gebhart/patrepeval huggingface dataset:
A Novel Amino Lipid Series for mRNA Delivery: Improved Endosomal Escape and Sustained Pharmacology and Safety in Non-human Primates (2018)

The success of mRNA-based therapies depends on the availability of a safe and efficient delivery vehicle. Lipid nanoparticles have been identified as a viable option. However, there are concerns whether an acceptable tolerability profile for chronic dosing can be achieved. The efficiency and tolerability of lipid nanoparticles has been attributed to the amino lipid. Therefore, we developed a new series of amino lipids that address this concern. Clear structure-activity relationships were developed that resulted in a new amino lipid that affords efficient mRNA delivery in rodent and primate models with optimal pharmacokinetics. A 1-month toxicology evaluation in rat and non-human primate demonstrated no adverse events with the new lipid nanoparticle system. Mechanistic studies demonstrate that the improved efficiency can be attributed to increased endosomal escape. This effort has resulted in the first example of the ability to safely repeat dose mRNA-containing lipid nanoparticles in non-human primate at therapeutically relevant levels.
In Vitro Resistance to Thrombin-Induced Platelet Microbicidal Protein Is Associated with Enhanced Progression and Hematogenous Dissemination in Experimental Staphylococcus aureus Infective Endocarditis (1998)

We examined the influence of thrombin-induced platelet microbicidal protein 1 (tPMP-1) on the progression and hematogenous dissemination of experimental endocarditis caused by isogenic Staphylococcus aureus strains differing in tPMP susceptibility (tPMPs) or resistance (tPMPr) in vitro. Following simultaneous challenge of animals with both strains, significantly higher tPMPr bacterial densities were present in vegetations (P < 0.0001), kidneys (P < 0. 0001), and spleens (P < 0.0001) compared with those for the tPMPs strain. These data indicate that tPMP-1 limits the intravegetation proliferation and hematogenous dissemination of a tPMPs strain in experimental endocarditis, while the tPMPr phenotype confers a selective advantage associated with the enhanced progression of this infection.
[Oxidative iodination of rabbit IgG: localization of markers in an Fc-fragment and effects of modification]. (1991)

A comparative study of rabbit IgG, both native and modified ones, designed to assess the functional activity of these proteins under oxidative iodination conditions has been carried out. Polyclonal IgG, its antigen-specific fraction and Iodogen as an oxidant were used. Polyclonal antibodies directed against the CH2 domain of IgG, protein A targeted at the CH-2-CH3 domain interface and ferritin testing the conformation of the antigen-binding Fv fragment, were applied as conformational probes for assessing the changes in the IgG conformation. By taking advantage of pepsin proteolysis of [125I]-IgG, from 80% to 92% of the label was found to be localized within the CH3 domain, thus implying the domain-selective nature of iodination, when the degree of modification was below 0.1 atom of iodine per IgG molecule. Yet, when the three above-mentioned conformational probes were used, considerable alterations in the conformation of not only the CH2 domain and CH2-CH3 domain interface, but in the Fv domain being a part of the Fab fragment, were observed. By using competitive enzyme immunoassay for the straightforward comparative evaluation of functional properties of "cold" (native) and 125I-modified IgG, the deleterious effect of the oxidant (Iodogen) rather than iodine atom substitution at the phenolic ring of Tyr residues was shown to be the major determinant of alterations in the IgG molecule.
Induction of a glibenclamide‐sensitive K‐current by modification of a delayed rectifier channel in rat portal vein and insulinoma cells (1993)

In insulinoma cells (RINm5F), the glibenclamide-sensitive K-current (IK(ATP)) which developed spontaneously or after exposure to levcromakalim or to butanedione monoxime was always accompanied by a reduction in the delayed rectifier current (IK(V)). At potentials over which IK(V) was fully activated, the total outward current remained constant. In rat portal vein, the delayed rectifier channel inhibitor, margatoxin, reduced the combined induction of IK(ATP) and inhibition of IK(V) by levcromakalim. These data suggest that the ATP-sensitive K-channel, K(ATP), is a voltage-insensitive state of the delayed rectifier, KV.
STRUCTURE, FUNCTION, AND REPLICATION OF SACCHAROMYCES CEREVISIAE TELOMERES (1996)

