gebhart/patrepeval huggingface dataset:
Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine (1998)

An isoform of the mammalian renal type II Na/Pi-cotransporter is described. Homology of this isoform to described mammalian and nonmammalian type II cotransporters is between 57 and 75%. Based on major diversities at the C terminus, the new isoform is designed as type IIb Na/Pi-cotransporter. Na/Pi-cotransport mediated by the type IIb cotransporter was studied in oocytes of Xenopus laevis. The results indicate that type IIb Na/Pi-cotransport is electrogenic and in contrast to the renal type II isoform of opposite pH dependence. Expression of type IIb mRNA was detected in various tissues, including small intestine. The type IIb protein was detected as a 108-kDa protein by Western blots using isolated small intestinal brush border membranes and by immunohistochemistry was localized at the luminal membrane of mouse enterocytes. Expression of the type IIb protein in the brush borders of enterocytes and transport characteristics suggest that the described type IIb Na/Pi-cotransporter represents a candidate for small intestinal apical Na/Pi-cotransport.
Peer Reviewed: Capillary Array Electrophoresis DNA Sequencing. (1999)

Sequencing with a single capillary is like using only one lane on a slab gel--you get a high-speed separation, but the overall throughput is low. Running many capillaries simultaneously becomes essential.
CRISPR families of the crenarchaeal genus Sulfolobus: bidirectional transcription and dynamic properties (2009)

Clusters of regularly interspaced short palindromic repeats (CRISPRs) of Sulfolobus fall into three main families based on their repeats, leader regions, associated cas genes and putative recognition sequences on viruses and plasmids. Spacer sequence matches to different viruses and plasmids of the Sulfolobales revealed some bias particularly for family III CRISPRs. Transcription occurs on both strands of the five repeat-clusters of Sulfolobus acidocaldarius and a repeat-cluster of the conjugative plasmid pKEF9. Leader strand transcripts cover whole repeat-clusters and are processed mainly from the 3'-end, within repeats, yielding heterogeneous 40-45 nt spacer RNAs. Processing of the pKEF9 leader transcript occurred partially in spacers, and was incomplete, probably reflecting defective repeat recognition by host enzymes. A similar level of transcripts was generated from complementary strands of each chromosomal repeat-cluster and they were processed to yield discrete approximately 55 nt spacer RNAs. Analysis of the partially identical repeat-clusters of Sulfolobus solfataricus strains P1 and P2 revealed that spacer-repeat units are added upstream only when a leader and certain cas genes are linked. Downstream ends of the repeat-clusters are conserved such that deletions and recombination events occur internally.
Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors (2006)

CCT018159 was recently identified as a novel inhibitor of heat shock protein (Hsp) 90, a promising target for cancer therapy. Pharmacokinetic and metabolic properties are likely to be important for efficacy and need to be optimized during drug development. Here, we define the preclinical metabolism and pharmacokinetics of CCT018159 and some early derivatives. In addition, we assess in vitro metabolic stability screening and in vivo cassette dosing (simultaneous administration of several compounds to a single animal) as approaches to investigate these compounds. The plasma clearance following individual i.v. administration to mice was rapid (0.128-0.816 L/h), exceeding hepatic blood flow. For CCT066950 and CCT066952, this could be attributed in part to extensive (>80%) blood cell binding. Oral bioavailability ranged from 1.8% to 29.6%. Tissue distribution of CCT066952 was rapid and moderate, and renal excretion of the compounds was minimal (<1% of dose excreted). Compounds underwent rapid glucuronidation both in vivo and following incubation with mouse liver microsomes. However, whereas CCT066965 was metabolized to the greatest extent in vitro, this compound displayed the slowest plasma clearance. The rank order of the compounds from the highest to lowest area under the curve was the same following discrete and cassette dosing. Furthermore, pharmacokinetic variables were similar whether the compounds were dosed alone or in combination. We conclude that the pharmacokinetics of CCT018159 are complex. Cassette dosing is currently the best option available to assess the pharmacokinetics of this promising series of compounds in relatively high throughput and is now being applied to identify compounds with optimal pharmacokinetic properties during structural analogue synthesis.
Adapting the User Interface of Integrated Development Environments (IDEs) for Novice Users. (2008)

