gebhart/patrepeval huggingface dataset:
Abstract B30: Structure-based drug discovery of MRTX1257, a selective, covalent KRAS G12C inhibitor with oral activity in animal models of cancer (2020)

Abstract The ability to effectively target mutated KRAS has remained elusive despite decades of research. By solving a highly informative set of ligand-complexed co-crystal structures coupled with iterative structure-based drug design, substituted tetrahydropyridopyrimidines were identified as selective, covalent inhibitors of mutant KRAS G12C. Key molecular interactions with the protein were optimized, with the potency of lead compounds evaluated by (a) mass spectrometric quantification of modified KRAS protein with and without treatment of test compounds, and (b) measurement of phospho-ERK in a whole-cell assay using H358 cells after incubation with test compounds for 3 hours. These efforts identified MRTX1257 as a potent and selective inhibitor of mutant KRAS G12C activity. This lead compound was utilized as a research tool to aid in a deeper understanding of therapeutic susceptibility and KRAS dependence. MRTX1257 makes a covalent bond with the codon 12 cysteine and binds in the “Switch-2” pocket of KRAS, stabilizing the protein in the inactive, GDP-bound state. MRTX1257 contains a cyanomethyl group that displaces a water found near Gly10 in co-crystal structures of less potent analogs and contains an 8-methylnaphthyl group that fills a hydrophobic pocket, resulting in enhanced potency compared with unsubstituted naphthyl analogs. MRTX1257 demonstrated rapid, irreversible modification of GDP-bound recombinant KRAS G12C and suppressed ERK phosphorylation with an IC50 = 1 nM in the H358 cell line. In proteomics studies designed to assess global protein modification, MRTX1257 was shown to be highly selective for the targeted Cys12 of KRAS G12C versus other surface-exposed cysteine residues in NCI-H358 cells. Finally, at a 30mg/kg PO dose, MRTX1257 exhibited 31% bioavailability in mouse, demonstrated near-complete inhibition of KRAS signaling in tumor tissue, and complete durable tumor regression in MIA PaCa-2 xenografts. The discovery of the tetrahydropyridopyrimidine series, the structure-based optimization to MRTX1257 and its preclinical potency, selectivity, ADME and efficacy profile will be presented. Citation Format: Matthew A. Marx, Brian R. Baer, Joshua Ballard, James F. Blake, Karyn Bouhana, David M. Briere, Laurence E. Burgess, Michael R. Burkhard, Harrah Chiang, Mark J. Chicarelli, James G. Christensen, John P. Fischer, Jill Hallin, Macedonia J. Mejia, Peter Olson, Pavel Savechenkov, Niranjan Sudhakar, Tony P. Tang, Guy P. Vigers, Jay B. Fell. Structure-based drug discovery of MRTX1257, a selective, covalent KRAS G12C inhibitor with oral activity in animal models of cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B30.
Dyrk1A Phosphorylates p53 and Inhibits Proliferation of Embryonic Neuronal Cells (2010)

Down syndrome (DS) is associated with many neural defects, including reduced brain size and impaired neuronal proliferation, highly contributing to the mental retardation. Those typical characteristics of DS are closely associated with a specific gene group "Down syndrome critical region" (DSCR) on human chromosome 21. Here we investigated the molecular mechanisms underlying impaired neuronal proliferation in DS and, more specifically, a regulatory role for dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 1A (Dyrk1A), a DSCR gene product, in embryonic neuronal cell proliferation. We found that Dyrk1A phosphorylates p53 at Ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor H19-7 cells. In addition, Dyrk1A-induced p53 phosphorylation at Ser-15 led to a robust induction of p53 target genes (e.g. p21(CIP1)) and impaired G(1)/G(0)-S phase transition, resulting in attenuated proliferation of H19-7 cells and human embryonic stem cell-derived neural precursor cells. Moreover, the point mutation of p53-Ser-15 to alanine rescued the inhibitory effect of Dyrk1A on neuronal proliferation. Accordingly, brains from embryonic DYRK1A transgenic mice exhibited elevated levels of Dyrk1A, Ser-15 (mouse Ser-18)-phosphorylated p53, and p21(CIP1) as well as impaired neuronal proliferation. These findings suggest that up-regulation of Dyrk1A contributes to altered neuronal proliferation in DS through specific phosphorylation of p53 at Ser-15 and subsequent p21(CIP1) induction.
Computational 3D displays (2014)

Compressive displays explore the co-design of optics, electronics, applied mathematics, and real-time computing. Existing device limitations in 3D image display as well as 2D resolution and contrast can be overcome.
Wide-bandgap epitaxial heterojunction windows for silicon solar cells (1990)

It is shown that the efficiency of a solar cell can be improved if minority carriers are confined by use of a wide-bandgap heterojunction window. For silicon (lattice constant a=5.43 AA), nearly lattice-matched wide-bandgap materials are ZnS (a=5.41 AA) and GaP (a=5.45 AA). Isotype n-n heterojunctions of both ZnS/Si and GaP/Si were grown on silicon n-p homojunction solar cells. Successful deposition processes used were metalorganic chemical vapor deposition (MO-CVD) for GaP and ZnS, and vacuum evaporation of ZnS. Planar
Immunoglobulin A Modulates Inflammatory Responses in an In Vitro Model of Pneumonia (2005)

PMN cytotoxic potential was decreased by the presence of SIgA but not IgG in an in vitro model to simulate pneumonia in vivo. SIgA may not only function to protect against microbial invasion of mucosal surfaces, but may also protect against tissue injury from an exaggerated inflammatory response.
cDNA cloning of three cecropin‐like antimicrobial peptides (Styelins) from the tunicate, <i>Styela clava</i> (1997)

We cloned precursors of three new antimicrobial peptides, Styelins C, D and E, from a pharyngeal cDNA library of a tunicate, Styela clava. Preprostyelins resembled dipteran preprocecropins, while the mature domain of Styelin C resembled Cecropin P1, an antimicrobial peptide purified from the porcine intestine. Beginning with the last 6 residues of their signal sequences, Styelin C and Cecropin 1 from Drosophila virilis had 8/11 identical amino acids (72.7%). Moreover, 4 of the last 6 residues of their mature peptide domains were also identical. Styelins were shorter, by 8 residues, than dipteran cecropins and preprostyelins contained a conserved, polyanionic C-terminal extension that was absent in preprocecropins. Delineation of cecropin-like antimicrobial peptides in a protochordate supports the antiquity of this family as effectors of innate immunity in animals and it increases the likelihood that additional cecropin-like peptides will be found among other evolutionary descendants of protochordates--vertebrates.
Rhodopsin reconstitution in vesicles formed from simple, fully synthetic amphiphiles (1982)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTRhodopsin reconstitution in vesicles formed from simple, fully synthetic amphiphilesErnst J. R. Sudhoelter, Willem J. De Grip, and Jan B. F. N. EngbertsCite this: J. Am. Chem. Soc. 1982, 104, 4, 1069–1072Publication Date (Print):February 1, 1982Publication History Published online1 May 2002Published inissue 1 February 1982https://pubs.acs.org/doi/10.1021/ja00368a025https://doi.org/10.1021/ja00368a025research-articleACS PublicationsRequest reuse permissionsArticle Views79Altmetric-Citations22LEARN 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-Alertsclose Get e-Alerts
Molecular Orientation Behavior with Drawing of Biaxially Stretched Film (1995)

Biaxially stretched poly (ethylene terephthalate) (PET) films have been characterized by wide angle X-ray diffraction. Pole figures were developed for wide angle diffraction peaks. These are used to interpret structural changes in the films associated with various degrees of biaxial stretching and subsequent constrained annealing. We investigated typical pole figures for (100) and (105) planes normal of biaxially stretched and annealed films. In the triclinic unit cell of PET crystal the phenyl ring planes are roughly parallel to (100) planes and (105) planes are roughly perpendicular to the chain axis.
Design Recommendations for Controlling the Jam-Clearing Hazard on Recycling Industry Balers (2005)

Between 1986 and 2002, there were 43 fatalities in the United States to operators of recycling industry balers. Of these fatalities, 29 involved horizontal balers that were baling paper and cardboard (Taylor, 2002). Balers often become jammed while the baling process is occurring, and the only way to remove the jam is manually. This requires an employee to place a limb of their body into the jamming area and remove the material that is causing the jam. While lockout and tagout procedures reduce the risk of hazardous energy being released, they can still be easily bypassed, ignored, or forgotten. Recent efforts to reduce machine-related injury and death involve the development of a control system for these machines that automatically detects hazardous operating conditions and responds accordingly. The system is being developed at the National Institute for Occupational Safety and Health (NIOSH). This system, JamAlert, automatically terminates the power to the machine when a jam is detected. JamAlert detects a jam by observing both the strain that is experienced by the shear bar of the baler and the hydraulic pressure at which the ram is operating. The strain that is experienced by the baler shear bar when a jam is initiated was calculated in this study through laboratory testing and finite element modeling. Design recommendations are presented on how best to tune the JamAlert’s operating program to most effectively control the jam-clearing hazard.
Platelet Response to Corneal Abrasion Is Necessary for Acute Inflammation and Efficient Re-epithelialization (2006)

Platelet localization in the limbus of abraded corneas contributes to re-epithelialization, and P-selectin provides a necessary step in this process.
Cumulative Live-Birth Rates after In Vitro Fertilization (2009)

Our results indicate that IVF may largely overcome infertility in younger women, but it does not reverse the age-dependent decline in fertility.
Holistic Optical Network Optimization across Network and Physical Layers (2017)

Holistic optical network optimization is becoming practical due to unprecedented flexibility in the physical layer and deployment of SDN. We discuss technologies for managing complexity and enabling optimization across physical and network layers.
Analytical and Computational Modeling of High Pressure Gas Injection (2001)

Abstract The topic of this paper is the analytical and computational modeling of the gas injection process in a large bore natural gas fueled engine. At high injection pressures, the overall gas injection and mixing process includes compressible flow features such as rarefaction waves and shock formation. The injection geometries examined in the paper include both a two dimensional slot and an axisymmetric nozzle. The computations examine the effect of the injection pressure/back pressure ratio, with ratios ranging from 3 to 80. The computational modeling was validated by comparison with results obtained from a 2D analytical method of characteristics solution. The validation process evaluated factors such as pressure and Mach number profiles, jet boundary shape and shock location.
Cognition and Affect: Architectures and Tools (1997)

Which agent architectures are capable of justifying descriptions in terms of the `higher level&apos; mental concepts applicable to human beings? We propose a new kind of architecturebased semantics for mentalistic descriptions in which mental concepts (e.g. `believes&apos;, `desires&apos;, `intends&apos;, `mood&apos;, `emotion &apos;, etc.) are grounded in assumptions about information processing architectures, and not merely in concepts based solely on Dennett&apos;s `intentional stance&apos;. These ideas have led to the design of the SIM AGENT toolkit which has been used to explore a variety of such architectures. 1 Architectures and mentalistic descriptions McCarthy [1] gives reasons why we shall need to describe intelligent robots in mentalistic terms, and why such a robot will need some degree of self consciousness. He also proposes a notation that we and the robot might use to describe its states. We extend that work by focusing on the underlying `high level&apos; architectures required to justify ascriptions of mentality...
Specific Properties of Artificial [Buna] Rubber (1937)

Abstract Developments in the Synthesis of Rubber Because of the peculiar properties of natural rubber, its usefulness is somewhat limited, and in many fields of application it is quite unsuitable. In contact with oils and fats it swells rapidly and loses almost completely its good mechanical properties, and besides this natural rubber has poor resistance to heat. Again it is attacked rather easily by oxygen, and on exposure to oxygen and light simultaneously there is a particularly strong tendency to develop cracks within a short time; it is for such reasons that the chemical industries of various countries have been looking for an artificial or synthetic product which is free from the shortcomings of natural rubber or exhibits them to only a relatively small extent. Experimentation on artificial rubber has depended fundamentally on the discovery of Harries that the natural rubber molecule is constructed of isoprene units. Isoprene and its allied hydrocarbons were prepared by Hoffmann and his coworkers at the Elberfeld dye works, and these compounds were in turn polymerized to masses similar to rubber. These experiments were carried out before the World War. Because of a shortage of raw materials during the War, it was necessary to adapt the laboratory results to a factory scale sooner than should logically have been done. At that time the most readily available technical raw material was dimethylbutadiene, a compound which differs from isoprene by the presence of an extra methyl group, as may be seen in Table I.
The Dark Side of IFN-γ: Its Role in Promoting Cancer Immunoevasion (2017)

Interferon-γ (IFN-γ) is a pleiotropic cytokine that has long been praised as an important effector molecule of anti-tumor immunity, capable of suppressing tumor growth through various mechanisms. On the contrary to such a bright side of IFN-γ, it has also been involved in promoting an outgrowth of tumor cells with immunoevasive phenotype suggesting an existence of a dark "tumor-promoting" side effect of IFN-γ. In this review, we will summarize this multi-functional role of IFN-γ in tumor context, how it promotes changes in tumor phenotype towards increased fitness for growth in immunocompetent host. Furthermore, we summarize how IFN-γ is involved in homeostatic or cancer-triggered mechanisms to establish an immunosuppressive tumor microenvironment.
Characterization of the interactions between various hexadecylmannoside–phospholipid model membranes with the lectin Concanavalin A (2000)

The specific interaction of Concanavalin A (ConA) with glycolipid-containing model membranes was investigated using (a) surface pressure–time (Π–t) curves, (b) epifluorescence microscopy connected to a film balance, (c) atomic force microscopy (AFM) of the monofilms after Langmuir–Blodgett (LB) transfer and (d) quartz crystal microbalance (QCMB) weight-quantification of the adhered protein on the glycolipid model membrane. The adsorption of ConA on a model membrane was mannose-specific and concentration-dependent in the range 1–50% (1% was the lower detection limit, whereas above 30% saturation began). Adsorption kinetics was followed by QCMB and Π–t measurements. Saturation was reached after 1 h. Hydrophilic spacers were introduced between the alkyl chain and the mannose headgroup of the ConA ligands. The quantity of specific ConA-adhesion increased with spacer length and also the adhesion kinetics was accelerated using protruding ligands. With AFM it was possible to detect morphological differences of mixed hexadecylmannoside–1,2-distearyl-sn-glycero-3-phosphocholine (DSPC) films in dependence on spacer length of the glycolipid before and after molecular contact with ConA.
A Precision High Voltage Vacuum-Tube Voltmeter (1948)

A vacuum-tube voltmeter circuit is described which is capable of measuring voltages within the range of from 0 to −5000 volts with an accuracy of 0.05 percent and a linear characteristic over the entire range. The input impedance is greater than 5×1010 ohms. The circuit was developed for the purpose of measuring accurately high voltage sources of extremely low current drain which were employed for cosmic-ray studies. It is based on a null method, using a vacuum tube having a high amplification factor as one arm of a balanced circuit and a constant current source as the other arm. The negative terminal of the measured voltage is applied to the plate of the tube, and the grid voltage is varied to maintain the same grid current which balances the current from the constant current source. Linearity results from the negligible varying space-charge effect at constant grid current, and high precision measurements are obtained by means of a special circuit for measuring the change in grid voltage. By setting the grid current equal to the value of 1/μ, where μ is the amplification factor of the tube, the meter can be made to read directly the measured voltage.
MUF1, A Novel Elongin BC-interacting Leucine-rich Repeat Protein That Can Assemble with Cul5 and Rbx1 to Reconstitute a Ubiquitin Ligase (2001)

The heterodimeric Elongin BC complex has been shown to interact in vitro and in mammalian cells with a conserved BC-box motif found in a growing number of proteins including RNA polymerase II elongation factor Elongin A, SOCS-box proteins, and the von Hippel-Lindau (VHL) tumor suppressor protein. Recently, the VHL-Elongin BC complex was found to interact with a module composed of Cullin family member Cul2 and RING-H2 finger protein Rbx1 to reconstitute a novel E3 ubiquitin ligase that activates ubiquitylation by the E2 ubiquitin-conjugating enzymes Ubc5 and Cdc34. In the context of the VHL ubiquitin ligase, Elongin BC functions as an adaptor that links the VHL protein to the Cul2/Rbx1 module, raising the possibility that the Elongin BC complex could function as an integral component of a larger family of E3 ubiquitin ligases by linking alternative BC-box proteins to Cullin/Rbx1 modules. In this report, we describe identification and purification from rat liver of a novel leucine-rich repeat-containing BC-box protein, MUF1, which we demonstrate is capable of assembling with a Cullin/Rbx1 module containing the Cullin family member Cul5 to reconstitute ubiquitin ligase activity. In addition, we show that the additional BC-box proteins Elongin A, SOCS1, and WSB1 are also capable of assembling with the Cul5/Rbx1 module to reconstitute potential ubiquitin ligases. Taken together, our findings identify MUF1 as a new member of the BC-box family of proteins, and they predict the existence of a larger family of Elongin BC-based E3 ubiquitin ligases.
Listen to the brain: a Biological perspective On musical emotions (2001)

Abstract The functioning of the brain is fascinating. It fascinates for the obvious reason that the brain is the commander of all our actions, thoughts, and motivations. By studying its functioning, the hope is to obtain crucial information about the biological determinants of human cognition and emotion. Neuropsychology is the discipline concerned with these questions. As its name indicates, neuropsychology aims to relate neural mechanisms to mental functions. It is an old discipline, dating back to the discovery that speech was related to the functioning of a small region of the left brain by Broca in 1861. Following this discovery, the neural correlates of musical abilities were similarly scrutinized (for a recent review, see Marin & Perry 1999). Although the neuropsychological approach to music is a century old, progress has been slow. term.
Extended composite right/left-handed (E-CRLH) metamaterial and its application as quadband quarter-wavelength transmission line (2006)

A novel extended composite right/left-handed (E-CRLH) transmission line (TL) metamaterial structure, constituted by the combination of the conventional CRLH (C- CRLH) and the recently introduced dual CRLH (D-CRLH) prototypes, is proposed. This E-CRLH metamaterial is characterized by eight LC parameters (four C-CRLH and four D-CRLH parameters), which allow unprecedented diversity in the manipulation of the dispersion relation of the resulting TL structure. In particular, an E-CRLH TL metamaterial, under an extended balance condition, exhibits two frequencies of infinite wavelength propagation. In addition, the E-CRLH is intrinsically a quadband (arbitrary quadruplet of frequencies) structure. The latter property is exploited here into the design of a quadband quarter- wavelength transformer, and may be applied in principle to any TL-based microwave component.
Mouse brain CD4 transcripts encode only the COOH-terminal half of the protein. (1988)

The T-cell surface glycoprotein CD4 is thought to function as a receptor for class II major histocompatibility complex molecules. Human CD4 is also the lymphoid cell receptor for human immunodeficiency virus, the causative agent of acquired immune deficiency syndrome. The observed infection of the central nervous system in acquired immune deficiency syndrome patients raises the possibility that CD4 is also present in nerve tissue and that a cell surface receptor for class II major histocompatibility complex antigens could play a role in central nervous system function. This possibility is reinforced by the detection of unique CD4-related transcripts in mouse and human brain tissue. In this study, the structure of the mouse brain CD4 transcript was determined. It is identical to the last two-thirds of the CD4 message and is capable of encoding a 217-residue protein that would consist of a truncated, 154-residue, cell surface region, together with the complete CD4 transmembrane and cytoplasmic regions. It would not include an amino-terminal hydrophobic leader peptide.