A combination of classical genetic, biochemical, and molecular biological approaches have generated a rather detailed understanding of the structure and function of Saccharomyces telomeres. Yeast telomeres are essential to allow the cell to distinguish intact from broken chromosomes, to protect the end of the chromosome from degradation, and to facilitate the replication of the very end of the chromosome. In addition, yeast telomeres are a specialized site for gene expression in that the transcription of genes placed near them is reversibly repressed. A surprisingly large number of genes have been identified that influence either telomere structure or telomere function (or both), although in many cases the mechanism of action of these genes is poorly understood. This article reviews the recent literature on telomere biology and highlights areas for future research.
A perspective on systems and controls engineering in the earth moving and construction industry (1998)

This paper focuses on the requirements of systems and controls engineering for production intent machines in the earth moving and construction industry. Mobile machinery operates in an ill-structured environment which subsequently makes it difficult to define requirements in complete engineering terms. This in turn makes it difficult to judge the feasibility of introducing a control or system onto a production machine. To address this problem, several top level metrics are introduced to evaluate performance. These include measuring the machine efficiency by the cost per ton of materials moved or quantity of materials moved per gallon of fuel, and machine utilization as the percentage of total shift time. These metrics are then used to gain a perspective of current controls development for mobile machinery and its feasibility in production.
Generating Descriptions with Grounded and Co-referenced People (2017)

Learning how to generate descriptions of images or videos received major interest both in the Computer Vision and Natural Language Processing communities. While a few works have proposed to learn a grounding during the generation process in an unsupervised way (via an attention mechanism), it remains unclear how good the quality of the grounding is and whether it benefits the description quality. In this work we propose a movie description model which learns to generate description and jointly ground (localize) the mentioned characters as well as do visual co-reference resolution between pairs of consecutive sentences/clips. We also propose to use weak localization supervision through character mentions provided in movie descriptions to learn the character grounding. At training time, we first learn how to localize characters by relating their visual appearance to mentions in the descriptions via a semi-supervised approach. We then provide this (noisy) supervision into our description model which greatly improves its performance. Our proposed description model improves over prior work w.r.t. generated description quality and additionally provides grounding and local co-reference resolution. We evaluate it on the MPII Movie Description dataset using automatic and human evaluation measures and using our newly collected grounding and co-reference data for characters.
Analgesic effect of octreotide in headache associated with acromegaly is not mediated by opioid mechanisms. Case report (1991)

We report a patient with acromegaly who had severe, intractable headache unrelated to tumor size which dramatically resolved with the somatostatin analog octreotide. The analgesic effects of octreotide were neither related to significant inhibition of growth hormone nor influenced by naloxone. Our data suggest that octreotide should be considered in patients with intractable headache associated with pituitary adenomas. Mechanisms other than tumor size or interaction with the opioid system, such as non-opioid algesic peptide secretion, may be the explanation for severe head pain in some pituitary adenomas.
On the Promoting Effect of Alkali Metals on the Adsorption of Nitriles on the Gold (100) Surface (1991)

Abstract Submolayer concentrations of (strongly electropositively polarized) Na and K on the Au(100) surface create three new acctonitrile (CH 3 CN) and benzonitrile (C 6 H 5 CN) binding states (the γ‐states) on the high‐temperature side of the corresponding molecular thermal desorption spectra (β‐state) observed for the clean, unpromoted Au surface. The additional states appear with both alkali metals and nitriles, whereby they are energetically about equally spaced (Δ T ≈ 30 K with K, and Δ T ≈ 50 K with Na) and sequentially populated, indicating a more general electrostatic modification of the nitrile's adsorptive bonding in the vicinity of an adsorbed alkali atom. The triplet of TD states is tentatively interpreted as being caused by a subsequent filling of a coordination shell formed by the nitriles around each individual alkali metal atom. Similar energetics involved in the formation of gas‐phase and surface cluster complexes of the kind Me δ+ {N  C–CH 3 } δ− is noted and discussed.
The Hemetsberger-Knittel Synthesis of Substituted 5-, 6-, and 7-Azaindoles (2005)

