gebhart/patrepeval huggingface dataset:
Monitoring Protein Refolding Induced by Disulfide Formation Using Capillary Isoelectric Focusing-Electrospray Ionization Mass Spectrometry (1998)

Rapid growth in the biotechnology industry has led to a dramatic increase in attention to the protein folding problem. Understanding protein-folding pathways is essential to the production of biopharmaceuticals since commercial production of recombinant proteins often requires a protein-refolding process for recovery of high yields. Protein folding coupled to the formation of disulfide bonds presents one of the simplest approaches to studying folding intermediates. On-line capillary isoelectric focusing-electrospray ionization mass spectrometry (CIEF-ESIMS) is demonstrated for kinetic studies of disulfide bond-induced protein refolding. Refolding intermediates of bovine pancreatic ribonuclease A, a model system for this study, are blocked at different stages by alkylating free thiols with iodoacetate. The alkylation reaction results in the introduction of charge (-1) and mass (59) differences for each alkylation site, providing the means for predictable separation and direct identification of refolding intermediates using CIEF-ESIMS. Besides the observation of refolding intermediates containing different numbers of disulfide bonds and even mixed disulfides, the two-dimensional resolving power of CIEF-ESIMS allows the determination of conformational heterogeneity among groups of refolding intermediates.
Purification and Characterization ofN-Acetylgalactosamine 4-Sulfate 6-O-Sulfotransferase from the Squid Cartilage (2000)

N-Acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S-6ST), which transfers sulfate from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to position 6 of N-acetylgalactosamine 4-sulfate in chondroitin sulfate and dermatan sulfate, was purified 19,600-fold to apparent homogeneity from the squid cartilage. SDS-polyacrylamide gel electrophoresis of the purified enzyme showed a broad protein band with a molecular mass of 63 kDa. The protein band coeluted with GalNAc4S-6ST activity from Toyopearl HW-55 around the position of 66 kDa, indicating that the active form of GalNAc4S-6ST may be a monomer. The purified enzyme transferred sulfate from PAPS to chondroitin sulfate A, chondroitin sulfate C, and dermatan sulfate. The transfer of sulfate to chondroitin sulfate A and dermatan sulfate occurred mainly at position 6 of the internal N-acetylgalactosamine 4-sulfate residues. Chondroitin sulfate E, keratan sulfate, heparan sulfate, and completely desulfated N-resulfated heparin were not efficient acceptors of the sulfotransferase. When a trisaccharide or a pentasaccharide having sulfate groups at position 4 of N-acetylgalactosamine was used as acceptor, efficient sulfation of position 6 at the nonreducing terminal N-acetylgalactosamine 4-sulfate residue was observed.
Synthesis and conformational assignment of cis- and trans-2-amino-1-arylcyclohexanols (1985)

The synthesis of cis- and trans-2-amino-1-arylcyclohexanols 1–8, conformationally restricted analogues of the α-adrenergic drugs norephedrine 9, methoxamine 10, and isopropylmethoxamine 11, is described. trans-Aminoalcohols were obtained through reaction of epoxides 12 or 13 with isopropylamine (to afford 4 and 8) or with sodium azide followed by lithium aluminum hydride reduction (to afford 2 and 6), whereas cis-aminoalcohols 1 and 5 were obtained by condensation of 2-aminocyclohexanone hydrobromide 26 with the appropriate organometallic reagent. Treatment of 1 and 5 with acetone followed by sodium borohydride reduction gave isopropylaminoalcohols 3 and 7. Configurational and conformational assignments of aminoalcohols 1–8 have been carried out on the basis of their 1 H nmr and 13 C nmr data and by comparison with reference diols 18 and 30. The major or exclusive chair conformation observed for all the compounds has an equatorial aryl group.
The Relationship Between Diabetes Mellitus and Parkinson'S Disease (1993)

