gebhart/patrepeval huggingface dataset:
Electrical Motor Power Measurement as the Key for Optimized Rod Pumping (1996)

Abstract The development of accurate digital measurement of instantaneous powerduring a pump stroke has made possible a very quick and detailed analysis ofthe efficiency of the pumping system. The efficiency is then used as thebenchmark for determining whether a complete well performance analysis iswarranted from the standpoint of making best use of personnel and economicresources to increase oil production. In addition, power measurement provides direct information about liftingcost per barrel of fluid and barrel of oil produced, electrical and mechanicalloading of the prime mover, peak power demand, power factor and minimumrequired ratings. These results give operating personnel information regardingpotential problems and give to management a complete picture of thedistribution of pumping costs. The power measurements are also converted, by the software, to instantaneoustorque and presented as continuous torque curves for the upstroke anddownstroke. This allows determination of the existing level of counterbalanceand provides the most rapid and accurate method for counterbalance adjustmentto achieve lower torque loading on the gear box and reduced energy utilization.One of the principal advantages of this balancing method is that counterbalanceadjustment can be made without need for an accurate description of the pumpingunit's geometry which is often unknown or inaccurate. The effect ofcounterweight displacement on torque and power is observed immediately byrepeating the power measurement after relocating the counterweights. This paper presents a series of case studies showing the Application ofpower measurement to a variety of pumping systems and components, includingconventional, Mark II, Rotaflexunits and high efficiency motors.
DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards is preserved in intact cells (1992)

Nitrogen mustard alkylating agents react with isolated DNA in a sequence selective manner, and the substituent attached to the drug reactive group can impose a distinct sequence preference. It is not clear however to what extent the observed DNA sequence preferences are preserved in intact cells. The highly reiterated sequence of human alpha DNA has been used to determine the sites of guanine-N7 alkylation following treatment of cells with three nitrogen mustards, mechlorethamine, uracil mustard and quinacrine mustard, known to react in isolated DNA with distinctly different sequence preferences. Alpha DNA from drug treated cells was extracted, purified, end-labeled, and a 296 base pair, singly end-labelled, fragment isolated. Following the quantitative conversion of alkylation sites to strand breaks the fragments were separated on DNA sequencing gels. Clear differences were observed between the alkylation patterns of the three compounds, and the selectivities were qualitatively similar to those predicted and observed in the same sequence alkylated in vitro. In particular the unique preferences of uracil and quinacrine mustards for 5'-PyGC-3' and 5'-GT/GPu-3' sequences, respectively, were preserved in intact cells suggesting that the pattern of sequence dependent reactivity is not grossly affected by the nuclear milieu.
HIV-1 Lentiviral Vector Immunogenicity Is Mediated by Toll-Like Receptor 3 (TLR3) and TLR7 (2010)

Lentiviral vectors are promising vaccine vector candidates that have been tested extensively in preclinical models of infectious disease and cancer immunotherapy. They are also used in gene therapy clinical trials both for the ex vivo modification of cells and for direct in vivo injection. It is therefore critical to understand the mechanism(s) by which such vectors might stimulate the immune system. We evaluated the effect of lentiviral vectors on myeloid dendritic cells (DC), the main target of lentiviral transduction following subcutaneous immunization. The activation of DC cultures was independent of the lentiviral pseudotype but dependent on cell entry and reverse transcription. In vivo-transduced DC also displayed a mature phenotype, produced tumor necrosis factor alpha (TNF-alpha), and stimulated naive CD8(+) T cells. The lentiviral activation of DC was Toll-like receptor (TLR) dependent, as it was inhibited in TRIF/MyD88 knockout (TRIF/MyD88(-/-)) DC. TLR3(-/-) or TLR7(-/-) DC were less activated, and reverse transcription was important for the activation of TLR7(-/-) DC. Moreover, lentivirally transduced DC lacking TLR3 or TLR7 had an impaired capacity to induce antigen-specific CD8(+) T-cell responses. In conclusion, we demonstrated TLR-dependent DC activation by lentiviral vectors, explaining their immunogenicity. These data allow the rational development of strategies to manipulate the host's immune response to the transgene.
T Cell Antigens in Cancer (2009)

This chapter contains sections titled: Introduction Generation of T-cell Epitopes Identification of T-cell Antigens and their Epitopes Conclusions References
Novel 4-Anilinoquinazolines with C-7 Basic Side Chains:  Design and Structure Activity Relationship of a Series of Potent, Orally Active, VEGF Receptor Tyrosine Kinase Inhibitors (2002)

We have previously shown that 4-anilinoquinazolines can be potent inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt-1 and KDR) tyrosine kinase activity. A novel subseries of 4-anilinoquinazolines that possess basic side chains at the C-7 position of the quinazoline nucleus have been synthesized. This subseries contains potent, nanomolar inhibitors of KDR (median IC(50) 0.02 microM, range 0.001-0.04 microM), which are comparatively less potent vs Flt-1 tyrosine kinase (median IC(50) 0.55 microM, range 0.02-1.6 microM). The compounds also retain some inhibitory activity against the tyrosine kinase associated to the endothelial growth factor receptor (EGFR) (median IC(50) 0.2 microM, range 0.075-0.8 microM) but demonstrate selectivity vs that associated to the FGF receptor 1 (median IC(50) 2.5 microM, range 0.9-19 microM). This selectivity profile is also evident in a growth factor-stimulated human endothelial cell (HUVEC) proliferation assay (i.e., inhibition of VEGF > EGF > FGF), with inhibition of VEGF-induced proliferation being achieved at nanomolar concentrations (median IC(50) 0.06 microM). Further examination of compound 2 (ZD6474) in recombinant enzyme assays revealed excellent selectivity for the inhibition of KDR tyrosine kinase (IC(50) 0.04 microM) vs the kinase activity of erbB2, MEK, CDK-2, Tie-2, IGFR-1R, PDK, PDGFRbeta, and AKT (IC(50) range: 1.1 to >100 microM). Anilinoquinazolines possessing basic C-7 side chains exhibited markedly improved aqueous solubility over previously described anilinoquinazolines possessing neutral C-7 side chains (up to 500-fold improvement at pH 7.4). In addition, aqueous solubility of the neutral fraction present at pH 7.4 of the basic subseries of anilinoquinazoline proved to be higher than that of the neutral analogue 1 (ZD4190). Oral administration of representative compounds to mice (50 mg/kg) produced plasma levels between 0.2 and 3 microM at 24 h after dosing. Our development candidate 2 demonstrated a very attractive in vitro profile combined with excellent solubility (330 microM at pH 7.4) and good oral bioavailability in rat and dog (> 80 and > 50%, respectively). This compound demonstrated highly significant, dose-dependent, antitumor activity in athymic mice. Once daily oral administration of 100 mg/kg of compound 2 for 21 days inhibited the growth of established Calu-6 lung carcinoma xenografts by 79% (P < 0.001, Mann Whitney rank sum test), and substantial inhibition (36%, P < 0.02) was evident with 12.5 mg/kg/day.
POT1 and TRF2 Cooperate To Maintain Telomeric Integrity (2005)

Mammalian telomeric DNA contains duplex TTAGGG repeats and single-stranded overhangs. POT1 (protection of telomeres 1) is a telomere-specific single-stranded DNA-binding protein, highly conserved in eukaryotes. The biological function of human POT1 is not well understood. In the present study, we demonstrate that POT1 plays a key role in telomeric end protection. The reduction of POT1 by RNA interference led to the loss of telomeric single-stranded overhangs and induced apoptosis, chromosomal instability, and senescence in cells. POT1 and TRF2 interacted with each other to form a complex with telomeric DNA. A dominant negative TRF2, TRF2(DeltaBDeltaM), bound to POT1 and prevented it from binding to telomeres. POT1 overexpression protected against TRF2(DeltaBDeltaM)-induced loss of telomeric single-stranded overhangs, chromosomal instability, and senescence. These results demonstrate that POT1 and TRF2 share in part in the same pathway for telomere capping and suggest that POT1 binds to the telomeric single-stranded DNA in the D-loop and cooperates with TRF2 in t-loop maintenance.
A Stochastic Spiking Neural Network for Virtual Screening (2017)

Virtual screening (VS) has become a key computational tool in early drug design and screening performance is of high relevance due to the large volume of data that must be processed to identify molecules with the sought activity-related pattern. At the same time, the hardware implementations of spiking neural networks (SNNs) arise as an emerging computing technique that can be applied to parallelize processes that normally present a high cost in terms of computing time and power. Consequently, SNN represents an attractive alternative to perform time-consuming processing tasks, such as VS. In this brief, we present a smart stochastic spiking neural architecture that implements the ultrafast shape recognition (USR) algorithm achieving two order of magnitude of speed improvement with respect to USR software implementations. The neural system is implemented in hardware using field-programmable gate arrays allowing a highly parallelized USR implementation. The results show that, due to the high parallelization of the system, millions of compounds can be checked in reasonable times. From these results, we can state that the proposed architecture arises as a feasible methodology to efficiently enhance time-consuming data-mining processes such as 3-D molecular similarity search.
Solution structure of human calcitonin gene-related peptide by proton NMR and distance geometry with restrained molecular dynamics (1991)

The structure of human calcitonin gene-related peptide 1 (hCGRP-1) has been determined by 1H NMR in a mixed-solvent system of 50% trifluoroethanol/50% H2O at pH 3.7 and 27 degrees C. Complete resonance assignment was achieved by using two-dimensional methods. Distance restraints for structure calculations were obtained by semiquantitative analysis of intra- and interresidue nuclear Overhauser effects; in addition, stereospecific or X1 rotamer assignments were obtained for certain side chains. Structures were generated from the distance restraints by distance geometry, followed by refinement using molecular dynamics, and were compared with experimental NH-C alpha H coupling constants and amide hydrogen exchange data. The structure of hCGRP-1 in this solvent comprises an amino-terminal disulfide-bonded loop (residues 2-7) leading into a well-defined alpha-helix between residues 8 and 18; thereafter, the structure is predominantly disordered, although there are indications of a preference for a turn-type conformation between residues 19 and 21. Comparison of spectra for the homologous hCGRP-2 with those of hCGRP-1 indicates that the conformations of these two forms are essentially identical.
[Role of bronchial epithelial cells in chronic obstructive pulmonary disease]. (2004)

Chronic obstructive pulmonary disease (COPD) is characterized by increased numbers of neutrophils in the airway lumen and increased infiltration of CD8 positive T lymphocytes both in the airways and in the lung parenchyma. However, the underlying reasons for these changes have not been fully investigated. Differences in bronchoepithelial activation in COPD patients may contribute to COPD pathophysiology since the bronchial epithelium does not act as a passive barrier but has the potential to orchestrate local inflammatory reactions by releasing a variety of inflammatory mediators. The expressions of several CXC and CC chemokines were studied in primary bronchial epithelial cells derived from COPD patients and smokers without airflow limitation. In addition, cDNA array technology was used to investigate the differential bronchoepithelial expression of cytokine and cytokine-related genes in COPD patients and lifelong non-smokers without airflow obstruction. Bronchial epithelial cells from COPD patients are characterized by increased expressions of CXC chemokines but not CC chemokines. In addition, CD 146 was identified as a new adhesion molecule showing significant upregulation in primary bronchial epithelial cells derived from COPD patients, on both the steady-state mRNA and protein level. These results suggest that the bronchial epithelium plays an important role in COPD pathophysiology.
A secondary RET mutation in the activation loop conferring resistance to vandetanib (2018)

Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with the drug is also observed in vitro for the S904F mutant by thermal shift assay. A crystal structure of the S904F mutant reveals a small hydrophobic core around F904 likely to enhance basal kinase activity by stabilizing an active conformer. Our findings indicate that missense mutations in the activation loop of the kinase domain are able to increase kinase activity and confer drug resistance through allosteric effects.
Suppression of Ocular Inflammation in Endotoxin-Induced Uveitis by Inhibiting Nonproteolytic Activation of Prorenin (2006)

These findings demonstrate for the first time that nonproteolytically activated prorenin plays a significant role in the development of ocular inflammation in the EIU model. The present study suggests the potential use of HRP, a decoy peptide binding to the prorenin receptor, as a therapeutic agent to reduce ocular inflammation.
Efficient Gene Targeting in Drosophila With Zinc-Finger Nucleases (2006)

