gebhart/patrepeval huggingface dataset:
The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development (2004)

The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially.
New Universal Instrumentation in Spinal Surgery (1988)

A new instrumentation for posterior spinal surgery consists of metallic rods carved with diamond-shaped asperities on which vertebral hooks or screws can be screwed in any position, level, or degree of rotation. The rods are interlocked by means of devices for transverse traction (DTTs), rectangular constructs with multiple vertebral grips, the stability of which allows suppression of any postoperative external support. Initially designed to treat scoliosis, this instrumentation design allows mobilization of the vertebrae located at the apex of the curve and obtains a three-dimensional correction. Correction of the areas of the most important structural deformation can also be obtained at the level of the end vertebrae, without any need to resort to an important distraction force. The technique varies according to the various types of curvatures. Approximately 250 patients were operated upon from 1983 to 1985. In idiopathic scoliotic curvatures, the mean percentage of correction was 66%. An important improvement of the associated sagittal deformations and of the apical derotation was observed in flexible curves. In paralytic curves, particularly with a pelvic obliquity, the percentage of correction of the frontal deformation is 77%. All of the spine patients were ambulatory in the first postoperative week, without any external support, and returned to their school or family activities. In 43 patients with follow-up periods longer than two years, there were no technical errors in 38. The final angular loss of correction was less than 2 degrees in the error-free group.
Optimization of the yield screening system of plant varieties based on probability efficiency indices. (2001)

Probability of success and its ratio to resource investment are introduced for the optimization of multi-step yield screening (MSS) procedures for a relatively small population of test varieties. Numerical calculations are made to determine the difference of three patterns (I, II and III ) of MSS. In pattern I which has been assumed in the traditional screening theories, a specifically allocated upper fraction of the test varieties is selected in each step, and in patterns II and III, varieties superior to a check variety and a critical fixed yield value, respectively, are selected in each step. It is shown that, while pattern I MSS is useful in yield competition trials of highly promising varieties, pattern II or III MSS of single to three steps, will be efficient in preliminary yield trials. Pattern III with an appropriate critical yield value will give much better results than II.
Vacuolar H + -ATPase in ocular ciliary epithelium (1997)

The mechanisms controlling the production of aqueous humor and the regulation of intraocular pressure are poorly understood. Here, we provide evidence that a vacuolar H+-ATPase (V-ATPase) in the ocular ciliary epithelium is a key component of this process. In intracellular pH (pHi) measurements of isolated ciliary epithelium performed with 2',7-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF), the selective V-ATPase inhibitor bafilomycin A1 slowed the recovery of pHi in response to acute intracellular acidification, demonstrating the presence of V-ATPase in the plasma membrane. In isolated rabbit ciliary body preparations examined under voltage-clamped conditions, bafilomycin A1 produced a concentration-dependent decrease in short-circuit current, and topical application of bafilomycin A1 reduced intraocular pressure in rabbits, indicating an essential role of the V-ATPase in ciliary epithelial ion transport. Immunocytochemistry utilizing antibodies specific for the B1 isoform of the V-ATPase 56-kDa subunit revealed localization of V-ATPase in both the plasma membrane and cytoplasm of the native ciliary epithelium in both rabbit and rat eye. The regional and subcellular distribution of V-ATPase in specific regions of the ciliary process was altered profoundly by isoproterenol and phorbol esters, suggesting that change in the intracellular distribution of the enzyme is a mechanism by which drugs, hormones, and neurotransmitters modify aqueous humor production.
In-situ quantitative analysis of a prostate-specific antigen (PSA) using a nanomechanical PZT cantilever (2004)

We report on a novel technique of resonant frequency shift measurement based on a nanomechanical cantilever with a PZT actuating layer for label-free detection of a prostate-specific antigen (PSA) in a liquid environment. The nanomechanical PZT thin film cantilever is composed of SiO(2)/Ta/Pt/PZT/Pt/SiO(2) on a SiN(x) supporting layer for simultaneous self-exciting and sensing; it was fabricated using a standard MEMS (micro electromechanical system) process. The specific binding characteristics of the PSA antigen to its antibody, which is immobilized with Calixcrown self-assembled monolayers (SAMs) on a gold surface deposited on a cantilever, are determined to a high sensitivity. For the bioassay in a liquid environment, a liquid test cell with a 20 microl volume reaction chamber has been fabricated, using a bonding technique between poly(dimethyl siloxane) (PDMS) bilayers. An observed trend of resonant frequency change with respect to time could be explained by the binding kinetics due to the Langmuir isotherm and diffusion and by the effects of a small volume reaction chamber. In the saturated regimes, the resonant frequency of the cantilever increased with increase of the PSA concentration in the reaction chamber, showing that the trend of the resonance frequency change was similar to that of the fluorescence results. The saturated resonance frequency shift of the cantilever was proportional to the PSA antigen concentration of analyte solution.
Putting Auction Theory to Work: The Simultaneous Ascending Auction (2000)