It has been reported that 50% to 80% of patients with Parkinson's disease have abnormal glucose tolerance which may be further exacerbated by levodopa therapy. Little is known about the impact of chronic hyperglycemia on the severity of the motor manifestations and the course of the disease as well as its impact on the efficacy of levodopa or other dopaminergic drugs. This issue, which has been largely ignored, is of clinical relevance since animal studies indicate that chronic hyperglycemia decreases striatal dopaminergic transmission and increases the sensitivity of postsynaptic dopamine receptors. In addition, evidence from experimental animal studies indicates that diabetic rats are resistant to the locomotor and behavioral effects of the dopamine agonist amphetamine. The resistance to the central effects of amphetamine is largely restored with chronic insulin therapy. In the present communication, I propose that in Parkinson's disease diabetes may exacerbate the severity of the motor disability and attenuate the therapeutic efficacy of levodopa or other dopaminergic agents as well as increase the risk of levodopa-induced motor dyskinesias. Thus, it is advocated that Parkinsonian patients should be routinely screened for evidence of glucose intolerance and that if found aggressive treatment of the hyperglycemia may improve the response to levodopa and potentially diminish the risk of levodopa-induced motor dyskinesias.
Strategies to minimize false positives and interpret novel microdeletions based on maternal copy-number variants in 87,000 noninvasive prenatal screens (2018)

Our study thoroughly investigates a common source of NIPS false positives and demonstrates how to bypass its corrupting effects. Our findings offer insight into the interpretation of NIPS results and inform the design of NIPS algorithms suitable for use in screening in the general obstetric population.
Quantifying uncertainty in the impacts of climate change on river discharge in sub-catchments of the Yangtze and Yellow River Basins, China (2011)

Abstract. Quantitative evaluations of the impacts of climate change on water resources are primarily constrained by uncertainty in climate projections from GCMs. In this study we assess uncertainty in the impacts of climate change on river discharge in two catchments of the Yangtze and Yellow River Basins that feature contrasting climate regimes (humid and semi-arid). Specifically we quantify uncertainty associated with GCM structure from a subset of CMIP3 AR4 GCMs (HadCM3, HadGEM1, CCSM3.0, IPSL, ECHAM5, CSIRO, CGCM3.1), SRES emissions scenarios (A1B, A2, B1, B2) and prescribed increases in global mean air temperature (1 °C to 6 °C). Climate projections, applied to semi-distributed hydrological models (SWAT 2005) in both catchments, indicate trends toward warmer and wetter conditions. For prescribed warming scenarios of 1 °C to 6 °C, linear increases in mean annual river discharge, relative to baseline (1961–1990), for the River Xiangxi and River Huangfuchuan are +9% and 11% per +1 °C respectively. Intra-annual changes include increases in flood (Q05) discharges for both rivers as well as a shift in the timing of flood discharges from summer to autumn and a rise (24 to 93%) in dry season (Q95) discharge for the River Xiangxi. Differences in projections of mean annual river discharge between SRES emission scenarios using HadCM3 are comparatively minor for the River Xiangxi (13 to 17% rise from baseline) but substantial (73 to 121%) for the River Huangfuchuan. With one minor exception of a slight (−2%) decrease in river discharge projected using HadGEM1 for the River Xiangxi, mean annual river discharge is projected to increase in both catchments under both the SRES A1B emission scenario and 2° rise in global mean air temperature using all AR4 GCMs on the CMIP3 subset. For the River Xiangxi, there is substantial uncertainty associated with GCM structure in the magnitude of the rise in flood (Q05) discharges (−1 to 41% under SRES A1B and −3 to 41% under 2° global warming) and dry season (Q95) discharges (2 to 55% under SRES A1B and 2 to 39% under 2° global warming). For the River Huangfuchuan, all GCMs project a rise in the Q05 flow but there is substantial uncertainty in the magnitude of this rise (7 to 70% under SRES A1B and 2 to 57% under 2° global warming). Differences in the projected hydrological changes are associated with GCM structure in both catchments exceed uncertainty in emission scenarios. Critically, estimated uncertainty in projections of mean annual flows is less than that calculated for extreme (Q05, Q95) flows. The common approach of reporting of climate change impacts on river in terms of mean annual flows masks the magnitude of uncertainty in flows that are of most importance to water management.
Discovery of Potent and Selective Small-Molecule PAR-2 Agonists (2008)

