gebhart/patrepeval huggingface dataset:
Computational Mechanistic Study of Fe-Catalyzed Hydrogenation of Esters to Alcohols: Improving Catalysis by Accelerating Precatalyst Activation with a Lewis Base (2014)

DFT calculations have been performed to gain mechanistic insight into ester hydrogenation to alcohols (exemplified by PhCO2CH3 +2H2 → PhCH2OH + CH3OH), catalyzed by a well-defined Fe-PNP pincer hydridoborohydride complex (1). The entire catalytic process includes precatalyst activation to an active species trans-dihydride complex 2, 2-catalyzed transformation of PhCO2CH3 + H2 → PhCHO + CH3OH, hydrogenation of PhCHO to PhCH2OH, and catalyst regeneration via H2 addition to the dehydrogenated 2 (i.e., complex 5). The transformation, PhCO2CH3 + H2 → PhCHO + CH3OH, proceeds via hydrogenation of PhCO2CH3 to a hemiacetal PhCH(OH)(OCH3), followed by decomposition of the hemiacetal to methanol and benzaldehyde. The Fe-complex 5 was found to be capable of facilitating the decomposition of the hemiacetal. The ineffectiveness of the catalytic system in hydrogenating methyl salicylate is attributed to the intrinsically lower reactivity of the ester toward C═O reduction and a very facile side-reaction, which is adding the phenol OH group of the hemiacetal intermediate stemmed from methyl salicylate to the Fe–N active site of 5. Computations of various catalyst initiation pathways show that the initiation without the aid of an additive is very unfavorable, thus we suggest the use of a Lewis base such as NR3 (R = Me and Et) and PR3 (R = nBu and tBu) to accelerate precatalyst (1) activation, because a Lewis base could form a stable adduct (BH3–NR3/PR3) with the BH3 moiety of 1. In agreement with greatly enhanced kinetics and thermodynamics of the initiation process suggested by the DFT calculations, experimental study shows that the addition of a catalytic amount of NEt3 doubled the yield of benzyl alcohol from the hydrogenation of methyl benzoate, when compared to the case without using any additive. The trans effect of the hydride on the reactivity of 2 and steric effect of the pincer substituents on the stability of 2 are also discussed.
Oxidative protein labeling in mass-spectrometry-based proteomics (2010)

Oxidation of proteins and peptides is a common phenomenon, and can be employed as a labeling technique for mass-spectrometry-based proteomics. Nonspecific oxidative labeling methods can modify almost any amino acid residue in a protein or only surface-exposed regions. Specific agents may label reactive functional groups in amino acids, primarily cysteine, methionine, tyrosine, and tryptophan. Nonspecific radical intermediates (reactive oxygen, nitrogen, or halogen species) can be produced by chemical, photochemical, electrochemical, or enzymatic methods. More targeted oxidation can be achieved by chemical reagents but also by direct electrochemical oxidation, which opens the way to instrumental labeling methods. Oxidative labeling of amino acids in the context of liquid chromatography(LC)-mass spectrometry (MS) based proteomics allows for differential LC separation, improved MS ionization, and label-specific fragmentation and detection. Oxidation of proteins can create new reactive groups which are useful for secondary, more conventional derivatization reactions with, e.g., fluorescent labels. This review summarizes reactions of oxidizing agents with peptides and proteins, the corresponding methodologies and instrumentation, and the major, innovative applications of oxidative protein labeling described in selected literature from the last decade.
Evaluation of statistical methods for normalization and differential expression in mRNA-Seq experiments (2010)

Our results have significant practical and methodological implications for the design and analysis of mRNA-Seq experiments. They highlight the importance of appropriate statistical methods for normalization and DE inference, to account for features of the sequencing platform that could impact the accuracy of results. They also reveal the need for further research in the development of statistical and computational methods for mRNA-Seq.
Protein kinase C delta is a prosurvival factor in human breast tumor cell lines. (2003)

