gebhart/patrepeval huggingface dataset:
Development of a Thermally Regulated Broad-Spectrum Promoter System for Use in Pathogenic Gram-Positive Species (2003)

Selectively regulating gene expression is an essential molecular tool that is lacking for many pathogenic gram-positive bacteria. In this report, we describe the evaluation of a series of promoters regulated by the bacteriophage P1 temperature-sensitive C1 repressor in Enterococcus faecium, Enterococcus faecalis, and Staphylococcus aureus. Using the lacZ gene to monitor gene expression, we examined the strength, basal expression, and induced expression of synthetic promoters carrying C1 operator sites. The promoters exhibited extremely low basal expression and, under inducing conditions, gave high levels of expression (100- to 1,000-fold induction). We demonstrate that the promoter system could be modulated by temperature and showed rapid induction and that the mechanism of regulation occurred at the level of transcription. Controlled expression with the same constructs was also demonstrated in the gram-negative bacterium Escherichia coli. However, low basal expression and the ability to achieve derepression were dependent on both the number of mismatches in the C1 operator sites and the promoter driving c1 expression. Since the promoters were designed to contain conserved promoter elements from gram-positive species and were constructed in a broad-host-range plasmid, this system will provide a new opportunity for controlled gene expression in a variety of gram-positive bacteria.
Optical Limiting Properties of Suspended and Solubilized Carbon Nanotubes (2000)

Full and shortened single-walled and multiple-walled carbon nanotubes were suspended in water to form stable suspensions in the presence of a surfactant. Optical limiting properties of the suspensions were determined for 532-nm pulsed laser irradiation, and the results were comparable with those of carbon black aqueous suspension. Solubilization of the shortened carbon nanotubes was achieved by attaching the nanotubes to highly soluble poly(propionylethylenimine-co-ethylenimine) or by functionalizing the nanotubes with octadecylamine. The soluble carbon nanotube samples formed homogeneous solutions in room-temperature chloroform. Optical limiting properties of these solutions were also determined for 532-nm pulsed laser irradiation, and the results were found to be quite different from those of the carbon nanotube aqueous suspensions. Apparently, the carbon nanotubes exhibit significantly weaker optical limiting responses in homogeneous solutions than in suspensions. Mechanistic implications of the experimental results are discussed.
Organic chemistry of L-tyrosine. 1. General synthesis of chiral piperazines from amino acids (1985)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTOrganic chemistry of L-tyrosine. 1. General synthesis of chiral piperazines from amino acidsMichael E. Jung and John C. RohloffCite this: J. Org. Chem. 1985, 50, 24, 4909–4913Publication Date (Print):November 1, 1985Publication History Published online1 May 2002Published inissue 1 November 1985https://pubs.acs.org/doi/10.1021/jo00224a051https://doi.org/10.1021/jo00224a051research-articleACS PublicationsRequest reuse permissionsArticle Views1742Altmetric-Citations77LEARN 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
Production of Recombinant Bispecific Antibodies (2004)

Recombinant bispecific antibodies have great potential as diagnostic and therapeutic reagents (1,2). Applications of recombinant bispecific antibodies include the recruitment of effector molecules (e.g., enzymes, complement components, immunoglobulins), effector cells (cytotoxic T-lymphocytes, natural killer [NK] cells, macrophages), or gene-therapeutic vectors (e.g., adenoviruses) to other molecules or target cells (3–10). Through genetic engineering, molecules with the desired properties can be generated and produced in various prokaryotic or eukaryotic expression systems (11). For example, by starting from antibody fragments isolated from human combinatorial libraries by phage display, completely human bispecific molecules can be generated.
Functional Conversion of Hemocyanin to Phenoloxidase by Horseshoe Crab Antimicrobial Peptides (2001)

