gebhart/patrepeval huggingface dataset:
BACE Inhibitors (2016)

Inhibition of BACE1 has emerged as a leading approach to the development of disease-modifying treatments for Alzheimer's disease (AD). Fragment-based drug discovery (FBDD) methods have played a major role in the discovery of novel, ligand-efficient BACE1 inhibitor chemotypes that subsequently have been optimized to have desirable pharmacokinetics (PK) and brain penetration with excellent ancillary profiles. Key components to the success of FBDD approaches targeting BACE1 were (i) identification of various amidine-containing fragments in which the amidine engaged in a network of hydrogen bond donor–acceptor interactions with the BACE1 catalytic dyad, (ii) design and/or identification of nonplanar cyclic amidine scaffolds, and (iii) structure and medicinal chemistry knowledge-based optimization with an emphasis on ligand efficiency. While a number of other fragments and scaffolds in addition to the amidines were identified through screening (e.g., primary amines and aminopyridines, among others), these have met with less success in producing advanced BACE1 inhibitors. This chapter will focus primarily on the role of fragment-based approaches to the discovery of the nonplanar cyclic amidine class of BACE1 inhibitors that have produced the most advanced inhibitors currently in clinical development as potential disease-modifying treatments for AD. Beyond the peptidomimetics, it has proven challenging to develop nonpeptidic “second-generation” BACE1 inhibitors that exhibit brain Ap lowering with a dose and safety profile suitable for clinical progression. Fragment-based approaches have provided novel and structurally diverse chemotypes that, together with extensive SAR exploration using in vitro and in vivo model systems, have afforded a wealth of structure- and property-based knowledge over the past decade, significantly advancing our understanding of what makes a “good” BACE inhibitor. This chapter discusses the major role FBDD played in the development of such chemotypes, including the nonplanar cyclic amidines, a chemotype that ultimately enabled researchers to develop selective BACE inhibitors that are more drug-like in terms of MW, ClogP, and PSA, that have lower susceptibility to P-gp efflux, and most importantly that penetrate the CNS and effectively reduce Ap levels, some of which progressed into clinical development.
The Spike Protein VP4 Defines the Endocytic Pathway Used by Rotavirus To Enter MA104 Cells (2012)

Rotaviruses are internalized into MA104 cells by endocytosis, with different endocytic pathways used depending on the virus strain. The bovine rotavirus UK strain enters cells through a clathrin-mediated endocytic process, while the simian rhesus rotavirus (RRV) strain uses a poorly defined endocytic pathway that is clathrin and caveolin independent. The viral surface protein VP7 and the spike protein VP4 interact with cellular receptors during cell binding and penetration. To determine the viral protein that defines the mechanism of internalization, we used a panel of UK × RRV reassortant viruses having different combinations of the viral structural proteins. Characterization of the infectivities of these reassortants in MA104 cells either transfected with a small interfering RNA (siRNA) against the heavy chain of clathrin or incubated with hypertonic medium that destabilizes the clathrin coat clearly showed that VP4 determines the pathway of virus entry. Of interest, the characterization of Nar3, a sialic acid-independent variant of RRV, showed that a single amino acid change in VP4 shifts the route of entry from being clathrin dependent to clathrin independent. Furthermore, characterizations of several additional rotavirus strains that differ in their use of cellular receptors showed that all entered cells by clathrin-mediated endocytosis, suggesting that diverse VP4-cell surface interactions can lead to rotavirus cell entry through this endocytic pathway.
Munsell Renotations Used to Study Color Space of Hunter and Adams* (1950)

The calorimetric scales of recent Hunter and Adams proposals are studied in terms of the smoothed curves of the Munsell renotation space. Three conversion tables prepared provide: I.C.I. (X, Y, Z) data; Adams’ chromatic value data; Hunter’s a and b. Each table extends to the theoretical hue, value, and chroma limits of the original table. Such use of Munsell renotation data makes it possible to visualize the color spacing of the coordinates of any color measuring instrument that is based upon or related to the I.C.I. system, and makes it possible to understand instrument results in terms of color experience, and thus assess the accuracy and precision of an instrument in terms of standard colorimetric practice and known color tolerance.
Biophysical Comparisons of Calicivirus Serotypes Isolated from Pinnipeds (1975)

