gebhart/patrepeval huggingface dataset:
Abstract A180: Selective inhibition of K-Ras G12C through allosteric control of GTP affinity and effector interactions. (2013)

Abstract Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to directly target this oncogene have faced difficulties due to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent upon relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. Here, we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras G12C. These compounds rely on the mutant cysteine for binding and therefore do not affect the wild type protein (WT). Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras G12C disrupts both switch-I and switch-II, subverting the native nucleotide preference to favor GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a novel allosteric regulatory site on Ras that is targetable in a mutant specific manner. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A180. Citation Format: Ulf Peters, Jonathan M. Ostrem, Martin L. Sos, James A. Wells, Kevan M. Shokat. Selective inhibition of K-Ras G12C through allosteric control of GTP affinity and effector interactions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A180.
Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature (2018)

Prostaglandins and thromboxane are lipid signaling molecules deriving from arachidonic acid by the action of the cyclooxygenase isoenzymes COX-1 and COX-2. The role of cyclooxygenases (particularly COX-2) and prostaglandins (particularly PGE₂) in cancer-related inflammation has been extensively investigated. In contrast, COX-1 has received less attention, although its expression increases in several human cancers and a pathogenetic role emerges from experimental models. COX-1 and COX-2 isoforms seem to operate in a coordinate manner in cancer pathophysiology, especially in the tumorigenesis process. However, in some cases, exemplified by the serous ovarian carcinoma, COX-1 plays a pivotal role, suggesting that other histopathological and molecular subtypes of cancer disease could share this feature. Importantly, the analysis of functional implications of COX-1-signaling, as well as of pharmacological action of COX-1-selective inhibitors, should not be restricted to the COX pathway and to the effects of prostaglandins already known for their ability of affecting the tumor phenotype. A knowledge-based choice of the most appropriate tumor cell models, and a major effort in investigating the COX-1 issue in the more general context of arachidonic acid metabolic network by using the systems biology approaches, should be strongly encouraged.
Regenerative Strategies for Craniofacial Disorders (2012)

Craniofacial disorders present markedly complicated problems in reconstruction because of the complex interactions of the multiple, simultaneously affected tissues. Regenerative medicine holds promise for new strategies to improve treatment of these disorders. This review addresses current areas of unmet need in craniofacial reconstruction and emphasizes how craniofacial tissues differ from their analogs elsewhere in the body. We present a problem-based approach to illustrate current treatment strategies for various craniofacial disorders, to highlight areas of need, and to suggest regenerative strategies for craniofacial bone, fat, muscle, nerve, and skin. For some tissues, current approaches offer excellent reconstructive solutions using autologous tissue or prosthetic materials. Thus, new "regenerative" approaches would need to offer major advantages in order to be adopted. In other tissues, the unmet need is great, and we suggest the greatest regenerative need is for muscle, skin, and nerve. The advent of composite facial tissue transplantation and the development of regenerative medicine are each likely to add important new paradigms to our treatment of craniofacial disorders.
Analysis of Flow and Cavitation Phenomena in Diesel Injection Nozzles and Its Effects on Spray and Mixture Formation (2003)

&lt;div class="htmlview paragraph"&gt;In modern DI Diesel engines the raw emissions of NOx and soot are affected, apart from the fuel injection rate, by atomization of the liquid jet and mixing of the fuel with the combustion air. Thereby details of the fuel flow inside the injection nozzle play an essential role. In order to determine the general mechanisms and the effect of individual nozzle configuration parameters on the fuel atomization and the fuel spray propagation, methods for optical diagnostics and CFD have been developed at the DaimlerChrysler Research.&lt;/div&gt; &lt;div class="htmlview paragraph"&gt;These methods are combined with an analysis of the injection system hydraulics and linked to a detailed analysis of mixture formation and combustion inside an optically accessible engine.&lt;/div&gt; &lt;div class="htmlview paragraph"&gt;The first part of the paper methods for the experimental investigation with transparent 1- and 6- hole nozzles in real size geometries under high pressure conditions are described. Special emphasis is put on CFD methods for modeling the cavitating two phase nozzle flow. In the second part the processes occurring in a sac hole nozzle of a common rail injector during the complete injection event are discussed. The influences of the spray hole position, inlet rounding and conical shape of the spray hole are presented. Finally a comparison between a needle lift controlled (CR = common rail) and a pressure controlled (PLN = pump line nozzle) injection system is made.&lt;/div&gt;
Genetic and Environmental Determinants for Lipoprotein Concentrations in Blood (1985)

