gebhart/patrepeval huggingface dataset:
Cross-neutralizing activity against divergent human immunodeficiency virus type 1 isolates induced by the gp41 sequence ELDKWAS (1994)

Previously we identified the highly conserved amino acids Glu-Leu-Asp-Lys-Trp-Ala (ELDKWA) on the ecto-domain of gp41 as the epitope of a neutralizing monoclonal antibody (2F5) directed against human immunodeficiency virus type 1. In the present study, the sequence defining the epitope was introduced into the loop of antigenic site B of the influenza virus hemagglutinin. The resulting chimeric virus was able to elicit ELDKWA-specific immunoglobulins G and A in antisera of mice. Moreover, the distantly related human immunodeficiency virus type 1 isolates MN, RF, and IIIB were neutralized by these antisera. These data suggest that this conserved B-cell epitope is a promising candidate for inclusion in a vaccine against AIDS. The results also show that influenza virus can be used to effectively present the antigenic structure of this B-cell epitope.
Effect of Alirocumab on Lipoprotein(a) Over ≥1.5 Years (from the Phase 3 ODYSSEY Program) (2016)

Elevated lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a).
Innovative Approaches to Plasminogen Activator Therapy (1989)

Plasminogen activator therapy for acute myocardial infarction has become standard medical practice. Bleeding complications, however, limit the utility of the currently available agents. This article reviews how the tools of molecular biology and protein engineering are being used to develop safer and more effective plasminogen activators.
High-Level Tissue-Specific Expression of Functional Human Factor VIII in Mice (1996)

Hemophilia A results from subnormal levels of blood coagulation factor VIII (FVIII) and is an attractive target for gene therapy. However, progress has been impeded by features of FVIII biology such as low mRNA accumulation and the instability of the protein. We have shown previously that a FVIII adenoviral vector, Av1ALH81, allowed high-level expression of human FVIII in mice sustained for several weeks. Here, we have generated a second FVIII adenoviral vector, Av1ALAPH81, in which an intron was introduced into the FVIII expression cassette. Administration of Av1ALAPH81 to mice resulted in significantly increased FVIII plasma levels, 1,046 +/- 163 ng/ml compared to 307 +/- 93 ng/ml of FVIII detected in mice that received Av1ALH81. Normal FVIII levels in humans are 100-200 ng/ml and therapeutic levels are as low as 10 ng/ml. Therapeutic levels are defined as the amount of FVIII necessary to convert severe hemophilia to a moderate or mild hemophiliac condition. The increased potency of the second FVIII adenoviral vector allowed the administration of significantly lower, less toxic vector doses, while retaining the potential for high FVIII expression. Furthermore, we demonstrate that adenoviral-mediated expression of human FVIII can be limited to the liver by inclusion of a liver-specific promoter, thereby achieving the first step in regulated expression of human FVIII in vivo.
Regulation of the Salmonella typhimurium pepT gene by cyclic AMP receptor protein (CRP) and FNR acting at a hybrid CRP-FNR site (1997)

The Salmonella typhimurium pepT gene is induced nearly 30-fold in response to anaerobiosis. Anaerobic expression is dependent on the transcriptional regulator encoded by fnr (previously oxrA). Primer extension analysis and site-directed mutagenesis experiments show that pepT is transcribed from two sigma 70 promoters. One promoter (P1) is FNR dependent and anaerobically induced, while the other (P2) appears to be constitutive. The potABCD operon is divergently transcribed from a promoter near pepT P2. Sequence analysis of pepT promoter mutations which either elevate anaerobic expression or confer constitutive expression revealed that these mutations affect the -10 region of the P1 or P2 promoter, respectively. The pepT200 mutation, which changes the -10 region of the FNR-dependent P1 promoter to the consensus, has the surprising effect of allowing five- to sevenfold anaerobic induction in the absence of FNR. We have shown that the anaerobic induction of pepT-lacZ in a pepT200 fnr strain is dependent on wild-type alleles of both crp and cya. In a pepT200 pepT-lacZ strain, beta-galactosidase activity was elevated aerobically in the presence of exogenous cyclic AMP (cAMP) and was elevated also in succinate minimal medium relative to its level in glucose minimal medium. Primer extension analysis confirmed that P1 is the cAMP receptor protein (CRP)-dependent promoter. Site-directed mutagenesis experiments indicated that a hybrid CRP-FNR binding site positioned at -41 of the P1 promoter is utilized by both FNR and CRP. CRP-cAMP also appeared to repress FNR-dependent transcription of pepT under anaerobic conditions in both the pepT+ and pepT200 backgrounds. Although both CRP and FNR are capable of binding the hybrid site and activating transcription of pepT, CRP requires the consensus -10 sequence for efficient activation.
Preparation of adenosine nucleotide derivatives suitable for affinity chromatography (1974)

