gebhart/patrepeval huggingface dataset:
Invited Review: Development of Fat Emulsions (1981)

The studies on the possibility of preparing IV fat emulsions began in the 1920's; since then, a very large number of emulsions with various fats and emulsifiers have been investigated. However, none of the early fat emulsions could be used safely in man. By the trial and error technique, a method was finally found to prepare soybean oil and egg yolk phospholipids to make a fat emulsion that had a low incidence of adverse reactions. A newly devised biological test system based on nutritional concepts was of crucial importance. It meant that any energy supplying nutrient should be tested in animals in relation to the energy requirement of the species used and not identical to the human dose/kg body weight as in the "classical" toxicity and tolerance tests. With the development of well-tolerated IV fat emulsions it has been possible to devise a TPN regimen that is adequate from a nutritional point of view as well as an adequate alternative to the ordinary oral food. This regimen, which can be administered by the peripheral route, means that the original aims for developing IV fat emulsions were finally achieved.
Photoswitchable binding of substrates to proteins : photoregulated binding of α-D-mannopyranose to concanavalin A modified by a thiophenefulgide dye (1992)

Macromolecules exhibiting photoswitchable physical or chemical properties are extensively examined as information storage and signal amplification materials. Photoregulated "on-of" biomaterials provide a novel means to design targeted therapeutic agents activated and deactivated by external light signals. Various means to photoregulate biotransformations by light-switchable enzymes have been described and include the modification of the enzyme active site and protein backbone by photochromic components and immobilization of enzymes in photochromic copolymers. Here we wish to report on the photoregulation of the binding properties of a protein by its chemical modification with photochromic units. We describe the photoswitchable binding of saccharides to concanavalin A modified by thiophenefulgide dye.
Crystal structure of phosphodiesterase 4D and inhibitor complex1 (2002)

Cyclic nucleotide phosphodiesterases (PDEs) regulate physiological processes by degrading intracellular second messengers, adenosine-3',5'-cyclic phosphate or guanosine-3',5'-cyclic phosphate. The first crystal structure of PDE4D catalytic domain and a bound inhibitor, zardaverine, was determined. Zardaverine binds to a highly conserved pocket that includes the catalytic metal binding site. Zardaverine fills only a portion of the active site pocket. More selective PDE4 inhibitors including rolipram, cilomilast and roflumilast have additional functional groups that can utilize the remaining empty space for increased binding energy and selectivity. In the crystal structure, the catalytic domain of PDE4D possesses an extensive dimerization interface containing residues that are highly conserved in PDE1, 3, 4, 8 and 9. Mutations of R358D or D322R among these interface residues prohibit dimerization of the PDE4D catalytic domain in solution.
Vaginitis: current microbiologic and clinical concepts. (1986)

Infectious vaginitis occurs when the normal vaginal flora is disrupted; it may arise when saprophytes overwhelm the host immune response, when pathogenic organisms are introduced into the vagina or when changes in substrate allow an imbalance of microorganisms to develop. Examples of these types of vaginitis include the presence of chronic fungal infection in women with an inadequate cellular immune response to the yeast, the introduction of trichomonads into vaginal epithelium that has a sufficient supply of glycogen, and the alteration in bacterial flora, normally dominated by Lactobacillus spp., and its metabolites that is characteristic of "nonspecific vaginitis". The authors review microbiologic and clinical aspects of the fungal, protozoal and bacterial infections, including the interactions of bacteria thought to produce nonspecific vaginitis, that are now recognized as causing vaginitis. Other causes of vaginitis are also discussed.
19F nuclear magnetic resonance studies of aromatic compounds. Part I. The effect of solvents on the chemical shift of fluorine nuclei in para-substituted fluorobenzenes, 4-substituted 4′-fluoro-trans-stilbenes, and 4-substituted 3′-fluoro-trans-stilbenes (1972)

Solvent effects upon 19F shielding in some aryl fluorides are examined. A criterion is established which, it is believed, enables solvents and reference to be chosen so that interactions other than those due to ‘reaction fields’ are minimised. The reaction field model appears to work satisfactorily for 4-substituted 3′- and 4′-fluoro-trans-stilbenes, but breaks down for para-substituted fluorobenzenes.
Distinguishing melanocytic nevi from melanoma by DNA copy number changes: comparative genomic hybridization as a research and diagnostic tool (2006)

