gebhart/patrepeval huggingface dataset:
A Systems-Level Framework for Drug Discovery Identifies Csf1R As A Novel Anti-Epileptic Drug Target (2017)

ABSTRACT The identification of mechanistically novel drug targets is highly challenging, particularly for diseases of the central nervous system. To address this problem we developed and experimentally validated a new computational approach to drug target identification that combines gene-regulatory information with a causal reasoning framework (“causal reasoning analytical framework for target discovery” – CRAFT). Starting from gene expression data, CRAFT provides a predictive functional genomics framework for identifying membrane receptors with a direction-specified influence over network expression. As proof-of-concept we applied CRAFT to epilepsy, and predicted the tyrosine kinase receptor Csf1R as a novel therapeutic target for epilepsy. The predicted therapeutic effect of Csf1R blockade was validated in two pre-clinical models of epilepsy using a small molecule inhibitor of Csf1R. These results suggest Csf1R blockade as a novel therapeutic strategy in epilepsy, and highlight CRAFT as a systems-level framework for predicting mechanistically new drugs and targets. CRAFT is applicable to disease settings other than epilepsy.
Reversible zwitterionic liquids, the reaction of alkanol guanidines, alkanol amidines, and diamines with CO2 (2010)

Alkanolamidines, alkanolguanidines and diamines each react with CO2 to form reversible zwitterionic liquids. CO2 is chemically bound to the alcohol on alkanolamidines and alkanolguanidines as zwitterionic alkylcarbonates, while CO2 is chemically bound on diamines as zwitterionic carbamates. All three classes of zwitterionic liquids could be reverted to their non-ionic forms by thermally stripping the CO2 at temperatures near 50 °C, while one derivative was found to irreversibly form a cyclic carbonate.
Effects of finite laser coherence in quasielastic multiple scattering (1991)

We have studied the amplitude and temporal correlations of intensity fluctuations of multiply scattered light transmitted through a colloidal suspension. When the coherence length ${\mathit{l}}_{\mathit{c}}$ of the incident light becomes comparable to the width of the probability distribution of photon-path lengths, both the amplitude and dynamics of intensity fluctuations become functions of ${\mathit{l}}_{\mathit{c}}$. In this article we present a simple theory that relates these coherence effects to the photon path-length distribution P(L). We have tested this theory using P(L) calculated from computer simulations and from the diffusion approximation, and find that our theory qualitatively accounts for the observed dependences on coherence length. Our results indicate when the effects of finite laser coherence must be taken into account in quasielastic multiple scattering. In the few-scattering regime of quasielastic multiple scattering, we find that the intensity autocorrelation function generally has a stretched-exponential form, and we discuss the origin of this behavior.
Radiation enteropathy and leucocyte-endothelial cell reactions in a refined small bowel model (2004)

This study presents a refinement of a previous method of examining mechanisms of radiation enteropathy, and a new approach at investigating radiation induced leucocyte responses in the ileal microcirculation. Radiation induced maximum leucocyte rolling at 2 hours and adhesion peaked at 16 hours. It also reduces the microflora count, which then starts to increase steadily afterwards. This model may be instrumental in developing strategies against pathological recruitment of leucocytes and changes in intestinal microflora in the small bowel after radiotherapy.
Impairment and delay of neutralizing antiviral antibody responses by virus-specific cytotoxic T cells. (1993)

After infection with some viruses that tend to persist, neutralizing antibodies are generated rather late, i.e., after 1 to 3 mo. This has been observed for HIV, Hepatitis B infection in man, or after infection with lymphocytic choriomeningitis virus (LCMV) in mice. In contrast, nonneutralizing antibodies to LCMV are generated by day 7 and reach high titers by day 10. This study attempts to evaluate reasons for late and low titered neutralizing antibody responses. After a primary infection with low doses (10(2) plaque forming units) of the poorly cytopathic LCMV-WE, neutralizing antibodies were rarely produced at detectable levels before days 60 to 120. In vivo depletion of CD8+ CTL led to a marked enhancement and acceleration of kinetics of the neutralizing antibody response. In contrast, nonneutralizing antibodies, including those specific for LCMV-GP carrying the neutralizing determinant, were detectable very early, i.e., 4 to 7 days after infection, with maximum titers usually by day 10 irrespective of the presence or absence of CTL. Mice completely lacking CD8+ T cells because of deletion by homologous recombination (CD8-/-) also exhibited neutralizing antibodies early by day 10 to 20, and by day 120 reached very high titers. The neurotropic isolate LCMV-ARMSTRONG induced low but significant titers of neutralizing antibodies relatively early (i.e., by days 7 to 10), whereas the lympho-viscerotrope mutant virus LCMV-ARMSTRONG Cl-13 did not. Early and effective CTL responses causing immunopathology (and immunosuppression) correlated with the absence of neutralizing antibodies. The discrepancy between the CTL-dependent inhibition of neutralizing versus unimpaired anti-GP ELISA responses cannot be explained by different Ag doses alone. Additionally, it may reflect different kinetics of the responses, whereby the later neutralizing responses possibly requiring IgG affinity maturation may be more susceptible to general immunosuppression; also B cells expressing neutralizing receptors, but not those with antibodies binding GP (or NP), may be actively infected, therefore they present viral peptides on class I MHC Ag and may become targets for anti-LCMV-specific CTL.
Optimizing Horizontal Completion Techniques in the Barnett Shale Using Microseismic Fracture Mapping (2004)

Abstract The Barnett Shale of North Texas is an ultra low permeability reservoir that must be effectively fracture stimulated in order to obtain commercial production. As a result, techniques to optimize hydraulic fracturing effectiveness have evolved over the past decade. The first Barnett Shale "discovery" well, the C.W. Slay #1, was drilled in 1981 and it was almost 17 years before any significant commercial success was found in the Barnett, so the Barnett is a relatively new play. In fact, 75% of the producing wells in the Barnett have been drilled since 2000. In 1995, when the USGS was performing a gas in place assessment of the significant gas fields in the United States, the Barnett was not even evaluated. In 2002, according to the Energy Information Administration, the Newark East Field produced 202 Bcf, more than any other field in Texas, and was the 7th largest gas producer in the United States! In some areas of the Barnett, horizontal drilling has recently been applied in an attempt to optimize gas production. Issues such as nearby water bearing intervals, inadequate surface locations, improved gas production rates and cost per scf can, in some cases, be addressed by the use of horizontal wellbores. The goal is to maximize fracture network surface area in the targeted pay intervals, and in some areas, reduce the probability of excessive fracture height growth. Several horizontal completion techniques have recently been utilized, including single and multiple stage treatments with multiple perforation clusters in uncemented casing and multiple stage treatments performed in cemented perforated casing. In order to understand created fracture geometry for various completion designs, fracture treatments are often mapped with microseismic and tilt sensors. Production results from this pilot study of the first twenty-three horizontal wells in the same general "Core" area of the Fort Worth Basin are compared in addition to mapped fracture geometry from eleven of these with vertical wellbores. This paper will discuss drilling and completion strategies, look at fracture network areas obtained from each, and then compare and contrast the fracture effectiveness with the standard procedures used in vertical Barnett wells.
Synthesis and Biological Activity of Some New Diaryl Sulphones Containing Fused Thiazolo Pyrimidines (2001)

Abstract This paper describes the synthesis of some pyrimido[2,1‐ b ]benzothiazol‐8‐yl sulphones ( 7, 9, 11, 13, 14, 16 ) starting from bis[2‐aminobenzothiazol‐6‐yl)sulphone 1. Reaction of 1 with acetic anhydride and/or benzoyl chloride gave substituted amino derivatives 2a,b , whereas its reaction with phenacyl bromide and/or p ‐chlorophenacyl bromide gave imidazo benzothiazol‐7‐yl sulphones 4a,b .
Photocurrent in ZnO nanowires grown from Au electrodes (2004)

ZnO nanowires were grown between two Au electrodes on an Al2O3-deposited Si wafer. Photoresponse, photoresponse spectrum, and current–voltage (I–V) studies were performed for the investigation into photoconduction mechanism in these nanowires. The photoresponse of the nanowires under the continuous illumination of light with above- or below-gap energies was slow, which indicates that photocurrent in the nanowires is surface-related rather than bulk-related. The photoresponse spectrum represents the above- and below-gap absorption bands for the photocurrents. The I–V characteristics under the illumination of the above-gap light are ohmic, but the characteristics under the illumination of the below-gap light are Schottky. This observation indicates that the above-gap light lowers the potential barrier built in the contact between the ZnO nanowires and electrodes, but that the below-gap light does not lower the potential barrier.
Bifidobacterium longum Requires a Fructokinase (Frk; ATP: d -Fructose 6-Phosphotransferase, EC 2.7.1.4) for Fructose Catabolism (2004)

Although the ability of Bifidobacterium spp. to grow on fructose as a unique carbon source has been demonstrated, the enzyme(s) needed to incorporate fructose into a catabolic pathway has hitherto not been defined. This work demonstrates that intracellular fructose is metabolized via the fructose-6-P phosphoketolase pathway and suggests that a fructokinase (Frk; EC 2.7.1.4) is the enzyme that is necessary and sufficient for the assimilation of fructose into this catabolic route in Bifidobacterium longum. The B. longum A10C fructokinase-encoding gene (frk) was expressed in Escherichia coli from a pET28 vector with an attached N-terminal histidine tag. The expressed enzyme was purified by affinity chromatography on a Co(2+)-based column, and the pH and temperature optima were determined. A biochemical analysis revealed that Frk displays the same affinity for fructose and ATP (Km(fructose) = 0.739 +/- 0.18 mM and Km(ATP) = 0.756 +/- 0.08 mM), is highly specific for D-fructose, and is inhibited by an excess of ATP (>12 mM). It was also found that frk is inducible by fructose and is subject to glucose-mediated repression. Consequently, this work presents the first characterization at the molecular and biochemical level of a fructokinase from a gram-positive bacterium that is highly specific for D-fructose.
Humoral immunity to aerosolized staphylococcal enterotoxin B (SEB), a superantigen, in monkeys vaccinated with SEB toxoid-containing microspheres (1995)

Staphylococcal enterotoxin B (SEB) toxoid-containing microspheres were tested for efficacy in rhesus monkeys as a vaccine candidate for respiratory SEB toxicosis and toxic shock. Forty monkeys were randomly separated into 10 groups of four monkeys each: 9 groups were vaccinated with the microspheres via combinations of mucosal and nonmucosal routes, and 1 group served as nonvaccinated controls. Both vaccinated and nonvaccinated monkeys were then challenged with a high lethal dose of SEB aerosol. Monkeys primed with an intramuscular dose of the microspheres followed by an intratracheal booster all survived the SEB challenge. Overall, monkeys with an intratracheal booster generally had the highest antibody levels, which is consistent with their high survival rate and lower rate of illness. Protective immunity was correlated with antibody levels in both the circulation and the respiratory tract. The protection was not due to the depletion or anergy of SEB-reactive T cells, since SEB-induced proliferation in cultures of circulating lymphocytes was not significantly reduced after the microsphere vaccination. It is evident that the nonsurvivors did not die of systemic anaphylaxis or hypersensitivity because the monkeys did not die immediately after SEB challenge and there were no significant differences in histamine levels between the vaccinated and control monkeys before and after SEB challenge. The antibodies seemed to neutralize the SEB that got into the airway and the circulation.
Design strategies in mineralized biological materials (1997)

Organisms have been producing mineralized skeletons for the past 550 million years. They have evolved many different strategies for improving these materials at almost all hierarchical levels from Ångstroms to millimetres. Key components of biological materials are the macromolecules, which are intimately involved in controlling nucleation, growth, shaping and adapting mechanical properties of the mineral phase to function. One interesting tendency that we have noted is that organisms have developed several strategies to produce materials that have more isotropic properties. Much can still be learned from studying the principles of structure–function relations of biological materials. Some of this information may also provide new ideas for improved design of synthetic materials.
A Geometric Modeller Based on the Exact Octtree Representation of Polyhedra (1986)

Abstract Geometric Modellers based on a Boundary Representation scheme are well suited for display operations, but boolean operations require algorithms with quadratic complexity. Using a class of extended octtrees which is presented here, boolean operations become linear, while exact recomputation of the boundary model in the case of polyhedral objects is possible, and memory requirements are less than in classical octtree encodings. Some bounds on the memory savings are given and discussed. The DMI system, a Geometric Modeller based on a hybrid model Boundary ‐ Extended Octtrees, is presented, discussing the main operations and the interface between both models. Some modelling examples are shown. Finally, a generalization of the extended octtree encoding which allows the exact representation of objects limited by sculptured surfaces is presented.
On the Structure of Amorphous Calcium Carbonate—A Detailed Study by Solid-State NMR Spectroscopy (2008)

The calcium carbonate phases calcite, aragonite, vaterite, monohydrocalcite (calcium carbonate monohydrate), and ikaite (calcium carbonate hexahydrate) were studied by solid-state NMR spectroscopy ( (1)H and (13)C). Further model compounds were sodium hydrogencarbonate, potassium hydrogencarbonate, and calcium hydroxide. With the help of these data, the structure of synthetically prepared additive-free amorphous calcium carbonate (ACC) was analyzed. ACC contains molecular water (as H 2O), a small amount of mobile hydroxide, and no hydrogencarbonate. This supports the concept of ACC as a transient precursor in the formation of calcium carbonate biominerals.
Imidazo[4,5‐d]pyridazines. IV. Synthesis of 4,7 disubstituted derivatives and 1‐benzyl‐2‐substituted thio derivatives (1965)

Abstract Seventy‐five new imidazo[4,5‐d]pyridazines and three new imidazoles have been prepared for antitumor testing. Antitumor screening results are reported for thirty‐five of these compounds. No significant activity was observed.
Whole Genome Expression Differences in Human Left and Right Atria Ascertained by RNA Sequencing (2012)

There are significant differences in miRNA and mRNA expression profiles between the left and right atria, which may yield insight into increased the arrhythmogenesis of the left atria.
Secondary structure of the pentraxin female protein in water determined by infrared spectroscopy: effects of calcium and phosphorylcholine (1992)

The secondary structure of hamster female protein in aqueous solutions in the presence or absence of calcium and phosphorylcholine has been investigated using Fourier transform infrared spectroscopy. Our present studies provide the first evaluation of the secondary structure of FP and its calcium- and phosphorylcholine-dependent conformational changes. Quantitative analysis indicated that FP is composed of 50% beta-sheet, 11% alpha-helix, 29% beta-turn, and 10% random structures. Calcium- and phosphorylcholine-dependent infrared spectral changes were observed in regions assigned to beta-sheet, alpha-helix, turn, and random structures. The infrared-based secondary structure compositions were used as constraints to compute theoretical locations for the different secondary structures along the amino acid sequence of the FP protein. Two putative calcium-binding sites were proposed for FP (residues 93-109 and 150-168) as well as other members of the pentraxin family on the basis of the theoretical secondary structure predictions and the similarity in sequence between the pentraxins and EF-hand calcium-binding proteins. The changes in protein conformation detected upon binding of calcium and phosphorylcholine provide a mechanism for the effects of these ligands on physiologically important properties of the protein, e.g., activation of complement and association with amyloids.
Evolutionary Optimization of the Catalytic Properties of a DNA-Cleaving Ribozyme (1994)

In a previous study [Beaudry, A. A., & Joyce, G. F. (1992) Science 257, 635-641], an in vitro evolution procedure was used to obtain variants of the Tetrahymena ribozyme with 100-fold improved ability to cleave a target single-stranded DNA under physiologic conditions. Here we report continuation of the in vitro evolution process to achieve 10(5)-fold overall improvement in DNA-cleavage activity. In addition, we demonstrate that, by appropriate manipulation of the selection constraints, one can optimize specific catalytic properties of the evolved ribozymes. We first reduced the concentration of the DNA substrate 50-fold to favor ribozymes with improved substrate binding affinity. We then reduced the reaction time 12-fold to favor ribozymes with improved catalytic rate. In both cases, the evolving population responded as expected, first improving substrate binding 25-fold, and then improving catalytic rate about 50-fold. The population of ribozymes has undergone 27 successive generations of in vitro evolution, resulting in, on average, 17 mutations relative to the wild type that are responsible for the improved DNA-cleavage activity.
Aggregation of Secreted Amyloid β-Protein into Sodium Dodecyl Sulfate-stable Oligomers in Cell Culture (1995)

Filamentous aggregates of the 40-42-residue amyloid beta-protein (A beta) accumulate progressively in the limbic and cerebral cortex in Alzheimer's disease, where they are intimately associated with neuronal and glial cytopathology. Attempts to model this cytotoxicity in vitro using synthetic peptides have shown that monomeric A beta is relatively inert, whereas aggregated A beta reproducibly exerts a variety of neurotoxic effects. The processes that mediate the conversion of monomeric A beta into a toxic aggregated state are thus of great interest. Previous studies of this conversion have employed high concentrations (10(-5)-10(-3) M) of synthetic A beta peptides under nonbiological conditions. We report here the detection of small amounts (< 10(-9) M) of SDS-stable A beta oligomers in the culture media of Chinese hamster ovary cells expressing endogenous or transfected amyloid beta-protein precursor genes. The identity of these oligomers (primarily dimers and trimers) was established by immunoprecipitation with a panel of A beta antibodies, by electrophoretic comigration with synthetic A beta oligomers, and by amino acid sequencing. The oligomeric A beta species comprised approximately 10-20% of the total immunoprecipitable A beta in these cultures. A truncated A beta species beginning at Arg 5 was enriched in the oligomers, suggesting that amino-terminal heterogeneity can influence A beta oligomerization in this system. Addition of Congo red (10 microM) during metabolic labeling of the cells led to increased monomeric and decreased oligomeric A beta. The ability to detect and quantitate oligomers of secreted A beta peptides in cell culture should facilitate dynamic studies of the critical process of initial A beta aggregation under physiological conditions.
Imaging of discontinuities in the inverse scattering problem by inversion of a causal generalized Radon transform (1985)

This paper treats the linearized inverse scattering problem for the case of variable background velocity and for an arbitrary configuration of sources and receivers. The linearized inverse scattering problem is formulated in terms of an integral equation in a form which covers wave propagation in fluids with constant and variable densities and in elastic solids. This integral equation is connected with the causal generalized Radon transform (GRT), and an asymptotic expansion of the solution of the integral equation is obtained using an inversion procedure for the GRT. The first term of this asymptotic expansion is interpreted as a migration algorithm. As a result, this paper contains a rigorous derivation of migration as a technique for imaging discontinuities of parameters describing a medium. Also, a partial reconstruction operator is explicitly derived for a limited aperture. When specialized to a constant background velocity and specific source–receiver geometries our results are directly related to some known migration algorithms.
Overexpression of Prostate-Specific TMPRSS2(exon 0)-ERG Fusion Transcripts Corresponds with Favorable Prognosis of Prostate Cancer (2009)

The expression of TMPRSS2(exon 0)-ERG fusion transcripts in prostate cancer is associated with a less-aggressive biological behavior.
Heritability of nociception I: Responses of 11 inbred mouse strains on 12 measures of nociception (1999)

It is generally acknowledged that humans display highly variable sensitivity to pain, including variable responses to identical injuries or pathologies. The possible contribution of genetic factors has, however, been largely overlooked. An emerging rodent literature documents the importance of genotype in mediating basal nociceptive sensitivity, in establishing a predisposition to neuropathic pain following neural injury, and in determining sensitivity to pharmacological agents and endogenous antinociception. One clear finding from these studies is that the effect of genotype is at least partially specific to the nociceptive assay being considered. In this report we begin to systematically describe and characterize genetic variability of nociception in a mammalian species, Mus musculus. We tested 11 readily-available inbred mouse strains (129/J, A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C58/J, CBA/J, DBA/2J, RIIIS/J and SM/J) using 12 common measures of nociception. These included assays for thermal nociception (hot plate, Hargreaves' test, tail withdrawal), mechanical nociception (von Frey filaments), chemical nociception (abdominal constriction, carrageenan, formalin), and neuropathic pain (autotomy, Chung model peripheral nerve injury). We demonstrate the existence of clear strain differences in each assay, with 1.2 to 54-fold ranges of sensitivity. All nociceptive assays display moderate-to-high heritability (h2 = 0.30-0.76) and mediation by a limited number of apparent genetic loci. Data comparing inbred strains have considerable utility as a tool for understanding the genetics of nociception, and a particular relevance to transgenic studies.