gebhart/patrepeval huggingface dataset:
Towards a roadmap in brain protection and recovery (2012)

This article briefly reviews some of the mechanisms involved in the pathogenesis of neurological diseases, i.e. damage mechanisms (DM), and their interactions and overlap with protection and reparatory processes (i.e. endogenous defence activities). A relationship between DM and endogenous defence activity (EDA) regarding therapy principles will also be described. Currently, it is difficult to find the correct therapeutic approach for brain protection and recovery, especially because we do not fully understand all of the endogenous neurobiological processes, the complete nature of the pathophysiological mechanisms and the links between these two categories. Moreover, we continue to use a simplistic and reductionist approach in this respect. Endogenous neurobiological processes, such as neurotrophicity, neuroprotection, neuroplasticity and neurogenesis, are central to protection and recovery and represent the background of EDA. The biological reality of the nervous system is far more complex. In fact, there is an endogenous holistic process of neuroprotection and neurorecovery that should be approached therapeutically in an integrated way. The current tendency to exclusively frame drug activity in terms of single mechanisms and single focus effect might distract from other paradigms with greater explanatory power and hinder the development of more effective treatment strategies. A change of concept is required in pharmacological brain protection and recovery. Prospective considerations include an integrated pharmacological approach, focusing on drugs with multimodal activity and pleiotropic neuroprotective effect which are biological drugs, rather than single mechanism drugs, which usually are chemical drugs.
Identification of Target Genes Regulated by the Two-Component System HP166-HP165 of Helicobacter pylori (2002)

Two-component systems are signal transduction systems which enable bacteria to regulate cellular functions in response to changing environmental conditions. In most cases regulation is accomplished on the transcriptional level by a response regulator protein, which, according to the phosphorylation state of its receiver domain, displays different affinities for its target promoters. Here we describe identification of genes regulated by the two-component system HP166-HP165 of Helicobacter pylori and characterization of the corresponding target promoters. We demonstrated that expression of the HP166-HP165 two-component system is negatively autoregulated under conditions favoring autophosphorylation of the histidine kinase. Furthermore, we found that response regulator HP166 activates transcription of genes encoding a protein family with an unknown function present in H. pylori 26695, as well as an operon composed of five H. pylori-specific genes. While open reading frame HP166 is an essential gene, the target genes of the response regulator are not required for growth under in vitro culture conditions.
Synaptic vesicle endocytosis mediates the entry of tetanus neurotoxin into hippocampal neurons (1996)

Tetanus neurotoxin causes the spastic paralysis of tetanus by blocking neurotransmitter release at inhibitory synapses of the spinal cord. This is due to the penetration of the toxin inside the neuronal cytosol where it cleaves specifically VAMP/synaptobrevin, an essential component of the neuroexocytosis apparatus. Here we show that tetanus neurotoxin is internalized inside the lumen of small synaptic vesicles following the process of vesicle reuptake. Vesicle acidification is essential for the toxin translocation in the cytosol, which results in the proteolytic cleavage of VAMP/ synaptobrevin and block of exocytosis.
Evaluation of live avian-human reassortant influenza A H3N2 and H1N1 virus vaccines in seronegative adult volunteers (1986)

