gebhart/patrepeval huggingface dataset:
Diversity Profiling and Design Using 3D Pharmacophores:  Pharmacophore-Derived Queries (PDQ) (1996)

The current interest in combinatorial chemistry for lead generation has necessitated the development of methods for design and evaluation of the diversity of the resultant compound libraries. Such methods also have application in selecting diverse sets of compounds for general screening from corporate databases and in the analysis of large sets of structures to identify common patterns. In this paper we describe a novel methodology for calculating diversity and identifying common features based on the three-point pharmacophores expressed by a compound.1 The method has been implemented within the environment of the Chem-X molecular modeling package (ChemDBS-3D), using a systematic analysis of 3D distance space with three point combinations of six pharmacophoric groups. The strategy used to define the pharmacophores is discussed, including an in-house developed atom type parameterization. The method is compared with the related approach being developed into the ChemDiverse module of Chem-X. Results from an analysis of a large corporate database and examples of combinatorial library profiling with both methods are presented. The use of 3D pharmacophores for assessing diversity, and the application of such methods to combinatorial library design, is discussed.
Glioblastoma multiforme: a rare manifestation of extensive liver and bone metastases (2008)

Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumours known collectively as gliomas. Gliomas are graded by their microscopic appearance. As a rule, their behaviour can be predicted from histology: Grade I (pilocytic astrocytomas) and Grade II (benign astrocytomas) tumours are of low grade and grow slowly over many years. Grade IV tumours (GBM) are the most aggressive and, unfortunately, also the most common in humans, growing rapidly, invading and altering brain function. These tumours arise from the supporting glial cells of the brain during childhood and in adulthood.These growths do not spread throughout the body like other forms of cancer, but cause symptoms by invading the brain. Untreated GBMs are rapidly lethal. Most patients with GBM die of their disease in less than a year and none have long term survival.Extracranial metastases from GBM are extremely rare, with a reported frequency of only 0.44% because of the absence of lymphatics in the brain and the difficulty of tumours to penetrate blood vessels. A case of glioblastoma multiforme with the rare features of extensive liver and bone metastases is presented in this paper.
Effect of axial base on dioxygen and carbon monoxide affinities of iron(II) porphyrins. Imidazole vs. pyridine (1983)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEffect of axial base on dioxygen and carbon monoxide affinities of iron(II) porphyrins. Imidazole vs. pyridineJames P. Collman, John I. Brauman, Kenneth M. Doxsee, Jonathan L. Sessler, Roger M. Morris, and Quentin H. GibsonCite this: Inorg. Chem. 1983, 22, 10, 1427–1432Publication Date (Print):May 1, 1983Publication History Published online1 May 2002Published inissue 1 May 1983https://pubs.acs.org/doi/10.1021/ic00152a003https://doi.org/10.1021/ic00152a003research-articleACS PublicationsRequest reuse permissionsArticle Views322Altmetric-Citations40LEARN 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
Cloning, sequencing and transcriptional studies of the genes for cytochrome c-553 and plastocyanin from Anabaena sp. PCC 7120 (1994)

In some cyanobacteria and eukaryotic algae, cytochrome c-553 (c-552) and plastocyanin function as alternative electron carriers between the cytochrome b6-f complex and Photosystem I. In these organisms plastocyanin is the electron carrier under copper-replete conditions, and cytochrome c-553 is the electron carrier during copper deprivation. In this paper we report the cloning, sequencing and transcriptional analysis of the genes for cytochrome c-553 and plastocyanin from Anabaena sp. PCC 7120. The gene for cytochrome c-553 encodes a preprotein containing 111 amino acids with a predicted N-terminal transit peptide sequence of 25 amino acids. The gene for plastocyanin encodes a preprotein containing 139 amino acids with a N-terminal transit peptide sequence of 34 amino acids. RNA transcript analyses indicate that the expression of the genes for cytochrome c-553 (petJ) and plastocyanin (petE) are regulated in reciprocal ways in response to copper concentration. In copper-replete conditions, petJ is expressed at very low levels, but is transcribed at high levels under copper deprivation; petE is down-regulated in the absence of copper, but is rapidly up-regulated when copper is added back to the medium.
Neutrophil serine proteinases and defensins in chronic obstructive pulmonary disease: effects on pulmonary epithelium (1998)

Neutrophils have the capacity to accumulate in high numbers in the lung during infection and inflammation. Because they play an important role in host defence against infection, but may also cause tissue injury, these cells are thought to be involved in the pathogenesis of various inflammatory lung disorders, including chronic bronchitis and chronic obstructive pulmonary disease. Neutrophil products that may mediate tissue injury at sites of neutrophil-dominated inflammation include the neutrophil serine proteinases elastase, cathepsin G and proteinase 3, and the nonenzymatic defensins. One of the targets of the neutrophil is the lung epithelium, and in vitro studies have revealed that both the serine proteinases and neutrophil defensins markedly affect the integrity of the epithelial layer, decrease the frequency of ciliary beat, increase the secretion of mucus, and induce the synthesis of epithelium-derived mediators that may influence the amplification and resolution of neutrophil-dominated inflammation. Both neutrophil elastase and defensins induce the release of the neutrophil chemoattractant chemokine interleukin-8 from respiratory epithelial cells. The alpha1-proteinase inhibitor (alpha1-PI) is a well-characterized inhibitor of neutrophil elastase, that also blocks the cytotoxic and stimulatory activity of defensins towards epithelial cells. The elastase inhibitory activity of alpha1-PI is also abrogated by the binding of defensins to this inhibitor. Incubation of epithelial cells with neutrophil defensins in combination with either elastase or cathepsin G resulted in decreased effects on the epithelial cells compared with those observed when the cells were incubated with defensins, elastase or cathepsin G separately. These results suggest that neutrophil defensins and serine proteinases cause injury and stimulate epithelial cells to produce chemokines that attract more neutrophils to the site of inflammation. The effects of neutrophil defensins and serine proteinases on epithelial cells appear to be restricted by proteinase inhibitors and by inhibitory interactions between these sets of neutrophil granule proteins.
Creating Shareholder Value: A Guide for Managers and Investors (1986)

List of Illustrations Preface CHAPTER 1. SHAREHOLDER VALUE AND CORPORATE PURPOSE Management Versus Shareholder Objectives Shareholders and Stakeholders Shareholders Are Us CHAPTER 2. SHORTCOMINGS OF ACCOUNTING NUMBERS Earnings--An Unreliable Bottom Line The Trouble with Accounting Return on Investment (ROI) ROI Versus DCF Return Illustrated Additional Shortcomings of ROI Shortcomings of Return on Equity (ROE) CHAPTER 3. SHAREHOLDER VALUE APPROACH Estimating Shareholder Value Estimating Shareholder Value Added (SVA) Threshold Margin The Shareholder Value Network Appendix: Conventional Versus Shareholder Value Break-Even Analysis CHAPTER 4. FORMULATING STRATEGIES Strategy Formulation Process Competitive Advantage and Shareholder Value Strategy Best Sellers CHAPTER 5. VALUING STRATEGIES Strategy Valuation Process Valuing Alternative Business Opportunities Valuing Interdivisional Synergies Choosing Optimal Investment Level for a New Business Do Stock Repurchases Create Value? Ten Value-Creation Questions CHAPTER 6. STOCK MARKET SIGNALS TO MANAGEMENT Reading the Market Corporate Versus Shareholder Rate of Return Management Implications CHAPTER 7. PERFORMANCE EVALUATION AND EXECUTIVE COMPENSATION CEOs and Other Corporate-Level Executives Operating Managers Performance Evaluation Alternatives--Shareholder Value Added (SVA) Performance Evaluation Alternatives--Residual Income Performance Evaluation Alternatives--Economic Value Added (EVA) Performance Evaluation Alternatives--Change in Residual Income or Change in EVA Leading Indicators of Value Target Level of Performance Linking Rewards to Superior Performance CHAPTER 8. MERGERS AND ACQUISITIONS The Acquisition Process Value Creation Framework Do Mergers Create Value for the Acquiring Company? Gillette's Acquisition of Duracell International Premium Advice for Targets CHAPTER 9. IMPLEMENTING SHAREHOLDER VALUE Implementation Objectives Gaining Commitment Introducing Shareholder Value Reinforcing Shareholder Value CHAPTER 10. THE SHAREHOLDER SCOREBOARD A Rising Tide Doesn't Lift All Stocks Investing as a Game of Expectations Notes Index About the Author
Telomeres: Beginning to Understand the End (1995)

