gebhart/patrepeval huggingface dataset:
Engineering Potent and Selective Analogues of GpTx-1, a Tarantula Venom Peptide Antagonist of the NaV1.7 Sodium Channel (2015)

NaV1.7 is a voltage-gated sodium ion channel implicated by human genetic evidence as a therapeutic target for the treatment of pain. Screening fractionated venom from the tarantula Grammostola porteri led to the identification of a 34-residue peptide, termed GpTx-1, with potent activity on NaV1.7 (IC50 = 10 nM) and promising selectivity against key NaV subtypes (20× and 1000× over NaV1.4 and NaV1.5, respectively). NMR structural analysis of the chemically synthesized three disulfide peptide was consistent with an inhibitory cystine knot motif. Alanine scanning of GpTx-1 revealed that residues Trp(29), Lys(31), and Phe(34) near the C-terminus are critical for potent NaV1.7 antagonist activity. Substitution of Ala for Phe at position 5 conferred 300-fold selectivity against NaV1.4. A structure-guided campaign afforded additive improvements in potency and NaV subtype selectivity, culminating in the design of [Ala5,Phe6,Leu26,Arg28]GpTx-1 with a NaV1.7 IC50 value of 1.6 nM and >1000× selectivity against NaV1.4 and NaV1.5.
Management of large amounts of data in interactive building walkthroughs (1992)

We describe techniques for managing large amounts of data during an interactive walkthrough of an architectural model. These techniques are based on a spatial subdivision, visibility analysis, and a display database containing objects described at multiple levels of detail. In each frame of the walkthrough, we compute a set of objects to render, i.e. those potentially visible from the observer's viewpoint, and a set of objects to swap into memory, i.e. those that might become visible in the near future. We choose an appropriate level of detail at which to store and to render each object, possibly using very simple representations for objects that appear small to the observer, thereby saving space and time. Using these techniques, we cull away large portions of the model that are irrelevant from the observer's viewpoint, and thereby achieve interactive frame rates.
Molecular Mechanics Investigation of Gadolinium(III) Complexes (1996)

Parameters for the commercially available modeling package SYBYL have been developed for Gd(3+) complexes allowing these to be studied with molecular mechanics. With these parameters and a technique termed the "coordination scan", the coordination numbers of Gd(III) based complexes can be predicted, and thus the hydration number q determined. Knowledge of q has allowed the prediction of molar relaxivities based on correlations to literature values. In addition, the calculated value DeltaE(coord) was found to successfully predict the thermodynamic stability constants for polyamino carboxylate ligands with Gd(3+). Gadolinium complexes are commonly utilized as MRI contrast agents, and thus the techniques utilized in this work should aid in the development of new contrast agents.
A Novel Hydrogen Peroxide Sensor Based on the Direct Electron Transfer of Catalase Immobilized on Nano‐Sized NiO/MWCNTs Composite Film (2011)

Abstract MWCNTs‐nanoNiO composite was used as a glassy carbon electrode modifier for construction of a novel catalase nanobiosensor for hydrogen peroxide. The immobilized catalase exhibited excellent electrocatalytic activity towards the reduction of H 2 O 2 . The resulting amperometric biosensor exhibited a linear response over a concentration range of 200 µM to 2.53 mM with a low detection limit of 19.0 µM. Electrochemical impedance measurements revealed that the modified electrode can be used for the sensitive detection of H 2 O 2 . The charge transfer resistance found to decrease significantly after enzymatic reaction of nanobiosensor with H 2 O 2 . The resulting impedance was highly sensitive to H 2 O 2 over a linear range of 19–170 nM with a detection limit of 2.4 nM.
Rat hepatocyte spheroids formed by rocked technique maintain differentiated hepatocyte gene expression and function # (2008)

Spheroid formation by rocker technique was more rapid and more efficient than by rotational technique. Rocker-formed spheroids appear suitable for application in a bioartificial liver or as an in vitro liver tissue construct.
mRNA acetylated at 2'‐OH‐groups of ribose residues is functionally active in the cell‐free translation system from wheat embryos (1990)

