gebhart/patrepeval huggingface dataset:
Role of murE in the Expression of β-Lactam Antibiotic Resistance in Staphylococcus aureus (2004)

It was shown earlier that Tn551 inserted into the C-terminal region of murE of parental methicillin-resistant Staphylococcus aureus strain COL causes a drastic reduction in methicillin resistance, accompanied by accumulation of UDP-MurNAc dipeptide in the cell wall precursor pool and incorporation of these abnormal muropeptides into the peptidoglycan of the mutant. Methicillin resistance was recovered in a suppressor mutant. The murE gene of the same strain was then put under the control of the isopropyl-beta-D-thiogalactopyranoside (IPTG)-inducible promoter P(spac). Bacteria grown in the presence of suboptimal concentrations of IPTG accumulated UDP-MurNAc dipeptide in the cell wall precursor pool. Both growth rates and methicillin resistance levels (but not resistance to other antibiotics) were a function of the IPTG concentration. Northern analysis showed a gradual increase in the transcription of murE and also in the transcription of pbpB and mecA, parallel with the increasing concentrations of IPTG in the medium. A similar increase in the transcription of pbpB and mecA, the structural genes of penicillin-binding protein 2 (PBP2) and PBP2A, was also detected in the suppressor mutant. The expression of these two proteins, which are known to play critical roles in the mechanism of staphylococcal methicillin resistance, appears to be-directly or indirectly-under the control of the murE gene. Our data suggest that the drastic reduction of the methicillin MIC seen in the murE mutant may be caused by the insufficient cellular amounts of these two PBPs.
Emerging standards for component software (1995)

Component software benefits include reusability and interoperability, among others. What are the similarities and differences between the competing standards for this new technology, and how will they interoperate? Object-oriented technology is steadily gaining acceptance for commercial and custom application development through programming languages such as C++ and Smalltalk, object oriented CASE tools, databases, and operating systems such as Next Computer's NextStep. Two emerging technologies, called compound documents and component software, will likely accelerate the spread of objectoriented concepts across system-level services, development tools, and application-level behaviours. Tied closely to the popular client/server architecture for distributed computing, compound documents and component software define object-based models that facilitate interactions between independent programs. These new approaches promise to simplify the design and implementation of complex software applications and, equally important, simplify human-computer interactive work models for application end users. Following unfortunate tradition, major software vendors have developed competing standards to support and drive compound document and component software technologies. These incompatible standards specify distinct object models, data storage models, and application interaction protocols. The incompatibilities have generated confusion in the market, as independent software vendors, system integrators, in-house developers, and end users struggle to sort out the standards' relative merits, weaknesses, and chances for commercial success. Let's take a look now at the general technical concepts underlying compound documents and component software. Then we examine the OpenDoc, OLE 2, COM, and CORBA standards being proposed for these two technologies. Finally, we'll review the work being done to extend the standards and to achieve interoperability across them.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Hydrophone for Measuring Particle Velocity (1956)

Mathematical expressions are derived for the motion of a rigid, uniform sphere in an underwater sound field. The results show that at low frequencies a neutrally buoyant sphere of this type has a velocity equal to the particle velocity of the water at the same location when the sphere is removed. A velocity pickup may be mounted inside such a sphere to form a hydrophone sensitive to particle velocity. Two practical design applications are presented. A low-frequency hydrophone with a diameter of five inches was constructed having an essentially flat response between 15 and 700 cps with a sensitivity of 0.18 volt/cm/sec working into a 500-ohm load. A higher frequency design with a 2.5-inch diameter operated from 70 to 7000 cps with somewhat lower sensitivity and impedance level. Velocity hydrophones of this type are easy to build, easily calibrated, stable, and possess good directionality.
Detection of circulating soluble CD28 in patients with systemic lupus erythematosus, primary Sjögren's syndrome and systemic sclerosis (2004)

The aim of this study was to evaluate the presence and the role of the serum soluble costimulatory molecule CD28 in patients with systemic lupus erythematosus (SLE), primary Sjögren's syndrome (SS), and systemic sclerosis (SSc). Soluble CD28 concentration was determined by ELISA in 45 patients with SLE, 45 patients with primary SS, 30 patients with SSc, and 45 healthy subjects. We also evaluated CD28 mRNA expression by semiquantitative RT-PCR, and the biological activity of recombinant soluble CD28 on T lymphocyte activity. Concentrations of soluble CD28 were significantly higher in patients with SLE, primary SS and SSc than in healthy subjects. Soluble CD28 concentrations were higher in patients with systemic primary SS than in patients with glandular-limited primary SS. PCR analysis suggested that soluble CD28 resulted from the shedding of the membrane form. In vitro assay revealed that soluble CD28 inhibits the anti-CD3 mAb induced T cell proliferation. Soluble CD28, which modulates the proliferation of T lymphocytes, could be associated with disease severity in patients with autoimmune disease, especially primary SS. These results suggest that soluble CD28 could play an important role in the regulation of autoimmune diseases.
PG490-88, a derivative of triptolide, causes tumor regression and sensitizes tumors to chemotherapy. (2003)

Treatment of solid tumors with combinations of chemotherapeutic agents has not led to significant increases in long-term survival. Recent studies support a role for inhibitors of checkpoint arrest as a means to enhance the cytotoxicity of chemotherapy. We have shown previously that triptolide (PG490), an oxygenated diterpene derived from a Chinese medicinal plant, induces apoptosis in cultured tumor cells and sensitizes tumor cells to topoisomerase inhibitors by blocking p53-mediated induction of p21. Here we extend our studies to a tumor xenograft model and evaluate the efficacy and safety of PG490-88 (14-succinyl triptolide sodium salt), a water-soluble prodrug of PG490. We also look at the combination of PG490 or PG490-88 with CPT-11, a topoisomerase I inhibitor, in cultured cells and in the tumor xenograft model. We show that PG490-88 is a safe and potent antitumor agent when used alone, causing tumor regression of lung and colon tumor xenografts. We also show that PG490-88 acts in synergy with CPT-11 to cause tumor regression. A phase I trial of PG490-88 for solid tumors began recently and safety and optimal dosing data should accrue within the next 12 months. Our findings that PG490-88 causes tumor regression and that it acts in synergy with DNA-damaging chemotherapeutic agents suggest a role as an antineoplastic agent and chemosensitizer for the treatment of patients with solid tumors.
Chromatic Dispersion Compensation In A Fresnel Lens By Means Of A Diffraction Grating (1989)

A Fresnel lens&apos;s imaging performance can be seriously impaired by chromatic dispersion which typically doubles the diameter of the focused sun image in a solar concentrator. This problem can be alleviated by means of a molded diffraction grating whose diffraction-induced dispersion offsets and substantially cancels the lens&apos;s intrinsic refractive index dispersion. The grating lines would comprise a second tier of small-scale, Fresnel-type facets superimposed on the lens facets, with a typical grating facet height of about 40 microinches and a facet width ranging from about 1 milliinch at the edge of the lens to around 5 or 10 milliinches near the center. In its primary intended application the grating would function in a core daylighting system to improve the optical performance of a collector which focuses direct sunlight into fiber optic couplers. For this application chromatic dispersion would be reduced by an order of magnitude with only a 2% loss in optical efficiency.
The role of phosphatidic acid in the regulation of the Ras/MEK/Erk signaling cascade (2002)

Phosphatidic acid (PA) is an important second messenger produced by the activation of numerous cell surface receptors. Recent data have suggested that PA regulates multiple cellular processes. This review addresses primarily the role of PA in the regulation of the Erk1/2 cascade pathway. A model for the regulation of Erk1/2 phosphorylation by cell surface receptors is presented. According to this model, agonists stimulate the binding of GTP to Ras and the activation of phospholipase D to generate phosphatidic acid. PA promotes the binding of cRaf-1 kinase to the membrane, where it interacts with Ras.GTP and other regulatory components of the pathway. Ras-Raf complexes remain bound to the surface of endosomes, where scaffolding complexes involving Ras, cRaf-1, MEK and Erk are formed. Complete activation and coupling of the cascade requires endocytosis, a process that is also modulated by PA.
Bone morphogenetic protein‐2 decorated silk fibroin films induce osteogenic differentiation of human bone marrow stromal cells (2004)

Bone morphogenetic protein (BMP)-2 has a critical role in bone formation and regeneration. Therefore, the ability to immobilize this molecule in certain matrices may be crucial in bone tissue engineering. Using carbodiimide chemistry, BMP-2 was directly immobilized on silk fibroin films. Whereas human bone marrow stromal cells cultured on unmodified silk fibroin films in the presence of osteogenic stimulants exhibited little if any osteogenesis, the same cells cultured on BMP-2 decorated films in the presence of osteogenic stimulants differentiated into an osteoblastic lineage as assessed by their significantly elevated alkaline phosphatase activity, calcium deposition, and higher transcript levels of collagen type I, bone sialoprotein, osteopontin, osteocalcin, BMP-2, and cbfa1. Using cell culture inserts, it was demonstrated that differentiation was induced by the immobilized protein and not by protein released into the culture medium. Comparison with a similar amount of medium-supplemented BMP-2, where no additional protein was added with medium changes, showed that delivery of BMP-2 immobilized on the biomaterial surface was more efficient than soluble delivery. The results illustrate that BMP-2 covalently coupled on silk biomaterial matrices retains biological function in vitro based on the induction of osteogenic markers in seeded bone marrow stromal cells.
Thy-1+ dendritic epidermal cells belong to the T-cell lineage. (1987)

The murine epidermis contains a population of dendritic, Thy-1+ cells (Thy-1+ DEC). Although it is now clear that these cells are of bone marrow origin, extensive morphological, histochemical, and cell-membrane marker studies have not definitively placed them in any known hematopoietic differentiation pathway. Based on the observation that Thy-1+ DEC can be propagated in vitro with Con A and interleukin 2, we have established three cell lines (Tehy 184, Tehy 245, and Yety 245) that can be continuously grown in medium with lectin-lymphokine-rich culture supernatants of rat spleen cells. With the exception of the loss of reactivity with anti-asialo-GM1 antibodies (Tehy 184 and Tehy 245) and the gain of interleukin 2 receptor expression, the cultured cell lines bear the same surface characteristics as freshly isolated Thy-1+ DEC: Thy-1+, Ly-5+, Lyt-1-, Lyt-2-, L3T4-, Ia-, sIg-. Using Southern and RNA gel blot analysis, we now demonstrate that these Thy-1+ DEC-derived cell lines exhibit various patterns of rearrangements in the gene complexes encoding the T-cell receptor (related) beta and gamma chains and contain mature and/or incomplete transcripts from the T-cell receptor alpha- and beta-chain genes, as well as transcripts from the receptor-related gamma-chain genes. Tehy 184 cells, the only cells containing both mature alpha- and beta-chain transcripts, react positively with the F23.1 monoclonal antibody, which recognizes the product of a subset of T-cell receptor beta-chain variable region gene segments. This antibody precipitates a surface protein of 84-88 kDa from these cells that after reduction separates into two 40- to 44-kDa chains, characteristic of Ti alpha/beta heterodimers. These data strongly suggest that Thy-1+ DEC belong to the T-cell lineage and point to the epidermis as a site either of immature thymocyte migration or of extrathymic T-cell differentiation.
Somatostatin-Dopamine Chimeras: A Novel Approach to Treatment of Neuroendocrine Tumors (2011)

A combination of basic research observations concerning the interaction of somatostatin (SST) and dopamine (DA) receptors, and clinical reports of enhanced efficacy of combined SST and DA analogue treatment in suppressing GH hypersecretion, lead to the concept of creating chimeric molecules combining structural features of both compound classes. The resulting SST/DA chimeras retain the ability to interact with receptors of both families and display greatly enhanced potency and efficacy, as compared with that of individual SST or DA receptor agonists. In vitro studies with pituitary adenoma cells from acromegalic patients have demonstrated that the chimeric molecules have exceptional activity with regard to suppression of GH and prolactin secretion. Similarly, potent suppression of ACTH secretion from Cushing's-causing corticotroph tumors, and suppression of nonfunctioning pituitary adenoma proliferation has been observed. The chimeric SST/DA compounds are also quite potent and efficacious in suppressing both GH and IGF1 in vivo when tested in nonhuman primates, with no effect on either insulin secretion or glycemic control. Initial clinical studies examining acute, subcutaneous administration of the chimeric SST/DA compound, BIM-23A760, revealed both prolonged circulating half-life and extended duration of biological effect. With chronic administration, however, BIM-23A760 was found to produce a metabolite with dopaminergic activity that gradually accumulates and interferes with the activity of the parent compound. Consequently, efforts are currently underway to produce a second-generation chimera for treatment of neuroendocrine disease.
A prostaglandin E (PGE) receptor EP4 antagonist protects natural killer cells from PGE2-mediated immunosuppression and inhibits breast cancer metastasis (2013)