Cancer typically results in loosened control over genomic integrity, resulting in alterations of the genome of cancer cells. Comparative genomic hybridization (CGH) is a method that can be used on DNA extracted from routinely fixed tissue to assess the entire genome for the presence of changes in DNA copy number. CGH analysis has revealed that melanoma differs from melanocytic nevi by the presence of frequent chromosomal aberrations. In contrast, melanocytic nevi typically show no chromosomal aberrations, or have a restricted set of alterations with basically no overlap to melanoma. These marked differences between aberration patterns in melanomas and melanocytic nevi can be exploited diagnostically to classify melanocytic tumors that are ambiguous based on histopathologic assessment. In addition to potential diagnostic applications, detailed analyses of recurrent aberrations can lead to the identification of genes relevant in melanocytic neoplasia.
Passive immunization with anti-glucosaminidase monoclonal antibodies protects mice from implant-associated osteomyelitis by mediating opsonophagocytosis ofStaphylococcus aureusmegaclusters (2014)

Towards the development of a methicillin-resistant Staphylococcus aureus (MRSA) vaccine we evaluated a neutralizing anti-glucosaminidase (Gmd) monoclonal antibody (1C11) in a murine model of implant-associated osteomyelitis, and compared its effects on LAC USA300 MRSA versus a placebo and a Gmd-deficient isogenic strain (ΔGmd). 1C11 significantly reduced infection severity, as determined by bioluminescent imaging of bacteria, micro-CT assessment of osteolysis, and histomorphometry of abscess numbers (p < 0.05). Histology also revealed infiltrating macrophages, and the complete lack of staphylococcal abscess communities (SAC), in marrow abscesses of 1C11 treated mice. In vitro, 1C11 had no direct effects on proliferation, but electron microscopy demonstrated that 1C11 treatment phenocopies ΔGmd defects in binary fission. Moreover, addition of 1C11 to MRSA cultures induced the formation of large bacterial aggregates (megaclusters) that sedimented out of solution, which was not observed in ΔGmd cultures or 1C11 treated cultures of a protein A-deficient strain (ΔSpa), suggesting that the combined effects of Gmd inhibition and antibody-mediated agglutination are required. Finally, we demonstrated that macrophage opsonophagocytosis of MRSA and megaclusters is significantly increased by 1C11 (p < 0.01). Collectively, these results suggest that the primary mechanism of anti-Gmd humoral immunity against MRSA osteomyelitis is macrophage invasion of Staphylococcal abscess communities (SAC) and opsonophagocytosis of megaclusters. .
Targeted Cancer Therapy: Conferring Specificity to Cytotoxic Drugs (2007)

The therapeutic activity of most anticancer drugs in clinical use is limited by their general toxicity to proliferating cells, including some normal cells. Although, chemists continue to develop novel cytotoxic agents with unique mechanisms of action, many of these compounds still lack tumor selectivity and have not been therapeutically useful. Monoclonal antibodies that bind to specific markers on the surface of tumor cells offer an alternative therapy that is tumor specific and thus less toxic. Although highly selective, very few monoclonal antibodies are therapeutically useful since they only display modest cell killing activity. The linkage of monoclonal antibodies to highly cytotoxic drugs can be viewed as a means of (a) conferring higher tumor selectivity to cytotoxic drugs that are too toxic to be used on their own or (b) conferring cell killing power to monoclonal antibodies that are tumor-specific but not sufficiently cytotoxic. This Account provides a brief history of the development of antibody-drug conjugates and shows how the lessons learned from the first generation of conjugates has guided the development of more effective antitumor agents. The three components of antibody-drug conjugates, that is, the monoclonal anitbody, the cytotoxic drug, and the linker connecting the drug to the antibody, have been methodically studied and optimized. The antimitotic drug maytansine was chosen for use in the targeted delivery approach because of its high in vitro potency. Analogues of maytansine bearing a disulfide substituent that allowed linkage to monoclonal antibodies via disulfide bonds were prepared. These analogues retain the high potency of the parent drug. The stability of the disulfide link in antibody-maytansinoid conjugates was varied by introduction of methyl substituents on the carbon atoms geminal to the disulfide link. The optimized disulfide linker was stable in circulation in vivo. The circulation half-life of the cytotoxic drug was increased from just a few hours for the unconjugated drug to several days for the conjugate. Upon binding of the conjugate to the tumor cell, internalization and lysosomal processing released the potent cytotoxic agent inside the cell. These conjugates displayed high target-specific cytotoxicity in vitro. The antitumor activity of these targeted agents was superior to that of the antibodies alone or the standard anticancer drugs in human tumor xenograft models. Several conjugates from this new class of tumor-targeted anticancer agents are currrently undergoing clinical evaluation. The progress made in the targeted delivery approach and initial clinical results opens the door to the future development of highly potent drugs that were too toxic on their own to be therapeutically useful.
The bubble cursor (2005)

