gebhart/patrepeval huggingface dataset:
Carrageenan Inhibits Insulin Signaling through GRB10-mediated Decrease in Tyr(P)-IRS1 and through Inflammation-induced Increase in Ser(P)307-IRS1 (2015)

Inflammation induced by exposure to the common food additive carrageenan leads to insulin resistance by increase in Ser(P)(307)-insulin receptor substrate 1 (IRS1) and subsequent decline in the insulin-stimulated increase in Ser(P)(473)-AKT. Inhibition of carrageenan-induced inflammation reversed the increase in Ser(P)(307)-IRS1 but did not completely reverse the carrageenan-induced decline in Ser(P)(473)-AKT. To identify the additional mechanism responsible for the decrease in Ser(P)(473)-AKT, studies were performed in human HepG2 cells and in C57BL/6J mice. Following carrageenan, expression of GRB10 (growth factor receptor-bound 10 protein), an adaptor protein that binds to the insulin receptor and inhibits insulin signaling, increased significantly. GRB10 silencing blocked the carrageenan-induced reduction of the insulin-stimulated increase in Tyr(P)-IRS1 and partially reversed the decline in Ser(P)(473)-AKT. The combination of GRB10 silencing with BCL10 silencing and the reactive oxygen species inhibitor Tempol completely reversed the decline in Ser(P)(473)-AKT. After carrageenan, GRB10 promoter activity was enhanced because of activation by GATA2. A direct correlation between Ser(P)(473)-AKT and Ser(P)(401)-GATA2 was evident, and inhibition of AKT phosphorylation by the PI3K inhibitor LY294002 blocked Ser(401)-GATA2 phosphorylation and the increase in GRB10 expression. Studies indicated that carrageenan inhibited insulin signaling by two mechanisms: through the inflammation-mediated increase in Ser(P)(307)-IRS1, a negative regulator of insulin signaling, and through a transcriptional mechanism leading to increase in GRB10 expression and GRB10-inhibition of Tyr(P)-IRS1, a positive regulator of insulin signaling. These mechanisms converge to inhibit the insulin-induced increase in Ser(P)(473)-AKT. They provide internal feedback, mediated by Ser(P)(473)-AKT, Ser(P)(401)-GATA2, and nuclear GATA2, which links the opposing effects of serine and tyrosine phosphorylations of IRS1 and can modulate insulin responsiveness.
Cryopreservation of Human Hepatocytes Alters the Mitochondrial Respiratory Chain Complex 1 (2007)

Transplantation of human hepatocytes has recently been demonstrated as a safe alternative to partially correct liver inborn errors of metabolism. Cryopreservation remains the most appropriate way of cell banking. However, mitochondrial-mediated apoptosis has been reported after cryopreservation and little is known on the involved molecular mechanisms. The aim of this study was to investigate mitochondrial functions of freshly isolated and cryopreserved/thawed hepatocytes from mice and humans. We report here that cryopreservation induced a dramatic drop of ATP levels in hepatocytes. The oxygen consumption rate of cryopreserved/ thawed hepatocytes was significantly lower compared to fresh cells. In addition, the uncoupling effect of 2,4-dinitrophenol was lost, in parallel with a reduction of mitochondrial membrane potential. Furthermore, a decrease in mitochondrial respiratory rate was evidenced on permeabilized hepatocytes in the presence of substrate for the respiratory chain complex 1. Interestingly, this effect was less marked with a substrate for complex 2. Electron microscopy examination indicated that mitochondria were swollen and devoid of cristae after cryopreservation. These changes could explain the cytosolic release of the proapoptotic protein cytochrome c in cryopreserved cells. Nevertheless, no caspase 9-3 activation and only few apoptotic and necrotic cells were found, indicating that the subsequent cell death program was not yet evidenced. Our results demonstrate that cryopreservation of hepatocytes induced alteration of the mitochondrial machinery. They also suggest that, in addition to technical progress in the cryopreservation procedure, protection of the respiratory chain complex 1 should be considered to improve the quality of cryopreserved hepatocytes.
Importance of the Major Extracellular Domain of CD9 and the Epidermal Growth Factor (EGF)-like Domain of Heparin-binding EGF-like Growth Factor for Up-regulation of Binding and Activity (2000)