Proteinase activated receptor-2 plays a crucial role in a wide variety of conditions with a strong inflammatory component. We present the discovery and characterization of two structurally different, potent, selective, and metabolically stable small-molecule PAR-2 agonists. These ligands may be useful as pharmacological tools for elucidating the complex physiological role of the PAR-2 receptors as well as for the development of PAR-2 antagonists.
Recent advances in silicon photonic integrated circuits (2016)

We review recent breakthroughs in silicon photonics technology and components and describe progress in silicon photonic integrated circuits. Heterogeneous silicon photonics has recently demonstrated performance that significantly outperforms native III-V components. The impact active silicon photonic integrated circuits could have on interconnects, telecommunications, sensors and silicon electronics is reviewed.
Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? (2001)

A majority of patients were able to deplete urate crystal stores in their knee joint fluids when their SUA levels were kept to < or = 6 mg/dl for several years. The mechanisms for persistence in some patients, and whether such crystals have clinical implications, are not known. Patients with chronic gout need serum urate concentrations to be kept low to prevent further attacks.
New Directions for Monoclonal Antibody Therapy (2005)

s: Abstracts for the 20th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer (Primary Authors are Italicized): NOVEL APPROACHES TO MONOCLONAL ANTIBODIES
Allergen‐induced mediator release tests (2003)

The diagnosis of allergic reactions in clinical practice is based on both clinical history and the determination of specific immunoglobulin E (IgE), either in the serum or on skin mast cells. However, for various reasons, identification of the causative factors is not possible in all the cases. Moreover, not all allergies are IgE-dependent. In an attempt to find sensitive, specific and cost-effective methods to investigate hypersensitivity reactions, in vitro tests were developed at a very early stage. Allergen-induced mediator release assays analyze the mediator released from effector cells, mainly peripheral blood cells, when stimulated in vitro with serial dilutions of the putative allergens. Described initially as research tools, they could well become diagnostic tests. However, relatively few high quality reports have been published so far. In this review, we will detail allergen-dependent histamine, tryptase, arachidonic acid metabolite, e.g. cysteinyl leukotrienes and 15-hydroxyeicosatetraenoic mediator release tests.
Morphologically Docked Synaptic Vesicles Are Reduced insynaptotagminMutants ofDrosophila (1998)

Nerve terminal specializations include mechanisms for maintaining a subpopulation of vesicles in a docked, fusion-ready state. We have investigated the relationship between synaptotagmin and the number of morphologically docked vesicles by an electron microscopic analysis of Drosophila synaptotagmin (syt) mutants. The overall number of synaptic vesicles in a terminal was reduced, although each active zone continued to have a cluster of vesicles in its vicinity. In addition, there was an increase in the number of large vesicles near synapses. Examining the clusters, we found that the pool of synaptic vesicles immediately adjacent to the presynaptic membrane, the pool that includes the docked population, was reduced to 24 +/- 5% (means +/- SEM) of control in the sytnull mutation. To separate contributions of overall vesicle depletion and increased spontaneous release from direct effects of synaptotagmin on morphological docking, we examined syt mutants in an altered genetic background. Recombining syt alleles onto a second chromosome bearing an as yet uncharacterized mutation resulted in the expected decrease in evoked release but suppressed the increase in spontaneous release frequency. Motor nerve terminals in this genotype contained more synaptic vesicles than control, yet the number of vesicles immediately adjacent to the presynaptic membrane near active zones was still reduced (33 +/- 4% of control). Our findings demonstrate that there is a decrease in the number of morphologically docked vesicles seen in syt mutants. The decreases in docking and evoked release are independent of the increase in spontaneous release. These results support the hypothesis that synaptotagmin stabilizes the docked state.
Programmable base editing of zebrafish genome using a modified CRISPR-Cas9 system (2017)

Precise genetic modifications in model animals are essential for biomedical research. Here, we report a programmable "base editing" system to induce precise base conversion with high efficiency in zebrafish. Using cytidine deaminase fused to Cas9 nickase, up to 28% of site-specific single-base mutations are achieved in multiple gene loci. In addition, an engineered Cas9-VQR variant with 5'-NGA PAM specificities is used to induce base conversion in zebrafish. This shows that Cas9 variants can be used to expand the utility of this technology. Collectively, the targeted base editing system represents a strategy for precise and effective genome editing in zebrafish.The use of base editing enables precise genetic modifications in model animals. Here the authors show high efficient single-base editing in zebrafish using modified Cas9 and its VQR variant with an altered PAM specificity.
Empirical energy functions for energy minimization and dynamics of nucleic acids (1986)

Abstract An improved empirical energy function for energy minimization and dynamics calculations of nucleic acids is developed and evaluated by an examination of its representation of both static and dynamic properties of model systems. Among the properties studied and used for parameter optimization are base pairing interactions, sugar and phosphate energy surfaces, small crystal heats of sublimation, base, phosphate and sugar analogue vibration spectra, and the overall behavior of a DNA hexamer duplex in vacuum molecular dynamics simulations. The results obtained are compared with those from two other energy functions that have been used recently for nucleic acids. Parameters for two energy functions are given; one includes heavy atoms and only polar hydrogens and the other includes all atoms.
Demethylation of the Same Promoter Sequence Increases CD70 Expression in Lupus T Cells and T Cells Treated with Lupus-Inducing Drugs (2005)

Exposing genetically predisposed individuals to certain environmental agents is believed to cause human lupus. How environmental agents interact with the host to cause lupus is poorly understood. Procainamide and hydralazine are drugs that cause lupus in genetically predisposed individuals. Understanding how these environmental agents cause lupus may indicate mechanisms relevant to the idiopathic disease. Abnormal T cell DNA methylation, a repressive epigenetic DNA modification, is implicated in procainamide and hydralazine induced lupus, as well as idiopathic lupus. Procainamide is a competitive DNA methyltransferase (Dnmt) inhibitor, hydralazine inhibits ERK pathway signaling thereby decreasing Dnmt expression, and in lupus T cells decreased ERK pathway signaling causing a similar Dnmt decrease. T cells treated with procainamide, hydralazine, and other Dnmt and ERK pathway inhibitors cause lupus in mice. Whether the same genetic regulatory elements demethylate in T cells treated with Dnmt inhibitors, ERK pathway inhibitors, and in human lupus is unknown. CD70 (TNFSF7) is a B cell costimulatory molecule overexpressed on CD4(+) lupus T cells as well as procainamide and hydralazine treated T cells, and contributes to excessive B cell stimulation in vitro and in lupus. In this report we identify a genetic element that suppresses CD70 expression when methylated, and which demethylates in lupus and in T cells treated with Dnmt and ERK pathway inhibitors including procainamide and hydralazine. The results support a model in which demethylation of specific genetic elements in T cells, caused by decreasing Dnmt expression or inhibiting its function, contributes to drug-induced and idiopathic lupus through altered gene expression.
[Differential expression of genes related to transcription in cultured hepatoma cells with intact genome of hepatitis C virus]. (2008)

Intact hepatitis C virus cell culture system provides an useful tool for study on the affects of HCV infection on transcription regulation genes in host cells.
Occupancy of CD11b/CD18 (Mac-1) divalent ion binding site(s) induces leukocyte adhesion (1991)

The group of leukocyte integrins CD11a-c/CD18 coordinate disparate adhesion reactions in the immune system through a regulated process of ligand recognition. The participation of the receptor divalent ion binding site(s) in this mechanism of ligand binding has been investigated. As compared with other divalent cations, Mn2+ ions have the unique property to dramatically stimulate the adhesive functions of the leukocyte integrin CD11b/CD18 (Mac-1), expressed on myelo-monocytic cells. This is reflected in a three- to fivefold increased early monocyte adhesion (less than 20 min) to resting, unperturbed endothelial cells, and increased association of CD11b/CD18 with its soluble ligands fibrinogen and factor X. CD11b/CD18 ligand recognition in the presence of Mn2+ ions is specific, time and concentration dependent, and inhibited by anti-CD11b mAb. At variance with Ca(2+)-containing reactions where CD11b/CD18 functions as an inducible receptor activated by adenine nucleotides or chemoattractants, Mn2+ ions induce per se a constitutive maximal ligand binding capacity of CD11b/CD18, that is not further modulated by cell stimulation. Rather than quantitative changes in surface density, Mn2+ ions increase the affinity of CD11b/CD18 for its complementary ligands up to 10-fold, as judged by Scatchard plot analysis of receptor:ligand interaction under these conditions. Furthermore, monocyte exposure to Mn2+ ions induces the expression of activation-dependent neo-antigenic epitopes on CD11b/CD18, selectively recognized by mAb 7E3. These data suggest that in addition to cell-activating stimuli, favorable engagement of divalent ion binding site(s) can provide an alternative pathway to rapidly regulate the receptor affinity of leukocyte integrins.
The ecdysone receptor puzzle (1999)