We present the bubble cursor - a new target acquisition technique based on area cursors. The bubble cursor improves upon area cursors by dynamically resizing its activation area depending on the proximity of surrounding targets, such that only one target is selectable at any time. We also present two controlled experiments that evaluate bubble cursor performance in 1D and 2D target acquisition tasks, in complex situations with multiple targets of varying layout densities. Results show that the bubble cursor significantly outperforms the point cursor and the object pointing technique [7], and that bubble cursor performance can be accurately modeled and predicted using Fitts' law.
Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: A randomized, open-label, placebocontrolled multicenter trial (1994)

This initial evaluation suggests that human recombinant IL-1ra is safe and may provide a dose-related survival advantage to patients with sepsis syndrome. A larger, definitive clinical trial is needed to confirm these findings.
Distribution functions in nonequilibrium theory of superconductivity and Andreev spectroscopy in unconventional superconductors (2000)

We develop a theoretical formulation of nonequilibrium superconducting phenomena, including singlet and triplet pairing, which is especially well suited for spatially inhomogeneous problems. We start from the general Keldysh-Nambu-Gor'kov Green's functions in the quasiclassical approximation and represent them in terms of $2\ifmmode\times\else\texttimes\fi{}2$ spin-matrix coherence functions and distribution functions for particle-type and hole-type excitations. The resulting transport equations for the distribution functions may be interpreted as a generalization to the superconducting state of Landau's transport equation for the normal Fermi liquid of conduction electrons. The equations are well suited for numerical simulations of dynamical phenomena. Using our formulation we solve an open problem in quasiclassical theory of superconductivity, the derivation of an explicit representation of Zaitsev's nonlinear boundary conditions (A. V. Zaitsev, Zh. \'Eksp. Teor. Fiz. 86, 1742 (1984) [Sov. Phys. JETP 59, 1015 (1984)]; A. L. Shelankov, Fiz. Tverd. Tela (Leningrad) 26, 1615 (1984) [Sov. Phys. Solid State 26, 981 (1984)]) at surfaces and interfaces. These boundary conditions include nonequilibrium phenomena and spin singlet and triplet unconventional pairing. We eliminate spurious solutions as well as numerical stability problems present in the original formulation. Finally, we formulate the Andreev scattering problem at interfaces in terms of the introduced distribution functions and present a theoretical analysis for the study of time reversal symmetry breaking states in unconventional superconductors via Andreev spectroscopy experiments at normal-metal--superconductor interfaces with finite transmission. We include impurity scattering self-consistently.
Towards A Rigorous Science of Interpretable Machine Learning (2017)

As machine learning systems become ubiquitous, there has been a surge of interest in interpretable machine learning: systems that provide explanation for their outputs. These explanations are often used to qualitatively assess other criteria such as safety or non-discrimination. However, despite the interest in interpretability, there is very little consensus on what interpretable machine learning is and how it should be measured. In this position paper, we first define interpretability and describe when interpretability is needed (and when it is not). Next, we suggest a taxonomy for rigorous evaluation and expose open questions towards a more rigorous science of interpretable machine learning.
Correction of Hunter syndrome in the MPSII mouse model by AAV2/8-mediated gene delivery (2006)