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a member of the EGF family of growth factors. The membrane-anchored form of HB-EGF (proHB-EGF) is mitogenically active to neighboring cells as well as being a precursor of the soluble form. In addition to its mitogenic activity, proHB-EGF has the property of binding to diphtheria toxin (DT), serving as the specific receptor for DT. Tetramembrane-spanning protein CD9, a member of the TM4 superfamily, is physically associated with proHB-EGF at the cell surface and up-regulates both mitogenic and DT binding activities of proHB-EGF. To understand this up-regulation mechanism, we studied essential regions of both CD9 and proHB-EGF for up-regulation. Immunoprecipitation experiments revealed that not only CD9 but also other TM4 proteins including CD63, CD81, and CD82 associate with proHB-EGF on the cell surface. However, these TM4 proteins did not up-regulate DT binding activity of proHB-EGF. Transfection of a series of chimeric constructs comprising CD9 and CD81 showed that the major extracellular domain of CD9 is essential for up-regulation. Assays of DT binding activity and juxtacrine mitogenic activity of the deletion mutants of proHB-EGF and chimeric molecules, derived from proHB-EGF and TGF-alpha, showed that the essential domain of proHB-EGF for up-regulation is the EGF-like domain. These results indicate that the interaction of the extracellular domains of both molecules is important for up-regulation.
The Second Enzyme in Pyrrolnitrin Biosynthetic Pathway Is Related to the Heme-Dependent Dioxygenase Superfamily (2007)

Pyrrolnitrin is a commonly used and clinically effective treatment for fungal infections and provides the structural basis for the more widely used fludioxinil. The pyrrolnitrin biosynthetic pathway consists of four chemical steps, the second of which is the rearrangement of 7-chloro-tryptophan by the enzyme PrnB, a reaction that is so far unprecedented in biochemistry. When expressed in Pseudomonas fluorescens, PrnB is red in color due to the fact that it contains 1 mol of heme b per mole of protein. The crystal structure unexpectedly establishes PrnB as a member of the heme-dependent dioxygenase superfamily with significant structural but not sequence homology to the two-domain indoleamine 2,3-dioxygenase enzyme (IDO). The heme-binding domain is also structurally similar to that of tryptophan 2,3-dioxygenase (TDO). Here we report the binary complex structures of PrnB with d- and l-tryptophan and d- and l-7-chloro-tryptophan. The structures identify a common hydrophobic pocket for the indole ring but exhibit unusual heme ligation and substrate binding when compared with that observed in the TDO crystal structures. Our solution studies support the heme ligation observed in the crystal structures. Purification of the hexahistidine-tagged PrnB yields homogeneous protein that only displays in vitro activity with 7-chloro-l-tryptophan after reactivation with crude extract from the host strain, suggesting that an as yet unknown cofactor is required for activity. Mutation of the proximal heme ligand results, not surprisingly, in inactive enzyme. Redox titrations show that PrnB displays a significantly different reduction potential to that of IDO or TDO, indicating possible differences in the PrnB catalytic cycle. This is confirmed by the absence of tryptophan dioxygenase activity in PrnB, although a stable oxyferrous adduct (which is the first intermediate in the TDO/IDO catalytic cycle) can be generated. We propose that PrnB shares a key catalytic step with TDO and IDO, generation of a tryptophan hydroperoxide intermediate, although this species suffers a different fate in PrnB, leading to the eventual formation of the product, monodechloroaminopyrrolnitrin.
Determination of scattering and absorption coefficients from experimental data : Application to sunscreen lotions (2013)