The present article reviews some recent findings on the functional ecdysone receptor which is a heterodimer of two proteins: ecdysone receptor (EcR) and Ultraspiracle (USP). Emphasis is given to some unique aspects of this receptor, in particular to its dimerization, binding to DNA, and transactivation capabilities. The effects of ligands (ecdysone, juvenile hormone) on these functions are discussed. In addition, perspectives on future work on this receptor are outlined, which are shaped by recent progress in the nuclear receptor field in general. This preview part of the present article concerns mainly the 3-D structure of receptor domains, the formation of large supramolecular receptor complexes, their influence on chromatin remodelling, receptor phosphorylation, as well as inter- and intramolecular cross-talks of receptor domains. Arch. Insect Biochem. Physiol. 41:99–106, 1999. © 1999 Wiley-Liss, Inc.
Targeting the Good Target (2013)

A person's judgeability, or the extent to which a person is easy to understand, plays an important role in how accurately a target will be perceived by others. Research on this topic, however, has not been systematic or well-integrated. The current review begins to remedy this by integrating the available research on judgeability from the fields of personality perception, nonverbal communication, and social cognition. Specifically, this review summarizes the characteristics that are likely to promote judgeability and explores its potential consequences. A diverse range of characteristics are identified as predictors of judgeability, all relating to three broader categories: psychological adjustment, social status, and socialization. Furthermore, being judgeable has a variety of potential, largely positive, consequences for the target, leaving good targets poised for greater personal and interpersonal well-being. Nevertheless, many questions on this topic remain and it is crucial for this relatively understudied topic to receive more systematic empirical attention.
Allergic rhinitis and its impact on asthma: an evidence-based treatment strategy for allergic rhinitis. (2002)

The overall pathogenic view of respiratory allergy has deeply changed and evolved during the last ten years. Much emphasis has been laid to the relationship between rhinitis and asthma, which is between the upper and the lower respiratory airways. This strict link has been evidenced through clinical observations and epidemiological studies and also on the basis of immunological observations and outcomes of therapy. Furthermore, the frequent co-existence of rhinitis and asthma (up to 80 percent of asthmatic patients have co-existing allergic rhinitis, while up to 40 percent of allergic rhinitis patients have asthma, the coexistence of sinusitis and asthma, the presence of rhinitis as a risk factor for developing asthma, further emphasize this link and together lead to the operative definition of Allergic Rhinobronchitis or, United Airways Disease (UAD). The strict link existing between upper and lower respiratory tract can be also regarded from the viewpoint of therapeutical outcomes. The more detailed knowledge of the intricate mechanisms sustaining allergic inflammation in the respiratory tract (i.e. antigen presentation, cytokines, chemokines and adhesion molecules) has clarified the functional relationships between nose and lung. Thus allergic rhinitis or asthma is not a disease confined to a specific target organ, but rather a disorder of the whole respiratory tract, with a range of clinical manifestations, leading to relevant diagnostic and therapeutic implications as indicated in the WHO Initiative ARIA, the first evidence-based guideline emphasizing the impact of allergic rhinitis on asthma and where a step-wise treatment strategy targeting both the upper and lower airway effectively has been proposed. Moreover, the use of novel potential therapies that target both rhinitis and asthma like antileukotrienes or anti-IgE are indeed a future strategy.