Path and segregation analyses have been performed on cholesterol and triglyceride contents of serum as well as on very low, low and high density lipoproteins in 78 Swedish nuclear families. The effect of environmental variables like alcohol and smoking on the concentrations of the different lipoproteins has been studied. Genetic heritability was 0.16-0.68 for the cholesterol fractions and 0-0.56 for the triglyceride fractions. No major gene was evident for any of the variables studied.
Serotonin Regulates Performance Nonmonotonically in a Spatial Working Memory Network (2013)

The prefrontal cortex (PFC) contains a dense network of serotonergic [serotonin, 5-hydroxytryptamine (5-HT)] axons, and endogenous 5-HT markedly modulates PFC neuronal function via several postsynaptic receptors. The therapeutic action of atypical antipsychotic drugs, acting mainly via 5-HT receptors, also suggests a role for serotonergic neurotransmission in cognitive functions. However, psychopharmacological studies have failed to find a consistent relationship between serotonergic transmission and cognitive functions of the PFC, including spatial working memory (SWM). Here, we built a computational network model to investigate 5-HT modulation of SWM in the PFC. We found that 5-HT modulates network's SWM performance nonmonotonically via 5-HT1A and 5-HT2A receptors, following an inverted U-shape. This relationship may contribute to blur the effects of serotonergic agents in previous SWM group-based behavioral studies. Our simulations also showed that errors occurring at low and high 5-HT concentrations are due to different network dynamics instabilities, suggesting that these 2 conditions can be distinguished experimentally based on their distinct dependency on experimental variables. We inferred specific predictions regarding the expected behavioral effects of serotonergic agents in 2 classic working-memory tasks. Our results underscore the relevance of identifying different error types in SWM tasks in order to reveal the association between neuromodulatory systems and SWM.
When Creators, Corporations and Consumers Collide: Napster and the Development of On-line Music Distribution (2003)

The Internet is often depicted as the ultimate arena for unfettered capitalism, erasing geographic boundaries and barriers to entry while providing a plethora of goods and services to consumers. This article traces how public and private reactions by the five major record companies to new Internet distribution technologies have undermined this popular myth. We use a political economic approach to examine the case of A&amp;M Records et al. v. Napster, and discuss how this case underscores the importance of controlling the Internet as an entertainment distribution pipeline. Expressed concerns about piracy mask the actual intentions of the `Big Five' - control of all modes of distribution. The strength of the Big Five's cartel has a momentum of its own based in its market oligopoly, which has been secured through its ownership and management of intellectual property; through format changes and setting standards for other technologies; and through lobbying and legal activities.
List of non‐EU phytoplasmas of Cydonia Mill., Fragaria L., Malus Mill., Prunus L., Pyrus L., Ribes L., Rubus L. and Vitis L. (2020)