Arthropod hemocyanins and phenoloxidases serve different physiological functions as oxygen transporters and enzymes involved in defense reactions, respectively. However, they are equipped with a structurally similar oxygen-binding center. We have shown that the clotting enzyme of the horseshoe crab, Tachypleus tridentatus, functionally converts hemocyanin to phenoloxidase by forming a complex without proteolytic cleavage (Nagai, T., and Kawabata, S. (2000) J. Biol. Chem. 275, 35297-35301). Here we show that chitin-binding antimicrobial peptides of the horseshoe crab induce the intrinsic phenoloxidase activity of hemocyanin. Tachyplesin, a major Tachypleus antimicrobial peptide with an amphiphilic structure, converted the hemocyanin to phenoloxidase. Surface plasmon resonance analysis revealed the specific interaction of tachyplesin with hemocyanin at K(d) = 3.4 x 10(-)6 m. The chemical modification of Trp or Tyr in tachyplesin, but not Lys or Arg, dramatically reduced the affinity to hemocyanin, suggesting that the binding site is located in the hydrophobic face of tachyplesin. Hemocyanin has no affinity with chitin, but it significantly binds to tachyplesin-coated chitin, leading to the expression of phenoloxidase activity. The chitin coated with antimicrobial peptides may serve as a scaffold for the binding of hemocyanin, and the resulting phenoloxidase activity appears to function as a trigger of exoskeleton wound healing.
Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer (2006)

The combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance.
Conformation State-sensitive Antibodies to G-protein-coupled Receptors (2006)

A growing body of evidence indicates that G-protein-coupled receptors undergo complex conformational changes upon agonist activation. It is likely that the extracellular region, including the N terminus, undergoes activation-dependent conformational changes. We examined this by generating antibodies to regions within the N terminus of micro-opioid receptors. We find that antibodies to the midportion of the N-terminal tail exhibit enhanced recognition of activated receptors, whereas those to the distal regions do not. The enhanced recognition is abolished upon treatment with agents that block G-protein coupling or deglycosylate the receptor. This suggests that the N-terminal region of mu receptors undergoes conformational changes following receptor activation that can be selectively detected by these region-specific antibodies. We used these antibodies to characterize micro receptor type-specific ligands and find that the antibodies accurately differentiate ligands with varying efficacies. Next, we examined if these antibodies can be used to investigate the extent and duration of activation of endogenous receptors. We find that peripheral morphine administration leads to a time-dependent increase in antibody binding in the striatum and prefrontal cortex with a peak at about 30 min, indicating that these antibodies can be used to probe the spatio-temporal dynamics of native mu receptors. Finally, we show that this strategy of targeting the N-terminal region to generate receptor conformation-specific antisera can be applied to other G(alpha)(i)-coupled (delta-opioid, CB1 cannabinoid, alpha(2A)-adrenergic) as well as G(alpha)(s)-(beta(2)-adrenergic) and G(alpha)(q)-coupled (AT1 angiotensin) receptors. Taken together, these studies describe antisera as tools that allow, for the first time, studies probing differential conformation states of G-protein-coupled receptors, which could be used to identify molecules of therapeutic interest.
Significance of phytic acid and supplemental phytase in chicken nutrition: a review (2008)

Phytic acid is an anti-nutritional constituent of plant derived feeds. As a reactive anion, it forms a wide variety of insoluble salts with minerals including phosphorus, calcium, zinc, magnesium and copper. Phytic acid is also known to form complexes with protein and proteolytic enzymes (pepsin and trypsin). Because of the lack of endogenous phytase enzymes that hydrolyze phytic acid; phosphorus, calcium, protein and other phytic acid bound nutrients are less available to poultry. Commercially-available microbial phytase has great nutritional significance and ecological importance. Poultry diets supplemented with microbial phytase result in improved growth performance and increased digestibility and availability of phytate bound phosphorous, calcium, zinc and copper. Microbial phytase supplementation has also been shown to increase ileal digestibility of crude protein and amino acids. The efficacy of supplemental microbial phytase depends on its rate of inclusion, dietary calcium and phosphorus ratio, vitamin D3, nature of diet, age and genotype of birds. Thus, microbial phytase can be used to exploit the inherent nutritional potential of feedstuffs for more economic and environmentally-friendly poultry production.
Isoleucine Auxotrophy as a Consequence of a Mutationally Altered Isoleucyl-Transfer Ribonucleic Acid Synthetase (1971)