The usability of a user interface is often neglected in the design and development of software applications. An Integrated Development Environment (IDE) is prone to poor usability problems due to the rich functionality offered through its User Interface (UI). Since an IDE targets a wide range of users (from novice to expert users), the usability requirement for an IDE vary considerably. Novice users, such as first year undergraduate students, often have difficulty in understanding many of the features provided in an IDE and have a hard time locating the appropriate menu elements. We propose an Adaptive User Interface (AUI) architecture which provides a simplified UI for the Eclipse IDE. The AUI assists novice users in using complex IDEs. We develop adaptive algorithms that modify the existing menu system for the Eclipse IDE based on statistical user interaction patterns. Our adaptive algorithms perform a cost-benefit analysis when modifying the menu system. The algorithms determine the optimal changes which reduce the time needed by novice users when searching for menu elements. A prototype AUI is developed as an Eclipse plug-in for novice users of the Eclipse IDE. Through an initial case study, we demonstrate the benefits of our AUI in improving the usability of the Eclipse IDE.
Self-Assembly of Conjugated Molecular Rods:  A High-Resolution STM Study (1996)

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTSelf-Assembly of Conjugated Molecular Rods: A High-Resolution STM StudyAl-Amin Dhirani, Robert W. Zehner, Richard P. Hsung, Philippe Guyot-Sionnest, and Lawrence R. SitaView Author Information James Franck Institute, The University of Chicago 5640 South Ellis Avenue, Chicago, Illinois 60637, and Searle Chemistry Laboratory, Department of Chemistry The University of Chicago, 5735 South Ellis Avenue Chicago, Illinois 60637 Cite this: J. Am. Chem. Soc. 1996, 118, 13, 3319–3320Publication Date (Web):April 3, 1996Publication History Received10 November 1995Published online3 April 1996Published inissue 1 January 1996https://pubs.acs.org/doi/10.1021/ja953782ihttps://doi.org/10.1021/ja953782irapid-communicationACS PublicationsCopyright © 1996 American Chemical SocietyRequest reuse permissionsArticle Views2222Altmetric-Citations315LEARN 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 (2)»Supporting Information Supporting Information SUBJECTS:Chemical structure,Molecular structure,Monolayers,Order,Scanning tunneling microscopy Get e-Alerts
Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody (2018)

Abstract Assisted Design of Antibody and Protein Therapeutics (ADAPT) is an affinity maturation platform interleaving predictions and testing that was previously validated on monoclonal antibodies (mAbs). This study expands the applicability of ADAPT to single-domain antibodies (sdAbs), a promising class of recombinant antibody-based biologics. As a test case, we used the camelid sdAb A26.8, a V H H that binds Clostridium difficile toxin A (TcdA) relatively weakly but displays a reasonable level of TcdA neutralization. ADAPT-guided A26.8 affinity maturation resulted in an improvement of one order of magnitude by point mutations only, reaching an equilibrium dissociation constant ( K D ) of 2 nM, with the best binding mutants having similar or improved stabilities relative to the parent sdAb. This affinity improvement generated a 6-fold enhancement of efficacy at the cellular level; the A26.8 double-mutant T56R,T103R neutralizes TcdA cytotoxicity with an IC 50 of 12 nM. The designed mutants with increased affinities are predicted to establish novel electrostatic interactions with the antigen. Almost full additivity of mutation effects is observed, except for positively charged residues introduced at adjacent positions. Furthermore, analysis of false-positive predictions points to general directions for improving the ADAPT platform. ADAPT guided the efficacy enhancement of an anti-toxin sdAb, an alternative therapeutic modality for C. difficile .
Site-specific DNA cleavage by antisense oligonucleotides covalently linked to phenazine di-N-oxide. (1991)