Following a request from the European Commission, the EFSA Panel on Plant Health prepared a list of non-EU phytoplasmas of <i>Cydonia</i> Mill., <i>Fragaria</i> L., <i>Malus</i> Mill., <i>Prunus</i> L., <i>Pyrus</i> L., <i>Ribes</i> L., <i>Rubus</i> L. and <i>Vitis</i> L. A systematic literature review and search of databases identified 27 phytoplasmas infecting one or more of the host genera under consideration. These phytoplasmas were assigned to three categories. The first group (a) consists of 10 non-EU phytoplasmas, known to occur only outside the EU ('<i>Candidatus</i> Phytoplasma australiense', '<i>Ca</i>. P. hispanicum', '<i>Ca</i>. P. pruni'-related strain (NAGYIII), '<i>Ca</i>. P. pyri'-related strain (PYLR) and Buckland valley grapevine yellows phytoplasma) or having only limited presence in the EU ('<i>Ca</i>. P. aurantifolia'-related strains, '<i>Ca</i>. P. fraxini', '<i>Ca</i>. P. phoenicium', '<i>Ca</i>. P. trifolii' and '<i>Ca</i>. P. ziziphi'). The second group (b) consists of three non-EU phytoplasmas, whose presence in the target plant species is not fully supported by the available literature. The third group (c) consists of 14 phytoplasmas with substantial presence in the EU (i.e. they are originally described or reported from the EU or known to occur or be widespread in some EU Member States or frequently reported in the EU). Phytoplasmas of categories (b) and (c) were excluded at this stage from further categorisation efforts. One phytoplasma from category (a) ('<i>Ca</i>. P. phoenicium') was excluded from further categorisation, as a pest risk assessment has been performed by EPPO. Comments provided by the EU Member States were integrated in the opinion. The main uncertainties of this listing concern: the geographic distribution and prevalence, the taxonomy, biology and host range. The phytoplasmas considered as non-EU and whose presence in target plant species is fully supported by literature (category (a)) are categorised by the Panel in a separate opinion.
A Phosphotyrosyl Mimetic Peptide Reverses Impairment of Insulin-Stimulated Translocation of GLUT4 Caused by Overexpression of PTP1B in Rat Adipose Cells (1998)

Biological actions of insulin are initiated by activation of the insulin receptor tyrosine kinase. Protein tyrosine phosphatases (PTPases) PTP1B and PTPalpha are known to dephosphorylate the insulin receptor and may contribute to insulin resistance in diseases such as diabetes. We previously reported that overexpression of PTP1B in rat adipose cells significantly impairs insulin-stimulated translocation of GLUT4 [Chen, H., et al. (1997) J. Biol. Chem. 272, 8026]. In the present study, we treated adipose cells with a PTPase inhibitor containing the phosphotyrosyl mimetic difluorophosphonomethyl phenylalanine (F2Pmp) to determine whether we could improve the insulin resistance caused by overexpression of PTP1B or PTPalpha. Rat adipose cells transfected by electroporation with either PTP1B or PTPalpha were treated without or with the inhibitor, and effects on insulin-stimulated translocation of a cotransfected epitope-tagged GLUT4 were studied. The IC50 of the F2Pmp-containing inhibitor is 180 nM for PTP1B and 10 mM for PTPalpha in vitro. As expected, in the absence of the inhibitor, overexpression of either PTP1B or PTPalpha caused a significant decrease in the amount of GLUT4 at the cell surface both in the absence and in the presence of insulin when compared with control cells transfected with epitope-tagged GLUT4 alone. Interestingly, the insulin resistance caused by overexpression of PTP1B (but not PTPalpha) was reversed by treating the transfected cells with the F2Pmp-containing inhibitor. Furthermore, the inhibitor blocked the insulin-stimulated association of PTP1B with the insulin receptor. We conclude that the F2Pmp-containing compound is a potent and specific inhibitor of overexpressed PTP1B that may be useful for designing rational therapies for treating insulin resistant diseases such as diabetes.
High frequency guided wave ultrasound measurements using low-cost equipment (2021)