Among mutants which require isoleucine, but not valine, for growth, we have found two distinguishable classes. One is defective in the biosynthetic enzyme threonine deaminase (l-threonine hydro-lyase, deaminating, EC 4.2.1.16) and the other has an altered isoleucyl transfer ribonucleic acid (tRNA) synthetase [l-isoleucine: soluble RNA ligase (adenosine monophosphate), EC 6.1.1.5]. The mutation which affects ileS, the structural gene for isoleucyl-tRNA synthetase, is located between thr and pyrA at 0 min on the map of the Escherichia coli chromosome. This mutationally altered isoleucyl-tRNA synthetase has an apparent K(m) for isoleucine ( approximately 1 mm) 300-fold higher than that of the enzyme from wild type; on the other hand, the apparent V(max) is altered only slightly. When the mutationally altered ileS allele was introduced into a strain which overproduces isoleucine, the resulting strain could grow without addition of isoleucine. We conclude that the normal intracellular isoleucine level is not high enough to allow efficient charging to tRNA(Ile) by the mutant enzyme because of the K(m) defect. A consequence of the alteration in isoleucyl-tRNA synthetase was a fourfold derepression of the enzymes responsible for isoleucine biosynthesis. Thus, a functional isoleucyl-tRNA synthetase is needed for isoleucine to act as a regulator of its own biosynthesis.
Oxytocin, "salting out," and water intoxication (1972)

Two patients developed water intoxication following transabdominal intraamniotic injection of hypertonic saline solution ("salting out") and oxytocin infusion. Oxytocin infusion alone has been reported to produce this complication. Salting out produces an expanded extracellular volume, which, combined with the antidiuretic effect of oxytocin drip, provides a greater danger of producing water intoxication. Patients receiving this combined treatment must have restricted fluid intake at the beginning of oxytocin infusion.
Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose (1999)

The glycation of proteins by glucose has been linked to the development of diabetic complications and other diseases. Early glycation is thought to involve the reaction of glucose with N-terminal and lysyl side chain amino groups to form Schiff's base and fructosamine adducts. The formation of the alpha-oxoaldehydes, glyoxal, methylglyoxal and 3-deoxyglucosone, in early glycation was investigated. Glucose (50 mM) degraded slowly at pH 7.4 and 37 degrees C to form glyoxal, methylglyoxal and 3-deoxyglucosone throughout a 3-week incubation period. Addition of t-BOC-lysine and human serum albumin increased the rate of formation of alpha-oxoaldehydes - except glyoxal and methylglyoxal concentrations were low with albumin, as expected from the high reactivity of glyoxal and methylglyoxal with arginine residues. The degradation of fructosyl-lysine also formed glyoxal, methylglyoxal and 3-deoxyglucosone. alpha-Oxoaldehyde formation was dependent on the concentration of phosphate buffer and availability of trace metal ions. This suggests that alpha-oxoaldehydes were formed in early glycation from the degradation of glucose and Schiff's base adduct. Since alpha-oxoaldehydes are important precursors of advanced glycation adducts, these adducts may be formed from early and advanced glycation processes. Short periods of hyperglycaemia, as occur in impaired glucose tolerance, may be sufficient to increase the concentrations of alpha-oxoaldehydes in vivo.
Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate. (1993)