A series of substituted 5-, 6-, and 7-azaindoles were prepared via the Hemetsberger-Knittel reaction. In general, better yields were obtained at higher temperatures and shorter reaction times than required for the formation of the analogous indoles, and in some cases, only decomposition occurred below a minimum temperature. The resulting templates offer up to five sites for subsequent functionalization to allow a wide range of chemical diversity.
Structure and organization of two linked ribosomal protein genes in yeast (1984)

The genes encoding yeast ribosomal proteins rp28 and S16A are linked and occur duplicated in the yeast genome. In both gene pairs the genes are approximately 600 bp apart and are both transcribed in the same direction. Both ribosomal protein genes resemble other ribosomal protein genes studied so far in many structural aspects. The genes are interrupted by an intron near the 5'-end of their coding sequence. In addition the flanking regions contain several conserved sequence elements, which may function in transcription initiation and termination. In agreement with findings concerning other cloned yeast ribosomal protein genes, upstream homology blocks occur that may be involved in coordinate control of ribosomal protein gene transcription. The complete pattern of conserved and diverged sequences between the two duplicate gene pairs is presented.
High sensitivity of cancer exome-based CD8 T cell neo-antigen identification (2014)

Recent data suggest that T-cell reactivity against tumor-specific neo-antigens may be central to the clinical efficacy of cancer immunotherapy. The development of personalized vaccines designed to boost T-cell reactivity against patient specific neo-antigens has been proposed largely on the basis of these findings. Work from several groups has demonstrated that novel tumor-specific antigens can be discovered through the use of cancer exome sequencing data, thereby providing a potential pipeline for the development of patient-specific vaccines. Importantly though, it has not been established which fraction of cancer neo-antigens that can be recognized by CD8<sup>+</sup> T cells is successfully uncovered with the current exome-based epitope prediction strategies. Here, we use a data set comprising human cancer neo-antigens that was previously identified through the use of unbiased, computational-independent strategies to describe the potential of cancer exome-based neo-antigen discovery. This analysis shows a high sensitivity of exome-guided neo-antigen prediction of approximately 70%. We propose that future research should focus on the analysis and optimization of the specificity of neo-antigen prediction, and should undoubtedly entail the clinical evaluation of patient-specific vaccines with the aim of inducing immunoreactivity against tumor-displayed neo-antigens in a physiologically relevant context.
Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme (2010)

Therapy options at the time of recurrence of glioblastoma multiforme are often limited. We investigated whether treatment with a new intratumoral thermotherapy procedure using magnetic nanoparticles improves survival outcome. In a single-arm study in two centers, 66 patients (59 with recurrent glioblastoma) received neuronavigationally controlled intratumoral instillation of an aqueous dispersion of iron-oxide (magnetite) nanoparticles and subsequent heating of the particles in an alternating magnetic field. Treatment was combined with fractionated stereotactic radiotherapy. A median dose of 30 Gy using a fractionation of 5 × 2 Gy/week was applied. The primary study endpoint was overall survival following diagnosis of first tumor recurrence (OS-2), while the secondary endpoint was overall survival after primary tumor diagnosis (OS-1). Survival times were calculated using the Kaplan-Meier method. Analyses were by intention to treat. The median overall survival from diagnosis of the first tumor recurrence among the 59 patients with recurrent glioblastoma was 13.4 months (95% CI: 10.6-16.2 months). Median OS-1 was 23.2 months while the median time interval between primary diagnosis and first tumor recurrence was 8.0 months. Only tumor volume at study entry was significantly correlated with ensuing survival (P < 0.01). No other variables predicting longer survival could be determined. The side effects of the new therapeutic approach were moderate, and no serious complications were observed. Thermotherapy using magnetic nanoparticles in conjunction with a reduced radiation dose is safe and effective and leads to longer OS-2 compared to conventional therapies in the treatment of recurrent glioblastoma.
Detection of peptidoglycan in human plasma using the silkworm larvae plasma test (2000)