Mucopolysaccharidosis type II (MPSII; Hunter syndrome) is a lysosomal storage disorder caused by a deficiency in the enzyme iduronate 2-sulfatase (IDS). At present, the therapeutic approaches for MPSII are enzyme replacement therapy and bone marrow transplantation, although these therapies have some limitations. The availability of new AAV serotypes that display tissue-specific tropism and promote sustained expression of transgenes offers the possibility of AAV-mediated gene therapy for the systemic treatment of lysosomal diseases, including MPSII. We have characterized in detail the phenotype of IDS-deficient mice, a model of human MPSII. These mice display a progressive accumulation of glycosaminoglycans (GAGs) in many organs and excessive excretion of these compounds in their urine. Furthermore, they develop skeleton deformities, particularly of the craniofacial bones, and alopecia, they perform poorly in open-field tests and they have a severely compromised walking pattern. In addition, they present neuropathological defects. We have designed an efficient gene therapy approach for the treatment of these MPSII mice. AAV2/8TBG-IDS viral particles were administrated intravenously to adult MPSII mice. The plasma and tissue IDS activities were completely restored in all of the treated mice. This rescue of the enzymatic activity resulted in the full clearance of the accumulated GAGs in all of the tissues analyzed, the normalization of the GAG levels in the urine and the correction of the skeleton malformations. Overall, our findings suggest that this in vivo gene transfer approach has potential for the systemic treatment of patients with Hunter syndrome.
Evidence That Fertilization Activates Starfish Eggs by Sequential Activation of a Src-like Kinase and Phospholipase Cγ (2000)

Recent evidence has indicated a requirement for a Src family kinase in initiating Ca(2+) release at fertilization in starfish eggs (Giusti, A. F., Carroll, D. J., Abassi, Y. A., Terasaki, M., Foltz, K. R., and Jaffe, L. A. (1999) J. Biol. Chem. 274, 29318-29322). We now show that injection of Src protein into starfish eggs initiates Ca(2+) release and DNA synthesis, as occur at fertilization. These responses depend on the phosphorylation state of the Src protein; only the kinase active form is effective. Like Ca(2+) release at fertilization, the Ca(2+) release in response to Src protein injection is inhibited by prior injection of the SH2 domains of phospholipase Cgamma. These findings support the conclusion that in starfish, sperm-egg interaction causes egg activation by sequential activation of a Src-like kinase and phospholipase Cgamma. Injection of the SH2 domain of Src, which inhibits Ca(2+) release at fertilization, does not inhibit Ca(2+) release caused by Src protein injection. This indicates that the requirement for a Src SH2 domain interaction is upstream of Src activation in the pathway leading to Ca(2+) release at fertilization.
Construction and compression of face models for multi-party videoconferencing with multi-camera (2013)

Multi-party videoconferencing systems have been recently used more and more, but they have still faced some challenges and problems. In this paper we present a novel method and framework to create face models and construct the gaze and face direction, which can make the user experience of multi-party videoconferencing more immersive and interactive. We utilize multi-camera and one display screen as the user terminal, so it can implement face modeling, gaze tracking and view synthesis. Applying our proposed method it can compress the transfer data and reduce the network bandwidth. Moreover it improves the effectiveness of video contents and lowers the requirements of system hardware.
Interactions Between a Symmetrical Minor Groove Binding Compound and DNA Oligonucleotides: 1H and 19F NMR Studies (1989)

High-resolution NMR techniques (proton and 19F) have been used to study the interactions between several DNA oligonucleotides with varying length of AT base pairs and the synthetic pyrrole-containing compound (P1-F4S-P1), which has properties similar to the DNA minor groove binding drug distamycin A. When this two-fold symmetrical DNA binding molecule is added to the self-complementary DNA oligomers, the resulting complex exhibits an NMR spectrum without any doubling of individual resonances, consistent with a two-fold symmetry of the complex. This is in contrast to all other complexes studied so far. The minimum length of an AT stretch for specific ligand binding is judged to be greater than 4 base pairs. Inter-molecular proton nuclear Overhauser effects between the ligand molecule and a DNA dodecamer d(CGCAAATTTGCG) provide evidence that P1-F4S-P1 binds DNA in the minor groove and interacts with the middle AT base pairs. The presence of a specific interaction between P1-F4S-P1 and DNA is conclusively demonstrated by 19F NMR studies, in which four previously chemically equivalent fluorine nuclei in the free molecule become two non-equivalent pairs (yielding an AB quartet pattern) upon the binding of P1-F4S-P1 to DNA duplex. A sequence-dependent binding behavior of P1-F4S-P1 is evident by comparing the 19F NMR spectra of the complexes between P1-F4S-P1 and two different but related DNA dodecamers, d(CGCAAATTTGCG) and d(CGCTTTAAAGCG). P1-F4S-P1 binds more strongly to the former dodecamer with an association constant of approximately 1 X 10(3) M-1.
Amendments to the Federal Law Limiting the Liability of Shipowners (2014)

The Steamboat Lexington burned in 1848 with a shipment of gold and silver coin on board, amounting to $18,000.The shipowner was held liable for its full value.'The Tel.Morro Castle burned on Sept. 8, 1934, off the Jersey coast with a loss of 135 lives.The owners petitioned the court to limit liability to $20,000 for all loss of life, personal injuries and property damage.
Biology and Clinical Management of Myeloproliferative Neoplasms and Development of the JAK Inhibitor Ruxolitinib (2012)

Myeloproliferative neoplasms (MPN) are debilitating stem cell-derived clonal myeloid malignancies. Conventional treatments for the BCR-ABL1-negative MPN including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) have, so far, been unsatisfactory. Following the discovery of dysregulated JAK-STAT signaling in patients with MPN, many efforts have been directed toward the development of molecularly targeted therapies, including inhibitors of JAK1 and JAK2. Ruxolitinib (previously known as INCB018424; Incyte Corporation, Wilmington, Delaware, USA) is a rationally designed potent oral JAK1 and JAK2 inhibitor that has undergone clinical trials in patients with PV, ET, and PMF. Ruxolitinib was approved on November 16, 2011 by the United States Food and Drug Administration for the treatment of intermediate or high-risk myelofibrosis (MF), including patients with PMF, post-PV MF, and post-ET MF. In randomized phase III studies, ruxolitinib treatment resulted in significant and durable reductions in splenomegaly and improvements in disease-related symptoms in patients with MF compared with placebo or best available therapy. The most common adverse events were anemia and thrombocytopenia, which were manageable and rarely led to discontinuation. This review addresses the cellular and molecular biology, and the clinical management of MPN.
Physiological Signaling and Structure of the HGF Receptor MET (2014)

The "hepatocyte growth factor" also known as "scatter factor", is a multifunctional cytokine with the peculiar ability of simultaneously triggering epithelial cell proliferation, movement and survival. The combination of those proprieties results in the induction of an epithelial to mesenchymal transition in target cells, fundamental for embryogenesis but also exploited by tumor cells during metastatization. The hepatocyte growth factor receptor, MET, is a proto-oncogene and a prototypical transmembrane tyrosine kinase receptor. Inhere we discuss the MET molecular structure and the hepatocyte growth factor driven physiological signaling which coordinates epithelial proliferation, motility and morphogenesis.
Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis (2006)

IL-23 is a member of the IL-12 cytokine family that drives a highly pathogenic T cell population involved in the initiation of autoimmune diseases. We have shown that IL-23-dependent, pathogenic T cells produced IL-17 A, IL-17 F, IL-6, and TNF but not IFN-gamma or IL-4. We now show that T-bet and STAT1 transcription factors are not required for the initial production of IL-17. However, optimal IL-17 production in response to IL-23 stimulation appears to require the presence of T-bet. To explore the clinical efficacy of targeting the IL-23 immune pathway, we generated anti-IL-23p19-specific antibodies and tested to determine whether blocking IL-23 function can inhibit EAE, a preclinical animal model of human multiple sclerosis. Anti-IL-23p19 treatment reduced the serum level of IL-17 as well as CNS expression of IFN-gamma, IP-10, IL-17, IL-6, and TNF mRNA. In addition, therapeutic treatment with anti-IL-23p19 during active disease inhibited proteolipid protein (PLP) epitope spreading and prevented subsequent disease relapse. Thus, therapeutic targeting of IL-23 effectively inhibited multiple inflammatory pathways that are critical for driving CNS autoimmune inflammation.
IL-1 and TNF receptor-deficient mice show decreased inflammation in an immune complex model of uveitis. (1999)

In contrast to endotoxin-induced uveitis, both IL-1 and TNF appear to have critical roles in RPAR uveitis. When receptors for these cytokines were deleted, the severity of immune complex-induced uveitis was profoundly reduced.