gebhart/patrepeval huggingface dataset:
Optimization of Tubulysin Antibody–Drug Conjugates: A Case Study in Addressing ADC Metabolism (2016)

As part of our efforts to develop new classes of tubulin inhibitor payloads for antibody-drug conjugate (ADC) programs, we developed a tubulysin ADC that demonstrated excellent in vitro activity but suffered from rapid metabolism of a critical acetate ester. A two-pronged strategy was employed to address this metabolism. First, the hydrolytically labile ester was replaced by a carbamate functional group resulting in a more stable ADC that retained potency in cellular assays. Second, site-specific conjugation was employed in order to design ADCs with reduced metabolic liabilities. Using the later approach, we were able to identify a conjugate at the 334C position of the heavy chain that resulted in an ADC with considerably reduced metabolism and improved efficacy. The examples discussed herein provide one of the clearest demonstrations to-date that site of conjugation can play a critical role in addressing metabolic and PK liabilities of an ADC. Moreover, a clear correlation was identified between the hydrophobicity of an ADC and its susceptibility to metabolic enzymes. Importantly, this study demonstrates that traditional medicinal chemistry strategies can be effectively applied to ADC programs.
Harvest of Patellar Tendon (Bone–Tendon–Bone) Autograft for ACL Reconstruction Significantly Alters Surface Strain in the Human Patella (1999)

The purpose of this study was to measure the effect of bone-patellar tendon-bone autograft harvest for anterior cruciate ligament (ACL) reconstruction on the surface strain of the human patella. Through progressive removal of bone from the patella, three different defect shapes as well as the intact patella were tested in each of seven knees. Maximum principal strain and corresponding principal direction were determined from each of three gages around the defect for the four conditions (intact plus three defect shapes). There were no statistically significant differences in overall average surface strain between any of the defect shapes. Following graft harvest, overall average strain (all three defects combined) increased in the patella both medial (15 percent increase) and lateral (34 percent increase) to the defect, while decreasing in the region directly proximal (22 percent decrease) to the harvest site compared to the intact patella. A statistically significant 7.5 deg shift of principal direction from longitudinal toward a more transverse (lateral-superior to medial-inferior) direction was observed in the medial region when a shallow-dome defect was made. We conclude that removal of a bone block from the anterior, inferior part of the patella induces a significant redistribution of the surface strain. This results in greater local strain adjacent to the upper border of the bone block increasing the risk for patella fracture. This effect may be of importance in various complications known to occur after ACL reconstruction.
Trichomonas vaginalis Associated With Low Birth Weight and Preterm Delivery (1997)

After considering other recognized risk factors including co-infections, pregnant women infected with T. vaginalis at mid-gestation were statistically significantly more likely to have a low birth weight infant, to deliver preterm, and to have a preterm low birth weight infant. Compared with whites and Hispanics, T. vaginalis infection accounts for a disproportionately larger share of the low birth weight rate in blacks.
High-capacity optical transport networks (2012)

Network traffic demands are forecast to increase for the foreseeable future, with the challenge being to meet the demand while maintaining or lowering network costs. Simply increasing capacity will not be sufficient; overall bandwidth utilization also needs to improve. A combination of improved transport capacity through increased spectral efficiency and bit rate along with better network utilization by integrating subchannel electrical grooming into the transmission system will be required. Smarter ways to utilize optical capacity are key since transmission costs have been decreasing slower than grooming and switching costs. Integrated transport and switching can improve the efficiency of the client network using techniques such as port virtualization and transit traffic reduction. The baseline for transport networks will be 100 Gb/s PM-QPSK using 50 GHz channel spacing. Moving from a fixed DWDM channel arrangement to support flexible grid and super channels will allow tighter channel (carrier) spacing and should increase capacity by 30 to 50 percent. For shorter distances higher-order modulation such as 16-QAM can double network capacity. To better optimize network efficiency, an architecture that flexibly combines lower rate (sub-100 Gb/s) clients to form channels (carriers) and then superchannels will be required.
Chemical Synthesis of Hydrocarbon‐Stapled Peptides for Protein Interaction Research and Therapeutic Targeting (2011)