Biophysical properties of three new San Miquel sea lion virus isolates from pinnipeds were examined and compared with those of previously characterized serotypes. The caliciviruses showed an identical sedimentation rate of 183S in 5-20% sucrose. Buoyant densities in CsCl were in the range of 1.35-1.39 g/ml, with differences among the serotypes.
First Total Synthesis of Martinellic Acid, a Naturally Occurring Bradykinin Receptor Antagonist (2001)

[reaction: see text] The first total synthesis of martinellic acid, a naturally occurring bradykinin receptor antagonist, via a CuI-catalyzed coupling reaction of beta-amino ester 6 with 1,4-diiodobenzene and a guanylation reaction of secondary amine 3 under mild conditions as key steps, is described.
Syntheses of heme d models (1984)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSyntheses of heme d modelsKevin M. Smith and Jan Ji LaiCite this: J. Am. Chem. Soc. 1984, 106, 19, 5746–5748Publication Date (Print):September 1, 1984Publication History Published online1 May 2002Published inissue 1 September 1984https://pubs.acs.org/doi/10.1021/ja00331a065https://doi.org/10.1021/ja00331a065research-articleACS PublicationsRequest reuse permissionsArticle Views81Altmetric-Citations7LEARN 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
6‐Isocyanatocapronsäure‐2‐isocyanatoäthylester aus €‐Caprolactam und 2‐Aminoäthanol (1975)

Abstract Durch heterogene Veresterung von Aminoäthanol‐hydrochlorid mit 6‐Aminocapronsäurehydrochlorid läβt sich in hoher Ausbeute 6‐Aminocapronsäure‐2‐aminoäthylester‐dihydrochlorid ( 1 ) gewinnen. Phosgenierung von 1 ergibt das neuartige aliphatische Diisocyanat 6‐Isocyanatocapronsäure‐2‐isocyanatoäthylester ( 2 ). Behandeln von 1 mit Natronlauge liefert 6‐Amino‐ N ‐(2‐hydroxyäthyl)capronamid (7). Reaktionen von 2 und 7 werden beschrieben.
Counter-Based Cache Replacement and Bypassing Algorithms (2008)

Recent studies have shown that, in highly associative caches, the performance gap between the least recently used (LRU) and the theoretical optimal replacement algorithms is large, motivating the design of alternative replacement algorithms to improve cache performance. In LRU replacement, a line, after its last use, remains in the cache for a long time until it becomes the LRU line. Such deadlines unnecessarily reduce the cache capacity available for other lines. In addition, in multilevel caches, temporal reuse patterns are often inverted, showing in the L1 cache but, due to the filtering effect of the L1 cache, not showing in the L2 cache. At the L2, these lines appear to be brought in the cache but are never reaccessed until they are replaced. These lines unnecessarily pollute the L2 cache. This paper proposes a new counter-based approach to deal with the above problems. For the former problem, we predict lines that have become dead and replace them early from the L2 cache. For the latter problem, we identify never-reaccessed lines, bypass the L2 cache, and place them directly in the L1 cache. Both techniques are achieved through a single counter-based mechanism. In our approach, each line in the L2 cache is augmented with an event counter that is incremented when an event of interest such as certain cache accesses occurs. When the counter reaches a threshold, the line ";expires"; and becomes replaceable. Each line's threshold is unique and is dynamically learned. We propose and evaluate two new replacement algorithms: Access interval predictor (AIP) and live-time predictor (LvP). AIP and LvP speed up 10 capacity-constrained SPEC2000 benchmarks by up to 48 percent and 15 percent on average (7 percent on average for the whole 21 Spec2000 benchmarks). Cache bypassing further reduces L2 cache pollution and improves the average speedups to 17 percent (8 percent for the whole 21 Spec2000 benchmarks).
Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE2-Mediated Suppression of Antitumor Immunity (2017)

Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progression. Moreover, COX2 overexpression and excess PGE<sub>2</sub> production were detected in HSCs in human HCCs with noncirrhotic, nonalcoholic steatohepatitis (NASH), indicating that a similar mechanism could function in humans.<b>Significance:</b> We showed the importance of the gut-liver axis in obesity-associated HCC. The gut microbiota-driven COX2 pathway produced the lipid mediator PGE<sub>2</sub> in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE<sub>2</sub> and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC. <i>Cancer Discov; 7(5); 522-38. ©2017 AACR.</i><i>This article is highlighted in the In This Issue feature, p. 443</i>.
Scanning positron microbeam (1988)

The construction and operation of a scanning positron microbeam is reported. The positrons are obtained from a doubly remoderated positron beam with a normalized brightness-per-volt of 1.8×105 e+ s−1 cm−2 rad−2 V−1 Ci−1. The beam of 8000 e+ s−1 is brought to a 10×50 μm2 focus by a sectored lens and is scanned across a test grid. Possible applications to defect spectroscopy and the observation of small samples will be discussed.
Analysis of gene-expression profiles by oligonucleotide microarray in children with influenza (2006)

In order to clarify the mechanism of the host response to influenza virus, gene-expression profiles of peripheral blood obtained from paediatric patients with influenza were investigated by oligonucleotide microarray. In the acute phase of influenza, 200 genes were upregulated and 20 genes were downregulated compared with their expression in the convalescent phase. Interferon-regulated genes, such as interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) and vipirin, were strongly upregulated in the acute phase. Gene ontology analysis showed that immune response genes were highly overrepresented among the upregulated genes. Gene-expression profiles of influenza patients with and without febrile convulsion were also studied. In patients with febrile convulsion, 22 genes were upregulated and five were downregulated compared with their expression in patients without febrile convulsion. These results should help to clarify the pathogenesis of influenza and its neurological complications.
SONET: a network management viewpoint (1990)

SONET network management features are described, covering the layered overhead structure, performance monitoring, maintenance signals, orderwire channels, user channels, and data communication channels (DCCs). Basic deployment and network management concerns are examined. These concerns relate to midspan meet management, intraoffice DCC connectivity, and integration of SONET elements in existing management architectures. The topic of mediation functions is introduced to provide a solution to some of the integration concerns.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">></ETX>
Phosphopeptide detection and sequencing by matrix‐assisted laser desorption/ionization quadrupole time‐of‐flight tandem mass spectrometry (2001)

A prototype matrix-assisted laser desorption/ionization quadrupole time-of-flight (MALDI-TOF) tandem mass spectrometer was used to sequence a series of phosphotyrosine-, phosphothreonine- and phosphoserine-containing peptides. The high mass resolution and mass accuracy of the instrument allowed the localization of one, three or four phosphorylated amino acid residues in phosphopeptides up to 3.1 kDa. Tandem mass spectra of two different phosphotyrosine peptides permitted amino acid sequence determination and localization of one and three phosphorylation sites, respectively. The phosphotyrosine immonium ion at m/z 216.04 was observed in these MALDI low-energy CID tandem mass spectra. Elimination of phosphate groups was evident from the triphosphorylated peptide but not from the monophosphorylated species. The main fragmentation pathway for the synthetic phosphothreonine-containing peptide and for phosphoserine-containing peptides derived from beta-casein and ovalbumin was the beta-elimination of phosphoric acid with concomitant conversion of phosphoserine to dehydroalanine and phosphothreonine to 2-aminodehydrobutyric acid. Peptide fragment ions of the b- and y-type allowed, in all cases, the localization of phosphorylation sites. Ion signals corresponding to (b-17), (b-18) and (y-17) fragment ions were also observed. The abundant neutral loss of phosphoric acid (-98 Da) is useful for femtomole level detection of phosphoserine-peptides in crude peptide mixtures generated by gel in situ digestion of phosphoproteins.
PARTICLES AS DRUG DELIVERY SYSTEMS (1987)

ABSTRACT Advances in genetically engineered products present an entirely new spectrum of drugs to the medical community. With these exciting new drugs come complex challenges for their delivery. The compounds are often high molecular weight proteins, many with extremely short in vivo half lives. The challenge is to deliver these new drugs to the body at a controlled rate. The rate can be uniform or programmed to a specific regimen, with time frames from hours to months. An additional challenge is posed by drugs that are highly toxic. If the drug were to home in directly on the site of action, systemic damage could be minimized. Drug loaded particles, (emulsions, liposomes or microcapsules), are being developed for both controlled and targeted drug delivery.
Baeyer–Villiger Oxidations with Hydrogen Peroxide in Fluorinated Alcohols: Lactone Formation by a Nonclassical Mechanism (2002)

What a difference the solvent makes! Unlike in conventional solvents, nonstrained ketones such as cyclohexanone react smoothly with hydrogen peroxide in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) to give lactones. The reaction proceeds via an isolatable spiro-bisperoxide, which undergoes a highly exothermic acid-catalyzed rearrangement to two equivalents of lactone (see Equation and IR thermogram). Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2002/z19329_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
A Trusted Approach for Decentralised and Privacy-Preserving Identity Management (2021)

Identity Management (IdM) systems have traditionally relied on a centralized model prone to privacy, trust, and security problems, like potential massive data breaches or identity spoofing. Identity providers accumulate excessive power that might allow them to become a big brother, analyzing and storing as much data as possible. Users should be able to trust identity providers and manage their personal information straightforwardly without compromising their privacy. The European OLYMPUS project introduces a distributed approach for IdM based on enhanced Attribute-Based Credentials (ABC) that splits the role of Identity Provider to limit their influence and chances to become a unique point of failure. However, the trust relationship between service providers, users, and identity providers is still a gap in those kinds of privacy-preserving ABC systems. Decentralized technologies are an opportunity to break away from the centralized model and propose systems that respect privacy while increasing users' trust. This paper presents an evolution of the OLYMPUS architecture, maintaining all the privacy features and incorporating distributed ledger technologies to enhance trust and security in online transactions and IdM systems. The proposed system has been implemented, tested, and validated, showing its performance and feasibility to manage user's identity in a fully privacy-preserving, distributed and reliable way.
Simulation and visualization of autonomous helicopter and service robots (2000)

To decrease the costs and the time it takes to develop and test new products, computer simulations are very helpful. Product models can be simulated, and their behavior can be examined. This applies not only to hardware, but even to software products that are composed of several components, so that their cooperative behaviour is simulated in a virtual environment. Some components of this environment can later be replaced by physical, real world devices. Some other components can be just prototypes, which are later replaced by more complex and realistic software components. In any case the idea is to construct a model and simulate both software and hardware before the actual production starts. In the WITAS project there is a need to develop a system which contains helicopters, robots and various control software and hardware. In particular there is a need to simulate the dynamic behavior of an autonomous aircraft within a virtual environment. There is a need to simulate a service environment, where robots can interact with the landed helicopter. In this report a study of object-oriented modeling of mechanical systems using Modelica is presented with applications to autonomous helicopters and robots. Mechanical features of an autonomous helicopter have been modeled in order to verify the control system. As the result the control system has been tested and tuned. However, the flight still is not stable in the cases when flight mission directions change too often. A robot which is able to grab, move, and release objects using automatic or manual control have been modeled. The problem of inverse geometry (and inverse kinematics) can be solved for robots using our approach. The robot models can be controlled interactively. The geometry and dynamic stru...
Self-Emulsifying Systems for Oral Bioavailability Enhancement (2015)

Hydrophobic drug entities are the major challenges for pharmaceutical scientists to deliver through oral route of administration due to limited drug solubility and bioavailability particularly emerged from combinatorial chemistry and computer aided drug design. Presently, self-emulsifying systems have been employed as the most common approach for delivery of numerous poor aqueous drugs. This unique strategy exploits many lipids, surfactants, co-surfactants and permeation enhancers to form an ideal isotropic mixture in water or gastric fluid by gentle agitation. The chapter attempts to explore components of SEDDS in designing of drug delivery system to accommodate significant amount of poorly soluble drugs, limitations of the system and their rectification, types of SEDDS, evaluation of SEDDS and a short review of research in last decade involved to improve oral bioavailability of drugs. The aim of this chapter is a throughout understanding of lipid based dosage form designing and application in self-emulsifying drug delivery system from enhanced oral bioavailability point of view for drugs possessing water solubility problem. Moreover, the present article would also provide a brief account of the patent instances filed/approved in this domain for providing an updated account of the concept. Keywords: Bioavailability, hydrophobic drugs, self-emulsifying drug delivery systems.
Smart Grid - a reliability perspective (2010)

Increasing complexity of power grids, growing demand, and requirement for greater grid reliability, security and efficiency as well as environmental and energy sustainability concerns continue to highlight the need for a quantum leap in harnessing communication and information technologies. This leap toward a ¿smarter¿ grid is now widely referred to as "smart grid". A framework for cohesive integration of these technologies facilitates convergence of acutely needed standards and protocols, and implementation of necessary analytical capabilities. The paper critically reviews the reliability impacts of major smart grid resources such as renewables, demand response, storage. We observe that an ideal mix of these resources leads to a flatter net demand that eventually accentuates reliability issues further. We then present a grid-wide IT architectural framework to meet the reliability challenges. This architecture supports a multitude of geographically and temporally coordinated hierarchical monitoring and control actions over time scales from milliseconds and up.
How can we cure a heart “in flame”? A translational view on inflammation in heart failure (2013)

The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated with a wide array of mechanisms subsumed under the term "inflammation". Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-α led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective.