate, and result in the inactivation of aromatase. Both steroidal and nonsteroidal aromatase inhibitors have shown clinical efficacy in the treatment of breast cancer. The potent and selective third-generation aromatase inhibitors, anastrozole, letrozole, and exemestane, were introduced into the market as endocrine therapy in postmenopausal patients failing antiestrogen therapy alone or multiple hormonal therapies. These agents are currently approved as first-line therapy for the treatment of postmenopausal women with metastatic estrogen-dependent breast cancer. Several clinical studies of aromatase inhibitors are currently focusing on the use of these agents in the adjuvant setting for the treatment of early breast cancer. Use of an aromatase inhibitor as initial therapy or after treatment with tamoxifen is now recommended as adjuvant hormonal therapy for a postmenopausal woman with hormone-dependent breast cancer.
The median paralysis unit: A more pharmacologically relevant unit of biologic activity for botulinum toxin (1995)

Although the LD50 has been used to quantify the biologically active toxin in clinical preparations of botulinum A toxin (Botox and Dysport), a discrepancy exists between the clinical potency of equivalent international units of different formulations of botulinum A toxin for multiple clinical indications. Our laboratory previously reported that a regional chemodenervation assay in the mouse could be utilized to detect the difference in the potencies of the clinical preparations of toxin [Pearce et al. (1994) Toxic. appl. Pharmac. 128, 69-77]. The purpose of this study was to quantify the regional paralysis produced by botulinum toxin and define a new pharmacologic/biologic unit of activity that more accurately reflects the mechanism of action of botulinum toxin in the clinical setting. Quantal analysis of regional paralysis revealed that the ED50, defined as the median paralysis unit (MPU) for Botox and Dysport, was 0.41 +/- 0.01 and 1.00 +/- 0.02 LD50 units, respectively. Differences in the potencies found in retrospective clinical studies comparing Botox and Dysport were accurately reflected, for the first time, by the dose of toxin expressed in terms of the MPU (median paralysis unit). The data suggested that the MPU may be a more appropriate measure of the biologic activity in therapeutic formulations of botulinum toxin.
Coalbed Methane Well Completions and Stimulations (1993)

Coal, "the black rock that burns," is the subject of song, story, and legend. The earliest literature citation of coal (combustible bodies, some of which by inference must be coal) is credited to Aristotle in his treatise "Meteorology," which may date near the middle of the fourth century B.C. Theophrastus, a student of Aristotle, at what is probably a slightly later date provides descriptions of different forms of coal based on their behavior in combustion, identifies areas of occurrence, and states that it was used by smiths (footnote by Hoover to Agricola, 1556).Though the Greek philosophers are responsible for the earliest known literature citations, China and perhaps other parts of eastern Asia are usually believed to have preceded the Mediterranean area in recognition of coal as a peculiar material with usable properties. Inouye (1913) states that although there is no authentic record of the history of the Fu-shun coal field in southern Manchuria, "it is said that the coal was used as fuel … for copper smelting in times as remote as 2,000 or even 3,000 years ago."Fires through most of man's history have been fed by "traditional fuels"—wood, straw, dung, and other plant materials. That coal could be of complementary usage is recorded in the remains of funeral pyres in Wales, dated about 3,000 years ago (Lindbergh and Proverse, 1977). However, the versatility of coal was not widely appreciated, and the discovery and use of charcoal satisfied most needs of primitive metal-working.By the end of the
Delegation of authority using domain-based access rules (1990)

Security is becoming increasingly important for commercial computer systems, which have received little academic attention compared with the security requirements of military systems. In particular, two major concerns of commercial security are discretionary access control and the delegation of authority to give access. It is essential to be able to specify policy for these in a way which gives flexibility while retaining management control. This is the subject of this thesis. Many of the systems are very large, with distributed processing. Systems such as these have two important characteristics. First, the number of objects in the systems, totalling hundreds of thousands in some cases, can be so large that it is impractical to specify access control policy in terms of individual objects or individual users. We need to be able to specify it as a relationship between groups of users and groups of objects. Second, the systems typically consist of multiple interconnected networks and span a number of different organisations. Authority cannot be delegated or imposed from one central point, but has to be negotiated between independent managers who wish to cooperate but who may have a very limited trust in each other. We introduce, model and validate two concepts: . Access rules, which are a means of specifying discretionary access control policy between groups of users and groups of objects. . Delegation of authority to create access rules, from an initial possessor of authority who we refer to as an owner, via managers, to security administrators. Both access rules and the delegation of authority are modelled using management domains as the means of grouping objects. A formal specification of the concepts is given in the Z specification language. Policies for delegat...
Macrophage Inflammatory Protein-1: a Prostaglandin-Independent Endogenous Pyrogen (1989)

Macrophage inflammatory protein-1 (MIP-1) produced a monophasic fever of rapid onset whose magnitude was equal to or greater than that of fevers produced with either recombinant human cachectin (or tumor necrosis factor) or recombinant human interleukin-1. However, in contrast to these two endogenous pyrogens, the fever induced by MIP-1 was not inhibited by the cyclooxygenase inhibitor ibuprofen. Thus, MIP-1 may participate in the febrile response that is not mediated through prostaglandin synthesis and clinically cannot be ablated by cyclooxygenase inhibitors.
A family of glycosylphosphatidylinositol-linked aspartyl proteases is required for virulence ofCandida glabrata (2007)

Candida glabrata is a yeast pathogen of humans. We have established a tissue culture model to analyze the interaction of C. glabrata with macrophages. Transcript profiling of yeast ingested by macrophages reveals global changes in metabolism as well as increased expression of a gene family (YPS genes) encoding extracellular glycosylphosphatidylinositol-linked aspartyl proteases. Eight of these YPS genes are found in a cluster that is unique to C. glabrata. Genetic analysis shows that the C. glabrata YPS genes are required for cell wall integrity, adherence to mammalian cells, survival in macrophages and virulence. By monitoring the processing of a cell wall adhesin, Epa1, we also show that Yps proteases play an important role in cell wall re-modeling by removal and release of glycosylphosphatidylinositol-anchored cell wall proteins.
Spontaneous activity of axotomized afferent neurons after L5 spinal nerve injury in rats (2000)

After mechanical injury of a peripheral nerve some axotomized afferent neurons develop spontaneous activity, which is thought to trigger abnormal pain behavior in rats and neuropathic pain in humans. Here, we analysed the ectopic activity in axotomized afferent fibers recorded from the L5 dorsal root in different time periods after L5 spinal nerve lesion and the effects of sympathectomy on it. The following results were obtained: (1) Up to 6 hours after spinal nerve transection there was almost no spontaneous activity in axotomized afferents, except short-lasting injury discharges at the time of transection; (2) Three to 8 days following spinal nerve lesion, the rate of spontaneous activity was 7.3+/-7.7 imp/s (mean+/-SD, median 5.0 imp/s, n=204); 41.6% of the spontaneously active afferent neurons exhibited a bursting pattern with interspike intervals of 32.4+/-18.3 ms; (3) Twenty to 53 days after nerve lesion the rate of spontaneous activity had decreased significantly to 3.4+/-4.3 imp/s (median 2.6 imp/s, n=120). The frequency of bursting and non-bursting neurons remained roughly the same; (4) In sympathectomized rats, 15-45 days following spinal nerve lesion, the mean discharge rate was 3.8+/-4.3 imp/s (median 2. 3 imp/s, n=255). However, the percentage of bursting neurons and the intraburst frequency decreased significantly; (5) Spontaneous activity occurred in afferent A-fibers but not in afferent C-fibers. These results suggest that ectopic activity in axotomized afferent neurons develops within the first days after L5 spinal nerve lesion, decreases with time and is only marginally dependent on the sympathetic innervation. There was a positive correlation between this ectopic activity and the allodynia-like behavior in spinal nerve-lesioned rats.
The Adenovirus Oncoprotein E1a Stimulates Binding of Transcription Factor ETF to Transcriptionally Activate the p53 Gene (1999)

Expression of the tumor suppressor protein p53 plays an important role in regulating the cellular response to DNA damage. During adenovirus infection, levels of p53 protein also increase. It has been shown that this increase is due not only to increased stability of the p53 protein but to the transcriptional activation of the p53 gene during infection. We demonstrate here that the E1a proteins of adenovirus are responsible for activating the mouse p53 gene and that both major E1a proteins, 243R and 289R, are required for complete activation. E1a brings about the binding of two cellular transcription factors to the mouse p53 promoter. One of these, ETF, binds to three upstream sites in the p53 promoter and one downstream site, whereas E2F binds to one upstream site in the presence of E1a. Our studies indicate that E2F binding is not essential for activation of the p53 promoter but that ETF is. Our data indicate the ETF site located downstream of the start site of transcription is the key site in conferring E1a responsiveness on the p53 promoter.
Hard Block Length Distribution in Segmented Block Copolymers (1976)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHard Block Length Distribution in Segmented Block CopolymersL. H. Peebles Jr.Cite this: Macromolecules 1976, 9, 1, 58–61Publication Date (Print):January 1, 1976Publication History Published online1 May 2002Published inissue 1 January 1976https://pubs.acs.org/doi/10.1021/ma60049a010https://doi.org/10.1021/ma60049a010research-articleACS PublicationsRequest reuse permissionsArticle Views462Altmetric-Citations86LEARN 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-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
Mechanism of action of sacral nerve stimulation using a transdermal (2013)

Introduction: Sacral neuromodulation (SNM) is an effective treatmentmodality for several urological problems, including neurogenicbladder. However, the invasiveness of this technique makesit unsuitable for many patients. We present a novel transdermalamplitude-modulated signal (TAMS) that may provide a non-invasivealternative to implantable SNM to treat neurogenic detrusoroveractivity (NDO).Methods: In this study, we investigated the mechanism of action of non-invasive SNM using TAMS on our established spinal cordinjury (SCI) animal model. We demonstrated that spinally transectedrats develop urinary bladder hyper-reflexia after 3 weeks of SCI,indicated by the presence of uninhibited contractions, increasedresting pressure, increased threshold pressure and increased maximum voiding pressure.Results: Short-term neurostimulation affected urodynamics parameters by significantly reducing the threshold pressure (p = 0.02). Spinal transection also increased calcitonin gene-related protein(CGRP) concentration in the L6 dorsal root ganglia; whereas,neurostimulation significantly reduced CGRP concentration in L6(p = 0.03).Conclusion: TAMS caused a reduction in NDO by inhibitingC-fibre activity.
Anterior–Posterior Patterning of Definitive Endoderm Generated from Human Embryonic Stem Cells Depends on the Differential Signaling of Retinoic Acid, Wnt-, and BMP-Signaling (2016)

As known from model organisms, such as frog, fish, mouse, and chicken, the anterior-posterior patterning of the definitive endoderm (DE) into distinct domains is controlled by a variety of signaling interactions between the DE and its surrounding mesoderm. This includes Wnt/FGFs and BMPs in the posterior half and all-trans-retinoic acid, TGF-β-ligands, Wnt-, and BMP-inhibitors in the anterior half of the DE sheet. However, it is currently unclear how these embryonic tissue interactions can be translated into a defined differentiation protocol for human embryonic stem cells. Activin A has been proposed to direct DE into a SOX2-positive foregut-like cell type. Due to the pleiotropic nature of SOX2 in pluripotency and developing cells of the foregut, we purified DE-cells by magnetic cell sorting and tested the effects of anteriorizing and posteriorizing factors on pure endoderm. We show in contrast to previous studies that the generation of the foregut marked by SOX2/FOXA2 double-positive cells does not depend on activin A/TGF-β-signaling but is mediated by the inhibition of Wnt- and BMP-signaling. Retinoic acid can posteriorize and at the same time dorsalize the foregut toward a PDX1-positive pancreatic duodenal cell type whereas active Wnt/beta-catenin signaling synergistically with FGF-2, BMP-4, and RA induces the formation of CDX2-positive posterior endoderm. Thus, these results provide new insights into the mechanisms behind cell specification of human DE derived from pluripotent stem cells. Stem Cells 2016;34:2635-2647.
THE MAMMALIAN CARBOXYLESTERASES: From Molecules to Functions (1998)