Protein kinase C (PKC) promotes cell survival in response to ionizing radiation in a variety of experimental models including human carcinoma, human glioblastoma, and transformed mouse embryo fibroblast cell lines. We have introduced specific antisense oligonucleotides into human mammary tumor cell lines in vitro to analyze the role of individual PKC isoforms in radiation-induced cell death in breast cancer. MDA-MB-231 and MCF-7 cells treated with oligonucleotide directed against the PKC delta isoform exhibited impaired survival in response to 5.6 Gy gamma-radiation as measured by mitochondrial metabolism of tetrazolium dye. The role of PKC delta in the breast tumor cell lines was of particular interest, because contradictory reports exist in the literature regarding the role of PKC delta in cell survival and apoptosis. A comparison of the effects of the PKC delta antisense oligonucleotide and a nucleotide scrambled version of this nucleotide revealed only the antisense oligonucleotide decreased cell survival. The PKC delta antisense oligonucleotide decreased cell survival after exposure to low (1.5 Gy) radiation doses and in the absence of radiation insult. We found 3 micro M rottlerin, a selective PKC delta inhibitor, to reduce MCF-7 and MDA-MB-231 cell survival. Furthermore, MCF-7 cells transformed to express a dominant-negative mutant of PKC delta exhibited reduced survival. Comet analysis showed that PKC delta oligonucleotide treatment caused an accumulation of cells containing damaged DNA similar to that seen in 1.5 Gy radiation-treated cells. We conclude that PKC delta acts as a prosurvival factor in human breast tumor cells in vitro.
Test harness and script design principles for automated testing of non-GUI or web based applications (2011)

Scarcity of commercially available testing tools that could support all native or application specific message formats as well as those that cater to non GUI or non web based backend applications leads to creating your own customized traffic generators or scripts. Also the test environment setup may differ from one system to another -- some may use simulators or mocks to stub out complex software, others may just be a scaled down (in terms of number of servers) replica of the production environment. So what are the factors that need to be considered when creating scripts that can be used for native request formats and for non GUI or web based applications? How do we design a script that is easy to maintain and extend when new test scenarios are added to accurately assess the performance of an application? This paper provides (1) the general design principles for a test script that can be used to generate traffic for any request format as well as (2) specific factors to keep in mind when creating a script that will work in a test environment that uses a mock. In addition to this the core activities of testing include not only traffic generation but also setting up the environment, verifying that both the hardware and software configurations are accurate prior to sending traffic and creating a report at the end of the test. Therefore the test script needs to be part of a complete harness that accomplishes these tasks. The paper will address the (3) design and properties of such a harness. It provides a simple framework that can be easily used to complete an end to end testing process -pre test, traffic generation and post test activities.
Pharmacologic therapy for diabetic retinopathy (2003)

Diabetic retinopathy remains one of the major causes of acquired blindness in developed nations. This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop macular oedema (ME) or proliferative diabetic retinopathy (PDR). ME is manifest by retinal vascular leakage and thickening of the retina. The hallmark of PDR is neovascularisation (NV) – abnormal angiogenesis that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment. Pharmacologic therapy aimed specifically at preventing vascular leakage and NV would be a welcome addition to the armamentarium. PDR and ME could be prevented by improved metabolic control or by pharmacologically blunting the biochemical consequences of hyperglycaemia (e.g., with aldose reductase inhibitors, inhibitors of non-enzymatic glycation or by protein kinase C [PKC] inhibition). The angiogenesis in PDR could be treated via growth factor (e.g., vascular endothelial growth factor [VEGF], insulin like growth factor-1 [IGF-1]) blockade, integrin (e.g., alpha-v beta-3) blockade, extracellular matrix alteration (e.g., with steroid compounds) or interference with intracellular signal transduction pathways (e.g., PKC and mitogen activated protein kinase [MAPK] pathway proteins). Some of these antiangiogenic agents may also prove useful for treating or preventing ME. Numerous potentially useful antiangiogenic compounds are in development; two drugs are presently in clinical trials for treatment of the preproliferative stage of PDR, while two are in clinical trials for treatment of ME.
Laboratory trials on the toxicity of hydramethylnon (Amdro; AC 217,300) to Reticulitermes santonensis Feytaud (Isoptera: Rhinotermitidae) and Microtermes lepidus Sjöstedt (Isoptera: Termitidae) (1990)

Abstract The amidinohydrazone insecticide hydramethylnon, exhibited delayed toxicity to workers of Reticulitermes santonensis Feytaud and Microtermes lepidus Sjöstedt over a range of concentrations, with deaths starting two to six days after exposure. R. santonensis workers which had been exposed to hydramethylnon passed the insecticide to untreated termite workers, larvae and nymphs by trophallaxis. Laboratory colonies of R. santonensis exposed to hydramethylnon were killed completely within 20 days. The possible use of hydramethylnon impregnated baits for the control of subterranean termites is discussed.
Targeting of HLA‐DR molecules transduces agonistic functional signals in cutaneous melanoma (2004)

