gebhart/patrepeval huggingface dataset:
Role of human cytochrome P‐450s in risk assessment and susceptibility to environmentally based disease (1993)

Cytochromes P-450 (P-450s) are a large group of heme-containing proteins that carry out oxidation of numerous chemicals. In mammals, a limited number of P-450s are involved in metabolic pathways of steroid synthesis, while most of these enzymes are involved in metabolism of foreign compounds. The principal beneficial function of P-450s is to convert chemicals into derivatives that can be easily eliminated from the body. This generally occurs through P-450-mediated oxidations of hydrophobic substances followed by conjugation reactions. For many foreign compounds, P-450 metabolism results in production of "activated" metabolites that can cause cell death and gene mutations. During the past several years, it has become widely recognized that marked species differences occur among the foreign compound-metabolizing P-450s. In addition to this interspecies variability in metabolism, marked intraspecies variability, frequently referred to as drug oxidation polymorphisms, occurs in virtually all mammals examined to date. Based on these observations, it is necessary to develop new human P-450-based systems that can be used to study foreign compound metabolism in order to predict human risk. This is being accomplished by use of cDNA-directed expression in B lymphoblastoid cells. These cells can be used to predict how humans will metabolize a chemical and whether it will be metabolically activated to a toxic or mutagenic metabolite. To study human P-450 polymorphisms, polymerase chain reaction (PCR) assays have been developed for diagnosis of known mutant P-450 genes. Molecular probes are also being used to screen populations for levels of expression of carcinogen-activating P-450s in an effort to determine whether expression of certain P-450 forms is associated with increased risk for development of environmentally based disease.
Effector Function Activities of a Panel of Mutants of a Broadly Neutralizing Antibody against Human Immunodeficiency Virus Type 1 (2001)

The human antibody immunoglobulin G1 (IgG1) b12 neutralizes a broad range of human immunodeficiency virus-type 1 (HIV-1) isolates in vitro and is able to protect against viral challenge in animal models. Neutralization of free virus, which is an antiviral activity of antibody that generally does not require the antibody Fc fragment, likely plays an important role in the protection observed. The role of Fc-mediated effector functions, which may reduce infection by inducing phagocytosis and lysis of virions and infected cells, however, is less clear. To investigate this role, we constructed a panel of IgG1 b12 mutants with point mutations in the second domain of the antibody heavy chain constant region (CH2). These mutations, as expected, did not affect gp120 binding or HIV-1 neutralization. IgG1 b12 mediated strong antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of HIV-1-infected cells, but these activities were reduced or abrogated for the antibody mutants. Two mutants were of particular interest. K322A showed a twofold reduction in FcgammaR binding affinity and ADCC, while C1q binding and CDC were abolished. A double mutant (L234A, L235A) did not bind either FcgammaR or C1q, and both ADCC and CDC functions were abolished. In this study, we confirmed that K322 forms part of the C1q binding site in human IgG1 and plays an important role in the molecular interactions leading to complement activation. Less expectedly, we demonstrate that the lower hinge region in human IgG1 has a strong modulating effect on C1q binding and CDC. The b12 mutants K322A and L234A, L235A are useful tools for dissecting the in vivo roles of ADCC and CDC in the anti-HIV-1 activity of neutralizing antibodies.
Altered Endocrine and Autocrine Metabolism of Vitamin D in a Mouse Model of Gastrointestinal Inflammation (2008)

The active form of vitamin D, 1,25-dihydroxyvitamin D3, [1,25(OH)2D3] has potent actions on innate and adaptive immunity. Although endocrine synthesis of 1,25(OH)2D3 takes place in the kidney, the enzyme that catalyzes this, 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27b1 in humans, Cyp27b1 in mice), is expressed at many extra-renal sites including the colon. We have shown previously that colonic expression of CYP27b1 may act to protect against the onset of colitis. To investigate this further, we firstly characterized changes in Cyp27b1 expression in a mouse model of colitis. Mice treated with dextran sodium sulfate (DSS) showed weight loss, histological evidence of colitis, and increased expression of inflammatory cytokines. This was associated with decreased renal expression of Cyp27b1 (5-fold, P=0.013) and lower serum 1,25(OH)2D3 (51.8+/-5.9 pg/nl vs. 65.1+/-1.6 in controls, P<0.001). However, expression of CYP27b1 was increased in the proximal colon of DSS mice (4-fold compared with controls, P<0.001). Further studies were carried out using Cyp27b1 null (-/-) mice. Compared with+/-controls the Cyp27b1-/-mice showed increased weight loss (4.9% vs. 22.8%, P<0.001) and colitis. This was associated with raised IL-1 in the distal colon and IL-17 in the proximal and distal colon. Conversely, DSS-treated Cyp27b1-/-mice exhibited lower IL-10 in the proximal colon and toll-like receptors 2 and 4 in the distal colon. These data indicate that both local and endocrine synthesis of 1,25(OH)2D3 affect colitis in DSS-treated mice. Lack of Cyp27b1 exacerbates disease in this model, suggesting that similar effects may occur with vitamin D deficiency.
Differential Effect of 5α-Reductase Inhibition and Castration on Androgen-Regulated Gene Expression in Rat Prostate (1991)

Castration reduces prostate size and causes intraprostatic testosterone (T) and dihydrotestosterone (DHT) to fall to very low levels. 5 alpha-Reductase inhibition also reduces prostate size, but results in a marked increase in intraprostatic T levels. To compare the effects of 5 alpha-reductase inhibition and castration on prostate physiology, male Sprague-Dawley rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride for up to 9 days. To be sure that finasteride itself did not directly affect gene expression, an additional group of rats was castrated and given finasteride for 4 days. The prostates were weighed, intraprostatic RNA, DNA, and androgen levels were measured, and mRNAs for two androgen-regulated genes, prostate steroid-binding protein (PSBP; an androgen-induced gene) and testosterone-repressed prostate message (TRPM-2), were quantitated by Northern and slot blot analyses. Finasteride caused a 95% reduction in intraprostatic DHT levels and a 10-fold increase in intraprostatic T levels. Finasteride, as expected, caused a pronounced decrease in prostate weight (45% on day 4). DNA content fell correspondingly (48% on day 4). Intraprostatic DNA (micrograms of DNA per gland) on day 4 was 328 +/- 53 in control rats, 171 +/- 10 in finasteride-treated rats (P less than 0.001 compared to controls), 115 +/- 2 in castrated rats (P less than 0.05 compared to finasteride), and 107 +/- 43 in finasteride-treated plus castrated rats (P = NS compared to castration alone). There were no significant differences in DNA levels among the groups when expressed per mg prostate tissue, indicating that mean prostate cell size was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Interaction of eukaryotic initiation factor eIF-4B with a picornavirus internal translation initiation site (1995)

We studied the interaction of cellular proteins with the internal ribosome entry site (IRES) of foot-and-mouth disease virus by UV cross-linking and observed specific binding of a 80-kDa protein contained in cytosolic HeLa cell extract and in rabbit reticulocyte lysate. Binding of the protein was dependent on the presence of ATP. Immunoprecipitation with eIF-4B antiserum revealed that the protein is identical to the initiation factor eIF-4B. Deletions in the 3' part, but not in the 5' part, of the IRES interfered with UV cross-linking, indicating that the binding site of eIF-4B is located close to the end of the element. Attempts to separate ribosome-associated from non-ribosome-associated protein fractions of cytosolic cell extracts led to the loss of cross-linking activity. This finding suggests that additional protein factors contribute to this interaction of eIF-4B with the IRES of foot-and-mouth disease virus.
Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling (2016)

Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases.
Cre-lox-regulated conditional RNA interference from transgenes (2004)

We have generated two lentiviral vectors for conditional, Cre-lox-regulated, RNA interference. One vector allows for conditional activation, whereas the other permits conditional inactivation of short hairpin RNA (shRNA) expression. The former is based on a strategy in which the mouse U6 promoter has been modified by including a hybrid between a LoxP site and a TATA box. The ability to efficiently control shRNA expression by using these vectors was shown in cell-based experiments by knocking down p53, nucleophosmin and DNA methyltransferase 1. We also demonstrate the usefulness of this approach to achieve conditional, tissue-specific RNA interference in Cre-expressing transgenic mice. Combined with the growing array of Cre expression strategies, these vectors allow spatial and temporal control of shRNA expression in vivo and should facilitate functional genetic analysis in mammals.
Effects of amide and amine plasma‐treated ePTFE vascular grafts on endothelial cell lining in an artificial circulatory system (1998)

We sought to examine whether surface modification of expanded polytetrafluoroethylene (ePTFE) vascular grafts might extend graft patency without modifying the graft structure. Amide and amine plasma (butylamine) were applied to graft surfaces using radio frequency glow discharge. Surface analyses by Fourier transform infrared spectroscopy-attenuated total reflectance, X-ray photoelectron spectroscopy, and dynamic contact angle measurements revealed the presence of nitrogen-containing functional groups on the plasma modified graft surfaces, along with an increased surface hydrophilicity. Bovine aortic endothelial cells were seeded on amide and amine plasma coated ePTFE vascular grafts and placed inside an artificial circulatory system under well-defined flow conditions. The seeded endothelial cells were exposed to either constant or pulsatile flow condition for 5 days. Their corresponding maximum wall shear stresses were 1 dyn/cm2 under constant flow and 65, 108, and 259 dyn/cm2 under various pulsatile flows. Plasma modified ePTFE vascular grafts enhanced the endothelial cell lining under constant and pulsatile flow conditions. Fluorescence nuclear staining, scanning electron microscopy, and histological staining indicated the formation of an endothelial cell monolayer on the plasma coated graft surfaces. © 1998 John Wiley & Sons, Inc. J Biomed Mater Res, 42, 188–198, 1998.
Terminal contributions for duplex oligonucleotide thermodynamic properties in the context of nearest neighbor models (2010)

Additive physical properties of DNA polymer duplexes have been expanded in terms of eight irreducible parameters that ultimately lead to consistency relations among the corresponding 10 duplex dimer contributions. End parameters are often added to allow for oligomer analysis which would add four extra degrees of freedom to the aforementioned parameters. Analysis of sufficient experimental data on oligomer duplexes allows for the unambiguous recovery of irreducible parameters. Values for free energy, enthalpy, and entropy are thus obtained, in terms of either irreducible or dimer decomposition sets. Here, a better adjust for the entropic (and enthalpic) irreducible parameters are obtained as we consider the more precise melting temperature data for the sequences of a given dataset. However, still large error estimates, and no clear distinction between the orientations of the terminal base pairs could yet be found. Finally, statistical mechanics approaches are applied for to connect the nearest neighbor approach to the two states model. Ad hoc end effects can be thus correlated to nucleation phenomena, leading to a critique for its role in nearest neighbor modeling.
Synergy of Nitric Oxide and Silver Sulfadiazine against Gram-Negative, Gram-Positive, and Antibiotic-Resistant Pathogens (2010)

The synergistic activity between nitric oxide (NO) released from diazeniumdiolate-modified proline (PROLI/NO) and silver(I) sulfadiazine (AgSD) was evaluated against Escherichia coli, Enterococcus faecalis, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis using a modified broth microdilution technique and a checkerboard-type assay. The combination of NO and AgSD was defined as synergistic when the fractional bactericidal concentration (FBC) was calculated to be <0.5. Gram-negative species were generally more susceptible to the individual antimicrobial agents than the Gram-positive bacteria, while Gram-positive bacteria were more susceptible to combination therapy. The in vitro synergistic activity of AgSD and NO observed against a range of pathogens strongly supports future investigation of this therapeutic combination, particularly for its potential use in the treatment of burns and chronic wounds.
Aggressive Peripheral T-Cell Lymphomas (Specified and Unspecified Types) (2005)

Peripheral T-cell lymphomas (PTCLs) are a biologically diverse and uncommon group of diseases. Compared to their B-cell counterparts, PTCLs remain largely unexplored and the optimal treatment ill-defined due to disease rarity and biological heterogeneity. For the majority of PTCL subtypes, prognosis is poor with a 5-year overall survival of approximately 30% in most series.The notable exception is ALK-positive anaplastic large-cell lymphoma (ALK-pos ALCL), which has a superior outcome. The international prognostic index can be used to some extent to define risk groups within some PTCL subtypes, including PTCL unspecified (PTCLUS). It is likely that the observed clinical heterogeneity reflects differences at the molecular level. With the more widespread availability of gene expression profiling, it may be possible in the future to further refine the classification of PTCLs and elucidate novel therapeutic targets. Future clinical trials are needed that focus specifically on PTCL to advance our understanding and define the optimal management in this disease.
Jet, Ultrasonic, and Mesh Nebulizers: An Evaluation of Nebulizers for Better Clinical Outcomes (2014)

For over a century, nebulizers have been commonly used to deliver aerosolized medications in the treatment of patients with pulmonary diseases. They are the aerosol device of choice when patients can not coordinate inhalation and actuation needed for the use of the pressurized metered-dose inhalers (pMDIs) or are not able to provide the necessary inspiratory flow required by the dry powder inhaler (DPI) for effective aerosol drug delivery. Three types of nebulizers exist: (1) jet nebulizers, (2) ultrasonic nebulizers, and (3) mesh nebulizers. The purpose of this paper is to explain the types of nebulizers available on the market and to evaluate their efficiencies in aerosol drug delivery while suggesting strategies for the optimal treatment of patients with pulmonary diseases.
Transgene detection in unpurified mouse tail DNA by polymerase chain reaction. (1991)

We describe here a method for the rapid identification of transgenic mice by polymerase chain reaction (PCR) using unpurified DNA extracts from tail digests. The method we have developed avoids the difficulty of obtaining blood from young animals and eliminates the need to purify DNA samples after tail digestion while allowing rapid determination of transgenic mice as young as 5 days. Although samples may be cut from newborn mice, we find a high risk of rejection of such pups by the mother
What is cluster headache? Fact sheet for patients and their families. A publication to mark Cluster Headache Day 2016 (2016)

In the last year the European Headache Alliance (EHA) has launched the "What's Under the Hat?" story-telling campaign, encouraging headache patients to share their stories of the impact that headache disorders have on their life.The goal is to inspire public compassion for headache sufferers by making the invisible visible, and also to provide a platform to give patients a voice (http://www.europeanheadachealliance.org/under-the-hat).On 21st March 2016 the EHA celebrated the first Cluster Headache Day as part of the What's Under the Hat? public awareness campaign.Even though cluster headache is considered the worst pain known to man it is largely underestimated.In fact more than 600,000 people in Europe live with cluster headache, with less than 50% of these seeing a specialist and more than a third having to miss work because of the condition, at a cost of 7 billion euros per year.This fact sheet has been prepared by expert headache patients and headache specialists to educate patients and their families about what cluster headache is.
In silico selection of therapeutic antibodies for development: Viscosity, clearance, and chemical stability (2014)

For mAbs to be viable therapeutics, they must be formulated to have low viscosity, be chemically stable, and have normal in vivo clearance rates. We explored these properties by observing correlations of up to 60 different antibodies of the IgG1 isotype. Unexpectedly, we observe significant correlations with simple physical properties obtainable from antibody sequences and by molecular dynamics simulations of individual antibody molecules. mAbs viscosities increase strongly with hydrophobicity and charge dipole distribution and decrease with net charge. Fast clearance correlates with high hydrophobicities of certain complementarity determining regions and with high positive or high negative net charge. Chemical degradation from tryptophan oxidation correlates with the average solvent exposure time of tryptophan residues. Aspartic acid isomerization rates can be predicted from solvent exposure and flexibility as determined by molecular dynamics simulations. These studies should aid in more rapid screening and selection of mAb candidates during early discovery.
Rib waveguide spot-size transformers: modal properties (1999)

Efficient spot-size convertors are an essential component of modern integrated optoelectronics, providing a simple and reliable interface with fibers. One recently proposed design functions by forcing the field from a small spot rib waveguide into a large spot one by using a taper. Accurate models of these structures, and a clear understanding of the coupling mechanisms they rely upon, are essential if optimized designs are to be produced. Furthermore, it is necessary to develop analysis techniques which are accurate yet not computationally intensive, suitable for use within an iterative design environment. Here, the well known and proven spectral index method is extended to efficiently analyze this class of vertically coupled rib waveguide spot-size transformer, providing both the guided modes and for the first time, the substrate radiation modes of the structure. These modes can then subsequently be used to design and determine the performance of the full tapered structure.
Introduction (1999)

In July 1998 the European Commission adopted the White Paper „Fair payment for infrastructure use: A phased approach to a common transport infrastructure charging framework in the EU“ which proposes an European intermodal approach for infrastructure charges. However, introducing a harmonised European framework for infrastructure charges requires first of all quantitative knowledge on infrastructure costs, congestion costs and accident and environmental costs for all modes and all EU-countries.
Multidimensional quantum normal forms, Moyal star product, and torus quantization (2005)

A normal form transformation is carried out on the operators of a complete set of commuting observables in a multidimensional, integrable quantum system, mapping them by unitary conjugation into functions of the harmonic oscillators in the various degrees of freedom. The transformation works at the level of the Weyl symbols of the operators, which are manipulated as formal power series in hbar by use of the Moyal star product. It is assumed that the Weyl symbol of one of the operators (the Hamiltonian) has a generic, stable fixed point in phase space. The normal form transformation takes place in a neighborhood of this fixed point. Once the normal form has been achieved, the Einstein-Brillouin-Keller or torus quantization rule follows easily, including higher order corrections in hbar. Crucial parts of the normal form transformation are not obvious generalizations of the one-dimensional case, nor is final quantization rule. The result raises some issues of differential geometry not found in the one-dimensional case.