An avian-human reassortant influenza A virus deriving its genes coding for the hemagglutinin and neuraminidase from the human influenza A/Washington/897/80 (H3N2) virus and its six "internal" genes from the avian influenza A/Mallard/NY/6750/78 (H2N2) virus (i.e., a six-gene reassortant) was previously shown to be safe, infectious, nontransmissible, and immunogenic as a live virus vaccine in adult humans. Two additional six-gene avian-human reassortant influenza viruses derived from the mating of wild-type human influenza A/California/10/78 (H1N1) and A/Korea/1/82 (H3N2) viruses with the avian influenza A/Mallard/NY/78 virus were evaluated in seronegative (hemagglutination inhibition titer, less than or equal to 1:8) adult volunteers for safety, infectivity, and immunogenicity to determine whether human influenza A viruses can be reproducibly attenuated by the transfer of the six internal genes of the avian influenza A/Mallard/NY/78 virus. The 50% human infectious dose was 10(4.9) 50% tissue culture infectious doses for the H1N1 reassortant virus and 10(5.4) 50% tissue culture infectious doses for the H3N2 reassortant virus. Both reassortants were satisfactorily attenuated with only 5% (H1N1) and 2% (H3N2) of infected vaccines receiving less than 400 50% human infectious doses developing illness. Consistent with this level of attenuation, the magnitude of viral shedding after inoculation was reduced 100-fold (H1N1) to 10,000-fold (H3N2) compared with that produced by wild-type virus. The duration of virus shedding by vaccines was one-third that of controls receiving wild-type virus. At 40 to 100 50% human infectious doses, virus-specific immune responses were seen in 77 to 93% of volunteers. When vaccinees who has received 10(7.5) 50% tissue culture infectious doses of the H3N2 vaccine were experimentally challenged with a homologous wild-type human virus only 2 of 19 (11%) vaccinees became ill compared with 7 of 14 (50%) unvaccinated seronegative controls ( P < 0.025; protective efficacy, 79%). Thus, three different virulent human influenza A viruses have been satisfactorily attenuated by the acquisition of the six internal genes of the avian influenza A/Mallard/NY/78 virus. The observation that this donor virus can reproducibly attenuate human influenza A viruses indicates that avian-human influenza A reassortants should be further studied as potential live influenza A virus vaccines.
The main function of IL-2 is to promote the development of T regulatory cells (2003)

Based primarily on vitro studies, interleukin (IL)-2 has been considered a key growth and death factor for antigen-activated T lymphocytes. IL-2 is also essential to maintain self-tolerance, as IL-2- and IL-2 receptor-deficient mice exhibit lethal autoimmunity. The intrinsic death-sensitizing activity of IL-2 was thought to be a key mediator for apoptosis of peripheral autoreactive T cells. However, recent in vivo studies strongly favor a model whereby IL-2 controls autoimmunity through the production of CD4+CD25+ T regulatory (Treg) cells. In this setting, IL-2 is essential for expansion of Treg cells within the thymus and in peripheral neonatal-immune tissue. Thus, from being considered the primary growth factor for antigen-activated T lymphocytes, these new findings redefine the pivotal role for IL-2 as the major inducer for the developmental production of suppressive Treg cells.
Diffractive Optical Elements for Passive Infrared Detectors (2000)

Complex diffractive lens arrays for passive infrared detection systems have been designed and fabricated by laser beam writing and injection moulding. Continuous relief profiles with depths up to 20 µm were originated, characterised and replicated.
Electrophoretic resolution of the ‘major outer membrane protein’ of Escherichia coli K12 into four bands (1975)

The cell envelope of Enterobacteriaceae consists of&#13;\ntwo membranes separated by a peptidoglycan layer.&#13;\nMethods have been developed to separate the cytoplasmic&#13;\nmembrane from the outer membrane.&#13;\nThe outer membrane of Escherichia coli contains 60%&#13;\nof the envelope protein. Using polyacrylamide&#13;\ngelelectrophoresis, Schnaitman found six protein&#13;\nbands in the outer membrane fraction, of which one&#13;\nband (mol. wt 44 000) accounted for 70% of the total&#13;\nouter membrane protein.
Advanced integrated-circuit reliability simulation including dynamic stress effects (1992)

A systematic approach to predict semiconductor degradation effects using reliability simulation is described. The DC degradation monitor is first extracted during transient circuit simulation. An AC degradation factor is then used to determine circuit performance degradation. By using these techniques on the design of CMOS components, proper long-term reliability can be achieved for high-speed circuits. Experimental results on digital circuits using an industrial submicrometer technology demonstrate the effectiveness of this approach in reliable VLSI circuit design. Results on two-input NAND gates, DRAM precharging circuit, and SRAM control circuits are presented.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Olefin Metathesis with 1,1-Difluoroethylene (2001)

Unsaturated halocarbene complexes can be synthesized in the first example of olefin metathesis with a directly fluorinated substrate. The ruthenium catalyst 1 reacts with 1,1-difluoroethylene to yield the corresponding methylidene [Ru]=CH2 (2) and difluorocarbene [Ru]=CF2 complexes (3). H2IMes=1,3-dimesityl-4,5-dihydroimidazol-2-ylidene; Cy=cyclohexyl.
Small-Molecule Ghrelin Receptor Antagonists Improve Glucose Tolerance, Suppress Appetite, and Promote Weight Loss (2007)

Ghrelin, through action on its receptor, GH secretagogue receptor type 1a (GHS-R1a), exerts a variety of metabolic functions including stimulation of appetite and weight gain and suppression of insulin secretion. In the present study, we examined the effects of novel small-molecule GHS-R1a antagonists on insulin secretion, glucose tolerance, and weight loss. Ghrelin dose-dependently suppressed insulin secretion from dispersed rat islets. This effect was fully blocked by a GHS-R1a antagonist. Consistent with this observation, a single oral dose of a GHS-R1a antagonist improved glucose homeostasis in an ip glucose tolerance test in rat. Improvement in glucose tolerance was attributed to increased insulin secretion. Daily oral administration of a GHS-R1a antagonist to diet-induced obese mice led to reduced food intake and weight loss (up to 15%) due to selective loss of fat mass. Pair-feeding experiments indicated that weight loss was largely a consequence of reduced food intake. The impact of a GHS-R1a antagonist on gastric emptying was also examined. Although the GHS-R1a antagonist modestly delayed gastric emptying at the highest dose tested (10 mg/kg), delayed gastric emptying does not appear to be a requirement for weight loss because lower doses produced weight loss without an effect on gastric emptying. Consistent with the hypothesis that ghrelin regulates feeding centrally, the anorexigenic effects of potent GHS-R1a antagonists in mice appeared to correspond with their brain exposure. These observations demonstrate that GHS-R1a antagonists have the potential to improve the diabetic condition by promoting glucose-dependent insulin secretion and promoting weight loss.
Enzyme Markers for the Presence of Circulating Interferon: 2-5A Synthetase in Blood Lymphocytes and Protein Kinase in Platelet-Rich Plasma (1984)

The level of 2-5A synthetase in extracts of peripheral blood lymphocytes and a specific protein kinase activity in platelet-rich plasma were measured in normal individuals and in patients suffering from viral or bacterial infections. The level of these enzymes was tested at different times during the disease. The level of 2-5A synthetase and the protein kinase activity was enhanced by several-fold during viral and bacterial infections and decreased during the course of the disease in parallel with clinical ameliorations and reversal of clinical symptoms. Among the different types of infections studied, higher levels of these enzymes were observed during viral than bacterial infections. Our results emphasize the use of these enzymes as markers to evaluate the state of the disease and recovery. Furthermore, they provide evidence for the production of interferon during different types of infection.
Toward Cocaine Esterase Therapeutics (2005)

Cocaine is among the most reinforcing of all drugs of abuse, yet no effective pharmacotherapy is available. Herein, we report the development and characterization of phage-displayed cocaine esterases with pharmacologically relevant kinetic parameters (kcat/Km approximately 104 M-1 s-1).
Agent-Agnostic Human-in-the-Loop Reinforcement Learning (2017)

Providing Reinforcement Learning agents with expert advice can dramatically improve various aspects of learning. Prior work has developed teaching protocols that enable agents to learn efficiently in complex environments; many of these methods tailor the teacher's guidance to agents with a particular representation or underlying learning scheme, offering effective but specialized teaching procedures. In this work, we explore protocol programs, an agent-agnostic schema for Human-in-the-Loop Reinforcement Learning. Our goal is to incorporate the beneficial properties of a human teacher into Reinforcement Learning without making strong assumptions about the inner workings of the agent. We show how to represent existing approaches such as action pruning, reward shaping, and training in simulation as special cases of our schema and conduct preliminary experiments on simple domains.
An immunodominant epitope of the human immunodeficiency virus envelope glycoprotein gp160 recognized by class I major histocompatibility complex molecule-restricted murine cytotoxic T lymphocytes. (1988)

Because cytotoxic T lymphocytes (CTL) may be important for preventing direct cell-to-cell transmission of human immunodeficiency virus (HIV), the agent responsible for acquired immunodeficiency syndrome, we have begun to investigate the epitope specificity and immune response (Ir) gene control of anti-HIV CTL responses in experimental animals. Mice were infected with a recombinant vaccinia virus expressing the HIV gp160 envelope gene, and the primed lymphocytes were restimulated in vitro with a transfected histocompatible cell line expressing the same gene. Our results show that H-2d mice are CTL high responders and H-2k mice are low responders to the HIV gp160 envelope protein under these conditions. Moreover, the H-2d mice respond predominantly to a single immunodominant site represented by a 15-residue synthetic peptide conforming to the amphipathic alpha-helix model of T-cell epitopes and seen by CD4- CD8+ CTL in association with the Dd class I major histocompatibility complex (MHC) molecules. The facts that CTL responses were detected in the context of only one of four class I MHC molecules tested and that the response was limited predominantly to a single epitope indicate that the CTL repertoire elicited by the HIV envelope protein in association with murine class I MHC molecules may be very limited. In addition, this epitope occurs in a highly variable segment of the envelope protein. This puts constraints on the use of a single peptide sequence from this region in a vaccine, as such a vaccine would have to be polyvalent. Nevertheless, this same variability suggests that this region may be under selective pressure from human CTL, and therefore that this site may be immunodominant in humans as well as mice and so of clinical importance in vaccine development.
Selective Chemical Imaging of Static Actin in Live Cells (2012)

We have characterized rationally designed and optimized analogues of the actin-stabilizing natural products jasplakinolide and chondramide C. Efficient actin staining was achieved in fixed permeabilized and non-permeabilized cells using different combinations of dye and linker length, thus highlighting the degree of molecular flexibility of the natural product scaffold. Investigations into synthetically accessible, non-toxic analogues have led to the characterization of a powerful cell-permeable probe to selectively image static, long-lived actin filaments against dynamic F-actin and monomeric G-actin populations in live cells, with negligible disruption of rapid actin dynamics.
Paired Overexpression of ErbB3 and Sox10 in Pilocytic Astrocytoma (2006)

Pilocytic astrocytoma (PA) is the most common glioma of childhood. Despite their relatively high incidence, the molecular mechanisms responsible for tumorigenesis and growth of PA are poorly understood. Previous in vitro studies in our laboratory showed that despite the absence of ErbB1, PA was sensitive to ErbB1 tyrosine kinase inhibitor gefitinib. To identify alternative targets of gefitinib in PA, we studied other members of the ErbB receptor tyrosine kinase family that have been identified in brain tumors. Using gene expression microarray and Western blot analyses, we found that ErbB3 is highly overexpressed in PA compared with other pediatric brain tumors (glioblastoma, ependymoma, medulloblastoma, atypical teratoid/rhabdoid tumor, and choroid plexus papilloma). Developmental biology studies have identified Sox10 as a regulator of ErbB3 expression during development of the neural crest. Investigation of Sox10 in PA revealed that it is highly overexpressed relative to other pediatric brain tumors, lending support to the theory that Sox10-regulated overexpression of ErbB3 may be driving growth in PA. Sox10-regulated ErbB3 overexpression is a novel insight into the biology of PA, suggests possible recapitulation of developmental pathways in tumorigenesis, and presents possible targets for therapeutic intervention that might be used for hypothalamic variants not amenable to surgical cure.
The Dynamic Impact of CpG Methylation in DNA (2000)

Solid-state deuterium NMR is used to investigate perturbations of the local, internal dynamics in the EcoRI restriction binding site, -GAATTC- induced by cytidine methylation. Methylation of the cytidine base in this sequence is known to suppress hydrolysis by the EcoRI restriction enzyme. Previous solid-state deuterium NMR studies have detected large amplitude motions of the phosphate-sugar backbone at the AT-CG junction of the unmethylated DNA sequence. This study shows that methylation of the cytidine base in a CpG dinucleotide reduces the amplitudes of motions of the phosphate-sugar backbone. These observations suggest a direct link between suppression of the amplitudes of localized, internal motions of the sugar-phosphate backbone of the DNA and inhibition of restriction enzyme cleavage.
Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor (2008)

Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, also alters vascular patterning. Here we show that Sema3A selectively interferes with VEGF- but not bFGF-induced angiogenesis in vivo. Consistent with this, Sema3A disrupted VEGF- but not bFGF-mediated endothelial cell signaling to FAK and Src, key mediators of integrin and growth factor signaling; however, signaling to ERK by either growth factor was unperturbed. Since VEGF is also a vascular permeability (VP) factor, we examined the role of Sema3A on VEGF-mediated VP in mice. Surprisingly, Sema3A not only stimulated VEGF-mediated VP but also potently induced VP in the absence of VEGF. Sema3A-mediated VP was inhibited either in adult mice expressing a conditional deletion of endothelial neuropilin-1 (Nrp-1) or in wild-type mice systemically treated with a function-blocking Nrp-1 antibody. While both Sema3A- and VEGF-induced VP was Nrp-1 dependent, they use distinct downstream effectors since VEGF- but not Sema3A-induced VP required Src kinase signaling. These findings define a novel role for Sema3A both as a selective inhibitor of VEGF-mediated angiogenesis and a potent inducer of VP.
Human Symbionts Use a Host-Like Pathway for Surface Fucosylation (2005)

The mammalian intestine harbors a beneficial microbiota numbering approximately 10(12) organisms per gram of colonic content. The host tolerates this tremendous bacterial load while maintaining the ability to efficiently respond to pathogenic organisms. In this study, we show that the Bacteroides use a mammalian-like pathway to decorate numerous surface capsular polysaccharides and glycoproteins with l-fucose, an abundant surface molecule of intestinal epithelial cells, resulting in the coordinated expression of this surface molecule by host and symbiont. A Bacteroides mutant deficient in the ability to cover its surface with L-fucose is defective in colonizing the mammalian intestine under competitive conditions.
Control of Recombination Pathways in TiO2 Nanowire Hybrid Solar Cells Using Sn4+ Dopants (2014)

Hybrid nanostructures have shown increasing potential as a replacement for Si solar cells due to the availability of low-cost material combinations. However, up to now, hybrid solar cells, where photon absorption occurs in a semiconducting polymer and charge separation occurs at a metal oxide-polymer interface, show limited efficiencies. One limitation is caused by a relative low charge carrier mobility in the metal oxide. Here we addressed this issue and describe the use of a Sn:TiO2|TiO2 core–shell nanowire array to increase the charge-carrier mobility in the core of the nanowires while decreasing the charge-carrier recombination at the metal oxide–polymer interface due to fast electron extraction from this interface, driven by a cascaded conduction band energy from shell to core of the nanowires. These doped cores with an undoped shell structure resulted in impressive efficiency improvement in hybrid solar cells of 33% over the reference TiO2-based device. Additionally, this device structure resulted in a 17% increase in recombination lifetimes based on both photovoltage decay measurements and impedance spectroscopy. Recombination mechanisms are proposed for the core and core–shell systems to highlight the various effects of the Sn4+-doped TiO2 nanowire arrays. Doped core–shell structures have the potential for application in the hybrid-type devices without the limitations that are seen with the current dual metal oxide structures due to the seamless interface of the metal oxide host for direct transport of the electrons into the highly mobile core material.