Cyclooxygenase-2 is frequently upregulated in epithelial tumors and contributes to poor outcomes in multiple malignancies. The COX-2 product prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) promotes tumor growth and metastasis by acting on a family of four G protein-coupled receptors (EP1-4). Using a novel small molecule EP4 antagonist (RQ-15986) and a syngeneic murine model of metastatic breast cancer, we determined the effect of EP4 blockade on innate immunity and tumor biology. Natural killer (NK)-cell functions are markedly depressed in mice bearing murine mammary tumor 66.1 or 410.4 cells owing to the actions of PGE<sub>2</sub> on NK cell EP4 receptors. The EP4 agonist PGE<sub>1</sub>-OH inhibits NK functions in vitro, and this negative regulation is blocked by RQ-15986. Likewise, the treatment of tumor-bearing mice with RQ-15986 completely protected NK cells from the immunosuppressive effects of the tumor microenvironment in vivo. RQ-15986 also has direct effects on EP4 expressed by tumor cells, inhibiting the PGE<sub>2</sub>-mediated activation of adenylate cyclase and blocking PGE<sub>2</sub>-induced tumor cell migration. The pretreatment of tumor cells with a non-cytotoxic concentration of RQ-15986 inhibited lung colonization, a beneficial effect that was lost in mice depleted of NK cells. The oral administration of RQ-15986 inhibited the growth of tumor cells implanted into mammary glands and their spontaneous metastatic colonization to the lungs, resulting in improved survival. Our findings reveal that EP4 antagonism prevents tumor-mediated NK-cell immunosuppression and demonstrates the anti-metastatic activity of a novel EP4 antagonist. These observations support the investigation of EP4 antagonists in clinical trials.
SOS-NMR:  A Saturation Transfer NMR-Based Method for Determining the Structures of Protein−Ligand Complexes (2004)

An NMR-based alternative to traditional X-ray crystallography and NMR methods for structure-based drug design is described that enables the structure determination of ligands complexed to virtually any biomolecular target regardless of size, composition, or oligomeric state. The method utilizes saturation transfer difference (STD) NMR spectroscopy performed on a ligand complexed to a series of target samples that have been deuterated everywhere except for specific amino acid types. In this way, the amino acid composition of the ligand-binding site can be defined, and, given the three-dimensional structure of the protein target, the three-dimensional structure of the protein-ligand complex can be determined. Unlike earlier NMR methods for solving the structures of protein-ligand complexes, no protein resonance assignments are necessary. Thus, the approach has broad potential applications--especially in cases where X-ray crystallography and traditional NMR methods have failed to produce structural data. The method is called SOS-NMR for structural information using Overhauser effects and selective labeling and is validated on two protein-ligand complexes: FKBP complexed to 2-(3'-pyridyl)-benzimidazole and MurA complexed to uridine diphosphate N-acetylglucosamine.
Protein engineering via site-specific incorporation of nonnatural amino acids (2007)

Nonnatural amino acid incorporation has been one of the most important protein engineering techniques. Particularly site-specific incorporation of nonnatural amino acids would allow design of artificial proteins containing a nonnatural amino acid with minimal perturbation of their native properties. Site-specific incorporation of phenylalanine (Phe) analogs and tryptophan (Trp) analogs, such as p -bromophenylalanine (pBrF), p -iodophenylalanine, p -azidophenylalanine, 6-chlorotrytophan, 6-bromotryptophan, 5-bromotrytophan, and benzothienylalanine, into proteins in Escherichia coli has been realized by E. coli strains outfitted with a mutant yeast phenylalanyl-tRNA suppressor (ytRNA Phe CUA ) and a mutant yeast phenylalanyl-tRNA synthetase (yPheRS (T415G)) with a point mutation in the active site of the enzyme. In order to reduce Trp and lysine (Lys) misincorporation at an amber codon, the ytRNA Phe CUA_UG containing the optimized sequence and the yPheRS (T415A) showing higher specificity toward pBrF were developed. Combining ytRNA Phe CUA_UG and yPheRS (T415A) allowed incorporation of pBrF into murine dihydrofolate reductase in response to an amber codon with at least 98% fidelity.