I review the uses of economic theory in the initial design and later improvement of the "simultaneous ascending auction," which was developed initially for the sale of radio spectrum licenses in the United States. I analyze some capabilities and limitations of the auction, the roles of various detailed rules, the possibilities for introducing combinatorial bidding, and some considerations in adapting the auction for sales in which revenue, rather than efficiency, is the primary goal.
Companded quantization of speech MDCT coefficients (2005)

Here, we propose speech-coding procedures achieving high subjective quality, avoiding speech-specific processing and interframe exploitation. Thus, the scheme is tractable for packet-based voice communication, and has the capability of coding generic audio. The architecture is based on an modified discrete cosine transform (MDCT) representation of the signal, and combines efficient vector quantization (VQ) techniques with psychoacoustic principles. Weighted quantization of MDCT coefficients is performed, using a codebook based on a statistical model of the multidimensional MDCT pdf. The weighting and the codebook are adapted for each frame to account for masking thresholds given by a psychoacoustic analysis. Actual quantization is performed using lattices, thereby, achieving close to rate independent complexity. The result is a coding scheme operational at a range of rates. Here, a particular instance at 16 kbits/s, using a sampling frequency of 8 kHz, is shown to perform better than an LD-CELP operating at the same rate, even though no interframe memory is exploited.
Apatite nano-crystalline surface modification of poly(lactide-co-glycolide) sintered microsphere scaffolds for bone tissue engineering: implications for protein adsorption (2007)

A number of bone tissue engineering approaches are aimed at (i) increasing the osteconductivity and osteoinductivity of matrices, and (ii) incorporating bioactive molecules within the scaffolds. In this study we examined the growth of a nano-crystalline mineral layer on poly(lactide-co-glycolide) (PLAGA) sintered microsphere scaffolds for tissue engineering. In addition, the influence of the mineral precipitate layer on protein adsorption on the scaffolds was studied. Scaffolds were mineralized by incubation in simulated body fluid (SBF). Scanning electron microscopy (SEM) analysis revealed that mineralized scaffolds possess a rough surface with a plate-like nanostructure covering the surface of microspheres. The results of protein adsorption and release studies showed that while the protein release pattern was similar for PLAGA and mineralized PLAGA scaffolds, precipitation of the mineral layer on PLAGA led to enhanced protein adsorption and slower protein release. Mineralization of tissue-engineered surfaces provides a method for both imparting bioactivity and controlling levels of protein adsorption and release.
The production and characterization of murine monoclonal antibodies to a DNA receptor on human leukocytes. (1988)

Two murine mAb have been generated with a reactivity toward a 30,000 m.w. DNA binding protein found on the cell surface of human leukocytes; mAb 12A has an IgG1/k isotype, and mAb 24T has an IgG2b/k isotype. Both react with the DNA binding domain or adjacent region of the putative DNA receptor and inhibit the binding of [3H]DNA to PBMC at concentrations as low as 100 ng/ml. Stoichiometric studies indicate that both mAb react with monocytes and T cells with a kDa of 10(-7) M; about 0.5 x 10(6) molecules bind per cell at saturation. Flow cytometry indicated that 67% of lymphocytes and 98% of monocytes bore the DNA receptor. Dual labeling studies showed that 90% of B cells and 50% of T cells express the receptor; 50% of CD4+ T cells are receptor positive. Immunomatrices constructed with both mAb 12A and 24T allowed the receptor to be purified to a high degree of purity. A single protein of Mr 30,000 was readily observed after SDS-PAGE and silver staining of the gel; after electropheretic transfer of nitrocellulose this protein was shown to be a DNA binding molecule by use of a probe of biotin labeled DNA. These experiments provide further evidence to support the existence of a specific DNA receptor on human leukocytes; the availability of mAb to the receptor should be useful in its further characterization.
Impact of the Assembly-Activating Protein on Molecular Evolution of Synthetic Adeno-Associated Virus Capsids (2018)