This report describes high-frequency germline gene targeting at two genomic loci in Drosophila melanogaster, y and ry. In the best case, nearly all induced parents produced mutant progeny; 25% of their offspring were new mutants and most of these were targeted gene replacements resulting from homologous recombination (HR) with a marked donor DNA. The procedure that generates these high frequencies relies on cleavage of the target by designed zinc-finger nucleases (ZFNs) and production of a linear donor in situ. Increased induction of ZFN expression led to higher frequencies of gene targeting, demonstrating the beneficial effect of activating the target. In the absence of a homologous donor DNA, ZFN cleavage led to the recovery of new mutants at three loci-y, ry and bw-through nonhomologous end joining (NHEJ) after cleavage. Because zinc fingers can be directed to a broad range of DNA sequences and targeting is very efficient, this approach promises to allow genetic manipulation of many different genes, even in cases where the mutant phenotype cannot be predicted.
A Preliminary Study on the Use of Betaine as a Cryoprotective Agent in Deep Freezing of Stallion Semen (1989)

In a preliminary experiment, betaine was added in concentrations ranging from 0 to 3.0 percent to stallion semen diluted with 4% glycerol extender. Motility of frozen-thawed semen was better in the extenders with high betaine concentration than in those of low concentration or the control. In a subsequent experiment, betaine was added to extended semen from five stallions to make a 2.5% betaine concentration. Two different cooling rates were used. The effect of betaine on spermatozoal motility was positive at both cooling rates studied. Motility of frozen-thawed 2.5% betaine semen samples was significantly (p less than 0.001) higher than that of the control samples.
Rapid Optimization of Gene Delivery by Parallel End-modification of Poly(β-amino ester)s (2007)

Poly(β-amino ester)s are cationic degradable polymers that have significant potential as gene delivery vectors. Here we present a generalized method to modify poly(β-amino ester)s at the chain ends to improve their delivery performance. End-chain coupling reactions were developed so that polymers could be synthesized and tested in a high-throughput manner, without the need for purification. In this way, many structural variations at the polymer terminus could be rapidly evaluated. End-modification of the terminal amine structure of a previously optimized poly(β-amino ester), C32, significantly enhanced its in vitro transfection efficiency. In vivo, intraperitoneal (IP) gene delivery using end-modified C32 polymers resulted in expression levels over one order of magnitude higher than unmodified C32 and jet-polyethylenimine (jet-PEI) levels in several abdominal organs. The rapid end-modification strategy presented here has led to the discovery of many effective polymers for gene delivery and may be a useful method to develop and optimize cationic polymers for gene therapy.
Studies in Spiroheterocycles. Part-XVIII. Synthesis and Antifertility Activity of New Fluorine containing 4',5'-Cycloalkyl-2' phenyl-spiro[3H-indole3,3'-[3H]pyrazol]-2(1H)-ones (1989)

Department of Chemistry, University of Rajasthan, Jaipur-302 004 <em>Manuscript received 10 November 1988, accepted 6 January 1989</em> A series of new fluorine containing 4' ,5'-cycloalkyl-2'-phenyl-spiro[3<em>H</em>-indole-3,3'- [3<em>H</em>]pyrazol]-2(1H)-ones and their N-substituted derivatives have been synthesised and characterised by their elemental analyses, ir, pmr and mass spectral studies. Representative compounds have been screened for their anti-implantation activity.
No More Than Necessary: Safety and Efficacy of Low-Dose Promethazine (2005)

Low-dose (6.25 mg) intravenous promethazine relieves nausea and vomiting as effectively as intravenous ondansetron 4 mg.
Vaccinia virus D10 protein has mRNA decapping activity, providing a mechanism for control of host and viral gene expression (2007)

