gebhart/patrepeval huggingface dataset:
Regulation of biosynthesis of aminoacyl-transfer RNA synthetases and of transfer-RNA in Escherichia coli. (1979)

We have isolated temperature resistant revertants from temperature sensitive E. coli strains containing either a thermolabile glutaminyl-tRNA synthetase or leucyl-tRNA synthetase. Among the revertants which still contained the thermolabile leucyl-tRNA synthetase we found two classes of regulatory mutants (leuX and leu Y) which have elevated levels of this enzyme. The leuX mutation specifies an operator-promoter region adjacent to the structural gene (leuS) for the enzyme. The leuY gene maps away from the leuS gene and codes for a protein. Using these mutants we demonstrated that the levels of leucyl-tRNA are related to the derepression of the leucine and isoleucine-valine operons. Among the revertants which still contained the thermolabile glutaminyl-tRNA synthetase were characterized three classes of mutants, glnT, glnU, and glnR. The glnT and glnU mutants contain elevated levels of tRNAgln, while the glnR mutant possesses elevated levels of glutaminyl-tRNA synthetase. The level of glutamine synthetase, the enzyme responsible for the formation of glutamine, is also derepressed in the glnT and glnR mutants.
Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia (2009)

Potent mGluR2 potentiators that span a broad range of structural diversity have been disclosed. Narrow patent filings within select series and drug-like properties of corresponding preferred compounds suggest that development candidates have likely been nominated.
Therapeutic Approaches to Preserve Islet Mass in Type 2 Diabetes (2006)

Type 2 diabetes is characterized by hyperglycemia resulting from insulin resistance in the setting of inadequate beta-cell compensation. Currently available therapeutic agents lower blood glucose through multiple mechanisms but do not directly reverse the decline in beta-cell mass. Glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by Exenatide (exendin-4), not only acutely lower blood glucose but also engage signaling pathways in the islet beta-cell that lead to stimulation of beta-cell replication and inhibition of beta-cell apoptosis. Similarly, glucose-dependent insulinotropic polypeptide (GIP) receptor activation stimulates insulin secretion, enhances beta-cell proliferation, and reduces apoptosis. Moreover, potentiation of the endogenous postprandial levels of GLP-1 and GIP via inhibition of dipeptidyl peptidase-IV (DPP-IV) also expands beta-cell mass via related mechanisms. The thiazolidinediones (TZDs) enhance insulin sensitivity, reduce blood glucose levels, and also preserve beta-cell mass, although it remains unclear whether TZDs affect beta-cell mass via direct mechanisms. Complementary approaches to regeneration of beta-cell mass involve combinations of factors, exemplified by epidermal growth factor and gastrin, which promote islet neogenesis and ameliorate diabetes in rodent studies. Considerable preclinical data support the concept that one or more of these therapeutic approaches, alone or in combination, may potentially reverse the decline in beta-cell mass that is characteristic of the natural history of type 2 diabetes.
Automation Infrastructure System for a Robotic 30-Ton Bridge Crane (1998)

This paper describes the sensing portion of a system used to convert an existing 30-ton bridge crane to computer control for automated placement of construction components. The system is being designed to permit either telepresent or fully autonomous assembly of representative parts of buildings and industrial plants, e.g., girders, tanks, and pipes. In order to achieve six degree-of-freedom manipulation of the components, the traditional crane cable and hook have been replaced by TETRA, an inverted cable-operated Stewart platform equipped with various manipulators. The sensing systems are primarily displacement, force, and other state sensors. What makes this application unique is the scale of the robot: the crane's workspace is 40 m long, 23 m wide, and 24 m high — a volume of more than 10,000 cubic meters. This scale, and the need to operate without wires has led to a control system based on wireless packet communication by intelligent modules known as "smart pods." The pods interface to one or several force, displacement, or state sensors. The pods broadcast their data via wireless ethernet to base stations which then communicate with the world via higher-speed networks. The present paper discusses issues relating to the architecture of the sensor array needed to operate this large construction robot and the communications infrastructure needed to supply that information to remote sites in real time.
Roles of the Heparin and Low Density Lipid Receptor-related Protein-binding Sites of Protease Nexin 1 (PN1) in Urokinase-PN1 Complex Catabolism (2000)