Over the last decade, the role of the assembly-activating protein (AAP) has begun to be dissected for the formation of adeno-associated virus (AAV) capsids based on different viral serotypes. Recently, the authors' group has specifically studied AAP's relevance during production of AAV gene therapy vectors in mammalian or insect cells, and AAP was found to be essential for capsid protein stabilization and generation of functional vector particles. Here, the lingering question is additionally addressed of whether molecular AAV evolution via DNA family shuffling of viral capsid genes would perturb AAP functionality due to concurrent and inadvertent recombination of the AAP open reading frame. To this end, a battery of complementary experiments was conducted in which: (1) the ability of chimeric AAP from AAVDJ, a hybrid of serotypes 2, 8, and 9, was tested to rescue AAP knockouts in the three parental serotypes; (2) the functionality of 60 chimeric AAPs extracted from five shuffled, unselected capsid libraries was measured; (3) whether production of different shuffled libraries, 10 wild-type serotypes or 25 individual chimeric capsids, can be enhanced by overexpression of AAP cocktails was assessed; and (4) the activity of 12 chimeric AAPs isolated from a shuffled library that was iteratively selected in vivo in mouse livers was studied. Collectively, the data demonstrate a remarkable tolerance of AAP for recombination via DNA family shuffling, evidenced by the findings that (1) all chimeric AAPs studied here retained at least partial activity, even in cases where the cognate hybrid capsid may be non-functional, and that (2) ectopic AAP overexpression did not enhance production of shuffled AAV chimeras or libraries, implying that the inherently encoded hybrid AAP variants are sufficiently active. Together, this work provides compelling evidence that AAP is not rate limiting during AAV capsid shuffling and thereby relieves a major concern in the field of AAV vector evolution.
Generate, Filter, and Rank: Grammaticality Classification for Production-Ready NLG Systems (2019)

Neural approaches to Natural Language Generation (NLG) have been promising for goal-oriented dialogue. One of the challenges of productionizing these approaches, however, is the ability to control response quality, and ensure that generated responses are acceptable. We propose the use of a generate, filter, and rank framework, in which candidate responses are first filtered to eliminate unacceptable responses, and then ranked to select the best response. While acceptability includes grammatical correctness and semantic correctness, we focus only on grammaticality classification in this paper, and show that existing datasets for grammatical error correction don't correctly capture the distribution of errors that data-driven generators are likely to make. We release a grammatical classification and semantic correctness classification dataset for the weather domain that consists of responses generated by 3 data-driven NLG systems. We then explore two supervised learning approaches (CNNs and GBDTs) for classifying grammaticality. Our experiments show that grammaticality classification is very sensitive to the distribution of errors in the data, and that these distributions vary significantly with both the source of the response as well as the domain. We show that it's possible to achieve high precision with reasonable recall on our dataset.
DNA vaccine coding for the full-length infectious Kunjin virus RNA protects mice against the New York strain of West Nile virus (2003)

A plasmid DNA directing transcription of the infectious full-length RNA genome of Kunjin (KUN) virus in vivo from a mammalian expression promoter was used to vaccinate mice intramuscularly. The KUN viral cDNA encoded in the plasmid contained the mutation in the NS1 protein (Pro-250 to Leu) previously shown to attenuate KUN virus in weanling mice. KUN virus was isolated from the blood of immunized mice 3-4 days after DNA inoculation, demonstrating that infectious RNA was being transcribed in vivo; however, no symptoms of virus-induced disease were observed. By 19 days postimmunization, neutralizing antibody was detected in the serum of immunized animals. On challenge with lethal doses of the virulent New York strain of West Nile (WN) or wild-type KUN virus intracerebrally or intraperitoneally, mice immunized with as little as 0.1-1 microg of KUN plasmid DNA were solidly protected against disease. This finding correlated with neutralization data in vitro showing that serum from KUN DNA-immunized mice neutralized KUN and WN viruses with similar efficiencies. The results demonstrate that delivery of an attenuated but replicating KUN virus via a plasmid DNA vector may provide an effective vaccination strategy against virulent strains of WN virus.
Identification of an Mhc-DPB1 allele involved in susceptibility to experimental autoimmune encephalomyelitis in rhesus macaques (1995)

Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disorder that in rodents is known to be influenced by genetic background, specifically the Mhc class II region. Immunization of a group of outbred rhesus macaques with bovine high homogenate results in induction of the disease in approximately 65% of the animals. No clear association between the Mamu-DR or -DQ subregion of the rhesus macaque MHC (MhcMamu) and susceptibility or resistance to the disease has been documented. In this communication we describe a CD4+ Th cell line, isolated from an animal diagnosed with EAE, which proliferated in response to purified bovine myelin basic protein (MBP), a major constituent of the myelin sheath surrounding nerve cells. More specifically it only recognized a peptide including residues 61-82 of the molecule. Analysis of the T cell receptor (Tcr) usage of this MBP reactive T cell line showed functional transcripts for only two members of the V alpha 1 and one of each of the V beta 3 and V beta 6 families. The antigen-specific proliferative response was inhibited by a mAb reactive with MHC-DP molecules. Molecular analysis of the Mamu-DP region, in concert with allogeneic antigen presentation studies, demonstrated that the Mamu-DPB1*01 gene product functions as the restriction element for MBP peptide presentation. Retrospective analyses showed that this particular allele is frequently found in the group of EAE susceptible animals but is absent in the resistant animals (P < 0.01). As a consequence, the Mamu-DPB1*01 allele may represent one of the risk factors involved in determining susceptibility to EAE in an outbred population of rhesus macaques.
Structure of Fok I has implications for DNA cleavage (1998)

FokI is a member an unusual class of restriction enzymes that recognize a specific DNA sequence and cleave nonspecifically a short distance away from that sequence. FokI consists of an N-terminal DNA recognition domain and a C-terminal cleavage domain. The bipartite nature of FokI has led to the development of artificial enzymes with novel specificities. We have solved the structure of FokI to 2.3 A resolution. The structure reveals a dimer, in which the dimerization interface is mediated by the cleavage domain. Each monomer has an overall conformation similar to that found in the FokI-DNA complex, with the cleavage domain packing alongside the DNA recognition domain. In corroboration with the cleavage data presented in the accompanying paper in this issue of Proceedings, we propose a model for FokI DNA cleavage that requires the dimerization of FokI on DNA to cleave both DNA strands.
Application of a New Bicyclic Triaminophosphine Ligand in Pd-Catalyzed Buchwald−Hartwig Amination Reactions of Aryl Chlorides, Bromides, and Iodides (2003)

The new bicyclic triaminophosphine ligand P(i-BuNCH2)3CMe (3) has been synthesized in three steps from commercially available materials and its efficacy in palladium-catalyzed reactions of aryl halides with an array of amines has been demonstrated. Electron-poor, electron-neutral, and electron-rich aryl bromides, chlorides, and iodides participated in the process. The reactions encompassed aromatic amines (primary or secondary) and secondary amines (cyclic or acyclic). It has also been shown that the weak base Cs2CO3 can be employed with ligand 3, allowing a variety of functionalized substrates (e.g., those containing esters and nitro groups) to be utilized in our amination protocols. This ligand provides a remarkably general, efficient, and mild palladium catalyst for aryl iodide amination. Although 3 is slightly air and moisture sensitive, easy procedures can be adopted that avoid the need of a glovebox. Comparisons of the efficacy of 3 in these reactions with that of the proazaphosphatrane P(i-BuNCH2CH2)3N (2) reveal that in addition to the opportunity for transannulation in 2 (but not in 3), other significant stereoelectronic contrasts exist between these two ligands which help account for differences in the activities of the Pd/2 and Pd/3 catalytic systems.
s-Tetrazines as Building Blocks for New Functional Molecules and Molecular Materials (2010)

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTs-Tetrazines as Building Blocks for New Functional Molecules and Molecular MaterialsGilles Clavier* and Pierre Audebert*View Author Information PPSM, ENS Cachan, CNRS, UniverSud, 61 av President Wilson, F-94230 Cachan, France* To whom correspondence should be addressed. E-mail: [email protected] (G.C.) and [email protected] (P.A.).Cite this: Chem. Rev. 2010, 110, 6, 3299–3314Publication Date (Web):March 22, 2010Publication History Received4 November 2009Published online22 March 2010Published inissue 9 June 2010https://pubs.acs.org/doi/10.1021/cr900357ehttps://doi.org/10.1021/cr900357ereview-articleACS PublicationsCopyright © 2010 American Chemical SocietyRequest reuse permissionsArticle Views11555Altmetric-Citations330LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Anions,Fluorescence,Molecules,Redox reactions,Substituents Get e-Alerts