Telomeres are the protein-DNA structures at the ends of eukaryotic chromosomes. In yeast, and probably most other eukaryotes, telomeres are essential. They allow the cell to distinguish intact from broken chromosomes, protect chromosomes from degradation, and are substrates for novel replication mechanisms. Telomeres are usually replicated by telomerase, a telomere-specific reverse transcriptase, although telomerase-independent mechanisms of telomere maintenance exist. Telomere replication is both cell cycle- and developmentally regulated, and its control is likely to be complex. Because telomere loss causes the kinds of chromosomal changes associated with cancer and aging, an understanding of telomere biology has medical relevance.
Activation of the GFRa1/NCAM pathway stimulates Sertoli cell proliferation in vitro (2008)

The proliferation and final density of Sertoli cells in the testis are regulated by hormones and local growth factors. Glial cell line-derived neurotrophic factor (GDNF), a distantly related member of the transforming growth factor-p (TGF-â) super-family, and its receptor components: GFRal, Ret and neural cell adhesion molecule (NCAM) have been recently reported to be expressed in the testis and to be involved in the proliferation regulation of immature Sertoli cells. However, the number of the reports is very low, and the signalling pathways have not been well characterized. In the present study, we used purified Sertoli cell cultures from 4- to 5-day-old mouse testis to detect the expression of GDNF, to examine the effect of GDNF on Sertoli cell proliferation and possible signalling pathways mediating such effect. GDNF expression in mouse Sertoli cells was detected at both RNA and protein levels by RT-PCR and immunocytochemistry methods. The expression was up-regulated by FSH. GDNF stimulated the proliferation of Sertoli cells and synergized with FSH to promote the proliferation to a higher level. GFRal/Ret and GFRα1/ NCAM are two receptor complexes for GDNF. As GFRal and NCAM not Ret were expressed in cultured Sertoli cells, we proposed that the stimulatory effect of GDNF on Sertoli cell proliferation was through pathways initiating from the GFRal/NCAM receptor. This proposition was supported by the fact that the stimulatory effect of GDNF was significantly reduced by anti-NCAM antibody.
Effects of low-intensity AC and/or DC electromagnetic fields on cell attachment and induction of apoptosis (1997)

Rat tendon fibroblast (RTF) and rat bone marrow (RBM) osteoprogenitor cells were cultured and exposed to AC and/or DC magnetic fields in a triaxial Helmholtz coil in an incubator for up to 13 days. The AC fields were at 60 and 1000 Hz and up to 0.25 mT peak to peak, and the DC fields were up to 0.25 mT. At various combinations of field strengths and frequencies, AC and/or DC fields resulted in extensive detachment of preattached cells and prevented the normal attachment of cells not previously attached to substrates. In addition, the fields resulted in altered cell morphologies. When RTF and RBM cells were removed from the fields after several days of exposure, they partially reattached and assumed more normal morphologies. An additional set of experiments described in the Appendix corroborates these findings and also shows that low-frequency EMF also initiates apoptosis, i.e., programmed cell death, at the onset of cell detachment. Taken together, these results suggest that the electromagnetic fields result in significant alterations in cell metabolism and cytoskeleton structure. Further work is required to determine the relative effect of the electric and magnetic fields on these phenomena. The research has implications for understanding the role of fields in affecting bone healing in fracture nonunions, in cell detachment in cancer metastasis, and in the effect of EMF on organisms generally.
A structural hypothesis for BH4 responsiveness in patients with mild forms of hyperphenylalaninaemia and phenylketonuria (2001)

