gebhart/patrepeval huggingface dataset:
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4 (2015)

The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins. Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3. The activity of MZ1 is dependent on binding to VHL but is achieved at a sufficiently low concentration not to induce stabilization of HIF-1α. Gene expression profiles of selected cancer-related genes responsive to JQ1 reveal distinct and more limited transcriptional responses induced by MZ1, consistent with selective suppression of BRD4. Our discovery opens up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4.
Gene therapy comes of age (2018)

After almost 30 years of promise tempered by setbacks, gene therapies are rapidly becoming a critical component of the therapeutic armamentarium for a variety of inherited and acquired human diseases. Gene therapies for inherited immune disorders, hemophilia, eye and neurodegenerative disorders, and lymphoid cancers recently progressed to approved drug status in the United States and Europe, or are anticipated to receive approval in the near future. In this Review, we discuss milestones in the development of gene therapies, focusing on direct in vivo administration of viral vectors and adoptive transfer of genetically engineered T cells or hematopoietic stem cells. We also discuss emerging genome editing technologies that should further advance the scope and efficacy of gene therapy approaches.
Low-cost digital passive optical networks (1990)

Techniques for reducing the cost of providing digital telephony and broadband services to the home over passive optical networks are proposed. These include the use of optical transceivers in an optical TDMA (time-division multiple access) telephony system and using low-cost consumer technology in providing a digital CATV (cable television) service using TDM (time division multiplexing).< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Audio-visual continuous speech recognition using a coupled hidden Markov model (2002)

With the increase in the computational complexity of recent computers, audio-visual speech recognition (AVSR) became an attractive research topic that can lead to a robust solution for speech recognition in noisy environments. In the audio visual continuous speech recognition system presented in this paper, the audio and visual observation sequences are integrated using a coupled hidden Markov model (CHMM). The statistical properties of the CHMM can describe the asyncrony of the audio and visual features while preserving their natural correlation over time. The experimental results show that the current system tested on the XM2VTS database reduces the error rate of the audio only speech recognition system at SNR of 0db by over 55%.
Insights into the Effects on Metal Binding of the Systematic Substitution of Five Key Glutamate Ligands in the Ferritin of Escherichia coli (2003)

Ferritins are nearly ubiquitous iron storage proteins playing a fundamental role in iron metabolism. They are composed of 24 subunits forming a spherical protein shell encompassing a central iron storage cavity. The iron storage mechanism involves the initial binding and subsequent O2-dependent oxidation of two Fe2+ ions located at sites A and B within the highly conserved dinuclear "ferroxidase center" in individual subunits. Unlike animal ferritins and the heme-containing bacterioferritins, the Escherichia coli ferritin possesses an additional iron-binding site (site C) located on the inner surface of the protein shell close to the ferroxidase center. We report the structures of five E. coli ferritin variants and their Fe3+ and Zn2+ (a redox-stable alternative for Fe2+) derivatives. Single carboxyl ligand replacements in sites A, B, and C gave unique effects on metal binding, which explain the observed changes in Fe2+ oxidation rates. Binding of Fe2+ at both A and B sites is clearly essential for rapid Fe2+ oxidation, and the linking of FeB2+ to FeC2+ enables the oxidation of three Fe2+ ions. The transient binding of Fe2+ at one of three newly observed Zn2+ sites may allow the oxidation of four Fe2+ by one dioxygen molecule.
Panning of a Phage VH Library Using Nitrocellulose Membranes: Application to Selection of a Human VH Library (2001)

We have established a method for selecting binding phages from a phage immunoglobulin heavy chain variable region (VH) library by panning with nitrocellulose membranes (membrane panning). To evaluate the concentrating ability of membrane panning for binding phages, a phage VH library containing clones that bind to hen egg white lysozyme (HEL) was used for panning against HEL. The efficiency of our method was as high as that of panning with magnetic beads. In addition, we performed membrane panning against target proteins and isolated the binding phages. The human VH genes of these phages were cloned and expressed as VH-bacterial alkaline phosphatase (PhoA) conjugates (VH-PhoA) in Escherichia coli. The dose-dependent binding of VH-PhoA to target proteins was confirmed by dot blotting. When applied to disease-associated antibodies, these methods will likely benefit clinical research. In addition, these techniques may be applicable to systematic analysis in proteome studies.
Combined approach of NMR and chemometrics for screening peptones used in the cell culture medium for the production of a recombinant therapeutic protein (2007)