Modification (acetylation) of 2'-OH groups of mRNA ribose residues does not result in a loss of their template activity in a cell-free translation system from wheat embryos and in some cases activates inactive mRNAs. Modification of 70-75% of 2'-OH groups makes mRNA stable to the effect of pancreatic ribonuclease.
Cysteine-less glycosylphosphatidylinositol-specific phospholipase C is inhibited competitively by a thiol reagent: evidence for glyco-mimicry by p-chloromercuriphenylsulphonate (2002)

Glycosylphosphatidylinositol (GPI)-specific phospholipases are highly valuable for studying the structure and function of GPIs. GPI-specific phospholipase C (GPI-PLC) from Trypanosoma brucei and phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus cereus are the most widely studied of this class of phospholipases C. Inhibition of protein activity by thiol reagents is indicative of the participation of cysteine residues in biochemical events. The thiol reagent p-chloromercuriphenylsulphonate (pCMPS) inhibits T. brucei GPI-PLC, which has eight cysteine residues. Surprisingly, we found that the activity of B. cereus PI-PLC is also blocked by pCMPS, although the protein does not contain cysteine residues. Inhibition of B. cereus PI-PLC was reversed when pCMPS was size-separated from a preformed pCMPS.PI-PLC complex. In contrast, no activity was recovered when T. brucei GPI-PLC was subjected to a similar protocol. Equimolar beta-mercaptoethanol (beta-ME) reversed the inhibition of PI-PLC activity in a pCMPS.PI-PLC complex. For T. brucei GPI-PLC, however, ultrafiltration of the pCMPS.GI-PLC complex and addition of a large excess of beta-ME was necessary for partial recovery of enzyme activity. Thus T. brucei GPI-PLC is susceptible to inactivation by covalent modification with pCMPS, whereas PI-PLC is not. Kinetic analysis indicated that pCMPS was a competitive inhibitor of PI-PLC when a GPI was a substrate. Curiously, with phosphatidylinositol as substrate, inhibition was no longer competitive. These data suggest that pCMPS is a glyco-mimetic that occupies the glycan binding site of PI-PLC, from where, depending on the substrate, it inhibits catalysis allosterically or competitively.
In Vivo Persistence, Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB) (2011)

Human T cells engineered to express a chimeric antigen receptor (CAR) specific for folate receptor-α (FRα) have shown robust antitumor activity against epithelial cancers in vitro but not in the clinic because of their inability to persist and home to tumor in vivo. In this study, CARs were constructed containing a FRα-specific scFv (MOv19) coupled to the T-cell receptor CD3ζ chain signaling module alone (MOv19-ζ) or in combination with the CD137 (4-1BB) costimulatory motif in tandem (MOv19-BBζ). Primary human T cells transduced to express conventional MOv19-ζ or costimulated MOv19-BBζ CARs secreted various proinflammatory cytokines, and exerted cytotoxic function when cocultured with FRα(+) tumor cells in vitro. However, only transfer of human T cells expressing the costimulated MOv19-BBζ CAR mediated tumor regression in immunodeficient mice bearing large, established FRα(+) human cancer. MOv19-BBζ CAR T-cell infusion mediated tumor regression in models of metastatic intraperitoneal, subcutaneous, and lung-involved human ovarian cancer. Importantly, tumor response was associated with the selective survival and tumor localization of human T cells in vivo and was only observed in mice receiving costimulated MOv19-BBζ CAR T cells. T-cell persistence and antitumor activity were primarily antigen-driven; however, antigen-independent CD137 signaling by CAR improved T-cell persistence but not antitumor activity in vivo. Our results show that anti-FRα CAR outfitted with CD137 costimulatory signaling in tandem overcome issues of T-cell persistence and tumor localization that limit the conventional FRα T-cell targeting strategy to provide potent antitumor activity in vivo.
A novel mechanism of action of tetracyclines: Effects on nitric oxide synthases (1996)