Deficiencies in the human enzyme phenylalanine hydroxylase (PAH) due to mutations in the PAH gene (PAH) result in the inborn error of metabolism phenylketonuria (PKU). The clinical symptom of this disease is an elevated concentration of L-phenylalanine (L-Phe) in blood serum. To prevent mental retardation due to the buildup of neurotoxic metabolites of L-Phe, patients with severe PKU must be treated with a low-L-Phe diet starting early in their life. Owing to extensive newborn screening programmes and genotyping efforts, more than 400 different mutations have been identified in the PAH gene. Recently, there have been several reports of PKU patients showing a normalization of their L-Phe concentrations upon oral administration of the natural cofactor to PAH, (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4). In an attempt to correlate the clinical responsiveness to BH4 administration with PKU genotype, we propose specific structural consequences for this subset of PAH mutations. Based on the location and proximity of this subset of mutations to the cofactor-binding site in the three-dimensional structure of PAH, a hypothesis for BH4 responsiveness in PKU patients is presented. It is believed that some of these mutations result in expressed mutant enzymes that are Km variants (with a lower binding affinity for BH4) of the standard PAH enzyme phenotype. Oral administration of excess BH4 thus makes it possible for these mutant enzymes to suppress their low binding affinity for BH4, enabling this subset of PAH mutations to perform the L-Phe hydroxylation reaction. Most of the BH4-responsive PAH mutations map to the catalytic domain of PAH in either of two categories. Residues are located in cofactor-binding regions or in regions that interact with the secondary structural elements involved in cofactor binding. Based on the series of known mutations that have been found to be responsive to BH4, we propose that other subsets of PAH mutations will have a high likelihood of being responsive to oral BH4 administration.
Interleukin‐1β, Interleukin‐18, and the Interleukin‐1β Converting Enzymea (1998)

When injected intravenously into humans and animals, interleukin-1 beta (IL-1 beta) is perhaps the most potent of the endogenous pyrogens. However, IL-1 beta is initially synthesized as a relatively inactive precursor molecule (proIL-1 beta) which lacks a signal peptide and hence remains inside the cell. To be active as a fever-producing molecule, proIL-1 beta must first be processed to an active mature molecule and secreted. Although several enzymes associated with inflammatory tissues are capable of processing proIL-1 beta into an active molecule in the extracellular compartment, the IL-1 beta converting enzyme (ICE, also called caspase-1) cuts intracellular proIL-1 beta after the aspartic acid residue in position 116, resulting in a highly active mature IL-1 beta that is secreted into the extracellular space. IL-18 is also initially synthesized as an inactive precursor molecule (proIL-18) lacking a signal peptide. IL-18 is a member of the IL-1 family, and like IL-1 beta, proIL-18 is cleaved by ICE to yield an active molecule. However, unlike IL-1 beta, IL-18 is not an endogenous pyrogen following intraperitoneal injection into mice. Nevertheless, IL-18 may contribute to inflammation and fever because IL-18 is a potent inducer of tumor necrosis factor, chemokines, and interferon-gamma production.
Spread spectrum communications handbook (1995)