Site-specific degradation of DNA was achieved by the use of DNA oligonucleotides covalently tethered to phenazine 5,10-di-N-oxide. When annealed to a complementary DNA target strand, the antisense oligonucleotide effected alkylation of guanosine residues in proximity to the phenazine di-N-oxide prosthetic group. Admixture of dithiothreitol to the formed duplex resulted in reductive activation of the phenazine di-N-oxide moiety with concomitant generation of diffusible oxygen radicals; the latter effected strand scission of the target DNA oligonucleotide. Several parameters of DNA degradation were studied, including the effect on DNA degradation of chain length in the tether connecting the oligonucleotides and prosthetic group, the relative efficiencies of DNA cleavage when the prosthetic group was in the middle or at the end of the antisense oligonucleotide, and the effect of O2 on DNA degradation. Also studied was the actual chemistry of DNA oligonucleotide degradation and the ability of individual diastereomers of the modified oligonucleotides to mediate degradation of the target DNA.
Interactions of Ficolin and Mannose-Binding Lectin with Fibrinogen/Fibrin Augment the Lectin Complement Pathway (2009)

Ficolin and mannose-binding lectin (MBL) are animal lectins that are involved in innate immunity by initiating the lectin complement pathway. Here, we report that interactions between these lectins and fibrinogen/fibrin augment the lectin pathway. An ELISA revealed that recombinant mouse ficolin A (rFcnA), rMBL-A and rMBL-C bind to fibrinogen in a dose-dependent manner. Affinity Western blotting showed that these lectins bind to the A alpha- and B beta-chains of fibrinogen and the alpha- and beta-chains of fibrin, but not to the gamma-chain, and that rMBL-A and rMBL-C preferentially bind to the alpha- and beta-chains. The C4 deposition activity on Fbg-coated plates was observed by using mouse serum, and the deposition on GlcNAc-coated plates was enhanced by fibrinogen supplementation and further enhanced by the addition of thrombin. Similar effects of fibrinogen and fibrin were observed in the bindings of these lectins to a Gram-positive pathogen, Staphylococcus aureus, and in the subsequent C3 deposition on the bacteria. In particular, the lectin pathway, through MBLs, seemed to synchronize with blood coagulation. Therefore, it is suggested that the lectin pathway collaborates with the coagulation system in the first-line host defense against pathogens under conditions such as injury and inflammation.
Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout (2014)

NCT00325195. Registered 10 May 2006, NCT01356498. Registered 27 October 2008.
A Persistent(ly) Enigmatic Ecological Mystery: Bacterial Vaginosis (2006)

Considering the vagina's central role in women's susceptibility to acquiring sexually transmitted infections (STIs), including HIV, we have a remarkably limited understanding of its microflora and mucosal immunology. We have known for >2 decades that the normal vagina is dominated by hydrogen peroxide-producing Lactobacillus species, particularly L. crispatus and L. jensenii [1]. Quantitative declines in numbers of these vaginal lactobacilli have been associated with an increased risk of the acquisition of bacterial vaginosis (BV) [2], gonorrhea [3], and HIV infection [3] and with cervicitis [4]. BV itself, in which the relative lack of lactobacilli is accompanied by a profound increase in the quantity of vaginal anaerobic bacteria, has been associated with an increased risk of some STIs [5] and HIV infection [6, 7]. BV is the most prevalent vaginal infection in women of reproductive age-it affects 8%-23% of women and is the most common cause of vaginal symptoms prompting women to seek medical care. Despite this, our collective
Identification of a superoxide-generating NADPH oxidase system in human fibroblasts (1991)