Silkworm larvae plasma (SLP) reagent, which is prepared from the body fluid of the silkworm, reacts with peptidoglycan (PG), a fragment of both the Gram-positive and Gram-negative bacterial cell wall, as well as with beta-glucan, a component of fungi. We developed a quantitative method for the detection of PG in human plasma from cases with bacterial infection using the SLP reagent. Tested in this way, the SLP method showed 86.2% sensitivity, 90.6% specificity, 89.3% positive predictive value, and 88.5% efficiency. The SLP method provides a valuable tool for the diagnosis of systemic infection using patients' blood.
Human adenovirus early region 4 open reading frame 1 genes encode growth-transforming proteins that may be distantly related to dUTP pyrophosphatase enzymes (1997)

An essential oncogenic determinant of subgroup D human adenovirus type 9 (Ad9), which uniquely elicits estrogen-dependent mammary tumors in rats, is encoded by early region 4 open reading frame 1 (E4 ORF1). Whereas Ad9 E4 ORF1 efficiently induces transformed foci on the established rat embryo fibroblast cell line CREF, the related subgroup A Ad12 and subgroup C Ad5 E4 ORF1s do not (R. T. Javier, J. Virol. 68:3917-3924, 1994). In this study, we found that the lack of transforming activity associated with non-subgroup D adenovirus E4 ORF1s in CREF cells correlated with significantly reduced protein levels compared to Ad9 E4 ORF1 in these cells. In the human cell line TE85, however, the non-subgroup D adenovirus E4 ORF1s produced protein levels higher than those seen in CREF cells as well as transforming activities similar to that of Ad9 E4 ORF1, suggesting that all adenovirus E4 ORF1 polypeptides possess comparable cellular growth-transforming activities. In addition, searches for known proteins related to these novel viral transforming proteins revealed that the E4 ORF1 proteins had weak sequence similarity, over the entire length of the E4 ORF1 polypeptides, with a variety of organismal and viral dUTP pyrophosphatase (dUTPase) enzymes. Even though adenovirus E4 ORF1 proteins lacked conserved protein motifs of dUTPase enzymes or detectable enzymatic activity, E4 ORF1 and dUTPase proteins were predicted to possess strikingly similar secondary structure arrangements. It was also established that an avian adenovirus protein, encoded within a genomic location analogous to that of the human adenovirus E4 ORF1s, was a genuine dUTPase enzyme. Although no functional similarity was found for the E4 ORF1 and dUTPase proteins, we propose that human adenovirus E4 ORF1 genes have evolved from an ancestral adenovirus dUTPase and, from this structural framework, developed novel transforming properties.
Structure-function correlations in the reaction of bis(thiosemicarbazonato) copper(II) complexes with Ehrlich ascites tumor cells. (1978)

Examination of a series of substituted bis(thiosemicarbazonato) copper(II) complexes shows that their reaction with Ehrlich ascites tumor cells can be understood in terms of the relative reactivity of the complexes with sulfhydryl groups. In general, the order of reactivity of the complexes correlates directly with their respective degrees of cytotoxicity and ability to inhibit DNA synthesis and cellular respiration. The parent complex, 3-ethoxy-2-oxobutyraldehyde bis(thiosemicarbazonato) copper(II), leads to widespread cellular effects with the suppression of DNA synthesis particularly sensitive to the complex. The apparent reversible inhibition of DNA synthesis and thymidine uptake hy 3-ethoxy-2-oxobutyraldehyde bis(N4-dimethylthiosemicarbazonato) copper(II) and its lack of cytotoxicity are explained in terms of the chemical properties of this complex.
Homodimerization of tumor-reactive monoclonal antibodies markedly increases their ability to induce growth arrest or apoptosis of tumor cells (1997)

Monoclonal antibodies (mAbs) that exert antitumor activity can do so by virtue of their effector function and/or their ability to signal growth arrest or cell death. In this study, we demonstrate that mAbs which have little or no signaling activity-i.e., anti-CD19, CD20, CD21, CD22 and Her-2-can become potent antitumor agents when they are converted into IgG-IgG homodimers. The homodimers exert antigrowth activity by signaling G0/G1 arrest or apoptosis, depending upon which cell surface molecule they bind. This activity is specific and, in the case of the anti-CD19 mAb, did not require an Fc portion. These results offer the possibility that homodimers of other tumor-reactive mAbs which have little antitumor activity as monomers might be potent, antitumor agents.
Utility of Amino-Terminal Pro–Brain Natriuretic Peptide Testing for Prediction of 1-Year Mortality in Patients With Dyspnea Treated in the Emergency Department (2006)

In addition to assisting in emergency department diagnosis and triage, NT-proBNP concentrations at presentation are strongly predictive of 1-year mortality in dyspneic patients.
Hybridization Behavior of Mixed DNA/Alkylthiol Monolayers on Gold:  Characterization by Surface Plasmon Resonance and 32P Radiometric Assay (2006)

Nucleic acid assay from a complex biological milieu is attractive but currently difficult and far from routine. In this study, DNA hybridization from serum dilutions into mixed DNA/mercaptoundecanol (MCU) adlayers on gold was monitored by surface plasmon resonance (SPR). Immobilized DNA probe and hybridized target densities on these surfaces were quantified using 32P-radiometric assays as a function of MCU diluent exposure. SPR surface capture results correlated with radiometric analysis for hybridization performance, demonstrating a maximum DNA hybridization on DNA/MCU mixed adlayers. The maximum target surface capture produced by MCU addition to the DNA probe layer correlates with structural and conformational data on identical mixed DNA/MCU adlayers on gold derived from XPS, NEXAFS, and fluorescence intensity measurements reported in a related study (Lee, C.-Y.; Gong, P.; Harbers, G. M.; Grainger, D. W.; Castner, D. G.; Gamble, L. J. Anal. Chem. 2006, 78, 3316-3325.). MCU addition into the DNA adlayer on gold also improved surface resistance to both nonspecific DNA and serum protein adsorption. Target DNA hybridization from serum dilutions was monitored with SPR on the optimally mixed DNA/MCU adlayers. Both hybridization kinetics and efficiency were strongly affected by nonspecific protein adsorption from a complex milieu even at a minimal serum concentration (e.g., 1%). No target hybridization was detected in SPR assays from serum concentrations above 30%, indicating nonspecific protein adsorption interference of DNA capture and hybridization from complex milieu. Removal of nonsignal proteins from nucleic acid targets prior to assay represents a significant issue for direct sample-to-assay nucleic acid diagnostics from food, blood, tissue, PCR mixtures, and many other biologically complex sample formats.
Review of the recent controlled experiments for study of local reconnection physics (2014)

The present paper reviews the recent laboratory experiments on magnetic reconnection focussing on the local features of the reconnection region. It is very important to recognize that magnetohydrodynamics (MHD) often breaks down locally in the thin reconnection layer, while globally, the reconnecting plasma has large Lundquist number and is well approximated by MHD equations. Precise measurements of the neutral sheet profile can provide important clues to help understand the non-MHD physics mechanisms of reconnection. Thanks to significant progress in data acquisition technology, the detailed magnetic field structure of the neutral sheet has been measured in laboratory plasmas. Extensive data have been accumulated in highly conductive MHD plasmas with large Lundquist numbers S = 10–1000. In this review we primarily focus on the physics data of the neutral sheet from the most recent laboratory experiments.
Elicitor-Inducible 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity Is Required for Sesquiterpene Accumulation in Tobacco Cell Suspension Cultures (1991)

Addition of cell wall fragments from Phytophthora species or cellulase from Trichoderma viride, but not pectolyase from Aspergillus japonicus, to tobacco (Nicotiana tabacum) cell suspension cultures induced the accumulation of the extracellular sesquiterpenoid capsidiol. Pulse-labeling experiments with [(14)C]acetate and [(3)H]mevalonate suggested that enzymatic steps preceding mevalonate were limiting capsidiol biosynthesis in the pectolyase-treated cell cultures. Treatment of the cell cultures with either Phytophthora cell wall fragments or cellulase induced 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) and sesquiterpene cyclase activities, enzymes of the sesquiterpene biosynthetic pathway, and phenylalanine ammonia lyase activity, an enzyme of the general phenylpropanoid pathway. Pectolyase treatment induced sesquiterpene cyclase and phenylalanine ammonia lyase activities, but not HMGR activity. These results corroborate the importance of inducible HMGR enzyme activity for sesquiterpene accumulation.