Spread-spectrum systems have found important commercial applications in CDMA cellular networks and wireless personal communication networks. Communications engineers and technicians now have ready access to a wealth of spread-spectrum information in this exhaustive handbook the most comprehensive and authoritative compendium on spread-spectrum systems available anywhere. Written by recognized authorities in the field, the Handbook presents both theoretical basics and practical applications, providing succinct, results-oriented solutions to engineering problems.Starting with basic concepts and system models, the book covers: Anti-jamming communication systems; Coherent direct-sequence systems; Non-coherent frequency-hopped systems; Coherent and differentially coherent modulation techniques; Pseudonoise acquistion and tracking in direct sequence receivers; Time and frequency synchronization of frequency-hopped receivers; and, Low probability of intercept communications. In addition, it offers an in-depth look at multiple access communications and positioning systems and discusses the growth of spread-spectrum applications.
Slowing and controlling the translocation of DNA in a solid-state nanopore (2011)

DNA sequencing methods based on nanopores could potentially represent a low-cost and high-throughput pathway to practical genomics, by replacing current sequencing methods based on synthesis that are limited in speed and cost. The success of nanopore sequencing techniques requires the solution to two fundamental problems: (1) sensing each nucleotide of a DNA strand, in sequence, as it passes through a nanopore; (2) delivering each nucleotide in a DNA strand, in turn, to a sensing site within the nanopore in a controlled manner. It has been demonstrated that a DNA nucleotide can be sensed using electric signals, such as ionic current changes caused by nucleotide blockage at a constriction region in a protein pore or a tunneling current through the nucleotide-bridged gap of two nanoelectrodes built near a solid-state nanopore. However, it is not yet clear how each nucleotide in a DNA strand can be delivered in turn to a sensing site and held there for a sufficient time to ensure high fidelity sensing. This latter problem has been addressed by modifying macroscopic properties, such as a solvent viscosity, ion concentration or temperature. Also, the DNA transistor, a solid state nanopore dressed with a series of metal-dielectric layers has been proposed as a solution. Molecular dynamics simulations provide the means to study and to understand DNA transport in nanopores microscopically. In this article, we review computational studies on how to slow down and control the DNA translocation through a solid-state nanopore.
Immune Endothelial-Cell Injury in Heparin-Associated Thrombocytopenia (1987)

We studied the possibility that immune injury to endothelial cells may have a role in the development of thrombosis in some patients with heparin-associated thrombocytopenia. Serum samples from each of 27 patients who had this clinical diagnosis contained heparin-dependent platelet antibodies and deposited more than normal amounts of IgG, IgA, or IgM on endothelial cells, stimulating the production of tissue factor. Binding of immunoglobulins to endothelial cells was no longer detected when the patients were studied after heparin was withdrawn, but reappeared within several days upon reexposure to heparin in a patient who experienced a clinical recurrence. Binding of immunoglobulin to endothelial cells was partially reduced by the preadsorption of serum samples with heparin or heparan sulfate bound to Sepharose or by enzymatic cleavage of cell-bound heparan sulfate, and was augmented by the addition of heparan sulfate. Thus, serum from some patients with heparin-associated thrombocytopenia may contain antibodies that react with heparin bound to endothelial cells or with heparan sulfate synthesized by endothelial cells. Immune injury to both platelets and endothelial cells may play a part in the development of thrombosis in some patients after heparin therapy.
Genotyping:The predictive power of haplotypes in clinical response (2000)

A variety of approaches have been proposed to find genetic markers that can be used in a clinical setting. Single nucleotide polymorphisms (SNPs) are the basis of the most commonly used approaches. Here we describe an approach using gene-based haplotypes, which are collections of SNPs located throughout the ftinctional regions of candidate genes, and organised as they occur separately on an individual's two chromosomes. The main point of this review is that the haplotype has greater power than any individual SNP to track an unobsenrved, but evolutionarily linked, variable site.
Drugs in Phase II clinical trials for the treatment of age-related macular degeneration (2014)

It is important to develop better more sensitive biomarkers, validating different approvable clinical trial endpoints and stratifying patients on their genetic polymorphisms. These developments should help to progress the already rapidly developing field of macular degeneration therapy.