Materials with pronounced light scattering are of large interest in a variety of scientific and technical disciplines. Their optical properties can to a good approximation be described by two-flux (Kubelka-Munk) theory [1]. This theory considers one light beam propagating in the forward direction and one beam propagating in the backward direction in the material. The optical properties of the material are described by phenomenological scattering (S) and absorption (K) coefficients. Additional parameters are the internal reflection coefficients for diffuse light at the interfaces and the reflection coefficient for incident collimated light at the front interface. The large amount of parameters makes it difficult to invert experimental measurements of transmittance (T) and reflectance (R) in order to obtain the parameters S and K characterizing the material [2,3]. We propose a method to partially overcome this problem in special cases by invoking physically realistic approximations for the reflection coefficients. We consider viscous emulsions or polymeric materials positioned between two transparent substrates separated by a spacer. Many organic and polymeric materials have refractive indices sufficiently close to those of glass and quartz substrates so that reflections between the material and the glass can be neglected. The reflection coefficient of the substrate for collimated light is known from its refractive index. Measurements of R and T in a region of weak scattering and absorption allow us to put quite stringent limits on the internal reflection coefficients for diffuse light. In this way good approximative values for S and K can be obtained. We apply this method to spectrophotometric measurements on two commercial sunscreen lotions. A drop of lotion was applied on a quartz substrate and a second quartz plate was put on top. The quartz plates were separated by aluminium foil of thickness 11 mm, except in the area covered by the lotion. Measurements of total R and T were taken by a Perkin-Elmer lambda-900 spectrophotometer equipped with an integrating sphere, in the wavelength range 250-800 nm. The samples were completely diffuse scattering and measurements in a low scattering region indicated a preferential forward scattering. The absorption coefficient was found to be low in the visible region and increased very much in the ultraviolet (UV). The scattering coefficient increased towards shorter wavelengths in the visible but exhibited differing behaviours in the UV. A sunscreen containing TiO2 particles exhibited a very low UV scattering together with higher scattering in the visible range, see fig. 1. Fig. 1. Scattering (S) and absorption (K) coefficients for a sunscreen containing a mix of chemical pigments and TiO [1] P. Kubelka, J. Opt. Soc. Am. 38 (1948) 448. [2] R. Levinson, P. Berdahl and H. Akbari, Solar Energy Mater. Solar Cells, 89 (2005) 319. [3] D. Barrios, R. Vergaz, J.M. Sanchez-Pena, C.G. Granqvist and G.A. Niklasson, Solar Energy Mater. Solar Cells, 111 (2013) 115.
Reduction of Structural Iron in Ferruginous Smectite by Free Radicals (1992)

Abstract The oxidation state of structural iron greatly influences the physical-chemical properties of clay minerals, a phenomenon that may have significant implications for pollutant fate in the environment, for agricultural productivity, and for industrial uses of clays. Knowledge of redox mechanisms is fundamental to understanding the underlying basis for iron's effects on clays. Past studies revealed that the extent of Fe reduction varied depending on the reducing agent used, but this variation may not have been a simple function of the reduction potential of the reducing agent. The objective of this study was to identify the relationship between the Fe reduction mechanism and free radical activity in the reducing agent. Several reducing agents and their mixtures with the Na-saturated, 0.5 to 2 μ m size fraction of ferruginous smectite (SWa-1) were analyzed by electron spin resonance (ESR) spectroscopy to determine the presence of unpaired electrons or free radicals. Only Na 2 S 2 O 4 exhibited paramagnetic free-radical behavior with a signal at about g = 2.011, which was attributed to the sulphoxylate (S0 2 − ·) free radical. The free radical was labile in aqueous solution, and the ability of Na 2 S 2 O 4 solution to reduce structural Fe in the smectite decreased with age of the solution and paralleled the disappearance of the free radical signal in the ESR spectrum. The paramagnetic species was preserved and enhanced if Na 2 S 2 O 4 was added to the clay suspension, indicating that either the clay surface stabilized the SO 2 − · radical or the additional unpaired electrons were produced in the clay structure.
Rainfuzz: Reinforcement-Learning Driven Heat-Maps for Boosting Coverage-Guided Fuzzing (2023)