Tetracyclines have recently been shown to have "chondroprotective" effects in inflammatory arthritides in animal models. Since nitric oxide (NO) is spontaneously released from human cartilage affected by osteoarthritis (OA) or rheumatoid arthritis in quantities sufficient to cause cartilage damage, we evaluated the effect of tetracyclines on the expression and function of human OA-affected nitric oxide synthase (OA-NOS) and rodent inducible NOS (iNOS). Among the tetracycline group of compounds, doxycycline > minocycline blocked and reversed both spontaneous and interleukin 1 beta-induced OA-NOS activity in ex vivo conditions. Similarly, minocycline > or = doxycycline inhibited both lipopolysaccharide- and interferon-gamma-stimulated iNOS in RAW 264.7 cells in vitro, as assessed by nitrite accumulation. Although both these enzyme isoforms could be inhibited by doxycycline and minocycline, their susceptibility to each of these drugs was distinct. Unlike acetylating agents or competitive inhibitors of L-arginine that directly inhibit the specific activity of NOS, doxycycline or minocycline has no significant effect on the specific activity of iNOS in cell-free extracts. The mechanism of action of these drugs on murine iNOS expression was found to be, at least in part, at the level of RNA expression and translation of the enzyme, which would account for the decreased iNOS protein and activity of the enzyme. Tetracyclines had no significant effect on the levels of mRNA for beta-actin and glyceraldehyde-3-phosphate dehydrogenase nor on levels of protein of beta-actin and cyclooxygenase 2 expression. These studies indicate that a novel mechanism of action of tetracyclines is to inhibit the expression of NOS. Since the overproduction of NO has been implicated in the pathogenesis of arthritis, as well as other inflammatory diseases, these observations suggest that tetracyclines should be evaluated as potential therapeutic modulators of NO for various pathological conditions.
Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation (1992)

Vascular endothelial growth factor (VEGF) is a secreted angiogenic mitogen whose target cell specificity appears to be restricted to vascular endothelial cells. Such factors are likely candidates for regulatory molecules involved in endothelial growth control. We have characterized the murine VEGF gene and have analysed its expression pattern in embryogenesis, particularly during brain angiogenesis. Analysis of cDNA clones predicted the existence of three molecular forms of VEGF which differ in size due to heterogeneity at the carboxy terminus of the protein. The predicted mature proteins consist of 120, 164 or 188 amino acid residues. Homodimers of the two lower molecular weight forms, but not of the higher molecular weight form, were secreted by COS cells transfected with the corresponding cDNAs and were equally potent in stimulating the growth of endothelial cells. During brain development, VEGF transcript levels were abundant in the ventricular neuroectoderm of embryonic and postnatal brain when endothelial cells proliferate rapidly but were reduced in the adult when endothelial cell proliferation has ceased. The temporal and spatial expression of VEGF is consistent with the hypothesis that VEGF is synthesized and released by the ventricular neuroectoderm and may induce the ingrowth of capillaries from the perineural vascular plexus. In addition to the transient expression during brain development, a persistent expression of VEGF was observed in epithelial cells adjacent to fenestrated endothelium, e.g. in choroid plexus and in kidney glomeruli. The data are consistent with a role of VEGF as a multifunctional regulator of endothelial cell growth and differentiation.
Alkylidene complexes of niobium and tantalum (1979)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAlkylidene complexes of niobium and tantalumRichard R. SchrockCite this: Acc. Chem. Res. 1979, 12, 3, 98–104Publication Date (Print):March 1, 1979Publication History Published online1 May 2002Published inissue 1 March 1979https://pubs.acs.org/doi/10.1021/ar50135a004https://doi.org/10.1021/ar50135a004research-articleACS PublicationsRequest reuse permissionsArticle Views2578Altmetric-Citations416LEARN 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 of the beta-amylase gene from Bacillus cereus and characteristics of the primary structure of the enzyme (1993)