Human fibroblasts have the capacity to release superoxide radicals upon stimulation of an electron transport system similar to the NADPH oxidase of leukocytes. Two components of the NADPH oxidase system, (1) a flavoprotein of 45 kDa which binds diphenylene iodonium (a compound described as a specific inhibitor of the leukocyte NADPH oxidase), and (2) a low-potential cytochrome b, are present in fibroblast membranes. Fibroblasts exhibit these compounds at lower concentrations than do polymorphonuclear leukocytes or B-lymphocytes. The superoxide-generating system is rather uniformly associated with the outer cell membrane, as shown by light and electron microscopy. Superoxide release upon stimulation with various agents was prevented by the addition of micromolar concentrations of diphenylene iodonium, making an NADPH oxidase a likely source.
Effect of Oxymetazoline on Healthy Human Nasal Ciliary Beat Frequency Measured with High-Speed Digital Microscopy and Mucociliary Transport Time (2008)

The clinical concentration of oxymetazoline, 0.05%, has no obvious inhibitory effect on human nasal CBF in vitro. The increased MTT caused by 0.05% oxymetazoline in vivo is within the normal range.
Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism (1999)

A mouse model of Rubinstein-Taybi syndrome (RTS) was generated by an insertional mutation into the cyclic AMP response element-binding protein (CREB)-binding protein (CBP) gene. Heterozygous CBP-deficient mice, which had truncated CBP protein (residues 1-1084) containing the CREB-binding domain (residues 462-661), showed clinical features of RTS, such as growth retardation (100%), retarded osseous maturation (100%), hypoplastic maxilla with narrow palate (100%), cardiac anomalies (15%) and skeletal abnormalities (7%). Truncated CBP is considered to have been acting during development as a dominant-negative inhibitor to lead to the phenotypes of RTS in mice. Our studies with step-through-type passive avoidance tests and with fear conditioning test showed that mice were deficient in long-term memory (LTM). In contrast, short-term memory (STM) appeared to be normal. These results implicate a crucial role for CBP in mammalian LTM. Our CBP +/- mice would be an excellent model for the study of the role of CBP in development and memory storage mechanisms.
Functional Characterization of the Human Interleukin-15 Receptor αChain and Close Linkage of IL15RA and IL2RA Genes (1995)

Interleukins-2 and -15 (IL-2 and IL-15) are cytokines with overlapping but distinct biological effects. Their receptors share two subunits (the IL-2R beta and -gamma chains) that are essential for signal transduction. The IL-2 receptor requires an additional IL-2-specific alpha subunit for high affinity IL-2 binding. Recently, a murine IL-15-specific alpha subunit was identified, cloned, and shown to be structurally related to IL-2R alpha. However, the murine IL-15R alpha alone bound IL-15 with a 1000-fold higher affinity than that seen with IL-2R alpha and IL-2. We now extend these studies into the human system with the isolation of three differentially spliced human IL-15R alpha variants that are all capable of high affinity binding of IL-15. The cytoplasmic domain of IL-15R alpha, like that of IL-2R alpha, is dispensable for mitogenic signaling, suggesting that the primary role of the alpha chains is to confer high affinity binding. At high concentrations, IL-15, like IL-2, is able to signal through a complex of IL-2R beta and -gamma in the absence of the alpha subunit. Furthermore, the IL15RA and IL2RA genes have a similar intron-exon organization and are closely linked in both human and murine genomes. However, the distribution of expression of the IL-15R alpha is much wider than that of the IL-2R alpha, suggesting a broader range of cellular targets for IL-15.
An Eye Lens Protein–Water Structure: 1.2 Å Resolution Structure of γB-Crystallin at 150 K (1996)

