gebhart/patrepeval huggingface dataset:
Competitive Antagonism of AMPA Receptors by Ligands of Different Classes:  Crystal Structure of ATPO Bound to the GluR2 Ligand-Binding Core, in Comparison with DNQX (2002)

Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion channels that are essential for mediating fast synaptic transmission in the central nervous system. This study presents a high-resolution X-ray structure of the competitive antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) in complex with the ligand-binding core of the receptor. Comparison with the only previous structure of the ligand-binding core in complex with an antagonist, 6,7-dinitro-2,3-quinoxalinedione (DNQX) (Armstrong, N.; Gouaux, E. Neuron 2000, 28, 165-181), reveals that ATPO and DNQX stabilize an open form of the ligand-binding core by different sets of interactions. Computational techniques are used to quantify the differences between these two ligands and to map the binding site. The isoxazole moiety of ATPO acts primarily as a spacer, and other scaffolds could potentially be used. Whereas agonists induce substantial domain closures compared to the apo structure, ATPO only induces minor conformational changes. These results are consistent with the hypothesis that domain closure is related to receptor activation. To facilitate the design of novel AMPA receptor antagonists, we present a modified model of the binding site that includes key residues involved in ligand recognition.
Identification of a pre-active conformation of a pentameric channel receptor (2017)

Pentameric ligand-gated ion channels (pLGICs) mediate fast chemical signaling through global allosteric transitions. Despite the existence of several high-resolution structures of pLGICs, their dynamical properties remain elusive. Using the proton-gated channel GLIC, we engineered multiple fluorescent reporters, each incorporating a bimane and a tryptophan/tyrosine, whose close distance causes fluorescence quenching. We show that proton application causes a global compaction of the extracellular subunit interface, coupled to an outward motion of the M2-M3 loop near the channel gate. These movements are highly similar in lipid vesicles and detergent micelles. These reorganizations are essentially completed within 2 ms and occur without channel opening at low proton concentration, indicating that they report a pre-active intermediate state in the transition pathway toward activation. This provides a template to investigate the gating of eukaryotic neurotransmitter receptors, for which intermediate states also participate in activation.
Figure S5 from Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy (2023)

&lt;p&gt;Non-uniform dynamics of single CpGs among CLL progression&lt;/p&gt;
Corrections to Aminoimidazoles as Potent and Selective Human β-Secretase (BACE1) Inhibitors (2010)

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrections to Aminoimidazoles as Potent and Selective Human β-Secretase (BACE1) InhibitorsMichael S. Malamas*, Jim Erdei, Iwan Gunawan, Keith Barnes, Matthew Johnson, Yu Hui, Jim Turner, Yun Hu, Erik Wagner, Kristi Fan, Andrea Olland, Jonathan Bard, and Albert J. RobichaudCite this: J. Med. Chem. 2010, 53, 4, 1882Publication Date (Web):January 21, 2010Publication History Published online21 January 2010Published inissue 25 February 2010https://pubs.acs.org/doi/10.1021/jm901921xhttps://doi.org/10.1021/jm901921xcorrectionACS PublicationsCopyright © 2010 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views973Altmetric-Citations1LEARN 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 PDF (542 KB) Get e-AlertscloseSUBJECTS:Inhibitors Get e-Alerts
Supramolecular interactions between catalytic species allow rational control over reaction kinetics (2019)

The adaptivity of biological reaction networks largely arises through non-covalent regulation of catalysts' activity. Such type of catalyst control is still nascent in synthetic chemical networks and thereby hampers their ability to display life-like behavior. Here, we report a bio-inspired system in which non-covalent interactions between two complementary phase-transfer catalysts are used to regulate reaction kinetics. While one catalyst gives bimolecular kinetics, the second displays autoinductive feedback, resulting in sigmoidal kinetics. When both catalysts are combined, the interactions between them allow rational control over the shape of the kinetic curves. Computational models are used to gain insight into the structure, interplay, and activity of each catalytic species, and the scope of the system is examined by optimizing the linearity of the kinetic curves. Combined, our findings highlight the effectiveness of regulating reaction kinetics using non-covalent catalyst interactions, but also emphasize the risk for unforeseen catalytic contributions in complex systems and the necessity to combine detailed experiments with kinetic modelling.
Clinical Characteristics and Biopsy Specimen Features in African-American and White Men Without Prostate Cancer (1998)

In this study, African-American men without histologic evidence of prostate cancer had significantly higher PSA levels and PSA densities than similarly aged white men. This finding was not accounted for by racial differences in patients' age, serum testosterone level, or prostate volume.
Synopsis diffusion for robust aggregation in sensor networks (2008)

Previous approaches for computing duplicate-sensitive aggregates in wireless sensor networks have used a tree topology, in order to conserve energy and to avoid double-counting sensor readings. However, a tree topology is not robust against node and communication failures, which are common in sensor networks. In this article, we present synopsis diffusion , a general framework for achieving significantly more accurate and reliable answers by combining energy-efficient multipath routing schemes with techniques that avoid double-counting. Synopsis diffusion avoids double-counting through the use of order- and duplicate-insensitive (ODI) synopses that compactly summarize intermediate results during in-network aggregation. We provide a surprisingly simple test that makes it easy to check the correctness of an ODI synopsis. We show that the properties of ODI synopses and synopsis diffusion create implicit acknowledgments of packet delivery. Such acknowledgments enable energy-efficient adaptation of message routes to dynamic message loss conditions, even in the presence of asymmetric links. Finally, we illustrate using extensive simulations the significant robustness, accuracy, and energy-efficiency improvements of synopsis diffusion over previous approaches.
Tailored chemical reactivity probes for systemic imaging of aldehydes in fibroproliferative diseases (2023)

During fibroproliferation, protein-associated extracellular aldehydes are formed by the oxidation of lysine residues on extracellular matrix proteins to form the aldehyde allysine. Here we report three Mn(II)-based, small molecule magnetic resonance (MR) probes that contain α-effect nucleophiles to target allysine in vivo and report on tissue fibrogenesis. We used a rational design approach to develop turn-on probes with a 4-fold increase in relaxivity upon targeting. The effects of aldehyde condensation rate and hydrolysis kinetics on the performance of the probes to detect tissue fibrogenesis noninvasively in mouse models were evaluated by a systemic aldehyde tracking approach. We showed that for highly reversible ligations, off-rate was a stronger predictor of in vivo efficiency, enabling histologically validated, three-dimensional characterization of pulmonary fibrogenesis throughout the entire lung. The exclusive renal elimination of these probes allowed for rapid imaging of liver fibrosis. Reducing the hydrolysis rate by forming an oxime bond with allysine enabled delayed phase imaging of kidney fibrogenesis. The imaging efficacy of these probes, coupled with their rapid and complete elimination from the body, make them strong candidates for clinical translation.
Repairability Smackdown: How Do the Latest Tablet Models Stack Up? (2013)

Tablets are the latest craze in the consumer electronics (CE) world. New models are hitting the shelves every few months, many featuring new screen and speaker technologies and the latest in low-power, high-performance mobile CPU with the latest models beginning to feature GPU and specialized multimedia IP cores.
TLR4 in skin cancer: From molecular mechanisms to clinical interventions (2019)

The health and economic burden imposed by skin cancer is substantial, creating an urgent need for the development of improved molecular strategies for its prevention and treatment. Cutaneous exposure to solar ultraviolet (UV) radiation is a causative factor in skin carcinogenesis, and TLR4-dependent inflammatory dysregulation is an emerging key mechanism underlying detrimental effects of acute and chronic UV exposure. Direct and indirect TLR4 activation, upstream of inflammatory signaling, is elicited by a variety of stimuli, including pathogen-associated molecular patterns (such as lipopolysaccharide) and damage-associated molecular patterns (such as HMGB1) that are formed upon exposure to environmental stressors, such as solar UV. TLR4 involvement has now been implicated in major types of skin malignancies, including nonmelanoma skin cancer, melanoma and Merkel cell carcinoma. Targeted molecular interventions that positively or negatively modulate TLR4 signaling have shown promise in translational, preclinical, and clinical investigations that may benefit skin cancer patients in the near future.
Raman tensor elements for multiferroic BiFeO3 with rhombohedral R3c symmetry (2009)

Abstract A quantitative assessment of the Raman spectrum emitted from a coarse‐grained polycrystal of multiferroic BiFeO 3 has been carried out by means of a polarized Raman microprobe. The dependence of the intensity of Raman phonon modes has been first theoretically modeled as a function of crystal rotation. Then, the Raman tensor elements have been experimentally determined from the analysis of the A g and E g vibrational modes. Copyright © 2009 John Wiley &amp; Sons, Ltd.
Numerical investigation of emission in finite-sized, three-dimensional photonic crystals with structural fluctuations (2009)

We investigate the inhibited emission of light-emitters embedded in finite, three-dimensional woodpile (or stacked-striped) photonic crystals (PCs) that exhibit structural fluctuations. Finite-difference time-domain calculations reveal that the influence of the positional fluctuations of stacked rods of dielectric material depends on the total number of structural periods. For PCs with up to nine stacked layers, the inhibition of emission is principally determined by intruding free-space modes resulting from the finite nature of the structure, with little influence from fluctuations. In PCs with more periods, the modes resulting from fluctuations dominate the emission properties. The influence of these fluctuations is strongly suppressed when the positional shifts are less than +/-20%.
ChemInform Abstract: CARBON MONOXIDE ACTIVATION BY ORGANOACTINIDES. MIGRATORY CARBON MONOXIDE INSERTION INTO METAL‐HYDROGEN BONDS TO PRODUCE MONONUCLEAR FORMYLS (1982)

Abstract Untersucht wird die Carbonylierungschemie der mit 80‐90% Ausb. wie aufgezeigt aus (I) und (III) erhaltenen Alkoxyhydride (II), (V) und (VII).
Bridging languages by SuperSense entity tagging (2009)

This paper explores a very basic linguistic phenomenon in multilingualism: the lexicalizations of entities are very often identical within different languages while concepts are usually lexicalized differently. Since entities are commonly referred to by proper names in natural language, we measured their distribution in the lexical overlap of the terminologies extracted from comparable corpora. Results show that the lexical overlap is mostly composed by unambiguous words, which can be regarded as anchors to bridge languages: most of terms having the same spelling refer exactly to the same entities. Thanks to this important feature of Named Entities, we developed a multilingual super sense tagging system capable to distinguish between concepts and individuals. Individuals adopted for training have been extracted both by YAGO and by a heuristic procedure. The general F1 of the English tagger is over 76%, which is in line with the state of the art on super sense tagging while augmenting the number of classes. Performances for Italian are slightly lower, while ensuring a reasonable accuracy level which is capable to show effective results for knowledge acquisition.
PHOCUS: A phase 3 randomized, open-label study comparing the oncolytic immunotherapy Pexa-Vec followed by sorafenib (SOR) vs SOR in patients with advanced hepatocellular carcinoma (HCC) without prior systemic therapy. (2016)

TPS4146 Background: Pexa-Vec (pexastimogene devacirepvec; JX-594) is an oncolytic and immunotherapeutic vaccinia virus designed to selectively replicate in and destroy cancer cells. It causes direct oncolysis accompanied by tumor vascular disruption and anti-tumor immunity mediated by expression of the transgene GM-CSF. SOR, a multi-targeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced HCC. Both preliminary preclinical and clinical data suggest complementary anti-tumor effects of a sequential combination of Pexa-Vec followed by SOR possibly by targeting the tumor vasculature via different mechanisms (Heo et al., Mol Ther 2011). A randomized phase II dose-finding study with 3 Pexa-Vec intratumoral (IT) liver injections in first line advanced HCC patients showed an acceptable safety profile and a significant increase in overall survival (OS) in the highest dose group (109pfu) (Heo et al., Nat Med 2013). Methods: This global, randomized, open-label, phase III study will compare the efficacy and tolerability of Pexa-Vec followed by SOR vs SOR in advanced HCC patients. Eligible patients are Child-Pugh A, ECOG PS 0-1, BCLC B/C, have at least 1 measurable and viable liver tumor (based on radiographic assessment) injectable under imaging guidance, have liver tumor mass < 50% of the total liver volume, no invasion of the inferior vena cava, and had no prior systemic therapy for HCC. 600 patients will be randomized 1:1 to either 3 Pexa-Vec IT injections administered every 2 weeks at a dose of 109pfu (D1, W2, W4) followed by 400 mg BID SOR starting at W6 or to SOR 400 mg BID (from D1). Patients are allocated to treatment arm using minimization by center, HCC etiology, presence of extra-hepatic disease, vascular invasion, PS 0-1, AFP levels. The primary endpoint is OS (1-sided stratified log-rank test; α = 0.025, 86% power, HR 0.83). Secondary endpoints include time to progression, progression-free survival, overall response rate and disease control rate (radiographic evaluation every 6 weeks). In addition, safety, biomarkers and quality of life will be evaluated. Clinical trial information: NCT02562755.
Mild Pd-Catalyzed Aminocarbonylation of (Hetero)Aryl Bromides with a Palladacycle Precatalyst (2014)

A palladacyclic precatalyst is employed to cleanly generate a highly active XantPhos-ligated Pd-catalyst. Its use in low temperature aminocarbonylations of (hetero)aryl bromides provides access to a range of challenging products in good to excellent yields with low catalyst loading and only a slight excess of CO. Some products are unattainable by traditional carbonylative coupling.
Challenges to manufacturing submicron, ultra-large scale integrated circuits (1990)

It is argued that the cost of manufacturing submicron, ultra-large-scale integration (ULSI) integrated circuits (ICs) (which is scaling upward at least in inverse proportion to the downward scaling of device feature sizes) is driven by a parameter budget crisis associated with the technological and complexity limits of IC design and fabrication. This budget crisis is defined for technologies associated with patterning, mechanical control, thermal treatments, particulates and contamination, defects, electrical parameters, and manufacturing, R&D priorities for silicon ULSI are identified and quantified, and the potential impact of some recent research results is discussed. It is pointed out that the R&D agenda to deal with the ULSI manufacturing budget crisis is enormous, and the semiconductor industry cannot perform all of it. Since the time for transferring new developments into production tools and technologies is five to seven years, it is concluded that critical funding decisions need to be made now for ULSI manufacturing science breakthroughs by the turn of the century.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Structural details of amyloid β oligomers in complex with human prion protein as revealed by solid-state MAS NMR spectroscopy (2021)

Human PrP (huPrP) is a high-affinity receptor for oligomeric amyloid β (Aβ) protein aggregates. Binding of Aβ oligomers to membrane-anchored huPrP has been suggested to trigger neurotoxic cell signaling in Alzheimer's disease, while an N-terminal soluble fragment of huPrP can sequester Aβ oligomers and reduce their toxicity. Synthetic oligomeric Aβ species are known to be heterogeneous, dynamic, and transient, rendering their structural investigation particularly challenging. Here, using huPrP to preserve Aβ oligomers by coprecipitating them into large heteroassemblies, we investigated the conformations of Aβ(1-42) oligomers and huPrP in the complex by solid-state MAS NMR spectroscopy. The disordered N-terminal region of huPrP becomes immobilized in the complex and therefore visible in dipolar spectra without adopting chemical shifts characteristic of a regular secondary structure. Most of the well-defined C-terminal part of huPrP is part of the rigid complex, and solid-state NMR spectra suggest a loss in regular secondary structure in the two C-terminal α-helices. For Aβ(1-42) oligomers in complex with huPrP, secondary chemical shifts reveal substantial β-strand content. Importantly, not all Aβ(1-42) molecules within the complex have identical conformations. Comparison with the chemical shifts of synthetic Aβ fibrils suggests that the Aβ oligomer preparation represents a heterogeneous mixture of β-strand-rich assemblies, of which some have the potential to evolve and elongate into different fibril polymorphs, reflecting a general propensity of Aβ to adopt variable β-strand-rich conformers. Taken together, our results reveal structural changes in huPrP upon binding to Aβ oligomers that suggest a role of the C terminus of huPrP in cell signaling. Trapping Aβ(1-42) oligomers by binding to huPrP has proved to be a useful tool for studying the structure of these highly heterogeneous β-strand-rich assemblies.
The high‐affinity peripheral benzodiazepine receptor ligand [11C]DAA1106 can be used to image microglia in animal models of Parkinson's disease and neuroinflammation in vivo using PET. (2007)

Activated microglia are an important feature of several neurological diseases. We propose that activated microglia can be imaged using Positron Emission Tomography (PET) by taking advantage of elevated levels of peripheral benzodiazepine receptors (PBR) on activated microglia. We tested the hypothesis that DAA1106, a novel high‐affinity ligand to PBR, will specifically label activated microglia in vivo using PET. [3H]DAA1106 showed significantly higher binding in brain tissues in rats injected intrastriataly with either 6‐hydroxydopamine (6‐OHDA) or lipopolysaccaride (LPS) at the site of lesion. Immunohistochemistry combined with autoradiography in lesioned rats as well as cell cultures showed increased [3H]DAA1106 binding corresponding to activated microglia. PET imaging in vivo showed greater retention [11C]DAA1106 at the site of lesion in animals injected with either LPS or 6‐OHDA. Finally, DAA1106 showed higher affinity binding when compared to the well‐characterized PBR PET ligand PK11195 in both brain tissues and in vivo. These results indicate that DAA1106 binds with high affinity to microglia in neuroinflammatory disorders.
Transport and metabolism of glucose by rat small intestine (1983)

Glucose transport and metabolism by rat small intestine was investigated by using a preparation for the combined perfusion of the lumen and the vascular bed. 2. When 5 mM-glucose was present in the lumen, only 29% was transported unchanged to the vascular side. Lactate output into the vascular and luminal fluids accounted for a further 53% and 4% respectively of the glucose taken up from the lumen. 3. Glucose was readily taken up when added at 5 mM to the vascular compartment only. Vascular lactate output accounted for approx. 33% of the glucose uptake, and luminal lactate for 6%. 4. When 2 mM-glucose was added to the lumen with 5 mM-glucose in the vascular perfusate, there was no detectable net transport of glucose to the vascular side. However, of the glucose taken up from the lumen, 31% and 2% could be accounted for by increases in vascular and luminal lactate respectively. 5. When 10 mM-glucose was added to the lumen, with 5 mM-glucose in the vascular perfusate, 33% of the glucose disappearing from the lumen was transported to the vascular side. Extra lactate output to the vascular and lumen perfusates accounted for 50% and 9% respectively of the glucose uptake from the lumen. 6. These studies indicate that at low luminal glucose concentrations no sugar is transferred to the blood unchanged, and at sugar concentrations of 5--10 mM only 25--50% of the glucose leaving the lumen reaches the serosal side intact. Furthermore, the small intestine has a greater propensity to form lactate from luminal glucose than from vascular glucose.