gebhart/patrepeval huggingface dataset:
Engineering of protease variants exhibiting high catalytic activity and exquisite substrate selectivity (2005)

The exquisite selectivity and catalytic activity of enzymes have been shaped by the effects of positive and negative selection pressure during the course of evolution. In contrast, enzyme variants engineered by using in vitro screening techniques to accept novel substrates typically display a higher degree of catalytic promiscuity and lower total turnover in comparison with their natural counterparts. Using bacterial display and multiparameter flow cytometry, we have developed a novel methodology for emulating positive and negative selective pressure in vitro for the isolation of enzyme variants with reactivity for desired novel substrates, while simultaneously excluding those with reactivity toward undesired substrates. Screening of a large library of random mutants of the Escherichia coli endopeptidase OmpT led to the isolation of an enzyme variant, 1.3.19, that cleaved an Ala-Arg peptide bond instead of the Arg-Arg bond preferred by the WT enzyme. Variant 1.3.19 exhibited greater than three million-fold selectivity (-Ala-Arg-/-Arg-Arg-) and a catalytic efficiency for Ala-Arg cleavage that is the same as that displayed by the parent for the preferred substrate, Arg-Arg. A single amino acid Ser223Arg substitution was shown to recapitulate completely the unique catalytic properties of the 1.3.19 variant. These results can be explained by proposing that this mutation acts to "swap" the P(1) Arg side chain normally found in WT substrate peptides with the 223Arg side chain in the S(1) subsite of OmpT.
STIMULATION OF INFLAMMATORY MARKERS AFTER BLUNT TRAUMA (1997)

Giannoudis, P V; Smith, R M; Banks, R E; Windsor, A CJ; Dickson, R A; Guillou, P J Author Information
Angelman syndrome: Current understanding and research prospects (2009)

Angelman syndrome is a neurogenetic disorder characterized by developmental delay, severe intellectual disability, absent speech, exuberant behavior with happy demeanor, motor impairment, and epilepsy, due to deficient UBE3A gene expression that may be caused by various abnormalities of chromosome 15. Recent findings in animal models demonstrated altered dendritic spine formation as well as both synaptic [including gamma-aminobutyric acid (GABA)(A) and N-methyl-D-aspartate (NMDA) transmission] and nonsynaptic (including gap junction) influences in various brain regions, including hippocampus and cerebellar cortex. Reversal of selected abnormalities in rescue genetically engineered animal models is encouraging, although it should not be misinterpreted as promising "cure" for affected patients. Much research is still required to fully understand the functional links between lack of UBE3A expression and clinical manifestations of Angelman syndrome. Studies of regulation of UBE3A expression, including imprinting-related methylation, may point to possibilities of therapeutic upregulation. Understanding relevant roles of the gene product might lead to targeted intervention. Further documentation of brain network dynamics, with particular emphasis on hippocampus, thalamocortical, and cerebellar networks is needed, including in a developmental perspective. There is also a need for further clinical research for improving management of problems such as epilepsy, behavior, communication, learning, motor impairment, and sleep disturbances.
PRODUCTION OF BREAKS IN SINGLE‐ AND DOUBLE‐STRANDED FORMS OF BACTERIOPHAGE øx174 DNA BY PROFLAVINE AND LIGHT TREATMENT (1979)

Abstract— Irradiation at 440 + 360 nm and a fluence rate of 3.8 kJm ‐2 min ‐1 , of both complexes previously formed between proflavine and either øX circular single‐stranded (ss) DNA or øX supercoiled duplex (RFI)DNA, induces single‐strand scissions in the two DNAs under consideration. Linear øXSS DNA molecules are detected by sedimentation through alkaline sucrose gradients. After treatment of the øXRFI DNA, however, the degree of degradation is the same whether it is measured under neutral or alkaline conditions, indicating that alkaline‐labile bonds are not created; moreover, double‐strand breaks can only be detected after accumulation of single‐strand breaks. In addition to the amount of proflavine bound to the DNA and the duration of irradiation, the following factors are shown to influence the nicking activity of the treatment: (1) the DNA structure (the øXRFI DNA is much more sensitive than the øXss DNA); (2) the ionic strength of the medium during irradiation (a high value of 0.5 leads to a markedly increased efficiency); (3) the addition of cysteamine (this latter compound decreases the reaction rate) and (4) the irradiation wavelength (after irradiation at 440 nm alone, the reaction occurs at a reduced rate and is sensitive to NaN 3 ). The kinetics of the nicking reaction does not follow a single‐hit curve showing that at least one primary lesion occurs prior to strand breakage. On the other hand, strand scission cannot be detected after irradiation of the proflavine‐DNA complexes at the low fluence rate causing a decrease in the infectivity of both øXSS and øXRFI DNAs. Similarly. the sedimentation pattern of the DNA extracted from treated øx174 phages 99.9% inactivated, is identical to that of the control ss DNA, although more drastic treatments are susceptible to induce single strand breaks inside the phage head. Finally, the unknown lesion (s) that is biologically important does not prevent the treated DNAs from penetrating into the hostcells.
Elementary Electronic Structure (1999)