The peptide α-helix represents one of nature's most featured protein shapes and is employed in a diversity of protein architectures, from the cytoskeletal infrastructure to the most intimate contact points between crucial signaling proteins. By installing an all-hydrocarbon crosslink into native sequences, the shape and biological activity of natural peptide α-helices can be recapitulated, yielding a chemical toolbox that can be used both to interrogate the protein interactome and to modulate interaction networks for potential therapeutic benefit. Here, current methodology for synthesizing stabilized α-helices (SAH) corresponding to key protein interaction domains is described. A stepwise approach is taken for the production of crosslinking non-natural amino acids, incorporation of the residues into peptide templates, and application of ruthenium-catalyzed ring-closing metathesis to generate hydrocarbon-stapled peptides. Through facile derivatization and functionalization steps, SAHs can be tailored for a broad range of applications in biochemical, structural, proteomic, cellular, and in vivo studies. Curr. Protoc. Chem. Biol. 3:99-117 © 2011 by John Wiley & Sons, Inc.
Spina bifida at the sacral level: more than minor gait disturbances (2004)

Gross motor and functional problems were seen in both groups. The MMC group showed more muscle weakness and motor problems. However, in both groups caregiver assistance was needed for a prolonged period, especially regarding bladder and bowel management. These findings need special attention, particularly in children who attend regular schools.
Trusted virtual platforms (2009)

This paper introduces our work around combining machine virtualization technology with Trusted Computing Group technology. We first describe our architecture for reducing and containing the privileged code of the Xen Hypervisor. Secondly we describe our Trusted Virtual Platform architecture. This is aimed at supporting the strong enforcement of integrity and security policy controls over a virtual entity where a virtual entity can be either a full guest operating system or virtual appliance running on a virtualized platform. The architecture includes a virtualization-specific integrity measurement and reporting framework. This is designed to reflect all the dependencies of the virtual environment of a guest operating system. The work is a core enabling component of our research around converged devices -- client platforms such as notebooks or desktop PCs that can safely host multiple virtual operating systems and virtual appliances concurrently and report accurately on the trustworthiness of the individually executing entities.
Changes in Extra- and Intracellular pH in the Brain during and following Ischemia in Hyperglycemic and in Moderately Hypoglycemic Rats (1986)

Incomplete forebrain ischemia of 15-min duration was induced in rats made hyperglycemic or moderately hypoglycemic prior to ischemia. Tissue CO2 tension, CO2 content, labile tissue metabolites, and extracellular pH (pHe) were measured, and intracellular pH (pHi) was derived by calculation on the assumption that cerebral intracellular fluids can be lumped into one space. In hypoglycemic animals, mean tissue lactate content increased from 2 to 10 mumol g-1. Tissue CO2 content was virtually unchanged and the CO2 tension increased from approximately 50 to approximately 145 mm Hg. In hyperglycemic animals, tissue lactate content rose to 20 mumol g-1, and the CO2 content decreased by 25%, demonstrating that some CO2 was lost to the blood supplied by the remaining perfusion. Accordingly, tissue CO2 tension did not rise above 200 mm Hg. pHe was reduced in proportion to the amount of lactate accumulated, the values obtained in hypo- and hyperglycemic animals showing relatively little scatter (6.76 +/- 0.03 and 6.25 +/- 0.04, respectively). In hypoglycemic animals the extracellular HCO-3 concentration was virtually unchanged, demonstrating that any influx of lactic acid from the cells must have been accompanied by H+ efflux and/or HCO-3 influx via independent routes. In hyperglycemic animals [HCO-3]e fell by greater than 10 mumol ml-1. In both groups [HCO-3]e was reduced during the first 5 min of recovery. Recovery of pHe was slower in hyper- than in hypoglycemic animals. During ischemia calculated pHi fell to 6.37 +/- 0.04 and 5.95 +/- 0.06 in hypo- and hyperglycemic animals, respectively. Differences in pHi were maintained for the first 15 min of recovery, but in both hypo- and hyperglycemic animals pHi had normalized after 30 min. It is concluded that preischemic hyperglycemia leads to a more pronounced intra- and extracellular acidosis than normo- and hypoglycemia, an acidosis that also resolves more slowly during recirculation.
Identification of a cis‐acting dendritic targeting element in the mRNA encoding the alpha subunit of Ca2+/calmodulin‐dependent protein kinase II (2001)

In mammalian neurons a selected group of mRNAs, including the transcript encoding the alpha subunit of Ca2+/calmodulin-dependent protein kinase II, is found in dendrites. The molecular mechanisms underlying extrasomatic RNA trafficking are not well described. It is thought that dendritic transcripts contain cis-acting elements that direct their selective subcellular sorting. Here we report the identification of an extrasomatic targeting element in the 3' untranslated region of the mRNA encoding the alpha subunit of Ca2+/calmodulin-dependent protein kinase II. In primary hippocampal neurons, this 1200-nucleotide-spanning, cis-acting element is sufficient to mediate dendritic localization of chimeric reporter transcripts. The trafficking signal does not share any striking sequence similarity with a previously characterized dendritic targeting element in transcripts encoding the microtubule-associated protein 2. In dendrites of transfected primary neurons, recombinant RNAs form granules with an average diameter of 0.45 microm that may represent preferential RNA docking sites or multimolecular transport units. These findings imply that extrasomatic sorting of individual dendritic mRNAs involves at least partially distinct molecular mechanisms, as well as large trafficking complexes.
Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats (1996)

Combined oral administration of morphine sulfate (MS) and the over-the-counter antitussive drug and N-methyl-D-aspartate receptor antagonist dextromethorphan (DM) prevented the development of tolerance to the antinociceptive effects of MS (15, 24, or 32 mg/kg) in rats. This combined oral treatment regimen also attenuated signs of naloxone-precipitated physical dependence on morphine in the same rats. A wide range of ratios of MS to DM (2:1, 1:1, and 1:2) were effective for preventing the development of morphine tolerance and dependence. In addition, we provide evidence that under certain circumstances DM increases the acute antinociceptive effects of MS. All of these results indicate that oral treatment that combines DM with opiate analgesics may be a powerful approach for simultaneously preventing opiate tolerance and dependence and enhancing analgesia in humans.
Cooperative local repair in distributed storage (2015)

Erasure-correcting codes, which support local repair of codeword symbols, have attracted substantial attention recently for their application in distributed storage systems. This paper investigates a generalization of the usual locally repairable codes. In particular, this paper studies a class of codes with the following property: any small set of codeword symbols can be reconstructed (repaired) from a small number of other symbols. This is referred to as cooperative local repair. The main contribution of this paper is bounds on the trade-off of the minimum distance and the dimension of such codes, as well as explicit constructions of families of codes that enable cooperative local repair. Some other results regarding cooperative local repair are also presented, including an analysis for the well-known Hadamard/Simplex codes.
Premelanosome Amyloid-like Fibrils Are Composed of Only Golgi-processed Forms of Pmel17 That Have Been Proteolytically Processed in Endosomes (2007)

Melanin pigments are synthesized within specialized organelles called melanosomes and polymerize on intraluminal fibrils that form within melanosome precursors. The fibrils consist of proteolytic fragments derived from Pmel17, a pigment cell-specific integral membrane protein. The intracellular pathways by which Pmel17 accesses melanosome precursors and the identity of the Pmel17 derivatives within fibrillar melanosomes have been a matter of debate. We show here that antibodies that detect Pmel17 within fibrillar melanosomes recognize only the luminal products of proprotein convertase cleavage and not the remaining products linked to the transmembrane domain. Moreover, antibodies to the N and C termini detect only Pmel17 isoforms present in early biosynthetic compartments, which constitute a large fraction of detectable steady state Pmel17 in cell lysates because of slow early biosynthetic transport and rapid consumption by fibril formation. Using an antibody to a luminal epitope that is destroyed upon modification by O-linked oligosaccharides, we show that all post-endoplasmic reticulum Pmel17 isoforms are modified by Golgi-associated oligosaccharide transferases, and that only processed forms contribute to melanosome biogenesis. These data indicate that Pmel17 follows a single biosynthetic route from the endoplasmic reticulum through the Golgi complex and endosomes to melanosomes, and that only fragments encompassing previously described functional luminal determinants are present within the fibrils. These data have important implications for the site and mechanism of fibril formation.
Quinoxalines. I. Preparation and Stereochemistry of Decahydroquinoxalines (1960)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTQuinoxalines. I. Preparation and Stereochemistry of DecahydroquinoxalinesH. Smith Broadbent, Evan L. Allred, Lynn Pendleton, and Charles W. WhittleCite this: J. Am. Chem. Soc. 1960, 82, 1, 189–193Publication Date (Print):January 1, 1960Publication History Published online1 May 2002Published inissue 1 January 1960https://pubs.acs.org/doi/10.1021/ja01486a043https://doi.org/10.1021/ja01486a043research-articleACS PublicationsRequest reuse permissionsArticle Views242Altmetric-Citations14LEARN 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
A bichromatic fluorescent reporter for cell-based screens of alternative splicing (2006)

Alternative splicing is the primary source of proteome complexity in metazoans and its regulation shapes the proteome in response to shifting physiological requirements. We developed a bichromatic splicing reporter that uses a peculiar feature of some fluorescent protein coding regions to express two different fluorescent proteins from a single alternative splicing event. The mutually exclusive expression of different fluorescent proteins from a single reporter provides a uniquely sensitive approach for high-throughput screening and analysis of cell-specific splicing events in mixed cell cultures and tissues of transgenic animals. This reporter is applicable to the majority of alternative splicing patterns and can be used to quantify alternative splicing within single cells and to select cells that express specific splicing patterns. The ability to perform quantitative single-cell analysis of alternative splicing and high-throughput screens will enhance progress toward understanding splicing regulatory networks and identifying compounds that reverse pathogenic splicing defects.
Motor rehabilitation using virtual reality (2004)

Virtual Reality (VR) provides a unique medium suited to the achievement of several requirements for effective rehabilitation intervention. Specifically, therapy can be provided within a functional, purposeful and motivating context. Many VR applications present opportunities for individuals to participate in experiences, which are engaging and rewarding. In addition to the value of the rehabilitation experience for the user, both therapists and users benefit from the ability to readily grade and document the therapeutic intervention using various systems. In VR, advanced technologies are used to produce simulated, interactive and multi-dimensional environments. Visual interfaces including desktop monitors and head-mounted displays (HMDs), haptic interfaces, and real-time motion tracking devices are used to create environments allowing users to interact with images and virtual objects in real-time through multiple sensory modalities. Opportunities for object manipulation and body movement through virtual space provide frameworks that, in varying degrees, are perceived as comparable to similar opportunities in the real world. This paper reviews current work on motor rehabilitation using virtual environments and virtual reality and where possible, compares outcomes with those achieved in real-world applications.
Nanoparticle Size Is a Critical Physicochemical Determinant of the Human Blood Plasma Corona: A Comprehensive Quantitative Proteomic Analysis (2011)

In biological fluids, proteins associate with nanoparticles, leading to a protein "corona" defining the biological identity of the particle. However, a comprehensive knowledge of particle-guided protein fingerprints and their dependence on nanomaterial properties is incomplete. We studied the long-lived ("hard") blood plasma derived corona on monodispersed amorphous silica nanoparticles differing in size (20, 30, and 100 nm). Employing label-free liquid chromatography mass spectrometry, one- and two-dimensional gel electrophoresis, and immunoblotting the composition of the protein corona was analyzed not only qualitatively but also quantitatively. Detected proteins were bioinformatically classified according to their physicochemical and biological properties. Binding of the 125 identified proteins did not simply reflect their relative abundance in the plasma but revealed an enrichment of specific lipoproteins as well as proteins involved in coagulation and the complement pathway. In contrast, immunoglobulins and acute phase response proteins displayed a lower affinity for the particles. Protein decoration of the negatively charged particles did not correlate with protein size or charge, demonstrating that electrostatic effects alone are not the major driving force regulating the nanoparticle-protein interaction. Remarkably, even differences in particle size of only 10 nm significantly determined the nanoparticle corona, although no clear correlation with particle surface volume, protein size, or charge was evident. Particle size quantitatively influenced the particle's decoration with 37% of all identified proteins, including (patho)biologically relevant candidates. We demonstrate the complexity of the plasma corona and its still unresolved physicochemical regulation, which need to be considered in nanobioscience in the future.
Chemical Synthesis, Backbone Cyclization and Oxidative Folding of Cystine-knot Peptides — Promising Scaffolds for Applications in Drug Design (2012)

Cystine-knot peptides display exceptional structural, thermal, and biological stability. Their eponymous motif consists of six cysteine residues that form three disulfide bonds, resulting in a notably rigid structural core. Since they highly tolerate either rational or combinatorial changes in their primary structure, cystine knots are considered to be promising frameworks for the development of peptide-based pharmaceuticals. Despite their relatively small size (two to three dozens amino acid residues), the chemical synthesis route is challenging since it involves critical steps such as head-to-tail cyclization and oxidative folding towards the respective bioactive isomer. Herein we describe the topology of cystine-knot peptides, their synthetic availability and briefly discuss potential applications of engineered variants in diagnostics and therapy.
A beam-modulated time-of-flight mass spectrometer. II. Experimental work (1974)

For pt.I see ibid., vol.6, 785 (1973). A straight path beam-modulated time-of-flight mass spectrometer has been constructed. The instrument consists of an ion source, a drift tube and a collector. The ion source is constructed by combining a conventional ionization chamber with an electron gun structure from a cathode ray tube incorporating an XY deflection system. The ion beam is modulated by applying to the X or Y plates a voltage varying in accordance with a step function. The mathematical analysis of the beam-modulation process has shown that the theoretical resolving power of this instrument should be inversely proportional to the beam plus collector slit width and proportional to the square of the flight path.