We have previously described thrombin (Th)-protease nexin 1 (PN1) inhibitory complex binding to cell surface heparins and subsequent low density lipid receptor-related protein (LRP)-mediated internalization. Our present studies examine the catabolism of urinary plasminogen activator (uPA)-PN1 inhibitory complexes, which, unlike Th.PN1 complexes, bind almost exclusively through the uPA receptor. In addition, the binding site in PN1 required for the LRP-mediated internalization of Th.PN1 complexes is not required for the LRP-mediated internalization of uPA.PN1 complexes. Thus, the protease moiety of the complex partially determines the mechanistic route of entry. Because cell surface heparins are only minimally involved in the binding and internalization of uPA.PN1 complexes, we then predicted that complexes between uPA and the heparin binding-deficient PN1 variant, PN1(K7E), should be catabolized at the same rate as complexes formed with native PN1. Surprisingly, the uPA.PN1(K7E) complexes were degraded at only a fraction of the rate of native complexes. Internalization studies revealed that both uPA. PN1(K7E) and native uPA.PN1 complexes were initially internalized at the same rate, but uPA.PN1(K7E) complexes were rapidly retro-endocytosed in an intact form. By examining the pH dependence of complex binding in the range of 4.0-7.0, it was determined that the uPA.PN1 inhibitory complexes must specifically bind to endosomal heparins at pH 5.5 to be retained and sorted to lysosomes. These studies are the first to document a role for heparins in the catabolism of SERPIN-protease complexes at a point further in the pathway than cell surface binding, and this role may extend to other heparin-binding LRP-internalized ligands.
Efficacy of fluralaner against Otodectes cynotis infestations in dogs and cats (2017)

In this study, fluralaner administered topically to cats and orally or topically to dogs was highly effective against Otodectes cynotis mite infestations.
ATR Inhibitors VE-821 and VX-970 Sensitize Cancer Cells to Topoisomerase I Inhibitors by Disabling DNA Replication Initiation and Fork Elongation Responses (2014)

Camptothecin and its derivatives, topotecan and irinotecan, are specific topoisomerase I (Top1) inhibitors and potent anticancer drugs killing cancer cells by producing replication-associated DNA double-strand breaks, and the indenoisoquinoline LMP-400 (indotecan) is a novel Top1 inhibitor in clinical trial. To develop novel drug combinations, we conducted a synthetic lethal siRNA screen using a library that targets nearly 7,000 human genes. Depletion of ATR, the main transducer of replication stress, came as a top candidate gene for camptothecin synthetic lethality. Validation studies using ATR siRNA and the ATR inhibitor VE-821 confirmed marked antiproliferative synergy with camptothecin and even greater synergy with LMP-400. Single-cell analyses and DNA fiber combing assays showed that VE-821 abrogates the S-phase replication elongation checkpoint and the replication origin-firing checkpoint induced by camptothecin and LMP-400. As expected, the combination of Top1 inhibitors with VE-821 inhibited the phosphorylation of ATR and Chk1; however, it strongly induced γH2AX. In cells treated with the combination, the γH2AX pattern changed over time from the well-defined Top1-induced damage foci to an intense peripheral and diffuse nuclear staining, which could be used as response biomarker. Finally, the clinical derivative of VE-821, VX-970, enhanced the in vivo tumor response to irinotecan without additional toxicity. A key implication of our work is the mechanistic rationale and proof of principle it provides to evaluate the combination of Top1 inhibitors with ATR inhibitors in clinical trials.
Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4 (2007)

Toll-like receptor 4 (TLR4) initiates both myeloid differentiation factor 88 (MyD88)-dependent and Toll/interleukin (IL)-1R domain-containing adapter, inducing interferon (IFN)-beta-dependent signaling, leading to production of proinflammatory mediators and type I interferon (IFN) to eliminate pathogens. However, uncontrolled TLR4 activation may contribute to pathogenesis of autoimmune and inflammatory diseases. TLR4 is transported from the plasma membrane to the endosome for ubiqutination and to the lysosome for degradation, and downregulation of TLR4 expression or promotion of TLR4 degradation are important ways for negative regulation of TLR4 signaling. We previously identified a lysosome-associated small guanosine triphosphatase (GTPase) Rab7b that may be involved in lysosomal trafficking and degradation of proteins. Here we demonstrate that Rab7b can negatively regulate lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-alpha, IL-6, nitric oxide, and IFN-beta, and potentiate LPS-induced activation of mitogen-activated protein kinase, nuclear factor kappaB, and IFN regulatory factor 3 signaling pathways in macrophages by promoting the degradation of TLR4. Rab7b is localized in LAMP-1-positive subcellular compartments and colocalized with TLR4 after LPS treatment and can decrease the protein level of TLR4. Our findings suggest that Rab7b is a negative regulator of TLR4 signaling, potentially by promoting the translocation of TLR4 into lysosomes for degradation.
Proliferation marker pKi‐67 occurs in different isoforms with various cellular effects (2004)

The Ki-67 antigen, pKi-67, is a commonly used proliferation marker in research and pathology. It has been recognized that the protein exists in two different splice variants that differ in one exon. In the current work, we present three new splice variants of human pKi-67 consisting of two naturally occurring isoforms and one atypical version. Additionally, data is presented indicating that alternative splicing of the pKi-67 N-terminus is common in tumor cell lines. Analyzing 93 tissues mainly consisting of brain tumor specimens, we found evidence that long and short isoform can be expressed independently of each other. Induction of mitosis in human peripheral blood mononuclear cells revealed that short pKi-67 appears earlier in the cell cycle than the long isoform and reaches its expression maximum when transcription of the latter sets in. Finally, transfection of mammalian culture cells with exon 7 (specific for the long pKi-67 isoform and not present in the short isoform) in a tetracycline regulated expression system decreased the rate of cell proliferation without affecting the cell cycle. In summary, we present evidence that the pKi-67 N-terminus is differentially spliced resulting in at least five different isoforms with different functions.
Regulation of Apo B Production in HepG2 Cells by Citrus Limonoids (2000)

In rabbits, dietary orange juice or grapefruit juice reduced the hypercholesterol-emia associated with elevation of LDL (low-density lipoprotein) cholesterol, induced by feeding casein. To determine whether this effect could be partly due to constituent limonoids, the ability of these compounds to lower overall production of apo B (the structural protein of LDL) was tested. Using cultured human liver cells HepG2, fourteen naturally occurring limonoid aglycones and glucosides, a limonoid glucoside mixture isolated from orange molasses, and five synthetic limonoids were evaluated. Limonin and methyl deoxylimonate very effectively reduced the production of medium apo B by HepG2 cells. Nomilin, deoxylimonin and methyl isolimonate reduced moderately, and other limonoids had practically no effect on the production of medium apo B. The apo B-lowering potential of limonin was 30% greater than the apo B-lowering potential of two citrus flavonoids, hesperetin and naringenin. The effects of limonin, hesperetin and naringenin were dose-dependent but limonin, unlike the citrus flavonoids, did not cause decreases in the cellular synthesis of cholesteryl esters. The results suggest that limonin, along with citrus flavonoids, could contribute to cholesterol-lowering action of citrus juices. Limonin might be liberated from its glucoside derivative, limonin 17 -D-glucopyranoside, which is present in high concentrations in citrus juices, by the action of bacteria in digestive tract.
Modeling and testing of cloud applications (2009)

What is a cloud application precisely? In this paper, we formulate a computing cloud as a kind of graph, a computing resource such as services or intellectual property access rights as an attribute of a graph node, and the use of a resource as a predicate on an edge of the graph. We also propose to model cloud computation semantically as a set of paths in a subgraph of the cloud such that every edge contains a predicate that is evaluated to be true. Finally, we present algorithms to compose cloud computations and a family of model-based testing criteria to support the testing of cloud applications.
Antibody responses to the capsular polysaccharide of Neisseria meningitidis serogroup B in patients with meningococcal disease (1995)

We measured antibody responses to meningococcal serogroup B (MenB) polysaccharide (PS) by enzyme-linked immunosorbent assay (ELISA) in sera from 94 patients from The Netherlands with disease caused by Neisseria meningitidis group B. The patients ranged in age from 3 to 73 years (mean age, 18.8 years). In initial studies we showed that the binding of a panel of MenB PS-reactive human immunoglobulin M (IgM) paraproteins to biotinylated MenB PS bound to avidin-coated microtiter wells was inhibited > 90% by the addition of soluble MenB PS or encapsulated group B meningococci. In contrast, inhibition of IgM anti-MenB PS antibody-binding activity in many of the patient sera was less than 50% (range, 20 to 94%). These data suggested a high frequency of nonspecific binding in the patient sera. Therefore, all serum samples were assayed in replicate in the presence or absence of soluble MenB PS, and only the inhibitable fraction of the binding signal was used to calculate the anti-MenB PS antibody concentrations. In 17 control patients with meningococcal disease caused by serogroup A or C strains, there was no significant difference in the respective IgM or IgG anti-MenB PS antibody concentrations in paired acute- and convalescent-phase sera. In contrast, in patients with MenB disease, the geometric mean IgM anti-MenB PS antibody concentration increased from 3.9 units/ml in acute-phase serum to 10.5 units/ml in convalescent-phase serum (P < 0.001). The corresponding geometric mean IgG anti-MenB PS antibody titers were 1:27 and 1:36 (P < 0.05). There was only a weak relationship between age and the magnitude of the logarithm of the antibody concentrations in convalescent-phase sera (for IgM, r2 = 0.06 and P < 0.05; for IgG, r2 = 0.08 and P < 0.01). Our data indicate that precautions are needed to avoid nonspecificity in measuring serum antibody responses to MenB PS by ELISA. Furthermore, although this PS is thought to be a poor immunogen, patients as young as 3 years of age recovering from MenB disease demonstrate both ImG and IgG antibody responses in serum.
Lung cancer screening: a systematic review of clinical practice guidelines (2015)

The qualities of the selected CPGs vary and there is potential to improve the qualities among and between each. Specifically, more evidence is needed to support the recommendations such as a larger cohort of high-risk participants, and further analysis of the lung cancer screening interval, the benefit vs. harm of lung cancer screening, the timing and rigour of follow-up and availability of effective treatments.
[Investigation of the preventive effect of CoQ10 against the side-effects of anthracycline antineoplastic agents]. (1984)

This study was designed to evaluate the usefulness of Coenzyme Q10 (CoQ10) in the prevention of side effects due to anthracycline agents-Adriamycin (ADM) and Daunorubicin (DNR)-by comparing the preventive effect between CoQ10-treated and non-treated groups. The subjects were 79 patients, 55 of whom had malignant lymphoma. The age range was from 16 to 77 years with a mean age of 45.4 years. CoQ10 was administered by intravenous drip at 1 mg/kg/day the day before ADM or DNR administration, on the day and for a further 2 days after administration. In mean total dose, complete remission rate and mortality, no significant differences were observed between the 2 groups. Although there were also no significant differences in the degree of alopecia, fever, nausea and vomiting, the incidences of diarrhea and stomatitis were significantly (p less than 0.10 and p less than 0.05, respectively) reduced in the CoQ10-treated group. Depression of ST waves (more than 0.05 mV) and changes in T waves (R/10 greater than T, flat, inversion) on ECG were regarded as a parameter of aggravation. Such ECG aggravation was found in 20 of 40 patients given CoQ10 (50.0%) and in 18 of 25 receiving none (72.0%); a cardiotoxicity-inhibiting tendency was thus evident (p less than 0.10). In heart rate, tachycardia was noted in the nontreated group when the period of use of anthracycline agents exceeded 8 weeks. Twenty nine patients received ADM or DNR for 8 weeks or more, and, of them, 17 were treated with CoQ10; 11 of the 17 (64.7%) showed ECG aggravation, while 11 of 12 patients (91.7%) not treated with CoQ10 showed ECG aggravation. A tendency to depress ECG aggravation was thus observed in the treated group (p less than 0.10).
Identification and Characterization of DEN1, a Deneddylase of the ULP Family (2003)

To identify deneddylases, proteases with specificity for hydrolysis of Nedd8 derivatives, a facile method was developed for the synthesis of Nedd8 amidomethylcoumarin (a substrate) and Nedd8 vinyl sulfone (an inhibitor). Deneddylase activity is necessary to reverse the conjugation of Nedd8 to cullin, a modification that regulates at least some ubiquitin ligases. The reaction of Nedd8 vinyl sulfone with L-M(TK-) mouse fibroblast lysates identified two deneddylases. The deubiquitinating enzyme UCH-L3 is labeled by both ubiquitin vinyl sulfone and Nedd8 vinyl sulfone. In contrast, a second and more selective enzyme is labeled only by Nedd8 vinyl sulfone. This protein, DEN1, is a 221-amino acid thiol protease that is encoded by an open reading frame previously annotated as SENP8. Recombinant human DEN1 shows significant specificity for Nedd8 and catalyzes the hydrolysis of Nedd8 amidomethylcoumarin with a Km of 51 nm and a kcat of7s-1. The catalytic efficiency of DEN1 acting upon ubiquitin amidomethylcoumarin is 6 x 10-4 that of Nedd8 amidomethylcoumarin and its activity on SUMO-1 amidomethylcoumarin is undetectable. This selectivity was unexpected as DEN1 is most closely related to enzymes that catalyze desumoylation. This observation expands to four the number of DUB families with members that can process the C terminus of Nedd8.
Synthetic Mimics of Antimicrobial Peptides with Immunomodulatory Responses (2012)

A new series of aryl-based synthetic mimics of antimicrobial peptides (SMAMPs) with antimicrobial activity and selectivity have been developed via systematic tuning of the aromatic groups and charge. The addition of a pendant aromatic group improved the antimicrobial activity against Gram-negative bacteria, while the addition of charge improved the selectivity. SMAMP 4 with six charges and a naphthalene central ring demonstrated a selectivity of 200 against both Staphylococcus aureus and Escherichia coli , compared with a selectivity of 8 for the peptide MSI-78. In addition to the direct antimicrobial activity, SMAMP 4 exhibited specific immunomodulatory activities in macrophages both in the presence and in the absence of lipopolysaccharide, a TLR agonist. SMAMP 4 also induced the production of a neutrophil chemoattractant, murine KC, in mouse primary cells. This is the first nonpeptidic SMAMP demonstrating both good antimicrobial and immunomodulatory activities.
Improvement in the Histochemical Localization of Leucine Aminopeptidase with a New Substrate, L-Leucyl-4-Methoxy-2-Naphthylamide (1960)

A new method for the histochemical demonstration of leucine aminopeptidase in fresh frozen sections was developed with the substrate L-leucyl-4-methoxy-2-naphthylamide. The superior enzyme localization is due to the more rapid rate of coupling of the hydrolysis product, 4-methoxy-2-naphthylamine as compared to 2-naphthylamine itself, and to the low lipid solubility and high substantivity for protein of the copper chelate of the dye formed on coupling with tetrazotized diorthoanisidine. A comparison of the old and the new method is illustrated, and a description is given of the localization of leucine aminopeptidase in the tissues of the rat and man.
Successful pregnancy following microsurgical epididymal sperm aspiration and intracytoplasmic sperm injection (1996)

Between June 1995 and November 1995, Micro-surgical Epididymal Sperm Aspiration (MESA), and Intracytoplasmic Sperm Injection (ICSI) was performed on 9 patients (10 cycles) who had congenital absence of the vas deferens (n=5), failed vaso-epididymostomy (n=2) or other irreparable obstructions (n-2). In two patients no epididymal spermatozoa were recovered and so testicular sperm extraction (TESE) was carried out. In one cycle frozen-thawed epididymal spermatozoa was used. A total of 75 oocytes were retrieved (7.5 oocytes/cycle) of which 69 oocytes were micromanipulated. The fertilization rate was 65.2 percent and the cleavage rate was 95.5 percent. Maturation arrest at the pronuclear stage was observed in 4.5 percent. The damage rate was 4.3 percent. Assisted hatching (Partial Zona Dissection) was carried out on 43 embryos. 4.3 embryos were transferred per cycle. The pregnancy rate per cycle was 10 percent and per patient was 11.2 percent. MESA and TESE in combination with ICSI is the treatment of choice for men with obstructive azoospermic conditions. This paper reports the first pregnancy in India by the combined technique of Microsurgical Epididymal Sperm Aspiration and Intracytoplasmic Sperm Injection.