gammabeta-crystallin is a structural protein of the eye lens with a role in the maintenance of an even distribution of protein and water over distances around the wavelength of light, preserving lens transparency. The structure of the 174-residue bovine protein has already been determined at room temperature to 1.47 A resolution. By flash freezing the protein crystals, data have now been collected to a nominal resolution limit of 1.2 A as radiation damage was essentially eliminated. The protein-water model has been refined against this data using the program RESTRAIN converging to an R factor of 18.5% with all data. Atomic positions are clearly indicated in the electron-density maps. Discrete bimodal disorder has been visualized for a few side chains. Out of a total of 498 water molecules present in the crystal asymmetric unit, 394 have been modelled and refined at unit occupancy. The solvent structure is extremely well ordered with an average B value of 23.4 A(2). Partially occupied sites have been identified where disorder in the protein induces concomitant disorder in the local solvent structure. The solvent structure covers 97% of the solvent-exposed surface of the protein in the crystal. 126 water molecules are distributed in second and higher hydration shells. There are networks of hydrogen-bonded solvent extending up to 64 molecules in a network, comprising trimers and tetramers as well as five- and six-membered water-ring structures. The hydration of the protein surface is dominated by arginine and aspartate side chains. Extensive cages of highly ordered solvent molecules are also observed around exposed non-polar groups.
Evidence for dual coupling of the murine luteinizing hormone receptor to adenylyl cyclase and phosphoinositide breakdown and Ca2+ mobilization. Studies with the cloned murine luteinizing hormone receptor expressed in L cells. (1992)

The murine receptor for luteinizing hormone (LHR) was cloned and expressed in L cells. This LHR (mature protein of 674 amino acids) is very similar to that of the rat (same length, 36 amino acid differences) but differs significantly more from that of man (673 amino acids, 109 differences). Expression of the murine LHR in L cells led to the appearance of binding sites for human chorionic gonadotropin (hCG) with a Kd of 150 pM and an LH- and hCG-stimulable adenylyl cyclase activity (EC50 = 50-100 pM hCG). Upon labeling pools of phosphoinositides with [3H]myo-inositol, L cells expressing the murine LHR responded to hCG with an increase in their rate of phosphoinositide hydrolysis (EC50 = 2,400 pM hCG). This was accompanied by an increase in intracellular Ca2+ [( Ca2+]i), as determined by the Fura2 method. This increase in [Ca2+]i in response to hCG was dependent on the LHR, for HCG did not affect [Ca2+]i in L cells not expressing the LHR. The effect was not due to the cAMP-forming activity of the LH receptor, for neither forskolin nor prostaglandin E1, which both increase cAMP levels in L cells, had a similar effect in either control or LHR-expressing cells and isoproterenol had no effect in L cells expressing a functionally active hamster beta-adrenergic receptor. The effect was also not due to overexpression of a Gs-coupled receptor, for L cells expressing 8-fold higher levels of the human V2 vasopressin receptor did not mimic the Ca(2+)-mobilizing response of the LH receptor. We conclude that the LH receptor has the capability of activating two intracellular signaling pathways: one leading to stimulation of adenylyl cyclase and resulting in increases in cAMP and a second leading to stimulation of phospholipase C and resulting in formation of inositol phosphates and elevations in [Ca2+]i. These data correlate positively with and provide a mechanistic explanation for previous reports on the ability of hCG to mobilize phosphoinositides and increasing [Ca2+]i in luteal and granulosa cells (e.g. Davis, J. S., West, L. A., and Farese, R. V. (1984) J. Biol. Chem. 259, 15028-15034).
Cerebral asymmetry and emotion: Conceptual and methodological conundrums (1993)

Abstract A diversity of methods have been used to study cerebral asymmetries associated with emotion. Many different conceptual schemes have also been invoked to guide research on this topic. The purpose of this article is to survey the critical methodological and conceptual issues in this area of research. Research in this area must acknowledge the multi-componential nature of emotion. Asymmetries associated with the perception of emotional information and the posing of emotional expressions are not necessarily the same as those that accompany the actual production of emotion. Asymmetries vary along the rostral/caudal plane both in their magnitude and direction, as well as in their functional significance. Research in this area must explicitly take this variable into account. Different measures of asymmetry do not reflect the same underlying process and so cannot be used interchangeably. In particular, behavioural measures which lack extensive localising validation, must be used with caution. Finally, the nature of the causal connection between alterations in asymmetric activation and emotion is not a simple one and extant data indicate that an asymmetric shift is not sufficient for the production of emotion. This fact has serious implications for the types of experimental designs that must be used to adequately test for relations between cerebral asymmetry and emotion. The article concludes with a discussion of some of the major outstanding questions that will occupy a central position in the future research agenda in this area.