Re-assignment of degenerate sense codons offers the prospect of a substantially expanded genetic code and a correspondingly enriched set of building blocks for natural and artificial proteins. Here we describe the use of a mutant yeast phenylalanine transfer RNA (ytRNA Phe AAA ) containing a modified anticodon to break the degeneracy of the genetic code in E. coli . By using an E. coli strain co-transformed with ytRNA Phe AAA and a mutant yPheRS (T415G), we demonstrated efficient replacement of Phe by L-3-(2-naphthyl)alanine (2Nal) at UUU, but not at UUC codons.

However, this method had two limitations. First, the yPheRS (T415G) also activated Trp, which led to Trp misincorporation. Second, 2Nal was misincorporated at UUC Phe codons, due to the relaxed codon recognition of AAA anticodon in the ytRNA Phe AAA . High-throughput screening of a yPheRS library led to a more selective yPheRS variant (yPheRS_naph). The rationally designed ytRNA Phe CAA , which has the CAA anticodon recognizing only a UUG (Leu) codon, allowed incorporation of 2Nal only at UUG codon. Combined use of yPheRS_naph and ytRNA Phe CAA achieved multiple-site-specific incorporation of 2Nal into proteins. These results illustrate a general method for increasing the number of distinct, genetically-encoded amino acids available for protein engineering.
Non-intrusive submetering of residential gas appliances (1996)

A new technique was developed to non-intrusively monitor the use of individual gas appliances in homes.It relied on a very sensitive master gas meter equipped with a pulse meter, data logger, and software.The procedure involves two steps: decomposition and identification of the end uses.The technique is about 95% accurate but the algorithms can still be confused by some relatively common situations.Further improvements in the software are expected to improve accuracy.The procedure was applied to over 600 homes in Tokyo, Japan.The aggregate data allow more accurate estimates of energy consumption by the major residential gas appliances in addition to their hourly load profiles.Key factors affecting energy demand by each gas appliance were obtained by combining the energy and demographic data.These data are essential for more accurate forecasting of gas consumption, system sizing, and other marketing activities.The system will not necessarily be as successful in America due to the presence of pilot lights, more appliances per household, and variable-rate gas appliances.Nevertheless, the approach appears promising because it is economical and accurate.
Pharmacokinetics of the enantiomers of bupivacaine following intravenous administration of the racemate. (1994)

1. The pharmacokinetics of R(+)-bupivacaine and S(-)-bupivacaine were investigated following a 10 min intravenous infusion of the racemate (dose 30 mg) in 10 healthy males. 2. The fractions unbound of R(+)- and S(-)-bupivacaine in pre-dose plasma were determined for each subject after in vitro addition of rac-bupivacaine (concentration of each enantiomer: approximately 300 ng ml-1). 3. The total plasma clearance of R(+)-bupivacaine (mean +/- s.d.: 0.395 +/- 0.076 l min-1) was greater (P < 0.0001) than that of S(-)-bupivacaine (0.317 +/- 0.067 l min-1). The volumes of distribution of R(+)-bupivacaine at steady state (84 +/- 29 l) and during the terminal log-linear phase (117 +/- 47 l) were larger (P < 0.0002) than those of S(-)-bupivacaine (54 +/- 20 l and 71 +/- 34 l, respectively). The terminal half-life (210 +/- 95 min) and mean residence time (215 +/- 74 min) of R(+)-bupivacaine were longer than those of S(-)-bupivacaine (157 +/- 77 min, P < 0.01, and 172 +/- 55 min, P < 0.02, respectively). 4. The free percentage of R(+)-bupivacaine (6.6 +/- 3.0 %) was greater (P < 0.0002) than that of S(-)-bupivacaine (4.5 +/- 2.1 %). 5. The plasma clearance of unbound R(+)-bupivacaine (7.26 +/- 3.60 1 min-1) was smaller (P < 0.01) than that of S(-)-bupivacaine (8.71 +/- 4.27 l min-1). Volumes of distribution based on unbound R(+)-bupivacaine concentrations (Vuss: 1576 +/- 934 l; Vu: 2233 +/- 1442 l) did not differ from those of S(-)-bupivacaine (Vuss: 1498 +/- 892 l; Vu: 1978 +/- 1302 l). 6. The enantioselective systemic disposition of bupivacaine can to a large extent be attributed to differences in the degree of plasma binding of the enantiomers.