Soy peptones or soy hydrolysates are widely used as key medium additives in serum-free cell culture processes for industrial production of therapeutic recombinant proteins. The heterogeneous nature of these vegetable-derived materials can lead to substantial lot- to-lot variability in cell culture processes. In this study, we demonstrated the feasibility of nuclear magnetic resonance (NMR) spectroscopy in combination with chemometrics in rapid screening peptone lots in order to optimize efficiency and consistency of large-scale protein production. This report is the first that shows a correlation between the intrinsic NMR spectral characteristics of complex heterogeneous materials and product titer using chemometrics.
Solid State Characterization of Spray-Dried Powders of Recombinant Human Deoxyribonuclease (RhDNase)† (1998)

rhDNase is a recombinant human protein approved as an aqueous solution for human use by inhalation. To study the feasibility of preparation of dry powders for inhalation, spray-dried powders of pure rhDNase and co-spray-dried mixtures of rhDNase with an excipient approved for inhalation products, lactose, were prepared. Both types of powders were initially amorphous. The lactose, however, was found to crystallize after exposure to a humid environment. The crystals in the powder were identified as the alpha-monohydrate polymorph of lactose by hot-stage optical and scanning electron microscopy, differential scanning calorimetry and thermogravimetry, FTIR spectroscopy, and X-ray powder diffraction. Moisture sorption isotherms indicated that crystallization occurred at high relative humidities (70-85%), depending on the temperature of the environment (5-40 degreesC). The practical implications for the manufacturing and storage of protein powders for inhalation are discussed.
Perceptual influence of the vibratory component on the audio component of alarms produced by rumble strips, by measuring reaction times (2012)

International audience
Cucurbitane Glycosides from the Fruits of Siraitia grosvenorii and Their Inhibitory Effects on Epstein−Barr Virus Activation (2007)

Six new cucurbitane glycosides, mogroside II B (2), 11-deoxymogroside III (4), 7-oxomogroside II E (5), 7-oxomogroside V (6), 11-oxomogroside II A1 (7), and 11-oxomogroside IV A (8), and two known but new naturally occurring cucurbitane glycosides, mogroside II A1 (1) and mogroside III A2 (3), were isolated from an ethanol extract of the fruits of Siraitia grosvenorii. Upon evaluation of compounds 1-8 for inhibitory effects against the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), all compounds exhibited inhibitory effects with IC50 values of 346-400 mol ratio/32 pmol TPA. In addition, compounds 1-8 showed weak inhibitory effects on activation of (+/-)-(E)-methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitric oxide (NO) donor.
"Buried" metal/dielectric/semiconductor reflectors for light trapping in epitaxial thin-film solar cells (1996)

Effective light trapping can be realized in thin film solar cells by including a reflector between the substrate and device structure. Light trapping can significantly improve the performance of almost any solar cell, although the practical attainment of high levels of light trapping has been elusive in at least several important types of solar cells. In many cases, the full potential of light trapping has not been realized due to difficulties in combining a thin solar cell structure with an effective backside reflector. We report a new method for incorporating so-called "buried mirrors" between the supporting substrate and epitaxial device layers that is widely applicable to thin-film crystalline silicon and Ill-V solar cells. We form the mirror as a multilayer coating of amorphous or polycrystalline dielectrics, metals, and/or semiconductors deposited as a mask on the substrate. The thin-film solar cell structure (emitter and base layers) is formed over the mask by epitaxial lateral overgrowth. This approach provides very high backside reflectivities over a wide wavelength bandwidth and over a wide range of angles of incidence. The technique is compatible with different mirror structures and materials, and is superior to the more common epitaxial AlAs/GaAs quarter-wavelength stack Bragg reflectors used for backside mirrors in GaAs-based solar cells, LEDs, and vertical cavity lasers.
Design of high speed Si/SiGe heterojunction complementary metal–oxide–semiconductor field effect transistors with reduced short-channel effects (2002)