The gene encoding the beta-amylase of Bacillus cereus BQ10-S1 (SpoII) was cloned into Escherichia coli JM 109. A sequenced DNA fragment of 2,001 bp contains the beta-amylase gene. The N-terminal sequences (AVNGKG MNPDYKAYLMAPLKKI), the C-terminal sequences (SHTSSW), and the amino acid sequences of the five regions in the beta-amylase molecules were determined. The mature beta-amylase contains 514 amino acid residues with a molecular mass of 57,885 Da. The amino acid sequence homology with those of known beta-amylases was 52.7% for Bacillus polymyxa, 52.0% for Bacillus circulans, 43.4% for Clostridium thermosulfurogenes, 31.8% for Arabidopsis thaliana, 31.5% for barley, 29.9% for sweet potato, and 28.9% for soybean. Ten well-conserved regions were found between the N terminus and the area around residue 430, but the C-terminal region of 90 residues has no similarity with those of the plant beta-amylases. The homology search revealed that this C-terminal region has homology with C-terminal regions of the beta-amylase from C. thermosulfurogenes, some bacterial alpha-amylases, cyclodextrin glucanotransferase, and glucoamylase. Some of these sequences are known as the raw-starch-binding domain. These results suggest that B. cereus beta-amylase has an extra domain which has raw-starch-binding ability and that the domain has considerable sequence homology with those of other amylases or related enzymes from a wide variety of microorganisms.
A simplified surgical procedure for the correction of stress incontinence in women (2002)

No AccessJournal of Urology1 Feb 2002A simplified surgical procedure for the correction of stress incontinence in women Armand J. PereyraM.D., F.A.C.S. Armand J. PereyraArmand J. Pereyra Ontario, Canada California, USA More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(02)80353-6AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail References 1. : The Female Bladder Before and After Correction for Stress Incontinence. Am. J. Obst. & Gynec.December, 1949; 58: 1145. Google Scholar 2. : Topographic Urethrography. Am. J. Obst. & Gynec.June, 1950; 59: 1243. Google Scholar 3. : Stress Incontinence of Urine. J. Obst. & Gynaec., British EmpireAugust, 1952; 59: 685. Google Scholar 4. : Observations on Stress Incontinence of Urine. Am. J. Obst. & Gynec.October, 1952; 64: 721. Crossref, Medline, Google Scholar 5. : Stress Incontinence of Urine. J. Obst. & Gynaec. British EmpireAugust, 1952; 59: 681. Google Scholar 6. : Relationship of the Female Urethra and Bladder in Urinary Stress Incontinence. Am. J. Obst. & Gynec.March, 1953; 65: 560. Crossref, Medline, Google Scholar 7. : The Correction of Stress Incontinence by Simple Vesicourethral Suspension. Surg. Gynec. & Obst.April, 1949; 88: 509. Medline, Google Scholar 8. : . New York: Grune & Stratton, Inc.1953. Google Scholar © 2002 by American Urological Association, IncFiguresReferencesRelatedDetails Volume 167Issue 2 Part 2February 2002Page: 1116-1118 Advertisement Copyright & Permissions© 2002 by American Urological Association, IncMetricsAuthor Information Armand J. Pereyra Ontario, Canada California, USA More articles by this author Expand All Advertisement PDF downloadLoading ...
Myocardin Is a Critical Serum Response Factor Cofactor in the Transcriptional Program Regulating Smooth Muscle Cell Differentiation (2003)

The SAP family transcription factor myocardin functionally synergizes with serum response factor (SRF) and plays an important role in cardiac development. To determine the function of myocardin in the smooth muscle cell (SMC) lineage, we mapped the pattern of myocardin gene expression and examined the molecular mechanisms underlying transcriptional activity of myocardin in SMCs and embryonic stem (ES) cells. The human and murine myocardin genes were expressed in vascular and visceral SMCs at levels equivalent to or exceeding those observed in the heart. During embryonic development, the myocardin gene was expressed abundantly in a precise, developmentally regulated pattern in SMCs. Forced expression of myocardin transactivated multiple SMC-specific transcriptional regulatory elements in non-SMCs. By contrast, myocardin-induced transactivation was not observed in SRF(-/-) ES cells but could be rescued by forced expression of SRF or the SRF DNA-binding domain. Furthermore, expression of a dominant-negative myocardin mutant protein or small-interfering-RNA-induced myocardin knockdown significantly reduced SM22 alpha promoter activity in SMCs. Most importantly, forced expression of myocardin activated expression of the SM22 alpha, smooth muscle alpha-actin, and calponin-h1 genes in undifferentiated mouse ES cells. Taken together, these data demonstrate that myocardin plays an important role in the SRF-dependent transcriptional program that regulates SMC development and differentiation.
Absolute quantification of regional myocardial uptake of 99mTc-sestamibi with SPECT: experimental validation in a porcine model. (2001)

