gebhart/patrepeval huggingface dataset:
Adenovirus 5–Fiber 35 Chimeric Vector Mediates Efficient Apical Correction of the Cystic Fibrosis Transmembrane Conductance Regulator Defect in Cystic Fibrosis Primary Airway Epithelia (2009)

In vivo gene transfer to the human respiratory tract by adenovirus serotype 5 (Ad5) vectors has revealed their limitations related to inefficient gene transfer, host antiviral response, and innate adenoviral toxicity. In the present work, we compared the cytotoxicity and efficiency of Ad5 and a chimeric Ad5F35 vector with respect to CFTR gene transfer to cystic fibrosis (CF) and non-CF human airway epithelial cells. We found that high doses of Ad5 vector had an adverse effect on the function of exogenous and endogenous CFTR. Results obtained with Ad5 capsid mutants suggested that the RGD motifs on the penton base capsomers were responsible for the negative effect on CFTR function. This negative interference did not result from a lower level of biosynthesis and/or altered cellular trafficking of the CFTR protein, but rather from an indirect mechanism of functional blockage of CFTR, related to the RGD integrin-mediated endocytic pathway of Ad5. No negative interference with CFTR was observed for Ad5F35, an Ad5-based vector pseudotyped with fibers from Ad35, a serotype that uses another cell entry pathway. In vitro, Ad5F35 vector expressing the GFP-tagged CFTR (Ad5F35-GFP-CFTR) showed a 30-fold higher efficiency of transduction and chloride channel correction in CFTR-deficient cells, compared with Ad5GFP-CFTR. Ex vivo, Ad5F35-GFP-CFTR had the capacity to transduce efficiently reconstituted airway epithelia from patients with CF (CF-HAE) via the apical surface, restored chloride channel function at relatively low vector doses, and showed relatively stable expression of GFP-CFTR for several weeks.
The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy (2010)

Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell non-Hodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway.
Water soluble nanoporous nanoparticle for in vivo targeted drug delivery and controlled release in B cells tumor context (2010)

Multitasking nanoparticles are gaining great attention for smart drug delivery systems. The exploration of the nano-scale opens new concrete opportunities for revealing new properties and undiscovered cell-particle interactions. Here we present a biodegradable nanoporous silicon nanoparticle that can be successfully employed for in vivo targeted drug delivery and sustained release. The bare nanoporous nanocarriers can be accurately designed and fabricated with an effective control of porosity, surface chemistry and particle size, up to a few nm. The proposed nanoparticles exhibit several remarkable features including high payload, biodegradability, no toxicity, and multiple loading in water without the need of additional chemical reagents at room temperature. The targeting strategy is based on phage display technology that was successfully used to discover cell surface binding peptide for murine B lymphoma A20 cell line. The peptide used in combination with the nanoporous nanoparticles allows an efficient in vivo targeting, a sustained release and a sensible therapeutic effect.
Thematic Review Series: Sphingolipids. Biodiversity of sphingoid bases (“sphingosines”) and related amino alcohols (2008)

“Sphingosin” was first described by J. L. W. Thudichum in 1884 and structurally characterized as 2S,3R,4E-2-aminooctadec-4-ene-1,3-diol in 1947 by Herb Carter, who also proposed the designation of “lipides derived from sphingosine as sphingolipides.” This category of amino alcohols is now known to encompass hundreds of compounds that are referred to as sphingoid bases and sphingoid base-like compounds, which vary in chain length, number, position, and stereochemistry of double bonds, hydroxyl groups, and other functionalities. Some have especially intriguing features, such as the tail-to-tail combination of two sphingoid bases in the α,ω-sphingoids produced by sponges. Most of these compounds participate in cell structure and regulation, and some (such as the fumonisins) disrupt normal sphingolipid metabolism and cause plant and animal disease. Many of the naturally occurring and synthetic sphingoid bases are cytotoxic for cancer cells and pathogenic microorganisms or have other potentially useful bioactivities; hence, they offer promise as pharmaceutical leads. This thematic review gives an overview of the biodiversity of the backbones of sphingolipids and the broader field of naturally occurring and synthetic sphingoid base-like compounds.
Tropism-Modified Adenoviral and Adeno-Associated Viral Vectors for Gene Therapy (2002)

