gebhart/patrepeval huggingface dataset:
Lagrangean Theory (2010)

The purpose of this chapter is to outline an overview of the basic criteria for characterizing the solution of static optimization problems. Its intent is neither rigor nor generality but a sufficient understanding for the logic leading to the conditions of optimization and a sufficient degree of practicality. An immediate issue is whether we are satisfied with relative optima or require global optima as the solution of our problems. Any further elaboration necessitates a definition of these two notions.
Late Complications of Immune Deviation Therapy in a Nonhuman Primate (1996)

The administration of antigens in soluble form can induce antigen-specific immune tolerance and suppress experimental autoimmune diseases. In a marmoset model of multiple sclerosis induced by myelin oligodendrocyte glycoprotein (MOG), marmosets tolerized to MOG were protected against acute disease, but after tolerization treatment a lethal demyelinating disorder emerged. In these animals, MOG-specific T cell proliferative responses were transiently suppressed, cytokine production was shifted from a T helper type 1 (TH1) to a TH2 pattern, and titers of autoantibodies to MOG were enhanced. Thus, immune deviation can increase concentrations of pathogenic autoantibodies and in some circumstances exacerbate autoimmune disease.
Copper Transfer from the Cu(I) Chaperone, CopZ, to the Repressor, Zn(II)CopY:  Metal Coordination Environments and Protein Interactions (2002)

Extracellular copper regulates the DNA binding activity of the CopY repressor of Enterococcus hirae and thereby controls expression of the copper homeostatic genes encoded by the cop operon. CopY has a CxCxxxxCxC metal binding motif. CopZ, a copper chaperone belonging to a family of metallochaperones characterized by a MxCxxC metal binding motif, transfers copper to CopY. The copper binding stoichiometries of CopZ and CopY were determined by in vitro metal reconstitutions. The stoichiometries were found to be one copper(I) per CopZ and two copper(I) per CopY monomer. X-ray absorption studies suggested a mixture of two- and three-coordinate copper in Cu(I)CopZ, but a purely three-coordinate copper coordination with a Cu-Cu interaction for Cu(I)2CopY. The latter coordination is consistent with the formation of a compact binuclear Cu(I)-thiolate core in the CxCxxxxCxC binding motif of CopY. Displacement of zinc, by copper, from CopY was monitored with 2,4-pyridylazoresorcinol. Two copper(I) ions were required to release the single zinc(II) ion bound per CopY monomer. The specificity of copper transfer between CopZ and CopY was dependent on electrostatic interactions. Relative copper binding affinities of the proteins were investigated using the chelator, diethyldithiocarbamic acid (DDC). These data suggest that CopY has a higher affinity for copper than CopZ. However, this affinity difference is not the sole factor in the copper exchange; a charge-based interaction between the two proteins is required for the transfer reaction to proceed. Gain-of-function mutation of a CopZ homologue demonstrated the necessity of four lysine residues on the chaperone for the interaction with CopY. Taken together, these results suggest a mechanism for copper exchange between CopZ and CopY.
Isolation of nonsense suppressor mutants in Pseudomonas (1976)

A strain of Escherichia coli harboring the drug resistance plasmid RP1 was treated with the mutagen N-methyl-N-nitro-N-nitro-N-nitrosoguanidine, and mutants were isolated in which ampicillin resistance had been lost due to an amber mutation in the plasmid. One of these mutants was again treated, and a strain was isolated in which tetracycline resistance was also lost due to an amber mutation in the plasmid. The plasmid containing amber mutations in the genes amp and tet was named pLM2. This plasmid could be transferred to strains of Pseudomonas aeruginosa, P. phaseolicola, and P. pseudoalcaligenes. Mutants resistant to ampicillin and tetracycline could not be obtained from P. phaseolicola carrying pLM2. However, strains of E. coli, P. aeruginosa, and P. pseudoalcaligenes carrying the plasmid did produce mutants simultaneously resistant to both antibiotics. All of the mutants of E. coli had developed nonsense suppressors since they became phenotypically lac+, although harboring a lac amber mutation, and formed plaques with amber mutants of phages PRR1 and PRD1 that attack organisms carrying RP1. Approximately 20% of the resistant mutants of P. aeruginosa and P. pseudoalcaligenes were sensitive to the amber mutant of PRD1. These mutants were of variable stability and grew somewhat more slowly than their parent strains. One of the suppressor mutants of P. pseudoalcaligenes, designated ERA(pLM2)S4, was used for the isolation of nonsense mutants of bacteriophage PHA6, a virus having a segmented genome of double-stranded ribonucleic acid and an envelope of lipids and proteins.
The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis (2015)

ALX-0061 represents a minimized bispecific biotherapeutic of 26 kDa, nearly six times smaller than monoclonal antibodies. High in vitro affinity and potency was demonstrated. Albumin binding as a half-life extension technology resulted in describable and expected pharmacokinetics. Strong IL-6R engagement was shown to translate to in vivo effect in non-human primates, demonstrated via biomarker deregulation as well as clinical effect. Presented results on preclinical pharmacological properties of ALX-0061 are supportive of clinical development in RA.
Nanomolar-Potency Aminophenyl-1,3,5-triazine Activators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Chloride Channel for Prosecretory Therapy of Dry Eye Diseases (2017)

Dry eye disorders are a significant health problem for which limited therapeutic options are available. CFTR is a major prosecretory chloride channel at the ocular surface. We previously identified, by high-throughput screening, aminophenyl-1,3,5-triazine CFTR<sub>act</sub>-K089 (1) that activated CFTR with EC<sub>50</sub> ≈ 250 nM, which when delivered topically increased tear fluid secretion in mice and showed efficacy in an experimental dry eye model. Here, functional analysis of aminophenyl-1,3,5-triazine analogs elucidated structure-activity relationships for CFTR activation and identified substantially more potent analogs than 1. The most potent compound, 12, fully activated CFTR chloride conductance with EC<sub>50</sub> ≈ 30 nM, without causing cAMP or calcium elevation. 12 was rapidly metabolized by hepatic microsomes, which supports its topical use. Single topical administration of 25 pmol of 12 increased tear volume in wild-type mice with sustained action for 8 h and was without effect in CFTR-deficient mice. Topically delivered 12 may be efficacious in human dry eye diseases.
Ganglioside-mediated modulation of cell growth. Specific effects of GM3 and lyso-GM3 in tyrosine phosphorylation of the epidermal growth factor receptor. (1988)

Epidermal growth factor-(EGF) dependent tyrosine phosphorylation of the EGF receptor was inhibited by the exogenous addition of GM3 to a membrane preparation and to purified EGF receptor adsorbed to anti-
The biosynthesis of oligosaccharides in intact Golgi preparations from rat liver. Analysis of N-linked and O-linked glycans labeled by UDP-[6-3H]N-acetylgalactosamine (1993)

Endogenous acceptors in a Golgi apparatus-enriched subcellular fraction from rat liver were labeled with UDP-[3H]GalNAc. The great majority of these acceptors were protected from protease degradation in the absence of detergent. These molecules are therefore present in intact vesicles of the correct topological orientation, which are likely to be similar to the Golgi compartments of the intact cell. Several distinct glycoproteins are labeled, but most are different from those labeled with UDP-[3H]GlcNAc. The enzyme peptide-N4(N-acetyl-beta-glucosiminyl)asparagine amidase releases label from a few specific proteins, indicating that [3H]GalNAc is transferred to N-linked oligosaccharides. Both neutral and anionic N-linked oligosaccharides are found, the great majority of which do not bind to ConA-Sepharose. Most of the [3H]GalNAc found in neutral oligosaccharides is terminal and beta-linked. The negative charge on the anionic molecules is due to sialic acid, and phosphate. A major portion of the [3H] GalNAc in this fraction is acid labile, and is released with kinetics consistent with it being in a phosphodiester linkage. These results show the existence of a whole new class of GalNAc-containing N-linked oligosaccharides, and demonstrates that this in vitro approach can detect previously undescribed structures. O-linked oligosaccharide biosynthesis was also studied in the same labeled rat liver Golgi apparatus preparations. beta-Elimination releases approximately 95% of the peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase (PNGase F)-resistant label which, in the absence of other added nucleotides, is almost exclusively [3H] GalNAcitol. If other unlabeled sugar nucleotides and adenosine 3'-phosphate,5'-phosphosulfate are added during the chase period two anionic O-linked oligosaccharides are synthesized, indicating that the UDP-GalNAc:peptide-N-acetylgalactosaminyltransferase is at least in part functionally co-localized with enzymes that extend and modify O-linked oligosaccharides.
Immunogenicity of Recombinant Fiber-Chimeric Adenovirus Serotype 35 Vector-Based Vaccines in Mice and Rhesus Monkeys (2005)

Preexisting immunity to adenovirus serotype 5 (Ad5) has been shown to suppress the immunogenicity of recombinant Ad5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 (HIV-1) in both preclinical studies and clinical trials. A potential solution to this problem is to utilize rAd vectors derived from rare Ad serotypes, such as Ad35. However, rAd35 vectors have appeared less immunogenic than rAd5 vectors in preclinical studies to date. In this study, we explore the hypothesis that the differences in immunogenicity between rAd5 and rAd35 vectors may be due in part to differences between the fiber proteins of these viruses. We constructed capsid chimeric rAd35 vectors containing the Ad5 fiber knob (rAd35k5) and compared the immunogenicities of rAd5, rAd35k5, and rAd35 vectors expressing simian immunodeficiency virus Gag and HIV-1 Env in mice and rhesus monkeys. In vitro studies demonstrated that rAd35k5 vectors utilized the Ad5 receptor CAR rather than the Ad35 receptor CD46. In vivo studies showed that rAd35k5 vectors were more immunogenic than rAd35 vectors in both mice and rhesus monkeys. These data suggest that the Ad5 fiber knob contributes substantially to the immunogenicity of rAd vectors. Moreover, these studies demonstrate that capsid chimeric rAd vectors can be constructed to combine beneficial immunologic and serologic properties of different Ad serotypes.
Fabrication and Characterization of Thermoelectric Thick Film Prepared from p-Type Bismuth Telluride Nanopowders (2012)

In this study, bismuth telluride (Bi2Te3)-based nanopowders with particle size ranging from 100 to 300 nm are prepared by high-energy ball milling. Then, the prepared nanopowders are homogeneously mixed with organic binders to form a paste; this paste is used as the raw material to prepare thick-film thermoelectric modules. The thick film prepared by screen printing followed by hot pressing of p-type pastes show reproducible thermoelectric properties, exhibiting an electrical resistivity of 2.0 m Omega cm and a Seebeck coefficient of 298 muVK-1. The prepared p-type Bi2Te3 thick film has a high power factor because its Seebeck coefficient is significantly higher than that of Bi2Te3 based-bulk materials. These results indicate that a thick film prepared from bismuth telluride nanopowders has potential for use as high-performance thermoelectric modules in practical applications such as power generation and cooling system in electronic devices.
Suppression by Flavonoids of Cyclooxygenase‐2 Promoter‐dependent Transcriptional Activity in Colon Cancer Cells: Structure‐Activity Relationship (2000)

Cyclooxygenase-2 (COX-2) plays an important role in carcinogenesis. Investigation of the suppressive action of twelve flavonoids of different chemical classes on the transcriptional activity of the COX-2 gene in human colon cancer DLD-1 cells using a reporter gene assay have revealed quercetin to be the most potent suppressor of COX-2 transcription (IC50 = 10.5 microM), while catechin and epicatechin showed weak activity (IC50 = 415.3 microM). Flavonoids have three heterocyclic rings as a common structure. A structure-activity study indicated that the number of hydroxyl groups on the B ring and an oxo group at the 4-position of the C ring are important in the suppression of COX-2 transcriptional activity. A low electron density of the oxygen atom in the hydroxyl group of the A ring was also important. Further examination of the role of the hydroxyl group in the A ring showed that bromination of resacetophenone to give 3,5-dibromo-2,4-dihydroxyacetophenone resulted in a 6.8-fold increase in potency for suppressing COX-2 promoter activity. These results provide a basis for the design of improved suppressors of COX-2 transcriptional activity.
Potent Noncovalent Thrombin Inhibitors That Utilize the Unique Amino Acid d-Dicyclohexylalanine in the P3 Position. Implications on Oral Bioavailability and Antithrombotic Efficacy (1997)

In an effort to prepare orally bioavailable analogs of our previously reported thrombin inhibitor 1, we have synthesized a series of compounds that utilize the unique amino acid D-dicyclohexylalanine as a P3 ligand. The resulting compounds are extremely potent and selective thrombin inhibitors, and the N-terminal Boc derivative 8 exhibited excellent oral bioavailability and pharmacokinetics in both rats and dogs. The des-Boc analog 6 was not orally bioavailable in rats. The high level of oral bioavailability observed with 8 appears to be a direct function of its increased lipophilicity versus other close analogs. Although increased lipophilicity may serve to increase the oral absorption of tripeptide thrombin inhibitors, it also appears to have detrimental effects on the antithrombotic properties observed with the compounds. Compound 6 performed extremely well in our in vivo antithrombotic assay, while the much more lipophilic but essentially equipotent analog 8 performed poorly. We have found that in general with this series of thrombin inhibitors as well as with other unreported series, increased lipophilicity and the associated increases in plasma protein binding have detrimental effects on 2X APTT values and subsequent performance in in vivo antithrombotic models.
The Biomechanics of Human Ribs: Material and Structural Properties from Dynamic Tension and Bending Tests (2007)

The purpose of this study was to quantify both the tensile material properties and structural response of human ribs in order to determine which variables contribute to regional variation in the strength of human ribs. This was done by performing 94 matched tests on human rib specimens; 46 tension coupon tests, 48 three-point bending tests. Contralateral matched specimens were dissected from anterior and lateral regions of ribs 4 through 7 of six male fresh frozen post mortem human subjects ranging from 42 to 81 years of age. Tension coupons were taken from one side of the thorax, while three-point bending specimens were taken from the opposite side as the tension coupons at corresponding anatomical locations. The results of the tension coupon testing showed that there were no significant differences with respect to region or rib level: ultimate stress (p=0.90; p=0.53), ultimate strain (p=0.49; p=0.86), or modulus (p=0.72; p=0.81). In contrast, lateral three-point bending specimens were found to have a significantly higher peak bending moment (p<0.01), peak strain (p=0.03), modulus (p=0.05), and stiffness (p<0.01) than anterior specimens. The lateral three-point bending specimens also had a significantly larger area moment of inertia (p<0.01), larger distance to the neutral axis (p<0.01), smaller ratio of distance to the neutral axis to area moment of inertia (p<0.01), larger cortical bone area (p<0.01), and larger radius of gyration (p<0.01) than the anterior specimens. In addition, the peak moment (Ant p=0.20; Lat p=0.02), peak strain (Ant p=0.05; Lat p=0.15), and stiffness (Ant p<0.01; Lat p<0.01) were found to vary significantly with respect to rib level. Similar to anatomical region, the changes in the structural response with respect to rib level were also accompanied by significant changes in geometry. For anterior specimens, distance to the neutral axis (p<0.01), ratio of the distance to the neutral axis to area moment of inertia (p=0.02) and radius of gyration (p=0.04) were found to be significantly different with respect to rib level. For lateral specimens, the area moment of inertia (p<0.01), distance to the neutral axis (p<0.01), ratio of the distance to the neutral axis to area moment of inertia (p<0.01), the cortical bone area (p=0.01), and radius of gyration (p=0.03) were found to be significantly different with respect to rib level. These results clearly illustrate that there is variation in the structural response of human ribs with respect to anatomical region and rib level and this variation is due to changes in local geometry of each rib while the material properties remain constant.
Thymidylate Synthase Expression in Patients with Colorectal Carcinoma Using a Polyclonal Thymidylate Synthase Antibody in Comparison to the TS 106 Monoclonal Antibody (2000)

Colorectal cancer is one of the most common human cancers, for which 5-fluorouracil (5FU) is usually part of the treatment. Thymidylate synthase (TS), the target enzyme for 5FU, can be predictive for the outcome of 5FU-based therapy. TS levels in tumor samples can be determined with radiochemical enzyme assays, RT-PCR, and immunohistochemical staining. We validated TS immunohistochemistry with a polyclonal rabbit anti-human TS antibody using the avidin-biotin method. This antibody can be used on paraffin-embedded, formalin-fixed material using an antigen retrieval method with citrate buffer and microwave treatment. The antibody shows a granular cytosolic staining pattern. The reproducibility in cross-sections from colorectal tumors from 50 patients was 90% and the interobserver variability was acceptable with a kappa of 0.45. On Western blotting it detects purified TS at 36 kD, while in 5FU-treated cells the ternary complex between FdUMP, TS, and 5, 10-methylene-tetrahydrofolate is clearly visible at 38 kD, with no other interfering bands. In a separate set of tumors, immunostaining was compared with enzyme levels; Western blots correlated with enzyme levels. Because both this polyclonal antibody and the monoclonal antibody TS-106 are being used for large-scale studies, we also determined whether they could be used interchangeably. No differences were observed. This polyclonal antibody is specific and gives reproducible results. A study on a larger scale is ongoing to determine the role of TS as a predictive parameter in patients with colorectal cancer treated either with postoperative adjuvant 5FU/levamisole or with surgery only.
Practical Domain and Type Enforcement for UNIX (2002)

Type enforcement is a table-oriented mandatory access control mechanism well-suited for confining applications and restricting information flows. Although both flexible and strong, type enforcement alone imposes significant administrative costs and has not been widely adopted. Domain and Type Enforcement (DTE) is an enhanced version of type enforcement designed to provide needed simplicity and compatibility. Two primary techniques distinguish DTE from simple type enforcement: DTE policies are expressed in a high-level language that includes file security attribute associations as well as other access control information; and during system execution, DTE file security attributes are maintained using a concise human-readable format in a runtime DTE policy database, thus removing the need for security-specific low-level data formats. Such formats are a major source of incompatibility for security-enhanced systems. A DTE UNIX prototype system has been implemented to evaluate these primary DTE concepts. This paper presents experiences gained and preliminary results indicating that DTE can provide cost effective security increases to UNIX systems while maintaining a high degree of compatibility with existing programs and media.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Stark Effects after Excited-State Interfacial Electron Transfer at Sensitized TiO2 Nanocrystallites (2010)

Photophysical studies were performed with [Ru(dtb)(2)(dcb)](PF(6))(2) and cis-Ru(dcb)(dnb)(NCS)(2,) where dtb is 4,4'-(C(CH(3))(3))(2)-2,2'-bipyridine, dcb is 4,4'-(COOH)(2)-2,2'-bipyridine, and dnb is 4,4'-(CH(3)(CH(2))(8))(2)-2,2'-bipyridine), anchored to anatase TiO(2) particles ( approximately 15 nm in diameter) interconnected in a mesoporous, 10 mum thick film immersed in Li(+)-containing CH(3)CN electrolytes with iodide or phenothiazine donors. Pulsed-laser excitation resulted in rapid excited-state injection and donor oxidation to yield TiO(2)(e(-))s and oxidized donors, while the metal-to-ligand charge-transfer (MLCT) absorption spectrum of the Ru(II) coordination compounds differed from that which was initially excited. The spectral data were consistent with an underlying Stark effect and indicated that the surface electric field was not completely screened from the molecular sensitizer. The magnitude of the electric field was estimated to be approximately 270 MV/m from Li(+) titration experiments, corresponding to a approximately 40 mV potential drop. With iodide donors, the amplitude of the Stark effect decreased over time periods where charge recombination was absent, behavior attributed to "screening" of the electric field by interfacial ionic reorganization. The screening kinetics were nonexponential but were well described by the Kohlrausch-Williams-Watts model, from which a characteristic rate constant, tau(o)(-1), of approximately 1.5 x 10(5) s(-1) was abstracted. At least seven other sensitizers and five different cations, as well as on SnO(2) nanoparticle films, exhibited similar transient absorption behavior with iodide donor molecules indicating that the effect was quite general. In the presence of phenothiazine donors (or in the absence of an external donor), there was no clear evidence for screening, and the Stark effect disappeared concurrent with interfacial charge recombination. Complementary spectroelectrochemical studies of these same sensitized films displayed similar absorption spectra when the TiO(2) thin film was partially reduced with a forward bias. Spectral modeling in the absence of donor molecules as well as studies of TiO(2) thin films sensitized with two different Ru(II) compounds demonstrated that the electric field created by excited-state injection from one sensitizer influenced the absorption spectra of other sensitizers that had not undergone photoinduced electron injection.
A YAC Contig Spanning a Cluster of Human Type III Receptor Protein Tyrosine Kinase Genes (PDGFRA-KIT-KDR) in Chromosome Segment 4q12 (1994)

We have mapped five genes encoding protein tyrosine kinases (PTKs) to the pericentromeric region of human chromosome 4. PTK4 and TYRO4, which encode nonreceptor intracellular PTKs, are located at 4p12 and 4q13, respectively. The other three genes, PDGFRA, KIT, and KDR, encode type III transmembrane receptor PTKs for known ligands. We have developed a contig of 29 yeast artificial chromosomes (YACs) spanning approximately 2 Mb of DNA at 4q12 that includes PDGFRA, KIT, and KDR, and we have used this YAC contig to map 12 different sequence-tagged sites in this region. PDGFRA, KIT, and KDR thus constitute a cluster of genes at 4q12 encoding closely related type III receptor PTKs. Mutations of the human KIT gene result in piebaldism, an autosomal dominant disorder of melanocyte development.