Multiple carboxylesterases (EC 3.1.1.1) play an important role in the hydrolytic biotransformation of a vast number of structurally diverse drugs. These enzymes are major determinants of the pharmacokinetic behavior of most therapeutic agents containing ester or amide bonds. Carboxylesterase activity can be influenced by interactions of a variety of compounds either directly or at the level of enzyme regulation. Since a significant number of drugs are metabolized by carboxylesterase, altering the activity of this enzyme class has important clinical implications. Drug elimination decreases and the incidence of drug-drug interactions increases when two or more drugs compete for hydrolysis by the same carboxylesterase isozyme. Exposure to environmental pollutants or to lipophilic drugs can result in induction of carboxylesterase activity. Therefore, the use of drugs known to increase the microsomal expression of a particular carboxylesterase, and thus to increase associated drug hydrolysis capacity in humans, requires caution. Mammalian carboxylesterases represent a multigene family, the products of which are localized in the endoplasmic reticulum of many tissues. A comparison of the nucleotide and amino acid sequence of the mammalian carboxylesterases shows that all forms expressed in the rat can be assigned to one of three gene subfamilies with structural identities of more than 70% within each subfamily. Considerable confusion exists in the scientific community in regards to a systematic nomenclature and classification of mammalian carboxylesterase. Until recently, adequate sequence information has not been available such that valid links among the mammalian carboxylesterase gene family or evolutionary relationships could be established. However, sufficient basic data are now available to support such a novel classification system.
Characterization of novel canine bocaviruses and their association with respiratory disease (2011)

We report the first identification, genetic characterization and disease association studies of several novel species of canine bocaviruses (CBoV). Evolutionary analysis confirmed that CBoV are genetically distinct from the only other known canine bocavirus, minute virus of canines, with which they share less than 63, 62 and 64 % protein identity in NS, NP and VP genes, respectively. Comparative genetic analysis of 37 VP gene variants found in diseased and healthy animals showed that these novel viruses are genetically highly diverse and are common in canine respiratory infections that have remained undetected until now. Interestingly, we observed that a CBoV genotype with a unique deletion in the VP2 gene was significantly more prevalent in animals with respiratory diseases compared with healthy animals.
End-to-end attention-based large vocabulary speech recognition (2016)

Many state-of-the-art Large Vocabulary Continuous Speech Recognition (LVCSR) Systems are hybrids of neural networks and Hidden Markov Models (HMMs). Recently, more direct end-to-end methods have been investigated, in which neural architectures were trained to model sequences of characters [1,2]. To our knowledge, all these approaches relied on Connectionist Temporal Classification [3] modules. We investigate an alternative method for sequence modelling based on an attention mechanism that allows a Recurrent Neural Network (RNN) to learn alignments between sequences of input frames and output labels. We show how this setup can be applied to LVCSR by integrating the decoding RNN with an n-gram language model and by speeding up its operation by constraining selections made by the attention mechanism and by reducing the source sequence lengths by pooling information over time. Recognition accuracies similar to other HMM-free RNN-based approaches are reported for the Wall Street Journal corpus.
From Single- to Multi-Target Drugs in Cancer Therapy: When Aspecificity Becomes an Advantage (2008)

Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy which acts on all dividing cells generating toxic effects and damage of normal tissues, targeted drugs allow to hit, in a more specific manner, subpopulations of cells directly involved in tumor progression. Molecules controlling cell proliferation and death, such as Tyrosine Kinase Receptors (RTKs) for growth factors, are among the best targets for this type of therapeutic approach. Two classes of compounds targeting RTKs are currently used in clinical practice: monoclonal antibodies and tyrosine kinase inhibitors. The era of targeted therapy began with the approval of Trastuzumab, a monoclonal antibody against HER2, for treatment of metastatic breast cancer, and Imatinib, a small tyrosine kinase inhibitor targeting BCR-Abl, in Chronic Myeloid Leukemia. Despite the initial enthusiasm for the efficacy of these treatments, clinicians had to face soon the problem of relapse, as almost invariably cancer patients developed drug resistance, often due to the activation of alternative RTKs pathways. In this view, the rationale at the basis of targeting drugs is radically shifting. In the past, the main effort was aimed at developing highly specific inhibitors acting on single RTKs. Now, there is a general agreement that molecules interfering simultaneously with multiple RTKs might be more effective than single target agents. With the recent approval by FDA of Sorafenib and Sunitinib--targeting VEGFR, PDGFR, FLT-3 and c-Kit--a different scenario has been emerging, where a new generation of anti-cancer drugs, able to inhibit more than one pathway, would probably play a major role.