The role of human leukocyte antigens (HLA) class II molecules in transducing intracellular signals in immune cells is well established. Solid tumors of different histotype can also express HLA class II antigens; however, their intracellular signaling ability is essentially unknown. Due to the frequent expression of HLA class II molecules in primary and metastatic lesions, cutaneous melanoma was utilized to investigate whether the engagement of HLA-DR molecules transduces functional intracellular signal(s). Triggering of HLA-DR molecules by the anti-HLA-DR monoclonal antibody (mAb) L243 induced a significant (P < 0.05) and dose-dependent growth-inhibition of metastatic melanoma cells Mel 120, as well as their homotypic aggregation. Furthermore, an increase in tyrosine phosphorylation of multiple cellular proteins with a molecular weight ranging from 66 to 130 kD, including p125 focal adhesion kinase, was observed. Lastly, the engagement of HLA-DR molecules by mAb L243 inhibited activator protein-1-DNA binding. Thus, HLA-DR molecules expressed on melanoma cells can transduce functional intracellular signals. This finding is consistent with evidences obtained in hematological malignancies, and suggests the potential usefulness of HLA-DR molecules to set-up new approaches of targeted therapy in metastatic melanoma.
Design, Synthesis and Antifibrotic Activities of Carbohydrate- Modified 1-(Substituted aryl)-5-trifluoromethyl-2(1H) Pyridones (2012)

Pirfenidone, a pyridone compound, is an effective and novel antifibrotic agent. In this article, we describe the design, synthesis and activity evaluation of novel antifibrotic agents, 1-(substituted aryl)-5-trifluoromethyl-2(1H) pyridones modified with carbohydrate. Most of the title compounds exhibited comparable or better inhibitory activity than fluorofenidone. Notably, compound 19a demonstrated the highest cell-based inhibitory activity against NIH 3T3 (IC(50) = 0.17 mM).
Impact of nanoscale particles and carbon nanotubes on current and future generations of liquid crystal displays (2008)

In this Highlight article we will describe the current impact of nanoscale materials (nanoparticles and carbon nanotubes) in liquid crystal nanocomposites on the improvement of LC display (LCD) applications, an industry currently worth more than $60 billion per year. First tendencies clearly demonstrate the potential of nanomaterials to improve upon current LCD technologies with the discovery of new or modified switching modes, lower operating voltages, faster switching speeds, and higher contrast ratios—enormous advantages in a world with more LCDs than people (see ref. : D. W. Bruce, J. W. Goodby, J. R. Sambles and H. J. Coles, Introduction: New directions in liquid crystal science, Philos. Trans. R. Soc. London, Ser. A, 2006, 364, 2567–2571).
Cephalosporin 3'-quinolone esters with a dual mode of action (1990)

According to the generally accepted mechanism by which bacterial enzymes react with cephalosporins, opening of the beta-lactam ring can lead to the expulsion of a 3'-substituent. A series of dual-action cephalosporins was prepared in which antibacterial quinolones were linked to the cephalosporin 3'-position through an ester bond in the expectation that, in addition to exerting their own beta-lactam activity, these cephalosporins would act as prodrugs for the second antibacterial agent. Compared to parent cephalosporins in which the 3'-substituent was acetoxy, the bifunctional cephalosporins exhibited a broadened antibacterial spectrum, suggesting that a dual mode of action may indeed be operative.
Copper- and silver-substituted yeast metallothioneins: Sequential proton NMR assignments reflecting conformational heterogeneity at the C terminus (1993)

Complete 1H NMR sequential assignments have been made for copper(I)- and silver (I)-substituted metallothionein (MT) from Saccharomyces cerevisiae using standard 2D 1H NMR methods. The fingerprint region of the COSY spectrum of both metalloproteins shows a doubling of a few backbone proton resonances from residue K41 onward in the C terminus. This doubling of resonances is absent in the spectrum of the truncated mutant protein that lacks the five C-terminal residues which includes two cysteines. Concurrently, it has been established from a comparison of the heteronuclear 1H-109 Ag multiple-quantum coherence transfer (HMQC) spectrum on the silver-substituted mutant and the wild-type protein that metal ligation is similar in both molecules. Thus, the 2 C-terminal Cys are not essential for metal cluster formation in the wild-type yeast MT and only 10 of the 12 Cys present in this protein appear to be involved in ligating the 7 mol of bound metal ions. A qualitative analysis of the coupling constant, hydrogen exchange, and NOE data indicates the presence of many type I beta-turns and the lack of any other regular secondary structural elements. A comparison of chemical shifts and NOE data for native copper- and silver-substituted yeast MT indicates a high degree of conservation of structural elements in both proteins. Therefore, it seems reasonable to conclude that the metal to Cys connectivities which are obtained directly from the HMQC data on silver-substituted metallothionein are conserved in the native copper protein. Interestingly, a mixture of both 2 and 3 coordination was found for the bound Ag(I) ions in a single Ag7Cys10 cluster. This mixed coordination number and a single cluster arrangement is most probably also shared with the Cu(I) ion coordination in the native protein.
Synthetic LXR ligand inhibits the development of atherosclerosis in mice (2002)

The nuclear receptors LXRalpha and LXRbeta have been implicated in the control of cholesterol and fatty acid metabolism in multiple cell types. Activation of these receptors stimulates cholesterol efflux in macrophages, promotes bile acid synthesis in liver, and inhibits intestinal cholesterol absorption, actions that would collectively be expected to reduce atherosclerotic risk. However, synthetic LXR ligands have also been shown to induce lipogenesis and hypertriglyceridemia in mice, raising questions as to the net effects of these compounds on the development of cardiovascular disease. We demonstrate here that the nonsteroidal LXR agonist GW3965 has potent antiatherogenic activity in two different murine models. In LDLR(-/-) mice, GW3965 reduced lesion area by 53% in males and 34% in females. A similar reduction of 47% was observed in male apoE(-/-) mice. Long-term (12-week) treatment with LXR agonist had differential effects on plasma lipid profiles in LDLR(-/-) and apoE(-/-) mice. GW3965 induced expression of ATP-binding cassettes A1 and G1 in modified low-density lipoprotein-loaded macrophages in vitro as well as in the aortas of hyperlipidemic mice, suggesting that direct actions of LXR ligands on vascular gene expression are likely to contribute to their antiatherogenic effects. These observations provide direct evidence for an atheroprotective effect of LXR agonists and support their further evaluation as potential modulators of human cardiovascular disease.
Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment (1991)

Platelets metabolize arachidonic acid to thromboxane A2, a potent platelet aggregator and vasoconstrictor compound. The first step of this transformation is catalyzed by prostaglandin (PG) G/H synthase, a target site for nonsteroidal antiinflammatory drugs. We have isolated the cDNA for both human platelet and human erythroleukemia cell PGG/H synthase using the polymerase chain reaction and conventional screening procedures. The cDNA encoding the full-length protein was expressed in COS-M6 cells. Microsomal fractions from transfected cells produced prostaglandin endoperoxide-derived products which were inhibited by indomethacin and aspirin. Mutagenesis of the serine residue at position 529, the putative aspirin acetylation site, to an asparagine reduced cyclooxygenase activity to barely detectable levels, an effect observed previously with the expressed sheep vesicular gland enzyme. Platelet-derived growth factor and phorbol ester differentially regulated the expression of PGG/H synthase mRNA levels in the megakaryocytic/platelet-like HEL cell line. The PGG/H synthase gene was assigned to chromosome 9 by analysis of a human--hamster somatic hybrid DNA panel. The availability of platelet PGG/H synthase cDNA should enhance our understanding of the important structure/function domains of this protein and its gene regulation.
Deletion of Nonstructural Proteins NS1 and NS2 from Pneumonia Virus of Mice Attenuates Viral Replication and Reduces Pulmonary Cytokine Expression and Disease (2008)

ABSTRACT Pneumonia virus of mice (PVM) strain 15 causes fatal pneumonia in mice and provides a convenient model for human respiratory syncytial virus pathogenesis and immunobiology. We prepared PVM mutants lacking the genes for nonstructural proteins NS1 and/or NS2. In Vero cells, which lack type I interferon (IFN), deletion of these proteins had no effect on the efficiency of virus growth. In IFN-competent mouse embryo fibroblasts, wild-type (wt) PVM and the ΔNS1 virus grew efficiently and strongly inhibited the IFN response, whereas virus lacking NS2 was highly attenuated and induced high levels of IFN and IFN-inducible genes. In BALB/c mice, intranasal infection with wt PVM caused overt disease that began on day 6 and was lethal by day 9 postinoculation. In comparison, ΔNS1 induced transient, reduced disease, and ΔNS2 and ΔNS12 caused no disease. Thus, NS1 and NS2 are virulence factors, with NS2 being a major antagonist of the type I IFN system. The pulmonary titers of wt PVM and ΔNS1 were high on day 3 and increased further by day 6; in addition, expression of IFN and representative proinflammatory cytokines/chemokines and T lymphocyte-related cytokines was undetectable on day 3 but increased dramatically by day 6 coincident with the onset of disease. The titers of ΔNS2 and ΔNS12 were somewhat lower on day 3 and decreased further by day 6; in addition, these viruses induced a more circumscribed set of cytokines/chemokines (IFN, interleukin-6 [IL-6], and CXCL10) that were detected on day 3 and had largely subsided by day 6. Lung immunohistology revealed abundant PVM-positive pneumocytes and bronchial and bronchiolar epithelial cells in wt PVM- and ΔNS1-infected mice on day 6 compared to few PVM-positive foci with ΔNS2 and ΔNS12. These results indicate that severe PVM disease is associated with high, poorly controlled virus replication driving the expression of high levels of pulmonary IFN and a broad array of cytokines/chemokines. In contrast, in the absence of NS2, there was an early, transient innate response involving moderate levels of IFN, IL-6, and CXCL10 that restricted virus replication and prevented disease.
Increased dependence on blood glucose in smokers during rest and sustained exercise (1994)

To evaluate the hypothesis that smoking increases the dependence on blood glucose as a fuel, seven male smokers [28.7 +/- 1.7 (SE) yr. 77.7 +/- 4.3 kg] and seven nonsmokers (NS; 29.1 +/- 0.9 yr, 78.7 +/- 5.3 kg) were studied in the postabsorptive condition. NS received a primed continuous infusion of [6,6-2H]glucose and [1-13C]glucose during 90 min of rest and 60 min of exercise at 49.7 +/- 0.8% of peak O2 consumption on one occasion; chronic smokers continued their overnight abstinence from smoking (CS) for one trial but, on another occasion, acutely smoked (AS) two cigarettes immediately before resting measurements and another cigarette before exercise. Plasma glucose levels were similar among all groups at all times during the trials; however, the glucose rates of appearance (Ra) at rest in CS (1.96 +/- 0.14 mg.kg-1 x min-1) and AS (2.02 +/- 0.14) were higher than in NS (1.41 +/- 0.15, P < 0.05). With exercise, the glucose Ra values rose in all groups above resting values but were significantly greater in CS (4.76 +/- 0.50) and AS (4.71 +/- 0.53) than in NS (3.31 +/- 0.16). Glucose oxidation during exercise was elevated in smokers (2.31 +/- 0.37 mg.kg-1 x min-1 in CS and 2.18 +/- 0.34 in AS) compared with NS (1.09 +/- 0.18, P < 0.05). Nicotine levels correlated with the glucose Ra in AS (r = 0.93, P < 0.01). In conclusion, the results indicate that long-term smoking, independent of acute smoking, increases the dependence on blood glucose as a fuel during rest and sustained submaximal exercise.
Optical frequency conversion in quasi-phase-matched stacks of nonlinear crystals (1982)

We present a quantitative theory of nonlinear frequency conversion in stacks of crystals where the phase mismatch due to dispersion is compensated by changing the sign of the nonlinear coupling coefficient in successive crystals-a method first proposed by Armstrong et al. We include pump depletion in our calculations of the second harmonic generation and sum and difference frequency generation. We start with ideal stacks in which the crystal lengths are tailored to achieve perfect phase compensation. When the conversion in each coherence length is small, all crystal lengths tend to equal the coherence length <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">\pi/\Deltak</tex> . Frequency conversion in such stacks is well approximated by that in an equivalent phase-matched crystal with the nonlinear coupling coefficient reduced by a factor of <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2/\pi</tex> . The effect of systematic as well as random departures in crystal lengths are studied with special attention to the evolution of the relative phase. We show that with appropriate choice of the signs of the nonlinear coupling coefficient in various crystals, high efficiency frequency conversion should be possible using practically any sufficiently large set of nonlinear crystals. The theory of second harmonic generation in periodic stacks and in rotationally twinned crystals of zinc-blend structure is described in detail.