Guided wave ultrasound can be applied to inspect large volumes of structures from a single transducer location and is particularly effective in one-dimensional structures such as rods, pipes and rail. An application, which is of interest in South Africa, is the inspection rock bolts in the mining industry. The difficulty in inspecting embedded rods is that there is rapid attenuation of the signals with distance. While guided wave systems generally operate at low frequencies (20 kHz to 200 kHz), high frequency operation (1 MHz to 10 MHz) can offer some advantages when inspecting rock bolts. Guided wave ultrasound testing is complicated by multi-modal propagation and dispersion, which require the use of sophisticated excitation signals, which are not available in equipment designed for conventional ultrasonic testing. It was therefore necessary to develop a measurement setup and the approach taken was to use standard lab instruments wherever possible and to only purchase the items that are unique to this measurement, using the very limited budget available. The measurement setup was used to perform measurements on a rod and confirmed theoretical predictions. These measurements identified the frequencies where modes propagate with low attenuation and allow the attenuation to be quantified.
The study of the chemical and phase composition of the diffusion interaction zone in layered composite Cr20Ni80-AD1 (2017)

The paper presents the research of chemical and phase composition of the zone of diffusion interaction in the layered composite Cr20Ni80-AD1. It is shown that interlayer border of bimetal Cr20Ni80-AD1 is a complex mixture of phases with the main phases in its composition in solid-phase interaction: Al3Ni2 and Al14.687Cr3.443Ni0.87, and in the liquid phase - Al3Ni2, Al0.987Cr0.017, Al14.687Cr3.44Ni0.87 and Al45Cr7. It is shown, that conditions of holding time of the heat treatment do not affect the phase and chemical composition of the diffusion zone.
Exploring the crossover between high-energy-density plasma and ultracold neutral plasma physics (2019)

In this paper, we present ideas that were part of the miniconference on the crossover between High Energy Density Plasmas (HEDP) and Ultracold Neutral Plasmas (UNPs) at the 60th Annual Meeting of the American Physical Society Division of Plasma Physics, November 2018. We give an overview of UNP experiments with an emphasis on measurements of the time-evolving ion density and velocity distributions, the electron-ion thermalization rate, and plasma self-assembly—all just inside the strongly coupled plasma regime. We also present theoretical and computational models that were developed to understand a subset of HEDP experiments. However, because HEDP experiments display similar degrees of strong coupling, many aspects of these models can be vetted using precision studies of UNPs. This comparison is important because some statistical assumptions used for ideal plasmas are of questionable validity in the strongly coupled plasma regime. We summarize two theoretical approaches that extend kinetic theories into the strong-coupling regime and show good agreement for momentum transfer and self-diffusion. As capabilities improve, both computationally and experimentally, UNP measurements may help guide the ongoing development of HEDP-appropriate plasma models. Future opportunities in viscosity, energy relaxation, and magnetized plasmas are discussed.
AlphaFold Models of Small Proteins Rival the Accuracy of Solution NMR Structures (2022)

Abstract Recent advances in molecular modeling using deep learning have the potential to revolutionize the field of structural biology. In particular, AlphaFold has been observed to provide models of protein structures with accuracy rivaling medium-resolution X-ray crystal structures, and with excellent atomic coordinate matches to experimental protein NMR and cryo-electron microscopy structures. Here we assess the hypothesis that AlphaFold models of small, relatively rigid proteins have accuracies (based on comparison against experimental data) similar to experimental solution NMR structures. We selected six representative small proteins with structures determined by both NMR and X-ray crystallography, and modeled each of them using AlphaFold. Using several structure validation tools integrated under the Protein Structure Validation Software suite (PSVS), we then assessed how well these models fit to experimental NMR data, including NOESY peak lists (RPF-DP scores), comparisons between predicted rigidity and chemical shift data (ANSURR scores), and 15 N- 1 H residual dipolar coupling data (RDC Q factors) analyzed by software tools integrated in the PSVS suite. Remarkably, the fits to NMR data for the protein structure models predicted with AlphaFold are generally similar, or better, than for the corresponding experimental NMR or X-ray crystal structures. Similar conclusions were reached in comparing AlphaFold2 predictions and NMR structures for three targets from the Critical Assessment of Protein Structure Prediction (CASP). These results contradict the widely held misperception that AlphaFold cannot accurately model solution NMR structures. They also document the value of PSVS for model vs . data assessment of protein NMR structures, and the potential for using AlphaFold models for guiding analysis of experimental NMR data and more generally in structural biology.
Tracing Anonymous Packets to Their Approximate Source (2000)