One of the most rapidly advancing areas of gene therapy is vector development. For the majority of gene therapy procedures, efficient and selective transduction would provide safe and more effective treatments at optimal vector doses. Advances in vector targeting strategies have been rapid within the field of DNA-based viruses, particularly adenovirus (Ad) and more recently adeno-associated virus (AAV) based vectors. Vector targeting at the level of virus: cell interaction can be achieved using both non-genetic and genetic methodology. Non-genetic approaches typically utilise bispecific antibodies that both neutralise wild-type virus tropism and provide a new cell binding capacity. For genetic targeting strategies, the virus capsid can be engineered to express foreign ligands that target selected receptors in the absence or presence of additional modification to ablate the virus' natural tropism. This review covers technological advances that have led to targeting of Ad and AAV and highlights the potential for these 'designer' viruses for future gene-based therapeutics.
CDK inhibitors as potential breast cancer therapeutics: new evidence for enhanced efficacy in ER+disease (2009)

Loss of cell cycle control is a hallmark of cancer, and aberrations in the cyclin-CDK-RB (cyclin-dependent kinase-retinoblastoma protein) pathway are common in breast cancer. Consequently, inhibition of this pathway is an attractive therapeutic strategy, but results from clinical trials of CDK inhibitors in breast cancer have been disappointing. A recent study now shows that in cell culture a selective CDK4/6 inhibitor is preferentially effective in estrogen receptor-positive (ER(+)) disease and apparently acts synergistically with tamoxifen or trastuzumab. These exciting new preclinical data set the scene for a more targeted approach to further clinical evaluation wherein this class of drugs is targeted to subgroups of ER(+) patients, including those with resistance to endocrine therapy, alone or in combination with current standard therapies.
Training load monitoring algorithms on highly sub-metered home electricity consumption data (2008)

The growing interest in energy-efficient buildings is driving changes in investment, design, and occupant behavior. To better focus cost and resource conservation efforts, electricity consumption feedback can be used to provide motivation, guidance, and verification. Disaggregating by end-use helps both consumers and producers to identify targets for conservation. While hardware-based sub-metering is costly and labor-intensive, non-intrusive load monitoring (N I LM) is capable of gathering detailed energy-use data with minimal equipment cost and installation time. However, variations in measurements between metering devices complicate the process of compiling the necessary appliance profiles. Future work involves the development of NILM algorithms using sensor fusion and detailed appliance-level data gathered from a highly-sensed house currently being constructed near Pittsburgh, Pennsylvania.
An Introduction to Sequence Similarity (“Homology”) Searching (2013)

Sequence similarity searching, typically with BLAST, is the most widely used and most reliable strategy for characterizing newly determined sequences. Sequence similarity searches can identify "homologous" proteins or genes by detecting excess similarity- statistically significant similarity that reflects common ancestry. This unit provides an overview of the inference of homology from significant similarity, and introduces other units in this chapter that provide more details on effective strategies for identifying homologs.
A disruption‐replacement approach for the targeted integration of foreign genes in Hansenula polymorpha (1995)

A system has been developed which allows the selection of integrative transformants with replacement of the Hansenula polymorpha methanol oxidase gene (MOX) with expression cassettes carrying heterologous gene under the control of the MOX promoter. The system is convenient for comparison of the expression levels of different constructs integrated into the same locus of the H. polymorpha genome. This system was used to compare the secretion levels of human urinary plasminogen activator, the secretion of which was directed by different signal sequences.
A Behavioral Task Predicts Conversion to Mild Cognitive Impairment and Alzheimer’s Disease (2012)

The present findings show that the VPC task can predict impending cognitive decline. To our knowledge, this is the first behavioral task that can identify CON participants who will develop MCI or patients with MCI who will develop AD within the next few years.
Synthesis and Optical Properties of Silver Nanobars and Nanorice (2007)

Silver nanobars with rectangular side facets and an average aspect ratio of 2.7 have been synthesized by modifying the concentration of bromide added to a polyol synthesis. Subsequent rounding of nanobars transformed them into nanorice. Due to their anisotropy, nanobars and nanorice exhibit two plasmon resonance peaks, scattering light both in the visible and in the near-infrared regions. With a combination of discrete-dipole approximation calculations and single-nanoparticle spectroscopy, we explored the effect of nanostructure aspect ratio and corner sharpness on the frequency of plasmon resonance. Near-field calculations and surface-enhanced Raman scattering measurements on single particles were performed to show how local field enhancement changes with both the wavelength and polarization of incident light.
Japanese and Korean voice search (2012)

This paper describes challenges and solutions for building a successful voice search system as applied to Japanese and Korean at Google. We describe the techniques used to deal with an infinite vocabulary, how modeling completely in the written domain for language model and dictionary can avoid some system complexity, and how we built dictionaries, language and acoustic models in this framework. We show how to deal with the difficulty of scoring results for multiple script languages because of ambiguities. The development of voice search for these languages led to a significant simplification of the original process to build a system for any new language which in in parts became our default process for internationalization of voice search.
Mdt(A), a New Efflux Protein Conferring Multiple Antibiotic Resistance in Lactococcus lactis and Escherichia coli (2001)