The regulation of the Ca(2+)- and phorbol ester-insensitive zeta isozyme of protein kinase C (PKC zeta) by phospholipids was studied. Phosphatidylserine (PS) stimulated the activity to the same extent as proteolysis by calpain. However, the PS stimulation was abolished by phosphatidylethanolamine (PE) or phosphatidylcholine. Phosphatidylinositol-3,4,5-P3 (PIP3) produced a large stimulation of PKC zeta in the absence or presence of PS plus PE that was equal to that seen with PS alone. In the presence of PS plus PE, PIP3 was half-maximally effective at 50 nM. Phosphatidylinositol-3,4-P2 also fully activated PKC zeta, but higher concentrations (0.5 microM) of phosphatidylinositol-3-P, phosphatidylinositol-4-P, and phosphatidylinositol-4,5-P2 produced only partial (11-30%) activation of the enzyme. In contrast, when tested with "conventional" PKC purified from rat brain, none of the inositol phospholipids produced more than one-third of the stimulation seen with PS plus Ca2+ plus phorbol ester, and there was little difference between the efficacy of PIP3 and that of the other phospholipids. PIP3 produced a marked stimulation of the autophosphorylation of PKC zeta, indicating that it interacted with the enzyme directly. These results suggest that PKC zeta may be a target for PIP3 and thus may be involved in the signaling mechanism(s) for growth factors and oncogenes that increase phosphatidylinositol 3-kinase activity.
Synthesis of 8‐methyl‐2‐azainosine and related nucleosides (1984)

Abstract The synthesis of 6‐methyl‐7‐(β‐D‐ribofuranosyl)imidazo[4,5‐ d ]‐ v ‐triazin‐4‐one (8‐methyl‐2‐azainosine ( 2) ) and 6‐methyl‐7‐(β‐D‐glucopyranosyl)imidazo[4,5‐ d ]‐ v ‐triazin‐4‐one ( 5 ) by diazotization of 5‐amino‐1‐(β‐D‐ribofuranosyl)‐2‐methylimidazole‐4‐carboxamide ( 1 ) and diazotization of 5‐amino‐1‐(2,3,4,6‐tetra‐ O ‐acetyl‐β‐D‐glucopyranosyl)‐2‐methylimidazole‐4‐carboxamide ( 3 ), followed by deacetylation of the resulting compound 4 , is described. The preparation of 6‐methyl‐5‐(β‐D‐ribofuranosyl)imidazo[4,5‐ d ]‐ v ‐triazin‐4‐one ( 10 ) and 6‐methyl‐5‐(β‐D‐glucopyranosyl)imidazo[4,5‐ d ]‐ v ‐triazin‐4‐one ( 11 ) by glycosylation of 6‐methylimidazo[4,5‐ d ]‐ v ‐triazin‐4‐one (8‐methyl‐2‐azahypoxanthine, ( 7) ) is also described. Structural assignments were made on basis of analytical and 1 H‐nmr and uv spectral data.
Discovery of Ritonavir, a Potent Inhibitor of HIV Protease with High Oral Bioavailability and Clinical Efficacy (1998)

The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 microM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.
The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1 (2010)

We conclude that PU-H71 is a promising drug for the treatment of myeloma. Our finding further suggests that PU-H71 and the geldanamycin analogues work in part by inhibiting the endoplasmic reticulum gp96 along with the cytosolic HSP90.
Statistical considerations and endpoints for clinical lung cancer studies: Can progression free survival (PFS) substitute overall survival (OS) as a valid endpoint in clinical trials for advanced non-small-cell lung cancer? (2012)

