gebhart/patrepeval huggingface dataset:
Effect of protein binding of daptomycin on MIC and antibacterial activity (1991)

A higher rate of clinical failures in patients treated with daptomycin (2 mg/kg of body weight, given once daily) compared with rates in patients treated with conventional regimens caused early termination of this comparative clinical trial. One explanation for these failures could be that daptomycin is highly protein bound and that the concentration of the unbound active drug is too low for antibacterial activity. To assess this explanation, we studied the binding of daptomycin to proteins by using an ultrafiltration method. pH (7.0 to 7.4), temperature (25 or 37 degrees C), or daily freezing and thawing over 2 months had no effect on binding of daptomycin to proteins. We found that daptomycin was bound to albumin (90%) at 4 g/100 ml. Binding of daptomycin was not concentration dependent (2.5 to 80 micrograms/ml). In human serum samples spiked with daptomycin, average binding was 94% +/- 2.4%. In 6 subjects given an intravenous infusion of daptomycin (3 mg/kg), average binding was 90% +/- 2.1%. Susceptibility studies showed that a concentration in serum 20 times the unbound concentration was needed to equal the MIC of the total drug. These results indicate that daptomycin is highly bound (90 to 94%) to albumin and that clinical failure to daptomycin can in part be explained by the low concentration of the unbound drug.
Reversible penetration of α-glutathione S-transferase into biological membranes revealed by photosensitized labelling in situ (1998)

Fluorescent lipid analogue 3,3'-dioctadecyloxacarbocyanine incorporated into biological membranes was used to induce photoactivation of a hydrophobic probe 5-[125I]iodonaphthyl-1-azide (125INA) by energy transfer and to thereby confine subsequent radiolabelling of proteins to the lipid bilayer. This approach was applied in bovine chromaffin cells to discover cytosolic proteins that reversibly penetrate into membrane domains. alpha-Glutathione S-transferase (alpha-GST) was identified as the only labelled protein in bovine chromaffin-cell cytosol, indicating that it inserts reversibly into the membrane lipid bilayer. The selectivity of the labelling towards the lipid bilayer is demonstrated by showing that influenza virus haemagglutinin becomes labelled by 125INA only after the insertion of this protein into the target membrane. The molar 125INA:protein ratio was used as a quantitative criterion for evaluation of the penetration of proteins into the membrane lipid bilayer. This ratio was calculated for four integral membrane proteins and four soluble proteins that interact with biological membranes. The values for four integral membrane proteins (erythrocyte anion transporter, multidrug transporter gp-170, dopamine transporter and fusion-competent influenza virus haemagglutinin) were 1, 8, 2 and 2, respectively, whereas for soluble proteins (annexin VII, protein kinase C, BSA and influenza virus haemagglutinin) the values were 0.002, 0, 0.002 and 0.02, respectively. The molar ratio for alpha-GST was found to be 1, compatible with the values obtained for integral membrane proteins.
Lack of toxicity of alpha-sarcoglycan overexpression supports clinical gene transfer trial in LGMD2D (2008)

Our data demonstrate robust and sustained adeno-associated virus type 1 alpha-sarcoglycan gene expression under control of muscle creatine kinase promoters, without evidence of cytotoxicity. These findings support the use of gene therapy as a potential treatment approach for limb-girdle muscular dystrophy type 2D.
Status and Future of High-Power Light-Emitting Diodes for Solid-State Lighting (2007)

Status and future outlook of III-V compound semiconductor visible-spectrum light-emitting diodes (LEDs) are presented. Light extraction techniques are reviewed and extraction efficiencies are quantified in the 60%+ (AlGaInP) and ~80% (InGaN) regimes for state-of-the-art devices. The phosphor-based white LED concept is reviewed and recent performance discussed, showing that high-power white LEDs now approach the 100-lm/W regime. Devices employing multiple phosphors for "warm" white color temperatures (~3000-4000 K) and high color rendering (CRI>80), which provide properties critical for many illumination applications, are discussed. Recent developments in chip design, packaging, and high current performance lead to very high luminance devices (~50 Mcd/m <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> white at 1 A forward current in 1times1 mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> chip) that are suitable for application to automotive forward lighting. A prognosis for future LED performance levels is considered given further improvements in internal quantum efficiency, which to date lag achievements in light extraction efficiency for InGaN LEDs
Discovery and development of purine-scaffold Hsp90 inhibitors (2007)

The heat-shock protein 90 (Hsp90), an important target in cancer and other diseases, has become recently the focus of several drug discovery and development efforts. The initially identified natural-product inhibitors of Hsp90, such as geldanamycin, played a major role in elucidating its biological function and in determining its clinical relevance. Upcoming synthetic inhibitors, such as the purine-scaffold class, furthered our understanding on Hsp90 in cancer and neurodegenerative diseases and delivered what are promised to be clinical candidates with favorable pharmacologic profiles. This review intends to inform the reader on efforts ranging from the discovery of purine-scaffold Hsp90 inhibitors to their clinical translation as well as on their use as chemical tools to dissect the roles of Hsp90 in pathogenic systems.
Expression Cloning of a Human Sulfotransferase That Directs the Synthesis of the HNK-1 Glycan on the Neural Cell Adhesion Molecule and Glycolipids (1998)

The HNK-1 carbohydrate is expressed on various adhesion molecules in the nervous system and is suggested to play a role in cell-cell and cell-substratum interactions. Here we describe the isolation and functional expression of a cDNA encoding a human sulfotransferase that synthesizes the HNK-1 carbohydrate epitope. A mutant Chinese hamster ovary cell line, Lec2, which stably expresses human neural cell adhesion molecule (N-CAM) (Lec2-NCAM), was first established. Lec2-NCAM was co-transfected with a human fetal brain cDNA library, a cDNA encoding the rat glucuronyltransferase that forms a precursor of the HNK-1 carbohydrate, and a vector encoding the polyoma large T antigen. The transfected Lec2-NCAM cells expressing the HNK-1 glycan were enriched by fluorescence-activated cell sorting. Sibling selection of recovered plasmids resulted in a cDNA encoding a sulfotransferase, HNK-1ST, that directs the expression of the HNK-1 carbohydrate epitope on the cell surface. The deduced amino acid sequence indicates that the enzyme is a type II membrane protein. Sequence analysis revealed that there is a short amino acid sequence in the presumed catalytic domain, which is highly homologous to the corresponding sequence in other Golgi-associated sulfotransferases so far cloned. The amount of HNK-1ST transcript is high in fetal brain compared with fetal lung, kidney, and liver. Expression of HNK-1ST resulted in the formation of the HNK-1 epitope on N-CAM and a soluble chimeric form of HNK-1ST was shown to add a sulfate group to a precursor, GlcAbeta1-->3Galbeta1-->4GlcNAcbeta1-->R, forming sulfo-->3GlcAbeta1-->3Galbeta1-->4GlcNAcbeta1-->R. The results combined together indicate that the cloned HNK-1ST directs the synthesis of the HNK-1 carbohydrate epitope on both glycoproteins and glycolipids in the nervous tissues.
PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2 (2002)

Programmed death-1 (PD-1) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor expressed upon T cell activation. PD-1(-/-) animals develop autoimmune diseases, suggesting an inhibitory role for PD-1 in immune responses. Members of the B7 family, PD-L1 and PD-L2, are ligands for PD-1. This study examines the functional consequences of PD-1:PD-L engagement on murine CD4 and CD8 T cells and shows that these interactions result in inhibition of proliferation and cytokine production. T cells stimulated with anti-CD3/PD-L1.Fc-coated beads display dramatically decreased proliferation and IL-2 production, while CSFE analysis shows fewer cells cycling and a slower division rate. Costimulation with soluble anti-CD28 mAb can overcome PD-1-mediated inhibition by augmenting IL-2 production. However, PD-1:PD-L interactions inhibit IL-2 production even in the presence of costimulation and, thus, after prolonged activation, the PD-1:PD-L inhibitory pathway dominates. Exogenous IL-2 is able to overcome PD-L1-mediated inhibition at all times, indicating that cells maintain IL-2 responsiveness. Experiments using TCR transgenic CD4(+) or CD8(+) T cells stimulated with antigen-presenting cells expressing PD-L1 show that both T cell subsets are susceptible to this inhibitory pathway. However, CD8(+) T cells may be more sensitive to modulation by the PD-1:PD-L pathway because of their intrinsic inability to produce significant levels of IL-2.
Design and Synthesis of Novel α1a Adrenoceptor-Selective Dihydropyridine Antagonists for the Treatment of Benign Prostatic Hyperplasia (1998)

We report the synthesis and evaluation of novel alpha1a adrenoceptor subtype-selective antagonists. Systematic modification of the lipophilic 4,4-diphenylpiperidinyl moiety of the dihydropyridine derivatives 1 and 2 provided several highly selective and potent alpha1a antagonists. From this series, we identified the 4-(methoxycarbonyl)-4-phenylpiperidine analogue SNAP 5540 (-) [(-)-63] for further characterization. When examined in an isolated human prostate tissue assay, this compound was found to have a Ki of 2.8 nM, in agreement with the cloned human receptor binding data (Ki = 2.42 nM). Further evaluation of the compound in isolated dog prostate tissue showed a Ki of 3.6 nM and confirmed it to be a potent antagonist (Kb = 1.6 nM). In vivo, this compound effectively blocked the phenylephrine-stimulated increase in intraurethral pressure (IUP) in mongrel dogs, at doses which did not significantly affect the arterial pressure (diastolic blood pressure, DBP), with a DBP Kb/IUP Kb ratio of 16. In addition, (-)-63 also showed greater than 40 000-fold selectivity over the rat L-type calcium channel and 200-fold selectivity over several G protein-coupled receptors, including histamine and serotonin subtypes. These findings prove that alpha1a adrenoceptor-subtype selective antagonists such as (-)-63 may be developed as uroselective agents for an improved treatment of BPH over nonselective alpha1 antagonists such as prazosin and terazosin, with fewer side effects.
Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors (2000)

Compounds that inhibit histone deacetylase may enable the re-expression of silenced regulatory genes in neoplastic cells, reversing the malignant phenotype. Although several molecules that inhibit histone deacetylase are undergoing preclinical development, butyric acid derivatives have undergone clinical investigation for several years, initially for non-malignant indications and more recently for the treatment of cancer. Of the butyric acid derivatives, sodium phenylbutyrate has undergone the most extensive systematic investigation. Administration of phenylbutyrate by iv. and oral routes is well-tolerated clinically at concentrations which effect acetylation of histones in vitro. Higher doses lead to reversible CNS depression. The studies presented to date have been Phase I studies and do not enable assessment of efficacy. However, current development of phenylbutyrate is proceeding in combination with other agents based on rational biologically-based in vitro studies. The parallel development of combination therapy including phenylbutyrate and early clinical development of other, more potent histone deacetylase inhibitors will hopefully lead to feasible, clinically tolerable strategies for altering the malignant phenotype of cancer cells.
Effect of Clopidogrel on Naproxen-Induced Gastrointestinal Blood Loss in Healthy Volunteers (1998)

The effect of clopidogrel, a potent inhibitor of platelet aggregation, on naproxen-induced faecal blood loss was investigated in 30 healthy volunteers in a randomized, double-blind, placebo-controlled, two parallel treatment groups study. All subjects first received naproxen 250 mg b.i.d. during 7 days, after which they were randomly allocated to additionally receive either clopidogrel 75 mg once daily (n = 15) or matching placebo (n = 15) for 11 days. Faecal blood loss was measured by the 51Cr-labelled erythrocyte method during the last four days of each of the four study periods, i.e. baseline, treatment with naproxen alone, combined treatment and wash-out. Mean daily faecal blood loss was below 0.5 ml/day during the baseline period in both treatment groups and increased during treatment with naproxen alone to (mean +/- SD) 1.14 +/- 0.58 ml/day in the naproxen + placebo group and to 1.93 +/- 1.51 ml/day in the naproxen + clopidogrel group. Addition of clopidogrel to naproxen treatment was associated with an increase of the mean daily blood loss to 6.83 +/- 9.32 ml/day, which was statistically significantly higher than 1.75 +/- 1.40 ml/day observed during treatment with naproxen + placebo. During the wash-out period, mean daily blood loss decreased to 0.98 +/- 0.51 ml/day in the naproxen + placebo group and to 1.07 +/- 0.46 ml/day in the naproxen + clopidogrel group. Based on these results, it can be concluded that clopidogrel increases naproxen-induced gastrointestinal blood loss in healthy volunteers. Caution should therefore be called for when these drugs are coadministered.
Syncope in hypertrophic cardiomyopathy: mechanisms and consequences for treatment (2007)

Hypertrophic cardiomyopathy (HCM) is an inherited disease with marked phenotypic variability that includes the extent of hypertrophy, the presence and severity of symptoms, and the natural history of the disease. Symptoms of impaired consciousness (syncope and pre-syncope) occur in approximately 15-25% of patients with hypertrophic cardiomyopathy (HCM). In young patients a history of recurrent syncope is associated with an increased risk of sudden death. Detailed investigations identify a probable mechanism in a minority of these, usually paroxysmal atrial fibrillation or ventricular tachycardia. In the majority, however, no likely mechanism is found despite extensive investigation. Although this may be the case, it is still of vital importance to exclude potentially treatable causes of syncope.
Relative molar Gibbs energies of cation transfer from a molecular liquid to ionic liquids at 298.15 K (2003)

Molar Gibbs energies of Ag+, Cu2+, Zn2+ and Cd2+ transfer from dimethylsulfoxide (DMSO), a reference molecular liquid, to a number of ionic liquids (IL), ΔtG(DMSO → IL), were obtained from M|Mn+ electrode potentials at 298.15 K. The ionic liquids consisted of various tetraalkylammonium cations and Cl−, Br−, BF4−, PF6− or N(CF3SO2)2− anions. The measured M|Mn+ (0.01 M, IL) potentials depend both on the tetraalkylammonium cation as well as on the anion. The transfer of cations from DMSO to ionic liquids brings about positive or negative changes of the molar Gibbs energy. The most important factor influencing the transfer molar Gibbs energy is the anionic component of the ionic liquid, which solvates the cation. In general, the molar Gibbs energy of cations in ionic liquids having N(CF3SO2)2− anion is lower than in those having halide or tetrafluoroborate anions.
Performance of a Dispersion Model to Estimate Methane Loss from Cattle in Pens (2009)

Accurate measurements of enteric methane (CH(4)) emissions from cattle (Bos taurus) are necessary to improve emission coefficients used in national emissions inventories, and to evaluate mitigation strategies. Our study was conducted to evaluate a novel approach that allowed near continuous CH(4) measurement from beef cattle confined in pens. The backward Lagrangian Stochastic (bLS) dispersion technique was used in conjunction with global position system (GPS) information from individual animals, to evaluate CH(4) emissions from pens of cattle. The dispersion technique was compared to estimates of CH(4) production using the SF(6) tracer technique. Sixty growing beef cattle were fed a diet containing 60% barley silage (dry matter basis) supplemented with either barley (Hordeum vulgare L.) grain or corn (Zea mays L.) distillers dried grains. The results show that daily CH(4) emissions were about 7% lower for the dispersion technique than for the tracer technique (185 vs. 199 g CH(4) animal(-1) d(-1)). The precision of the dispersion technique, relative to the SF(6) tracer technique, expressed by the Pearson coefficient was 0.76; the relative accuracy given by the concordance coefficient was 0.69. The bLS dispersion technique was able to detect differences (P < 0.05) due to diet and has the added advantage of measuring the pattern of CH(4) production during the 24-h period, with emissions ranging from 161 to 279 g CH(4) animal(-1) d(-1). Configuring the cattle as point sources resulted in more accurate CH(4) emissions than assuming a uniform area release from the pen surface. The results indicate that the bLS dispersion technique using cattle as point sources can be used to accurately measure enteric CH(4) from cattle and to evaluate the impact of dietary mitigation strategies.
Hemagglutinating Virus of Japan Liposome-Mediated Gene Delivery to Vascular Cells (2003)

Since the first report of in vivo direct gene transfer to the vessel wall in 1990 (1) several vectors, such as adenovirus, liposomes, and adeno-associated virus have been employed to introduce foreign genes to the vascular tissue in vivo. Hemagglutinating virus of Japan (HVJ, Sendai virus), a member of the mouse paramyxovirus family, has been combined with liposomes to produce a novel gene transfer system, namely, HVJ liposomes (2,3). This vector system is constructed with inactivated viral particles and nonviral lamellar liposomes, and is defined as a "viral, nonviral hybrid vector." We and others have shown that this vector system can introduce foreign genes into the vascular tissue efficiently (4-9), and have also demonstrated that these genes and synthetic oligodeoxynucleotides (ODNs) transferred by this system could add some functions to the vessel wall (4-6) or prevent the vascular proliferative diseases (7-9).
Does mammalian heart contain only the m2 muscarinic receptor subtype? (1997)