The mdt(A) gene, previously designated mef214, from Lactococcus lactis subsp. lactis plasmid pK214 encodes a protein [Mdt(A) (multiple drug transporter)] with 12 putative transmembrane segments (TMS) that contain typical motifs conserved among the efflux proteins of the major facilitator superfamily. However, it also has two C-motifs (conserved in the fifth TMS of the antiporters) and a putative ATP-binding site. Expression of the cloned mdt(A) gene decreased susceptibility to macrolides, lincosamides, streptogramins, and tetracyclines in L. lactis and Escherichia coli, but not in Enterococcus faecalis or in Staphylococcus aureus. Glucose-dependent efflux of erythromycin and tetracycline was demonstrated in L. lactis and in E. coli.
PA Residues in the 2009 H1N1 Pandemic Influenza Virus Enhance Avian Influenza Virus Polymerase Activity in Mammalian Cells (2011)

The 2009 pandemic influenza virus (pH1N1) is a swine-origin reassortant containing human, avian, and swine influenza genes. We have previously shown that the polymerase complex of the pH1N1 strain A/California/04/2009 (Cal) is highly active in mammalian 293T cells, despite the avian origin of both its PA and PB2. In this study, we analyzed the polymerase residues that are responsible for high pH1N1 polymerase activity in the mammalian host. Characterization of polymerase complexes containing various combinations of Cal and avian influenza virus A/chicken/Nanchang/3-120/01 (H3N2) (Nan) by reporter gene assay indicates that Cal PA, but not PB2, is a major contributing factor to high Cal polymerase activity in 293T cells. In particular, Cal PA significantly activates the otherwise inactive Nan polymerase at 37 and 39°C but not at the lower temperature of 34°C. Further analysis using site-directed mutagenesis showed that the Cal PA residues 85I, 186S, and 336M contribute to enhanced activity of the Cal polymerase. Recombinant A/WSN/33 (H1N1) (WSN) viruses containing Nan NP and polymerase (PA, PB1, PB2) genes with individual mutations in PA at residues 85, 186, and 336 produced higher levels of viral protein than the virus containing wild-type (WT) Nan PA. Interestingly, compared to the WT, the virus containing the 85I mutation grew faster in human A549 cells and the 336M mutation most significantly enhanced pathogenicity in a mouse model, among the three PA mutations tested. Our results suggest that multiple mutations in PA, which were rarely present in previous influenza isolates, are involved in mammalian adaptation and pathogenicity of the 2009 pH1N1.
Visual segmentation of lawn grass for a mobile robotic lawnmower (2010)

We investigate the existence of computationally inexpensive first and second order statistics that uniquely describe grass for application in an autonomous lawnmower. We then segment images based on these statistics to determine locations of driveable terrain in an image. Tight statistical clustering of illuminated grass versus artificial texture suggests that this method is sufficient for identifying driveable terrain for an autonomous lawnmower.
An Architecture for Intelligent Interfaces: Outline of an Approach to Supporting Operators of Complex Systems (1987)

The conceptual design of a comprehensive support system for operators of complex systems is presented. Key functions within the support system architecture include information management, error monitoring, and adaptive aiding. One of the central knowledge sources underlying this functionality is an operator model that involves a combination of algorithmic and symbolic models for assessing and predicting an operator's activities, awareness, intentions, resources, and performance. Functional block diagrams are presented for the overall architecture as well as the key elements within this architecture. A variety of difficult design issues are discussed, and ongoing efforts aimed at resolving these issues are noted.
Mesoporous Silica Nanospheres as Highly Efficient MRI Contrast Agents (2008)

Mesoporous silica nanoparticles (MSNs) containing a hexagonal array of one-dimensional channels with diameters of 2.4 nm were synthesized using a surfactant-templated, base-catalyzed condensation reaction. After extraction of the template, the highly porous 75 nm nanospheres were coated with a Gd−Si−DTTA complex to give MSN−Gd particles that exhibit very high MR relaxivities. The MSN−Gd nanoparticles were characterized using SEM, TEM, TGA, BET, PXRD, and DCP, and the relaxivities were determined on both a 3.0 T and a 9.4 T MR scanner. The MSN−Gd particles exhibit very high MR relaxivity on a per Gd basis and even more impressive MR relaxivity on a per nanoparticle basis, owing to the ready access of water molecules through the nanochannels of the MSN−Gd particles and a high payload of Gd centers. The in vivo efficacy of these particles as MR contrast agents was further demonstrated with monocyte cells and mouse models. Both T1-weighted and T2-weighted signal enhancement can be obtained at doses much lower than what is currently being used. In vitro MTS assay and in vivo mouse studies indicated no acute toxicity of the MSN−Gd nanoparticles. This work thus demonstrates the design and synthesis of highly efficient nanoparticulate MRI contrast agents based on MSNs and suggests the potential of using these new hybrid nanomaterials for early disease diagnosis.
Theory of Prism–Film Coupler and Thin-Film Light Guides (1970)