By taking advantages of higher carrier mobility and bandgap engineering in the Si/SiGe system, we explore the channel and source/drain (S/D) designs for Si/SiGe heterojunction complementary metal–oxide–semiconductor field effect transistors (CMOSFETs). A planar CMOS structure is proposed in which a strained SiGe layer (the hole channel) and a strained Si layer (the electron channel) grown on relaxed SiGe wells are designed for p- and n-MOSFETs, respectively, to provide better current drive capability. On the other hand, a strained-SiGe S/D heterojunction is also included in the CMOSFET device structure in that the band offset between S/D and the channel is found to be very effective in suppressing short-channel effects such as drain-induced barrier lowering/bulk punchthrough and drain leakage. With proper structure design, the near symmetrical n-MOS/p-MOS VT, enhanced current-drive capability and reduced short channel effects are achievable within the proposed planar structure.
The Role of Oxidative Stress in Diabetic Vascular and Neural Disease (2003)

This review will focus on the impact of hyperglycemia-induced oxidative stress in the development of diabetes-induced vascular and neural dysfunction. Oxidative stress occurs when the balance between the production of oxidation products and the ability of antioxidant mechanisms to neutralize these products is tilted in the favor of the former. The production of reactive oxygen species has been shown to be increased in patients with diabetes. The possible sources for the overproduction of reactive oxygen species is widespread and include enzymatic pathways, autoxidation of glucose and the mitochondria. Increase in oxidative stress has clearly been shown to contribute to the pathology of vascular disease not only in diabetes but also in hypertension, stroke and ischemia. Since the etiology of diabetic neuropathy is considered to have a large vascular component, prevention of oxidative stress in diabetes is considered by many investigators to be a primary defense against the development of diabetic vascular disease. Potential therapies for preventing increased oxidative stress in diabetes and the neural vasculature will be discussed.
Haplotype assembly in polyploid genomes and identical by descent shared tracts (2013)

Supplementary data are available at Bioinformatics online.
A 30-Week Randomized Controlled Trial of High-Dose Tacrine in Patients With Alzheimer's Disease (1994)

Tacrine produced statistically significant, dose-related improvements on objective performance-based tests, clinician- and caregiver-rated global evaluations, and measures of quality of life. There was no evidence that the large number of patient withdrawals biased the overall conclusions of the study.
Characterization of contact module failure mechanisms for SOI technology using E-beam inspection and in-line TEM (2010)

Electron-beam inspection (eBI) of the contact (CA) module for silicon-on-insulator (SOI) technology is discussed in this paper. Voltage contrast is used to detect CA opens in the SRAM and both CA opens and shorts in special test structures. The inspection is performed after the tungsten chemical mechanical planarization (W CMP) step. In-line transmission electron microscope (TEM) samples at select defect sites are then prepared and imaged to determine the failure mechanism. This methodology greatly enhances yield learning and provides quick feedback for lithography and etch process adjustments.
Loss of transcriptional activity of a transgene is accompanied by DNA methylation and histone deacetylation and is prevented by insulators (1998)

The constitutive DNase I hypersensitive site at the 5' end of the chicken beta-globin locus marks the boundary of the active chromatin domain in erythroid cells. The DNA sequence containing this site has the properties of an insulator, as shown by its ability in stable transformation experiments to block enhancer-promoter interaction when it lies between the two, but not when it lies outside, and to protect against position effects in Drosophila. We now show that the chicken insulator can protect a stably integrated gene, which is otherwise subject to great variability of expression, from chromatin-mediated repression in cell culture. When the integrated reporter gene is surrounded by insulator elements, stably transformed cell lines display consistent enhancer-dependent expression levels, in accord with the strength of the enhancer. In the absence of insulators, long-term nonselective propagation of cells carrying the integrated reporter gene results in gradual extinction of the reporter's expression, with expression patterns from tandemly repeated inserted genes suggesting that the extinction of adjacent genes is coupled. We show that the uninsulated reporter genes, in addition to becoming transcriptionally inactive, lose several epigenetic hallmarks of active chromatin, including nuclease accessibility, DNA hypomethylation, and histone hyperacetylation during time in culture. Treatment with inhibitors of histone deacetylase or DNA methylation reverses the extinction of the uninsulated genes. Extinction is completely prevented by flanking the reporter construct with insulators. Furthermore, in contrast to the uninsulated reporter genes, chromatin over the insulated genes retains nuclease accessibility and histone hyperacetylation. However, there is no clear correlation between the presence of the insulators and the level of DNA methylation. This leads us to propose a model for the insulator's ability to protect against extinction in the transformed cell lines and to function as a chromatin boundary for the chicken beta-globin locus in normal erythroid cells.
Über 4‐Merkaptoverbindungen des 2‐Methylpyridins (1960)

Abstract Ausgehend von dem 2‐Methylpyridin wird ein mit guter Gesamtausbeute verlaufender Weg zu dem 4‐Merkapto‐2‐methyl‐pyridin bzw. subst. N‐oxyden und dem Disulfid beschrieben. Einige Methoden zur Darstellung von 4‐Alkylmerkapto‐2‐methylpyridinen und deren N‐oxyden werden verglichen und die jeweils günstigsten Bedingungen für ihre Synthese ermittelt. Durch Oxydation wurden aus einem Glied der Reihe sowohl die Sulfonyl‐Verbindung als auch das Sulfonyl‐N‐oxyd dargestellt.
Secreted Frizzled-related Protein-1 Binds Directly to Wingless and Is a Biphasic Modulator of Wnt Signaling (2000)

Secreted Frizzled-related protein-1 (sFRP-1) contains a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzleds. To facilitate the biochemical and biological analysis of sFRP-1, we developed a mammalian recombinant expression system that yields approximately 3 mg of purified protein/liter of conditioned medium. Using this recombinant protein, we demonstrated that sFRP-1 and Wg (wingless) interact in enzyme-linked immunosorbent and co-precipitation assays. Surprisingly, a derivative lacking the cysteine-rich domain retained the ability to bind Wg. Cross-linking experiments performed with radioiodinated sFRP-1 provided definitive evidence that sFRP-1 and Wg bind directly to each other. Besides detecting a cross-linked complex consistent in size with 1:1 stoichiometry of sFRP-1 and Wg, we also observed a larger complex whose size suggested the presence of a second sFRP-1 molecule. The formation of both complexes was markedly enhanced by an optimal concentration of exogenous heparin, emphasizing the potential importance of heparan-sulfate proteoglycan in Wnt binding and signaling. sFRP-1 exerted a biphasic effect on Wg activity in an armadillo stabilization assay, increasing armadillo level at low concentrations but reducing it at higher concentrations. These results provide new insights about the Wnt binding and biological activity of sFRPs.
Pharmacokinetics of an Implanted Osmotic Pump Delivering Sufentanil for the Treatment of Chronic Pain (2003)

An implantable osmotic pump delivered sufentanil in vivo at the rate predicted from in vitro experiments. The rate at which sufentanil was absorbed from the subcutaneous space (half-life > 16 h) was markedly slower than reported with subcutaneous or intramuscular administration of large volumes of dilute opioids; this slow absorption dampens potential changes in Cp if release rate is perturbed.
Elevated source/drain MOSFET (1984)

The fabrication of both n- and p-channel MOSFET's with the souce/drain regions elevated above the electrical channel is described. The realization of effective shallow junctions is demonstrated and the device properties are compared to those of conventional MOSFET's.
DOWNY MILDEW RESISTANT 6 and DMR6‐LIKE OXYGENASE 1 are partially redundant but distinct suppressors of immunity in Arabidopsis (2014)

Arabidopsis downy mildew resistant 6 (dmr6) mutants have lost their susceptibility to the downy mildew Hyaloperonospora arabidopsidis. Here we show that dmr6 is also resistant to the bacterium Pseudomonas syringae and the oomycete Phytophthora capsici. Resistance is accompanied by enhanced defense gene expression and elevated salicylic acid levels. The suppressive effect of the DMR6 oxygenase was confirmed in transgenic Arabidopsis lines overexpressing DMR6 that show enhanced susceptibility to H. arabidopsidis, P. capsici, and P. syringae. Phylogenetic analysis of the superfamily of 2-oxoglutarate Fe(II)-dependent oxygenases revealed a subgroup of DMR6-LIKE OXYGENASEs (DLOs). Within Arabidopsis, DMR6 is most closely related to DLO1 and DLO2. Overexpression of DLO1 and DLO2 in the dmr6 mutant restored the susceptibility to downy mildew indicating that DLOs negatively affect defense, similar to DMR6. DLO1, but not DLO2, is co-expressed with DMR6, showing strong activation during pathogen attack and following salicylic acid treatment. DMR6 and DLO1 differ in their spatial expression pattern in downy mildew-infected Arabidopsis leaves; DMR6 is mostly expressed in cells that are in contact with hyphae and haustoria of H. arabidopsidis, while DLO1 is expressed mainly in the vascular tissues near infection sites. Strikingly, the dmr6-3_dlo1 double mutant, that is completely resistant to H. arabidopsidis, showed a strong growth reduction that was associated with high levels of salicylic acid. We conclude that DMR6 and DLO1 redundantly suppress plant immunity, but also have distinct activities based on their differential localization of expression.
Fluoro-Jade B Stains Quiescent and Reactive Astrocytes in the Rodent Spinal Cord (2003)

In an attempt to label dying neurons in the injured spinal cord, we used the novel fluorescein derivative Fluoro-Jade B, which has been reported to specifically label dead or dying neurons in the brain. Rats and mice were subjected to a moderate level of spinal cord injury using an IH impact device and sacrificed at 1, 2, 4, 7, 14, and 21 days post injury. Spinal cord tissue was processed for Fluoro-Jade B histochemistry and included sections throughout the injured region of the cord. No Fluoro-Jade positive neurons were observed in sections from any time point postinjury at any level of the spinal cord. Instead, Fluoro-Jade labeled astrocytes in uninjured control animals and injured animals. The specificity of astrocytic staining was confirmed by co-localizaton of Fluoro-Jade with glial fibrillary acidic protein. We also subjected a group of rats to a sequential cortical contusion injury and spinal cord injury. Sections from these animals showed numerous Fluoro-Jade positive neurons in the hippocampal formation and thalamus underlying the cortical contusion; however, the staining pattern in the spinal cord was identical to those animals that had received spinal cord injury alone.
Bivalent Ligands That Target μ Opioid (MOP) and Cannabinoid1 (CB1) Receptors Are Potent Analgesics Devoid of Tolerance (2013)

Given that μ opioid (MOP) and canabinoid (CB1) receptors are colocalized in various regions of the central nervous system and have been reported to associate as heteromer (MOP-CB1) in cultured cells, the possibility of functional, endogenous MOP-CB1 in nociception and other pharmacologic effects has been raised. As a first step in investigating this possibility, we have synthesized a series of bivalent ligands 1-5 that contain both μ agonist and CB1 antagonist pharmacophores for use as tools to study the functional interaction between MOP and CB1 receptors in vivo. Immunofluorescent studies on HEK293 cells coexpressing both receptors suggested 5 (20-atom spacer) to be the only member of the series that bridges the protomers of the heteromer. Antinociceptive testing in mice revealed 5 to be the most potent member of the series. As neither a mixture of monovalent ligands 9 + 10 nor bivalents 2-5 produced tolerance in mice, MOR-CB1 apparently is not an important target for reducing tolerance.
The Illusion of Life: Disney Animation (1995)

That being said, the book does contain information that deals in all facets of animation, and, sometimes, on the wider scale of dramatic and literary techniques relating to the visual medium. Since animation is essentially a unification of film, acting, drawing, and writing, techniques from all four are important. This book does contain the twelve principles of animation essentially, several key elements to any good animation, which are employed by any good animator, in anything from Disneys Steamboat Willie to Pixars Up.