Five muscarinic acetylcholine receptor (mAChR) subtypes, m1-m5, have been cloned and sequenced to date. The question as to which mAChR subtypes exist in mammalian heart has been studied extensively and is still under considerable debate. We used the reverse transcriptase-polymerase chain reaction to amplify mRNA from adult rat ventricular myocytes, and found that these cells express mRNA for m1 and m2 mAChRs. Immunocytochemical analysis confirmed that m1 and m2, but not m3, mAChR proteins are present on the surface of these cells. Finally, the functional significance of these receptors was examined. Administration of the m1 mAChR antagonist pirenzepine inhibited the stimulatory effect of the muscarinic agonist carbachol on Ca transients. These findings are consistent with the presence of at least two mAChR subtypes in mammalian heart, m1 and m2, and suggest that activation of m1 mAChRs is involved in the stimulatory effects of muscarinic agonists in mammalian heart.
Individual variations of platelet inhibition after loading doses of clopidogrel (2002)

Clopidogrel evoked platelet inhibition exhibits a considerable individual heterogeneity. Some individuals only had weak responses whereas others displayed strong platelet inhibition. The present flow cytometry technique appears suitable for identifying patients with abnormal reactions after clopidogrel exposure.
The synthesis and chemistry of azolenines. Part 2. A general synthesis of pyrrole-2-carboxylic acid derivatives by the reaction of 2H-azirines with enamines, and the crystal and molecular structure of ethyl 3-phenyl-4,5,6,7-tetrahydroindole-2-carboxylate (1984)

A new general synthesis of 1H-pyrrole-2-carboxylic acid derivatives is described. Reaction between appropriately substituted 2H-azirines and enamines gives a mixture of 2,3- and 3,4-dihydropyrroles, which on acid treatment yields the title compounds in moderate to high yields. Attempts to extend the reaction to the preparation of 2H- and 3N-pyrroles were unsuccessful; reasons are discussed. The crystal and molecular structure of ethyl 3-phenyl-4,5,6,7-tetrahydroindole-2-carboxylate has been determined. The molecules pack in highly coplanar, centrosymmetric, hydrogen-bonded pairs.
Colchicine-binding protein of mammalian brain and its relation to microtubules (1968)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTColchicine-binding protein of mammalian brain and its relation to microtubulesRichard C. Weisenberg, Gary G. Broisy, and Edwin William. TaylorCite this: Biochemistry 1968, 7, 12, 4466–4479Publication Date (Print):December 1, 1968Publication History Published online1 May 2002Published inissue 1 December 1968https://doi.org/10.1021/bi00852a043RIGHTS & PERMISSIONSArticle Views1293Altmetric-Citations890LEARN 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 InReddit PDF (3 MB) Get e-Alerts Get e-Alerts
Reprograming the Replisome of a Semisynthetic Organism for the Expansion of the Genetic Alphabet (2018)

Semisynthetic organisms (SSOs) created from Escherichia coli can replicate a plasmid containing an unnatural base pair (UBP) formed between the synthetic nucleosides dNaM and dTPT3 (dNaM-dTPT3) when the corresponding unnatural triphosphates are imported via expression of a nucleoside triphosphate transporter. The UBP can also be transcribed and used to translate proteins containing unnatural amino acids. However, UBPs are not well retained in all sequences, limiting the information that can be encoded, and are invariably lost upon extended growth. Here we explore the contributions of the E. coli DNA replication and repair machinery to the propagation of DNA containing dNaM-dTPT3 and show that replication by DNA polymerase III, supplemented with the activity of polymerase II and methyl-directed mismatch repair contribute to retention of the UBP and that recombinational repair of stalled forks is responsible for the majority of its loss. This work elucidates fundamental aspects of how bacteria replicate DNA and we use this information to reprogram the replisome of the SSO for increased UBP retention, which then allowed for the first time the construction of SSOs harboring a UBP in their chromosome.