The basic approach bonding in tetrahedral semiconductors elastic properties of semiconductors the dielectric properties of semiconductors semiconductor energy bands electronic properties effects of lattice distortions impurities and defects bonding in ionic crystals elastic properties of ionic crystals dielectric properties of ionic solids covalent insulators, SiO2 simple metals, electronic structure simple metals, bonding properties transition metals f-shell metals transition-metal (AB) compounds other transition and f-shell compounds surfaces and interfaces other systems.
Antiviral activities of the soluble extracellular domains of type I interferon receptors (2001)

Alternative splicing leads to the expression of multiple isoforms of the subunits (IFNAR1 and IFNAR2) of the type I IFN receptor. Here we describe two transcripts representing extracellular forms of ovine IFNAR1 and show that soluble extracellular forms of both IFNAR2 and IFNAR1, prepared in recombinant form in Escherichia coli, have antiviral (AV) activity in the absence of IFN. Exposure of Madin-Darby bovine kidney cells to the extracellular domain (R2E) of IFNAR2 at concentrations as low as 10 nM afforded complete protection against vesicular stomatitis virus and led to the rapid activation of the transcription factors ISGF3 and GAF. Although R2E can bind IFN (K(d) approximately 70 nM), activity was observed irrespective of whether or not ligand was present. R2E was inactive on mouse L929 cells but active on L929 cells expressing a membraneanchored, ovine/human chimeric IFNAR2 with an ovine extracellular domain. The data suggest that AV activity is conferred by the ability of soluble R2E to associate with the transfected IFNAR2 subunit rather than resident murine IFNAR1. Soluble extracellular forms of IFNAR1 have lower AV activity than R2E on Madin-Darby bovine kidney cells but are less species-specific and protect wild-type L929 cells as efficiently as the transfected cell line, presumably by interacting with one of the murine receptor subunits.
Functional correction of established central nervous system deficits in an animal model of lysosomal storage disease with feline immunodeficiency virus-based vectors (2002)

Gene transfer vectors based on lentiviruses can transduce terminally differentiated cells in the brain; however, their ability to reverse established behavioral deficits in animal models of neurodegeneration has not previously been tested. When recombinant feline immunodeficiency virus (FIV)-based vectors expressing beta-glucuronidase were unilaterally injected into the striatum of adult beta-glucuronidase deficient [mucopolysaccharidosis type VII (MPS VII)] mice, an animal model of lysosomal storage disease, there was bihemispheric correction of the characteristic cellular pathology. Moreover, after the injection of FIV-based vectors expressing beta-glucuronidase into brains of beta-glucuronidase-deficient mice with established impairments in spatial learning and memory, there was dramatic recovery of behavioral function. Cognitive improvement resulting from expression of beta-glucuronidase was associated with alteration in expression of genes associated with neuronal plasticity. These data suggest that enzyme replacement to the MPS VII central nervous system goes beyond restoration of beta-glucuronidase activity in the lysosome, and imparts improvements in plasticity and spatial learning.
Novel therapeutic agents under investigation for malignant melanoma (2003)

Malignant melanoma presents a therapeutic challenge. Patients at high risk for recurrence (stage III) are eligible for adjuvant treatment with IFN-α or may enrol in a clinical trial. Both options offer no meaningful survival advantage. Patients with metastatic disease (stage IV) have a 5-year survival of < 10% and have no effective treatment options. Despite aggressive investigations into vaccine therapy, no vaccine has yet received FDA approval. Biological therapies with IFN-α and IL-2 have demonstrated a real but minimal effect. Chemotherapeutic options are even more dismal. Single-agent chemotherapy yields a 15 – 20% response rate of short lived duration. Combination chemotherapy alone or with immunological adjuvants yields response rates of 35 – 45% but with significant toxicity and no significant improvement in survival. Novel treatment agents that target metabolic pathways, angiogenesis inhibitors, antisense therapies, gene therapies and innovative vaccines may offer hope for an otherwise grave disease.
The role of bacteriocins as selfish genetic elements (2013)

Bacteria produce a wide arsenal of toxic compounds in order to kill competing species. Bacteriocins, protein-based toxins produced by nearly all bacteria, have generally been considered a ubiquitous anti-competitor strategy, used to kill competing bacterial strains. Some of these bacteriocins are encoded on plasmids, which also code for closely linked immunity compounds (thereby rendering toxin producing cells immune to their own toxin). However, the production of bacteriocins can also be interpreted as a means to promote plasmid stability by preferentially selecting for cells carrying the plasmid. If, for example, a cell were to lose the plasmid, it would no longer produce the immunity compound and would be killed by its bacteriocin-producing clone mates. In this respect, bacteriocins can be regarded as similar to previously described toxin-antitoxin systems that are able promote the stable transmission of plasmids to daughter cells. In order to test this prediction, we carried out an experimental evolution study using the bacterium Escherichia coli, finding that bacteriocins can indeed select for the stable maintenance of plasmids. This suggests that bacteriocins can act primarily as selfish genetic elements promoting their own transmission in the population, which may help explain their unique ecology and evolution.
Base excision repair deficient mice lacking the Aag alkyladenine DNA glycosylase (1997)

3-methyladenine (3MeA) DNA glycosylases remove 3MeAs from alkylated DNA to initiate the base excision repair pathway. Here we report the generation of mice deficient in the 3MeA DNA glycosylase encoded by the Aag (Mpg) gene. Alkyladenine DNA glycosylase turns out to be the major DNA glycosylase not only for the cytotoxic 3MeA DNA lesion, but also for the mutagenic 1,N6-ethenoadenine (epsilonA) and hypoxanthine lesions. Aag appears to be the only 3MeA and hypoxanthine DNA glycosylase in liver, testes, kidney, and lung, and the only epsilonA DNA glycosylase in liver, testes, and kidney; another epsilonA DNA glycosylase may be expressed in lung. Although alkyladenine DNA glycosylase has the capacity to remove 8-oxoguanine DNA lesions, it does not appear to be the major glycosylase for 8-oxoguanine repair. Fibroblasts derived from Aag -/- mice are alkylation sensitive, indicating that Aag -/- mice may be similarly sensitive.
Multichannel surface EMG: Basic aspects and clinical utility (2003)

The generation of the surface electromyogram (sEMG) is described with regard to the properties of the single muscle fiber action potential as source, the physical aspects of volume conduction and recording configuration, and the properties and firing pattern of motor units (MUs). The spatial aspect of the motor unit action potential (MUP) is emphasized in relation to the results of high-density, multichannel sEMG measurements. The endplate zone, depth, size, and position of MUs can be estimated. The use of muscle fiber conduction velocity measurements in channelopathies and the changes in pathological fatigue are described. Using the unique patterns of spatial spread of MUPs over the skin (MU fingerprint), MU classification and the determination of firing moments is done noninvasively. Clinical applications of high-density sEMG measurements are reviewed. Emerging possibilities provided by MUP size and fingerprint measurements in neuromuscular disease and motor control are discussed. We conclude that multichannel sEMG adds unique, and sometimes indispensable, spatial information to our knowledge of the motor unit.
Glucose-regulated insulin production in hepatocytes1 (2002)

These studies demonstrate in vivo glucose-regulated insulin secretion from an autologous non-beta cell leading to fasting euglycemia and an improved glucose tolerance, thereby supporting the feasibility of hepatocyte-based insulin gene-therapy for treatment of type 1 diabetes mellitus.
Dronedarone: A New Treatment for Atrial Fibrillation (2008)

Dronedarone. Dronedarone is a benzofuran derivative pharmacologically related to amiodarone but without the iodine moiety. It is designed for the treatment of atrial fibrillation and atrial flutter. Historically, amiodarone has proved most effective in maintaining sinus rhythm and has been used safely in patients with advanced heart failure. However, its use has been limited by cumulative and often irreversible organ toxicity, especially in younger patients. Dronedarone was developed in an effort to provide equivalent efficacy and safety with less toxicity. Dronedarone has proved efficacious without toxic or proarrhythmic effects and has minimal side effects, but remaining concerns exist regarding its use in patients with advanced heart failure.
Structure and Properties of Members of the hGH Family (2000)