Previous studies indicated that the vaccinia virus D10 protein, which is conserved in all sequenced poxviruses, participates in the rapid turnover of host and viral mRNAs. D10 contains a motif present in the family of Nudix/MutT enzymes, a subset of which has been shown to enhance mRNA turnover in eukaryotic cells through cleavage of the 5' cap (m7GpppNm-). Here, we demonstrate that a purified recombinant D10 fusion protein possesses an intrinsic activity that liberates m7GDP from capped RNA substrates. Furthermore, point mutations in the Nudix/MutT motif abolished decapping activity. D10 has a strong affinity for capped RNA substrates (Km approximately 3 nm). RNAs of 24-309 nt were decapped to comparable extents, whereas the cap of a 12-nt RNA was uncleaved. At large molar ratios relative to capped RNA substrate, competitor m7GpppG, m7GTP, or m7GDP inhibited decapping, whereas even higher concentrations of unmethylated analogs did not. High concentrations of uncapped RNA were also inhibitory, suggesting that D10 recognizes its substrate through interaction with both cap and RNA moieties. Thus far, poxviruses represent the only virus family shown to encode a Nudix hydrolase-decapping enzyme. Although it may seem self-destructive for a virus to encode a decapping and a capping enzyme, accelerated mRNA turnover helps eliminate competing host mRNAs and allows stage-specific synthesis of viral proteins.
Vacuolar ATPase as a Drug Discovery Target (2006)

Vacuolar ATPases (V-ATPases) are present not only in the plasma membranes of specialized cells but also in ubiquitous intracellular acidic compartments, which are essential for physiological cellular function. Consequently, although V-ATPases are important etiologically in several diseases, it seems that they might not be good molecular targets. In fact, bafilomycin A1, a potent and specific inhibitor of V-ATPase, exerts severe and acute toxic reaction when administered to animals. On the other hand, disruption of subunit a3 of V-ATPase is not embryonic lethal, but knockout mice merely exhibit osteopetrosis due to loss of osteoclastic bone resorption. In addition, recent studies have demonstrated that novel V-ATPase inhibitors, which have inhibition selectivity, can be systemically administered to animals and are highly efficacious against bone loss in lytic bone disease models. Therefore, the key issue regarding the therapeutic usefulness of V-ATPase inhibitors is their selectivity in the inhibition.
Inhibiting Gene Expression with Peptide Nucleic Acid (PNA)−Peptide Conjugates That Target Chromosomal DNA (2007)

Peptide nucleic acids (PNAs) are nonionic DNA/RNA mimics that can recognize complementary sequences by Watson-Crick base pairing. The neutral PNA backbone facilitates the recognition of duplex DNA by strand invasion, suggesting that antigene PNAs (agPNAs) can be important tools for exploring the structure and function of chromosomal DNA inside cells. However, before agPNAs can enter wide use, it will be necessary to develop straightforward strategies for introducing them into cells. Here, we demonstrate that agPNA-peptide conjugates can target promoter DNA and block progesterone receptor (PR) gene expression inside cells. Thirty-six agPNA-peptide conjugates were synthesized and tested. We observed inhibition of gene expression using cationic peptides containing either arginine or lysine residues, with eight or more cationic amino acids being preferred. Both 13 and 19 base agPNA-peptide conjugates were inhibitory. Inhibition was observed in human cancer cell lines expressing either high or low levels of progesterone receptor. Modification of agPNA-peptide conjugates with hydrophobic amino acids or small molecule hydrophobic moieties yielded improved potency. Inhibition by agPNAs did not require cationic lipid or any other additive, but adding agents to cell growth media that promote endosomal release caused modest increases in agPNA potency. These data demonstrate that chromosomal DNA is accessible to agPNA-peptide conjugates and that chemical modifications can improve potency.
Synthesis of 4-(Phenylamino)pyrimidine Derivatives as ATP-Competitive Protein Kinase Inhibitors with Potential for Cancer Chemotherapy (2000)

The 4-(phenylamino)pyrimidine pharmacophore is found in a variety of different compounds that function as ATP-competitive inhibitors of several important protein kinase enzymes. Specific inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase have received the most attention, and several elaborations of the fundamental 4-(phenylamino)pyrimidine pharmacophore have now been reported as potent and selective inhibitors of this class of enzyme. Three separate pharmaceutical companies have now entered quinazoline EGFR inhibitors into clinical trials for the treatment of cancer, demonstrating the competitive nature of this area. Recent work with vascular endothelial growth factor (VEGF) and cyclin-dependent kinase (CDK) inhibitors has shown that the field is still expanding, and will undoubtably continue to show potential for some time to come. This review article concentrates on the synthetic approaches and chemical procedures that have been used for the production of these novel pharmaceutical agents.