In the last decades significant progress has been achieved in the biological understanding of non-small-cell lung cancer (NSCLC) and its tumor heterogeneity has become more evident. The identification of novel tumor targets with different pathways has stimulated the search for anti-tumor agents with a specific target directed mode of action, stipulating the need of testing these agents in clinical trials with an appropriate choice of the study endpoint. Gold standard as an endpoint has been so far overall survival (OS). By definition there are 3 categories of classical endpoints applied generally in clinical lung cancer studies: survival time endpoints, symptom endpoints, and endpoints relying on patients' reporting. Beside classical endpoints like OS which are tending to show the direct clinical effect of treatment, efforts have been taken to substitute these classical endpoints by surrogates. As a surrogate candidate for OS progression-free survival (PFS) should have the inherent considerable advantage, that it can detect subpopulations with longer PFS intervals early. Based on the (sub-) population treated and having in mind the risk-benefit profile of the drug under consideration, PFS can be considered for regulatory decision making. If accompanied by some independent measures like quality of life or treatment toxicity, PFS should be able to cover the clinical benefit achieved by treatment. Selecting PFS as primary endpoint in Phase III trials of advanced NSCLC may be based on a number of questions such as: Does the definition of PFS fit into the setting used by other trials? Are there accepted consensus standards? Are there consistent surveillance intervals? Is validation for each agent group planned? Is the incremental improvement of PFS big enough (≥30%)? And are there some additional measures to confine clinical benefit? OS is still accepted as the gold standard in trials investigating advanced NSCLC. OS is easy to measure and precise but it may be difficult to interpret if treatment action takes place only in a small subinterval of overall survival. PFS with some additional measures has become attractive when it seems advisable to make study results available earlier. Candidates for supporting PFS as "additional measures" may be treatment toxicity and quality of life measures. PFS allows a more precise detection and attribution to effects of the investigational treatment without being compromised by subsequent treatments. Therefore "enriched PFS" can be considered as an alternative primary endpoint replacing OS in studies investigating advanced NSCLC. The endpoint selection process should always be performed carefully considering all true and surrogate endpoint options in respect to the hypotheses to be proven.
Specific Targeting of Tumor Endothelial Cells by a Shiga-like Toxin-Vascular Endothelial Growth Factor Fusion Protein as a Novel Treatment Strategy for Pancreatic Cancer (2010)

SLT-VEGF is toxic for tumor vasculature rather than for normal endothelial or pancreatic cancer cells. SLT-VEGF treatment in combination with gemcitabine may provide a novel approach for pancreatic cancer.
<title>Detecting small anatomical change with 3D serial MR subtraction images</title> (1999)

Spoiled gradient echo volume MR scans were obtained from 5 growth hormone (GH) patients and 6 normal controls. The patients were scanned before treatment and after 3 and 6 months of GH therapy. The controls were scanned at similar intervals. A calibration phantom was scanned on the same day as each subject. The phantom images were registered with a 9 degree of freedom algorithm to measure scaling errors due to changes in scanner calibration. The second and third images were each registered with a 6 degree of freedom algorithm to the first (baseline) image by maximizing normalized mutual information, and transformed, with and without scaling error correction, using sinc interpolation. Each registered and transformed image had the baseline image subtracted to generate a difference image. Two neuro-radiologists were trained to detect structural change with difference images containing synthetic misregistration and scale changes. They carried out a blinded assessment of anatomical change for the unregistered; aligned and subtracted; and scale corrected, aligned and subtracted images. The results show a significant improvement in the detection of structural change and inter-observer agreement when aligned and subtracted images were used instead of unregistered ones. The structural change corresponded to an increase in brain: CSF ratio.
Advances in surface plasmon resonance biomolecular interaction analysis mass spectrometry (BIA/MS) (1999)

Ongoing, worldwide efforts in genomic and protein sequencing, and the ability to readily access corresponding sequence databases, have emphatically driven the development of high-performance bioanalytical instrumentation capable of characterizing proteins and protein-ligand interactions with great accuracy, speed and sensitivity. Two such analytical techniques have arisen over the past decade to play key roles in the characterization of proteins: surface plasmon resonance biomolecular interaction analysis (SPR-BIA) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF). SPR-BIA is used in the real-time investigation of biomolecular recognition events, and is thereby capable of providing details on the association and dissociation kinetics involved in the interaction, information ultimately leading to the determination of dissociation constants involved in the event. MALDI-TOF is used in the structural characterization, identification and sensitive detection of biomolecules. Although the two techniques have found many independent uses in bioanalytical chemistry, the combination of the two, to form biomolecular interaction analysis mass spectrometry (BIA/MS), enables a technique of analytical capabilities greater than those of the component parts. Reviewed here are issues of concern critical to maintaining high-levels of performance throughout the multiplexed analysis, as well as examples illustrating the potential analytical capabilities of BIA/MS.