This review will summarize the properties of five variant forms of human growth hormone: a disulfide dimer, a glycosylated form, 20 kD-hGH, and two peptides made up of portions of 22 kD-hGH. The two pituitary peptides (hGH(1-43) and hGH(44-191)) have, respectively, insulin-potentiating and anti-insulin properties. Both have been detected in serum. The shorter peptide may prove to be useful in decreasing the amount of exogenous insulin required by diabetics. The larger, strongly anti-insulin peptide, may be involved in diabetic retinopathy. We believe that this peptide is the long sought after diabetogenic substance of the pituitary gland.
CXC Chemokine Receptor 4 Expression and Function in Human Anaplastic Thyroid Cancer Cells (2003)

Anaplastic thyroid carcinomas (ATCs) are highly aggressive, extremely lethal human cancers with poor therapeutic response. Chemokines are a superfamily of small cytokine-like proteins that induce, through their interaction with G protein-coupled receptors, cytoskeletal rearrangement, firm adhesion to endothelial cells, and directional migration. In this study, we characterized the expression of CXC chemokine receptor 4 (CXCR4) and analyzed its functions in ARO cells, a human ATC cell. The normal primary cultured thyroid cells and ATC cell lines expressed CXCR4 and stromal cell-derived factor (SDF)-1 alpha transcripts, detected by RT-PCR. Fluorescence activated cell sorting analysis of CXCR4 expression in normal and ATC cells showed that ARO cells expressed significant levels of CXCR4. FRO, NPA, and normal thyroid cells did not express membrane CXCR4, as determined by fluorescence activated cell sorting analysis. To identify the functional role of CXCR4 in ARO cells, we treated ARO cells with SDF-1 alpha and analyzed the signaling pathways, cellular migration, and proliferation. SDF-1alpha enhanced the migration but did not affect the proliferation of ARO cells or activate the Janus kinase/signal transducer and activator of transcription signaling pathways. However, SDF-1 alpha/CXCR4 activation resulted in phosphorylation of the p70S6 kinase and its target protein, ribosomal S6 protein, and also activation of the ERK1/ERK2 signaling pathways. Furthermore, SDF-1 alpha/CXCR4- mediated activation of the p70S6 kinase and phosphorylation of the S6 protein were inhibited by treatment with an mTOR/FRAP inhibitor. The specificity of the CXCR4-mediated migration of ARO cells was demonstrated by the dose-dependent inhibition of migration by neutralizing anti-CXCR4. The ATC cells, FRO and NPA, which do not express CXCR4, did not demonstrate significant SDF-1 alpha-mediated migration in vitro. In addition, the CXCR4-mediated migration of ARO cells was inhibited by treatment with pertussis toxin (a Gi-protein inhibitor) and PD 98059 (a mitogen-activated ERK kinase inhibitor) but not by LY294002 and wortmanin, phosphatidylinositol 3-kinase inhibitors. These findings suggest that a subset of ATC cells expresses functional CXCR4, which may be important in tumor cell migration and local tumor invasion.
Highly Conductive Li Garnets by a Multielement Doping Strategy (2015)

Highly conductive Li7La3Zr2O12 (LLZ) garnet-type solid electrolytes were further optimized to improve Li-ion conduction by La(3+)-sites substitution with Ba(2+) and Zr(4+)-sites substitution with Ta(5+) and Nb(5+). Garnet-structured metal oxides of the nominal chemical compositions Li6.65La2.75Ba0.25Zr1.4Ta0.5Nb0.1O12, Li6.4La3Zr1.4Ta0.6-xNbxO12 (x = 0, 0.1, 0.2, and 0.3), and the parent LLZ, as a reference, were prepared via conventional solid-state reaction to investigate the effect of multielement doping on ionic conductivity. The phase formation, morphology, and Li ion conductivity were characterized using powder X-ray diffraction (PXRD), scanning electron microscopy, and alternating current impedance spectroscopy methods, respectively. In addition, solid-state (27)Al and (7)Li magic-angle spinning (MAS) NMR was used to study the effect of "Al doping" on the investigated multielement doped Li-stuffed garnet metal oxides. All the prepared samples obtained the cubic garnet-type structure (space group: Ia3̅d; No. 230) at 1150 °C, similar to that of cubic LLZ. Except for Li6.4La3Zr1.4Ta0.6O12, all the members show Al content by Al MAS NMR. However, it was not possible to detect Al-based impurity phases using PXRD in any of the investigated garnets. Among the samples investigated in this work, "Al-free" Li6.4La3Zr1.4Ta0.6O12 demonstrated a bulk Li ion conductivity of 0.72 mS cm(-1) at 25 °C, with apparent activation energy of 0.26 eV, significantly higher than the parent LLZ.
Biofilm matrix of Candida albicans and Candida tropicalis: chemical composition and role in drug resistance (2006)

Matrix material was extracted from biofilms of Candida albicans and Candida tropicalis and analysed chemically. Both preparations contained carbohydrate, protein, hexosamine, phosphorus and uronic acid. However, the major component in C. albicans matrix was glucose (32%), whereas in C. tropicalis matrix it was hexosamine (27%). Biofilms of C. albicans were more easily detached from plastic surfaces by treatment with the enzyme lyticase (beta-1,3-glucanase) than were those of C. tropicalis. Biofilms of C. albicans were also partially detached by treatment with proteinase K, chitinase, DNase I, or beta-N-acetylglucosaminidase, whereas C. tropicalis biofilms were only affected by lipase type VII or chitinase. To investigate a possible role for the matrix in biofilm resistance to antifungal agents, biofilms of C. albicans were grown under conditions of continuous flow in a modified Robbins device (MRD). These biofilms produced more matrix material than those grown statically, and were significantly more resistant to amphotericin B. Biofilms of C. tropicalis synthesized large amounts of matrix material even when grown statically, and such biofilms were completely resistant to both amphotericin B and fluconazole. Mixed-species biofilms of C. albicans and a slime-producing strain of Staphylococcus epidermidis (RP62A), when grown statically or in the MRD, were also completely resistant to amphotericin B and fluconazole. Mixed-species biofilms of C. albicans and a slime-negative mutant of S. epidermidis (M7), on the other hand, were completely drug resistant only when grown under flow conditions. These results demonstrate that the matrix can make a significant contribution to drug resistance in Candida biofilms, especially under conditions similar to those found in catheter infections in vivo, and that the composition of the matrix material is an important determinant in resistance.
Syntheses of Pyridazine Derivatives. II (1955)

Eight kinds of 3-alkoxy-6-chloropyridazine and 3 kinds of 3-alkylthio-6-chloropyridazine, and their derivatives prepared and their behavior to anionoid substitution was examined. 3-Alkylthio-4- and -5-methyl-6-chloropyridazines were also prepared.
Extremely Large Enhancement Factors in Surface-Enhanced Raman Scattering for Molecules on Colloidal Gold Clusters (1998)

In agreement with previous results reported for colloidal silver clusters, effective surface-enhanced Raman cross sections of about 10- 16 cm 2 per molecule, corresponding to enhancement factors on the order of 10 14 , have also been obtained for molecules attached to colloidal gold clusters. Spatially isolated nearly spherical colloidal gold particles of about 60 nm size show maximum enhancement factors on the order of 10 3 at 514 nm excitation, close to the single plasmon resonance. The enhancement factor increases by eleven orders of magnitude when colloidal gold clusters are formed by aggregation of the gold colloids and when near-infrared excitation is applied. The large effective surface-enhanced Raman cross section has been estimated by a straightforward method based on steady-state population redistribution due to the pumping of molecules to the first excited vibrational state via the strongly enhanced Raman process. Our experimental finding confirms the important role of colloidal clusters for extremely large surface-enhanced Raman scattering (SERS) enhancement factors. Simultaneously, it suggests colloidal gold clusters as a substrate for high-sensitivity surface-enhanced Raman scattering, which can provide an enhancement level sufficient for Raman single molecule detection. Due to its chemical inactivity, gold might have some advantages compared to silver, particularly in biomedical spectroscopy.
Epigenetic susceptibility factors for prostate cancer with aging (2013)

Epigenetic changes with aging represent molecular mechanisms to explain the increased susceptibly of the prostate to develop cancer in older men. These changes may provide an opportunity for diagnostic and chemopreventive strategies given the epigenome can be modified.