A prism–film coupler has been discussed recently by Tien, Ulrich, and Martin as a device to couple efficiently a laser beam into thin-film dielectric light guides. This coupler also allows an accurate measurement of the spectrum of propagating modes from which the refractive index and the thickness of the film can be determined. We present here a theory of the prism–film coupler. The physical principles involved are illustrated by a method that combines wave and ray optics. We study the modes in the thin-film light guide and their modification by the effect of coupling. We also calculate the field distributions in the prism and the film, the power transfer between the prism and the film, and derive a condition of optimum operation. In one example, 81% of the laser power can be fed into any desired mode of propagation in the film.
Retinal Detachment during Glaucoma Therapy (1985)

Miotic-induced retinal detachment (RD) is a condition that is not recognized as such by common consent. Clinically it has been shown that all miotic agents, whether strong or weak, can precipitate an RD, if there are additional contributing factors like high myopia, peripheral lattice degeneration of the retina, pathological vitreoretinal changes and previous history of an RD in the other eye, which all increase the basic risk of RD. Pilokarpin lameller 11 mg represents a form of miotic therapy having initially only a moderate accommodative and miotic effect, which further declines to a level of steady state during the next hours. Because the time interval after which a new Pilokarpin lameller unit is required lasts up to 1 week, the total amount of accommodation and miosis is much smaller than when applying daily 2% pilocarpine drops. However, it seems important, before the start of any kind of miotic therapy, to perform a careful examination and management of virtually all detachment-prone patients. This case report deals with an RD which occurred after 2 days of treatment with Pilokarpin lameller (Ocusert) 11 mg in a myopic patient who had a juvenile type of glaucoma and previous history of an RD in the other eye.
The cyanase operon and cyanate metabolism (1990)

Cyanase is an inducible enzyme in E. coli that catalyzes bicarbonate-dependent decomposition of cyanate. It is encoded as part of an operon we have named the cyn operon, which includes three genes in the following order: cynT (cyanate permease), cynS (cyanase), and cynX (protein of unknown function). The direction of transcription is opposite to that of the lac operon, and the 3'-end of the cyn operon overlaps the 3'-end of the lac operon by 98 nucleotides. The gene cynR (regulatory protein) is located upstream from the cyn operon, and its transcription is opposite that of the cyn operon. The genes of the cyn operon and the cynR gene have been cloned, sequenced and over-expressed. Cyanate at concentrations of about 1 mM is toxic to strains of E. coli lacking the cyanase gene, but strains in which the inducible gene for cyanase is present can grow on cyanate as the sole source of nitrogen at concentrations as high as 20 mM. The presence of cyanase itself is not sufficient to overcome cyanate toxicity--the permease must also be present. Strains lacking the cyanase gene, but having a functional permease gene, are extremely sensitive to cyanate. Uptake of cyanate involves the product of the permease gene in an energy-dependent process. It appears that the cyn operon has evolved to function in detoxification/decomposition of cyanate arising from both intra- and extracellular sources.
Direct Binding of Radioiodinated Monoclonal Antibody to Tumor Cells: Significance of Antibody Purity and Affinity for Drug Targeting or Tumor Imaging (1983)

For MoAb to be used efficiently for drug targeting and tumor imaging, the fraction of antibody binding to tumor cells must be maximized. We have studied the binding of 125I MoAb in three different tumor systems. The fraction of antibody that could be bound to the cell surface was directly proportional to the antibody purity. The affinity constant also limits the fraction of antibody that can bind to cells at a given antigen concentration. Rearrangement of the standard expression for univalent equilibrium binding between two reactants shows that in antigen excess, the maximum fraction of antibody that can bind (formula; see text). Binding data using four different MoAb with three cell systems confirm this relationship. Estimates for reasonable concentrations of tumor antigens in vivo indicate that antibodies with binding constants less than 10(8) M-1 are not likely to be useful for drug targeting or tumor imaging.