Most denial-of-service attacks are characterized by a flood of packets with random, apparently valid source addresses. These addresses are spoofed, created by a malicious program running on an unknown host, and carried by packets that bear no clues that could be used to determine their originating host. Identifying the source of such an attack requires tracing the packets back to the source hop by hop. Current approaches for tracing these attacks require the tedious continued attention and cooperation of each intermediate Internet Service Provider (ISP). This is not always easy given the world-wide scope of the Internet.We outline a technique for tracing spoofed packets back to their actual source host without relying on the cooperation of intervening ISPs. First, we map the paths from the victim to all possible networks. Next, we locate sources of network load, usually hosts or networks offering the UDP chargen service [5]. Finally, we work back through the tree, loading lines or router, observing changes in the rate of invading packets. These observations often allow us to eliminate all but a handful of networks that could be the source of the attacking packet stream. Our technique assumes that routes are largely symmetric, can be discovered, are fairly consistent, and the attacking packet stream arrives from a single source network.We have run some simple and single-blind tests on Lucent's intranet, where our technique usually works, with better chances during busier network time periods; in several tests, we were able to determine the specific network containing the attacker.An attacker who is aware of our technique can easily thwart it, either by covering his traces on the attacking host, initiating a whack-a-mole attack from several sources, or using many sources.
Multiple Threshold Percolation in Polymer/Filler Composites (2005)

Abstract Local variations in filler particle concentration and/or shape and orientation in static filler/polymer composites are modelled as distributions of percolation thresholds. The concentration variations can be due to insufficient mixing, formation of semicrystalline voids during cooling from the melt, shrinkage during polymer curing, flow during physical compression or the like. Irregular filler shapes, especially elongated shapes, reduce the percolation threshold; thus natural variations in the shapes and orientations of filler particle aggregates lead to locally varying percolation thresholds. A distribution of percolation thresholds leads to an apparent percolation threshold based on the conductivity below the mean percolation threshold. For filler concentrations above the apparent percolation threshold the dielectric constant continues to increase before reaching a lowered peak value at the mean percolation threshold and then decreasing. Own experimental results on EBA /carbon black composites support the theory.
Longitudinal investigation of neuroinflammation and metabolite profiles in the APPswe×PS1Δe9 transgenic mouse model of Alzheimer's disease (2017)

There is increasing evidence linking neuroinflammation to many neurological disorders including Alzheimer's disease (AD); however, its exact contribution to disease manifestation and/or progression is poorly understood. Therefore, there is a need to investigate neuroinflammation in both health and disease. Here, we investigate cognitive decline, neuroinflammatory and other pathophysiological changes in the APP<sub>swe</sub> ×PS1<sub>Δe9</sub> transgenic mouse model of AD. Transgenic (TG) mice were compared to C57BL/6 wild type (WT) mice at 6, 12 and 18 months of age. Neuroinflammation was investigated by [<sup>18</sup> F]DPA-714 positron emission tomography and myo-inositol levels using <sup>1</sup> H magnetic resonance spectroscopy (MRS) in vivo. Neuronal and cellular dysfunction was investigated by looking at N-acetylaspartate (NAA), choline-containing compounds, taurine and glutamate also using MRS. Cognitive decline was first observed at 12 m of age in the TG mice as assessed by working memory tests . A significant increase in [<sup>18</sup> F]DPA-714 uptake was seen in the hippocampus and cortex of 18 m-old TG mice when compared to age-matched WT mice and 6 m-old TG mice. No overall effect of gene was seen on metabolite levels; however, a significant reduction in NAA was observed in 18 m-old TG mice when compared to WT. In addition, age resulted in a decrease in glutamate and an increase in choline levels. Therefore, we can conclude that increased neuroinflammation and cognitive decline are observed in TG animals, whereas NAA alterations occurring with age are exacerbated in the TG mice. These results support the role of neuroinflammation and metabolite alteration in AD and in ageing.