Fuzzing is a dynamic analysis technique that repeatedly executes the target program with many different inputs to trigger abnormal behavior, such as a crash. One of the most successful techniques consists in generating inputs to increase code-coverage by using a mutational approach: this type of fuzzers maintains a population of inputs, they perform mutations on the inputs in the current population, and they add mutated inputs to the population if they discover new code-coverage in the target program. Researchers are continuously looking for techniques to increment the efficiency of fuzzers; one of these techniques consists in generating heat-maps for targeting specific bytes during the mutation of the input, as not all bytes might be useful for controlling the program's workflow. We propose the first approach in the literature that uses reinforcement learning for building heat-maps, by formalizing the problem of choosing the position to be mutated within the input as a reinforcement-learning problem. We model the policy by means of a neural network, and we train it by using Proximal Policy Optimization (PPO). We implement our approach in Rainfuzz, and we show the effectiveness of its heat-maps by comparing Rainfuzz against an equivalent fuzzer that performs mutations at random positions. We achieve the best performance by running AFL++ and Rainfuzz in parallel (in a collaborative fuzzing setting), outperforming a setting where we run two AFL++ instances in parallel.
Transglutaminases in mineralized tissues (2006)

Bone development and formation during embryogenesis as well as postnatally during bone remodeling is a complex process controlled systemically and locally by hormones, growth factors and matrix molecules. Transglutaminases (TGases) are the protein cross-linking enzymes, which have long been implicated in bone development and formation. Two members of TGase family, TG2 (also called tissue transglutaminase) and FXIIIA (the enzymatic A subunit of coagulation factor XIII), are expressed in chondrocytes and osteoblasts. The results of analyses in vivo and in vitro accumulated to date indicate an important role of these enzymes in promoting chondrocyte and osteoblast differentiation and matrix mineralization. These effects could be mediated by protein cross-linking activity of TGases, by GTPase activity of TG2 or via non-catalytic signaling effects. The aim of this review is to summarize the available data regarding the expression, localization and activity of TG2 and FXIIIA in mineralizing tissues and to discuss a number of mechanisms by which TGases could exert their promineralizing effects.
Undersampled dynamic X-ray tomography with dimension reduction Kalman\n filter (2018)

In this paper, we consider prior-based dimension reduction Kalman filter for\nundersampled dynamic X-ray tomography. With this method, the X-ray\nreconstructions are parameterized by a low-dimensional basis. Thus, the\nproposed method is a) computationally very light; and b) extremely robust as\nall the computations can be done explicitly. With real and simulated\nmeasurement data, we show that the method provides accurate reconstructions\neven with very limited number of angular directions.\n
Reliability and Variability of Metal Measurements in Permanent Tooth Enamel (2020)

Background: The enamel of permanent teeth forms in well-defined developmental periods and can be used to reconstruct early-life exposures to metals. However, little is known about how consistent metal measurements are when derived from the same tooth. We evaluated the reliability and variability of metal measurements within permanent tooth enamel to aid in its use as a biomarker for metals. Methods: Twenty-two tooth samples (4 incisors, 7 canines, 3 premolars, 4 first or second molars, 4 third molars) from the Metal Exposures and Alzheimer’s Disease Study were analyzed for aluminum (Al), arsenic (As), cadmium (Cd), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), nickel (Ni), and zinc (Zn) using laser ablation inductively coupled plasma mass spectrometry. Up to three laser ablation lines in the enamel were analyzed per tooth. Metal levels were normalized to calcium to account for variability in tooth mineralization and log-transformed due to skewed distributions. Adjusting for tooth type, we calculated the intraclass correlation coefficient (ICC) between ablation lines in enamel capturing overall exposures and the coefficient of variation (CV) across five segments of an ablation line capturing exposures over time. Results: ICCs were greater than 0.70 for most metals: Al (0.73), As (0.99), Fe (0.96), Pb (0.95), Mn (0.85), and Ni (0.90). ICCs were lower for Cd (0.52), Cu (0.61), and Zn (0.44). CVs were highest for Cd (61-154%), between 12-30% for Mn, Ni, As, and Pb, 12-44% for Al and Fe, 35-64% for Cu, and 78-107% for Zn. Conclusions: Repeated measurements of overall exposures in enamel are consistent for most metals. Higher CVs suggest more variation in metal measurements over time. These results can facilitate using permanent teeth as a biomarker for early-life exposures to metals.
Antagonistic effect of glucocorticoids on retinoic acid induced growth inhibition and morphological alterations of a human cell line. (1986)