Methods of synthesizing a series of chemically-defined AMP, ADP, ATP, adenylyl imidodiphosphate and pyrophosphate derivatives suitable for affinity chromatography are extensively described. Each derivative has a single primary amino group at the end of a hexamethylene ;spacer' chain for attachment to CNBr-activated agarose. The synthesis of the derivative where the ;spacer' arm is attached directly to the 8 position of the adenine ring to produce 8-(6-aminohexyl)amino-AMP involves the direct bromination of AMP in the 8 position followed by displacement of the halogen by 1,6-diaminohexane. This monophosphate derivative can then be converted into the corresponding di- or triphosphate forms by direct phosphate condensation with carbonyl di-imidazole. A second series of adenosine phosphate derivatives with the phosphate moieties unsubstituted has been similarly prepared from N(6)-(6-aminohexyl)-AMP (Guilford et al., 1972). A third type of ligand has been synthesized by condensing the phosphoryl imidazolide of AMP with 6-aminohex-1-yl phosphate. This compound, P(1)-(6-aminohex-1-yl) P(2)-(5'-adenosyl) pyrophosphate, has an unsubstituted adenine ring. The synthesis of a fourth type of ligand, 6-aminohex-1-yl pyrophosphate, was done by heating 6-aminohexan-1-ol with crystalline pyrophosphoric acid under reduced pressure. The structures of the synthesized compounds were confirmed by chemical, electrophoretic and chromatographic methods and by u.v. spectrometry. The general applicability of the synthetic methods used is discussed in relation to the preparation of other affinity adsorbents. Examples are given where these derivatives have been successful in reversibly binding dehydrogenases, kinases and myosin and its proteolytic subfragments. The partial purification of rat liver glucokinase on an ADP derivative is shown.
Free-space nano-optical devices and integration: Design, fabrication, and manufacturing (2005)

Lithographically defined optical nanostructures can be used to design various fundamental optical functions, including polarization, phase, refraction, and wavelength management. This paper describes the design, fabrication, and manufacturing of free-space discrete and integrated optical devices based on optical nanostructures. These devices are fabricated using a nanomanufacturing platform based on wafer-level nanoreplication with mold and nanopattern transfer by means of nanolithography. The nanoreplication process, based on imprinting a single-layer spin-coated ultraviolet (UV)-curable resist, achieved excellent nanopatterning fidelity and on-wafer uniformity with high throughput. It also achieved excellent wafer-level performance and yield. Nano-optical devices (NODs) (e.g., infrared polarizers and true zero-order quarter waveplates) and integrated NODs (e.g., monolithically integrated semi-isolators and visible circular polarizers) may be fabricated using the nanomanufacturing platform. The developed technology is suitable for the high-throughput and low-cost manufacturing needed to commercialize nanostructure-based optical devices and integrated optical devices. The success of the developed nano-engineering technology will lead to a redefinition of optical device manufacturing and integration and the functional and economic displacement of traditional bulk-optics devices.
Luminescence spectrum thermal properties of Rhodamine 6G doped polymethyl metacrylate film sandwiched between cholesteric liquid crystal layers (2012)

We experimentally investigate fluorescence spectrum properties of multilayer system consisting of Rhodamine 6G doped polymethyl metacrylate thin film sandwiched between two right handed cholesteric liquid crystal layers at various temperatures and pumping powers. We observe fluorescence intensity enhancement while increasing sample temperature from 16 to 22°C when pumping sample with constant power laser irradiation. At constant temperature fluorescence intensity also increases with increasing pumping power.
Structure-activity relationships defining the ACD-tricyclic cannabinoids: cannabinoid receptor binding and analgesic activity. (1995)

Previous studies of the structure-activity relationships (SAR) for binding of a series of AC-bicyclic cannabinoid structures to the cannabinoid receptors in rat brain (believed to comprise the CB1 subtype) demonstrated the importance of the A-ring aryl C-3 side chain and phenolic hydroxyl substituents, and elucidated the importance of a C-ring hydroxyalkyl substituent [Melvin et al. Mol. Pharmacol. 44, 1008-1015 (1993)]. The present investigation examines the SAR surrounding this region (D-ring) of the molecule that is not present in the structure of delta(9)-THC and other classical cannabinoid compounds. Both rigid fused ring benzo and cyclohexyl derivatives (creating the D-ring) retained binding affinity for the cannabinoid receptor. Extension of ketone or hydroxyl substituents from the C2 position of the D-ring resulted in a 3-fold increase in binding affinity over the unsubstituted structure. However, the fused ring structure is not critical for the interaction with the receptor in as much as opening the ring did not decrease the potency. Extension of the D-ring C-2 alcohol by one carbon in length resulted in a pair of structures, for which the greatest affinity for the CB1 receptor occurred for the hydroxymethyl group in the axial conformation [(+/-)-CP-55,244]. Upon resolution, the latter provided a pair of enantiomers: (-)-CP-55,244 was approximately 3-fold more potent than the racemic mixtures, and (+)-CP-55,244 failed to bind to the CB1 receptor with an IC50 below 1 mM. Opening of the D-ring of these structures resulted in a loss of binding affinity. This study demonstrates that the potency could be optimized in (-)-CP-55,244 for both binding to the CB1 receptor and the biological activity of analgesia. In addition, the rigid positioning of the hydroxypropyl moiety of CP-55,940 enforced by the decalin ring structure of CP-55,244 increased the enantioselectivity by greater than 100-fold. These data define the critical stereochemistry for a region of the nonclassical ACD-tricyclic cannabinoid structure that contributes a potential hydrogen bonding component to the ligand-receptor interaction mechanism. Inasmuch as this region of the molecule is not present on classical ABC-tricyclic cannabinoid compounds, these studies elucidate a unique agonist recognition site on the CB1 receptor.
Heavy metals toxicity in plants: An overview on the role of glutathione and phytochelatins in heavy metal stress tolerance of plants (2009)

Plants experience oxidative stress upon exposure to heavy metals that leads to cellular damage. In addition, plants accumulate metal ions that disturb cellular ionic homeostasis. To minimize the detrimental effects of heavy metal exposure and their accumulation, plants have evolved detoxification mechanisms. Such mechanisms are mainly based on chelation and subcellular compartmentalization. Chelation of heavy metals is a ubiquitous detoxification strategy described in wide variety of plants. A principal class of heavy metal chelator known in plants is phytochelatins (PCs), a family of Cys-rich peptides. PCs are synthesized non-translationally from reduced glutathione (GSH) in a transpeptidation reaction catalyzed by the enzyme phytochelatin synthase (PCS). Therefore, availability of glutathione is very essential for PCs synthesis in plants at least during their exposure to heavy metals. Here, I reviewed on effect of heavy metals exposure to plants and role of GSH and PCs in heavy metal stress tolerance. Further, genetic manipulations of GSH and PCs levels that help plants to ameliorate toxic effects of heavy metals have been presented.
Demonstration of Intracellular Mycobacterium Species in Crohnʼs Disease Using Novel Technologies (2015)

Introduction: Impaired neutrophil chemotaxis was demonstrated in Crohn's Disease (CD) in 1976. Later, impaired chemokine release by dysfunctional macrophages was shown responsible for defective neutrophil migration. Genome Wide Association Studies linked impaired autophagy with innate immune deficiency in CD and persistence of intracellular pathogens. We studied the characteristics of an intracellular cell-wall-deficient Mycobacterium speciesin CD isolated from circulating blood cells. We set out to detect/culture non-TB cell-wall-deficient bacteria in dendritic cells and macrophages in CD patients before and during Anti-Mycobacterium avium ss paratuberculosis (MAP) treatment and in controls. Methods: Peripheral blood samples were stained with conventional Ziehl-Neelsen (ZN) stain after 8d and 30d incubation in a range of supplemented broths. Cells containing stainable intracellular bacteria were expressed as a ratio of total cells using x1000 oil immersion microscopy. The investigator staining the cells was blinded to the diagnosis. Results: ZN staining of spheroplasts was achieved in a subset of 80 individuals. CD was correctly identified in 64/68(94%) and by 30d the stained spherules had often multiplied to fill the macrophage. In controls 11/12 had a low-level staining of spherules at 30d with 5/12 correctly identified as normal due to the morphology and sparcity of the spherules. Only one normal individual did not exhibit spherules. Later we cultured extracellular spheroplasts on media as replicating L forms. Probing the samples with Mycobacterium species-specific probes confirmed the presence of Mycobacterium species which awaits further characterisation. Morphology of human spheroplasts resembles that in Red Deer infected with MAP and in the blood of patients immunised with BCG. Previous work with CD patients showing spheroplasts indicated a relationship with MAP. Anti-MAP antibiotics in CD patients profoundly suppressed growth of spheroplasts but did not eradicate them. Conclusion: 1. We confirm presence of intracellular Mycobacterium spheroplasts in blood macrophages of CD patients and in a proportion of controls. 2. Spheroplast growth is suppressed with Anti-MAP antibiotics paralleling clinical improvement, which further confirms the causal association.
Recent advances in positive allosteric modulators of metabotropic glutamate receptors. (2005)

Positive allosteric modulators of metabotropic glutamate receptors (mGluRs) are the subject of intensive research due to their emerging therapeutic potential for a range of psychiatric and neurological disorders such as pain, anxiety, cognition, Parkinson's disease and schizophrenia. Positive allosteric modulators, which are small molecules capable of enhancing agonist-mediated receptor activity while possessing no intrinsic agonist activity, have recently been described for group I (mGluR1 and mGluR5), group II (mGluR2) and group III (mGluR4) mGluRs. Relative to classical mGluR agonists, these molecules offer improved selectivity versus other mGluRs and chemical tractability, and may reduce the liability of receptor desensitization.
Expression of the art/trs Protein of HIV and Study of Its Role in Viral Envelope Synthesis (1987)

The art/trs transactivator protein of human immunodeficiency virus (HIV) was expressed in mammalian cells as a 19-kilodalton protein that was immunoreactive with sera from HIV-infected patients. Separate plasmids encoding the art/trs protein, the tat protein, or the envelope glycoprotein gp120 were used to demonstrate that both art/trs and tat are absolutely required for the synthesis of gp120 from its cognate messenger RNA. In addition, both the tat and art/trs proteins influence the level of envelope RNA. The results suggest that art/trs and tat may be ideal targets for potential anti-HIV agents in AIDS therapy.
대형 인공호에서 양이온 , 음이온 및 전기전도도의 연변화에 대한 수리수문학적 중요성 (2001)

During April 1993 to November 1994, cations, anions, and conductivity were analyzed to examine how summer monsoon influences the ionic content of Taechung Reservoir, Korea. Interannual variability of ionic content reflected hydrological characteristics between the two years (high-flood year in 1993 vs. draught year in 1994). Cations, anions and conductivity were lowest during peak inflow in 1993 and highest during a drought in 1994. Floods in 1993 markedly decreased total salinity as a result of reduced Ca^(2+) and HCO₃^- and produced extreme spatial heterogeneity (i.e., longitudinal, vertical, and horizontal variation) in ionic concentrations. The dominant process modifying the longitudinal (the headwaters-to-downlake) and vertical (top-to-bottom) patterns in salinity was an interflow current during the 1993 monsoon. The interflow water plunged near a 27 ∼ 37 km-location (from the dam) of the mid-lake and passed through the 10∼30 m stratum of the reservoir, resulting in an isolation of epilimnetic high conductivity water ( > 100 μS/cm) from advected river water with low conductivity (65 ∼ 75 μS/cm). During postmonsoon 1993, the factors regulating salinity differed spatially; salinity of downlake markedly declined as a result of dilution through the mixing of lake water with river water, whereas in the headwaters it increased due to enhanced CaCO₃ (originated from limestone/metamorphic rock) of groundwaters entering the reservoir. This result suggests an importance of the basin geology on ion compositions with hydrological characteristics. In 1994, salinity was markedly greater (p < 0.001) relative to 1993 and ionic dilution did not occur during the monsoon due to reduced inflow. Overall data suggest that the primary factor influencing seasonal ionic concentrations and compositions in this system is the dilution process depending on the intensity of monsoon rainfall.
KEX2 Influences Candida albicans Proteinase Secretion and Hyphal Formation (1997)

Candida albicans possesses at least seven differentially expressed genes that encode virulence-related secretory aspartyl proteinases (Saps). Sap DNA sequences predict post-translational processing at lysine-arginine residues in the preproteins, reminiscent of the maturation of Saccharomyces cerevisiae alpha-factor, where a prepropolypeptide is converted into a biologically active pheromone by Kex2, a subtilisin-like proprotein convertase. To investigate involvement of a C. albicans KEX2 homologue in Sap activation, a genetic selection was performed based on KEX2 function. A kex2 strain of S. cerevisiae was transformed with a C. albicans genomic DNA library and screened for the production of active alpha-factor. Positive clones were assayed for killer toxin activity, another Kex2-dependent phenotype. Plasmids that rescued both defects contained a sequence encoding a protein homologous to S. cerevisiae Kex2. Both alleles of the C. albicans KEX2 were inactivated by successive mutations. Null mutants continued to secrete active Sap2; however, the enzyme was abnormally processed and secreted at reduced levels. Unexpectedly, null mutants were incapable of forming hyphae, instead differentiating into aberrantly shaped cells. The ability to normally process Sap2 and form hyphae was restored upon transformation of null mutants with a KEX2-containing plasmid.
Über Zirkonate, Hafnate und Thorate von Barium, Strontium, Lithium und Natrium (1968)

Abstract In den Systemen M II O/X IV O 2 (M II = Sr, Ba; X IV = Zr, Hf) existieren neben den Metaverbindungen basenreichere Verbindungen des Typs M 2 II X IV O 4 mit tetragonaler K 2 NiF 4 ‐Struktur. Eingehende Untersuchungen in den Systemen Li 2 O/X IV O 2 (X IV = Zr, Hf) führten zur Darstellung und Charakterisierung der neuen Verbindungstypen Li 4 X IV O 4 und Li 8 X IV O 6 . ThO 2 bildet mit Erdalkali‐ und Alkalioxiden nur Metaverbindungen, tritt jedoch mit Li 2 O überhaupt nicht in Reaktion. Zwischen Na 2 ThO 3 und Li 2 ZrO 3 besteht nach den Röntgenpulverdiagrammen eine enge strukturelle Beziehung.
Optimal transmitter eigen-beamforming and space-time block coding based on channel correlations (2003)

Optimal transmitter designs obeying the water-filling principle are well-documented, and widely applied when the propagation channel is deterministically known and regularly updated at the transmitter. Because channel state information may be costly or impossible to acquire in rapidly varying wireless environments, we develop in this paper statistical water-filling approaches for stationary random fading channels. The resulting optimal designs require only knowledge of the channel's second order statistics that do not require frequent updates, and can be easily acquired. Optimality refers to minimizing a tight bound on the symbol error rate. Applied to a multiple transmit-antenna paradigm, the optimal precoder turns out to be a generalized eigen-beamformer with multiple beams pointing to orthogonal directions along the eigenvectors of the channel's covariance matrix, and with proper power loading across the beams. Coupled with orthogonal space time block codes, two-directional eigen-beamforming emerges as a more attractive choice than conventional one-directional beamforming, with uniformly better performance, and without rate reduction or complexity increase.