We have shown that, by applying object-specific attenuation corrections and suitable partial-volume corrections, absolute regional activity concentration can be measured accurately in the porcine myocardium.
Targeted Delivery of Multifunctional Magnetic Nanoparticles (2007)

Magnetic nanoparticles and their magnetofluorescent analogues have become important tools for in vivo imaging using magnetic resonance imaging and fluorescent optical methods. A number of monodisperse magnetic nanoparticle preparations have been developed over the last decade for angiogenesis imaging, cancer staging, tracking of immune cells (monocyte/macrophage, T cells) and for molecular and cellular targeting. Phage display and data mining have enabled the procurement of novel tissue- or receptor-specific peptides, while high-throughput screening of diversity-oriented synthesis libraries has identified small molecules that permit or prevent uptake by specific cell types. Next-generation magnetic nanoparticles are expected to be truly multifunctional, incorporating therapeutic functionalities and further enhancing an already diverse repertoire of capabilities.
New Generation Dopaminergic Agents. 6. Structure−Activity Relationship Studies of a Series of 4-(Aminoethoxy)indole and 4-(Aminoethoxy)indolone Derivatives Based on the Newly Discovered 3-Hydroxyphenoxyethylamine D2Template (1999)

A series of 4-(aminoethoxy)indoles 7 and a related series of 4-(aminoethoxy)indolones 8 were synthesized and evaluated for their affinity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 4-aminoethoxy derivatives (i.e., 7 and 8) were designed as bioisosteric analogues based on the phenol prototype 4. The indolones 8 were observed to have high affinity for the D2High receptor. Comparison of their previously reported chroman analogues with the more flexible 4-(aminoethoxy)indoles revealed the chroman analogues to be more potent, whereas little loss in D2High affinity was observed when comparing the 4-(aminoethoxy)indolones with their respective chroman analogues. Several regions of the phenoxyethylamine framework were modified and recognized as potential sites to modulate the level of intrinsic activity. A conformational analysis was performed and a putative bioactive conformation was proposed which fulfilled the D2 agonist pharmacophore criteria based on the McDermed model. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.
Immunotherapeutic Approaches for Hematologic Malignancies (2004)

Abstract The immune system has two complementary arms: one is older and seemingly more primitive, called the innate immune system, found in both plants and animals. The second (already many millions of years old!) is the adaptive or antigen-specific immune system, limited to vertebrate animals. The human innate immune system has many cellular elements that include granulocytes, monocytes, macrophages, natural killer (NK) cells, mast cells, eosinophils, and basophils. Receptors for these cells are non-clonal, fixed in the genome, requiring no rearrangement, and recognize conserved molecular patterns that are specific to pathogens. The adaptive immune system (B cells and T cells) have receptors with great variation, able to recognize an almost an unlimited number of highly specific pathogens through rearrangement of receptor gene segments, and can also provide immunological memory so critical for vaccination. As the immune system has evolved to recognize non-self, malignant transformation of self can likely escape immune surveillance with relative ease. Contributors to this chapter are utilizing distinct components of either the innate or adaptive immune system that recognize non-self, in combination with what we know about differences between malignant and normal self, in an effort to develop novel and effective immunologic approaches against hematologic malignancies. In Section I, Dr. Andrea Velardi reviews the benefits of NK cell alloreactivity in mismatched hematopoietic transplantation, provides updates on current clinical trials, and discusses further therapeutic perspectives emerging from murine bone marrow transplant models. In Section II, Dr. David Scheinberg reviews novel leukemic antigens being targeted by humanized monoclonal antibodies as well as mechanisms by which antibody-mediated cytotoxicity occurs in vivo. In Section III, Dr. Ivan Borrello reviews vaccine and adoptive T cell immunotherapy in the treatment of hematologic malignancies. Specifically, he discusses the various vaccine approaches used as well as strategies aimed at augmenting the tumor specificity of T cell therapies.