When the human cell line NHIK 3025 was exposed to retinoic acid (1 nM; 10 microM), the cell cycle time was prolonged. Experiments using cells synchronized by mitotic selection showed that the retinoic acid induced growth delay was barely seen within the first cell cycle after exposure to 10 microM retinoic acid, whereas the next cell cycle durations were increased 30-60%. The effect was reversible as normal growth rate was restored after removal of the drug. DNA histograms indicated a prolongation of G1 of the cell cycle. We have shown earlier that glucocorticoid steroids also induce a prolongation of the cell cycle, located within G1. When the cells were exposed to the synthetic glucocorticoid, dexamethasone, in addition to retinoic acid, no additive effect was found; on the contrary, growth inhibition was less than that with retinoic acid alone. Dexamethasone from 1 nM upwards antagonized the growth inhibitory effect of retinoic acid. This glucocorticoid mediated effect seemed to be mediated via the glucocorticoid receptor, as no effect was seen when the receptor was blocked by the antagonist 17 beta hydroxy-11 beta, 4-dimethylaminophenyl-17 alpha-propynyl estra 4,9 diene-3-one [RU 38486]. The growth inhibition studies were supported by morphological observations showing that dexamethasone induced cytoskeletal alterations dominated when the cells were exposed to both drugs simultaneously. These findings might be of importance in cancer therapy where both drugs are used.
Driving forces for changes in geographical distribution of Ixodes ricinus ticks in Europe (2013)

Many factors are involved in determining the latitudinal and altitudinal spread of the important tick vector Ixodes ricinus (Acari: Ixodidae) in Europe, as well as in changes in the distribution within its prior endemic zones. This paper builds on published literature and unpublished expert opinion from the VBORNET network with the aim of reviewing the evidence for these changes in Europe and discusses the many climatic, ecological, landscape and anthropogenic drivers. These can be divided into those directly related to climatic change, contributing to an expansion in the tick's geographic range at extremes of altitude in central Europe, and at extremes of latitude in Scandinavia; those related to changes in the distribution of tick hosts, particularly roe deer and other cervids; other ecological changes such as habitat connectivity and changes in land management; and finally, anthropogenically induced changes. These factors are strongly interlinked and often not well quantified. Although a change in climate plays an important role in certain geographic regions, for much of Europe it is non-climatic factors that are becoming increasingly important. How we manage habitats on a landscape scale, and the changes in the distribution and abundance of tick hosts are important considerations during our assessment and management of the public health risks associated with ticks and tick-borne disease issues in 21(st) century Europe. Better understanding and mapping of the spread of I. ricinus (and changes in its abundance) is, however, essential to assess the risk of the spread of infections transmitted by this vector species. Enhanced tick surveillance with harmonized approaches for comparison of data enabling the follow-up of trends at EU level will improve the messages on risk related to tick-borne diseases to policy makers, other stake holders and to the general public.
Stereoselective chelation-controlled reduction of .alpha.-iodo-.beta.-alkoxy esters under radical conditions (1991)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStereoselective chelation-controlled reduction of .alpha.-iodo-.beta.-alkoxy esters under radical conditionsY. Guindon, J. F. Lavallee, M. Llinas-Brunet, G. Horner, and J. RancourtCite this: J. Am. Chem. Soc. 1991, 113, 25, 9701–9702Publication Date (Print):December 1, 1991Publication History Published online1 May 2002Published inissue 1 December 1991https://pubs.acs.org/doi/10.1021/ja00025a061https://doi.org/10.1021/ja00025a061research-articleACS PublicationsRequest reuse permissionsArticle Views376Altmetric-Citations73LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts