gebhart/patrepeval huggingface dataset:
Anti-influenza virus activities of 4-substituted 2,4-dioxobutanoic acid inhibitors (1996)

We previously identified a series of compounds which specifically inhibited the transcription of influenza A and B viruses (J. Tomassini, H. Selnick, M.E. Davies, M.E. Armstrong, J. Baldwin, M. Bourgeois, J. Hastings, D. Hazuda, J. Lewis, W. McClements, G. Ponticello, E. Radzilowski, G. Smith, A. Tebben, and A. Wolfe, Antimicrob. Agents Chemother. 38:2827-2837, 1994). The compounds, 4-substituted 2,4-dioxobutanoic acids, selectively targeted the cap-dependent endonuclease activity of the transcriptase complex. Additionally, several of these compounds effectively inhibited the replication of influenza virus but not other viruses in cell culture assays. Here, we report on the anti-influenza virus activities of other potent derivatives of the series evaluated in both in vitro and in vivo infectivity assays. These compounds inhibited the replication of influenza virus in yield reduction assays, with 50% inhibitory concentrations ranging from 0.18 to 0.71 microM. These 50% inhibitory concentrations were similar to those observed for inhibition of in vitro transcription (0.32 to 0.54 microM). One selected compound also elicited a dose-dependent inhibition of influenza virus replication in mice following an upper respiratory tract challenge. These studies demonstrate the antiviral efficacy of this inhibitor class and thereby establish the utility of influenza virus endonuclease as a chemotherapeutic target.
Use of ultrasound imaging to map propagating action potential waves in the heart (2009)

Presently, the nature of action potential propagation deep within myocardial tissue is unclear. As a result, a complete understanding of cardiac dynamics remains elusive. Here we present a technique using ultrasound and electromechanical modeling that has the potential to unlock this mystery. We also present information suggesting tension in the heart behaves as a long-range force incapable of being captured through only local observation of myocardial tissue deformation.
Derivatives of 5-hydroxy-6-methyl-2-aminotetralin (1980)

The title compounds were designed to provide semirigid congeners of m-tyramine in which the ring position ortho to the phenolic OH is blocked to metabolic hydroxylation. A sequence leading to a key synthetic intermediate, 5-methoxy-6-methyl-2-tetralone, has been developed. In animal test models for dopamine-like effects, the title compounds demonstrated qualitative and quantitative differences from the isomeric 5-methyl-6-hydroxy-2-aminotetralins and from 5,6-dihydroxy-2-aminotetralins. Two of the compounds were potent in a cat cardioaccelerator nerve assay, which involves dopamine receptors.
Estradiol enhances leukocyte binding to tumor necrosis factor (TNF)-stimulated endothelial cells via an increase in TNF-induced adhesion molecules E-selectin, intercellular adhesion molecule type 1, and vascular cell adhesion molecule type 1. (1994)

Adhesion of leukocytes to endothelial cells is a critical step in the development of acute and chronic inflammatory lesions. We report here that estradiol treatment of cultured human umbilical vein endothelial cells stimulated up to a twofold increase in TNF-induced adhesion of both polymorphonuclear leukocytes and PMA-activated peripheral blood mononuclear cells. This effect was more evident (threefold increase) when endothelial cells were cultured on the basement membrane glycoprotein laminin. Progesterone, but not testosterone, had a similar stimulatory effect. Estradiol also promoted a slight increase in interferon gamma-stimulated endothelial cell adherence for peripheral blood mononuclear cells, but no effect of estradiol was observed when adhesion of leukocytes to endothelial cells was stimulated with IL-1 or IL-4. The estradiol-induced increase in leukocyte binding to human umbilical vein endothelial cells was partially blocked by antibodies to the adhesion molecules E-selectin, intercellular adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule type 1 (VCAM-1). Indirect immunofluorescence techniques showed that estradiol produces an increase in TNF-induced cell surface expression of these molecules. Northern blot analysis demonstrated a transient increase in TNF-induced expression of mRNA for E-selectin, ICAM-1, and VCAM-1 in endothelial cells treated with estradiol. Our data demonstrate that estradiol has important regulatory functions in promoting leukocyte-endothelial cell interactions that might contribute to the observed predominance in females of some autoimmune inflammatory diseases.
Transplantation tolerance: lessons from experimental rodent models (2007)

Immunological tolerance or functional unresponsiveness to a transplant is arguably the only approach that is likely to provide long-term graft survival without the problems associated with life-long global immunosuppression. Over the past 50 years, rodent models have become an invaluable tool for elucidating the mechanisms of tolerance to alloantigens. Importantly, rodent models can be adapted to ensure that they reflect more accurately the immune status of human transplant recipients. More recently, the development of genetically modified mice has enabled specific insights into the cellular and molecular mechanisms that play a key role in both the induction and maintenance of tolerance to be obtained and more complex questions to be addressed. This review highlights strategies designed to induce alloantigen specific immunological unresponsiveness leading to transplantation tolerance that have been developed through the use of experimental models.
From gene profiling to diagnostic markers: IL‐18 and FGF‐2 complement CA125 as serum‐based markers in epithelial ovarian cancer (2005)

We used an oligonucleotide-based DNA microarray to identify potential markers in 39 primary cultures of ovarian cancer specimens compared with 11 primary cultures of normal ovarian epithelia. Differential gene expression of IL-18 and FGF-2 was validated on a subset of samples by quantitative PCR and by IHC, using an independent tissue array of 90 cores of 20 normal ovarian surface epithelia and 70 EOCs representing different grades and pathologies of ovarian disease. We further compared, by ELISA, these two markers with CA125 in sera from 25 cancer-free and 47 ovarian cancer patients. IL-18 and FGF-2 proteins were significantly elevated in tumor tissues (p<0.04) and sera (p<0.05) from patients with ovarian cancer. In combination, the three markers (IL-18, FGF-2, and CA125) showed similar sensitivity in scoring for ovarian cancer (35/45 patients) compared to that of CA125 alone (37/45) and significantly improved the specificity of detection (20/25 patients) compared to each marker individually (15/25 for CA125; 18/25 FGF-2; 16/25 for IL-18). In conclusion we show that a combination of the three serum markers (IL-18, FGF-2 and CA125) is associated with EOC, with higher specificity than CA125 alone. Prospective studies with a large cohort of susceptible ovarian cancer patients will be required to expand these findings.
Effect of Low‐Level Er:YAG Laser Irradiation on Cultured Human Gingival Fibroblasts (2005)

Our results showed that the low-level Er:YAG laser irradiation stimulates the proliferation of cultured gingival fibroblasts. The optimal stimulative energy density was found to be 3.37 J/cm(2). This result suggests that Er:YAG laser irradiation may be of therapeutic benefit for wound healing.
Femtosecond Corneal Collagen Crosslinking in Treatment of Patients with Progressive Keratoconus Stages I–II (2016)

The aim of the investigation was to assess safety and efficacy of corneal collagen crosslinking technique using femtosecond laser for intrastromal pocket creation in patients with progressive keratoconus.
Solid-Phase Synthesis of Thalidomide and Its Analogues (2002)

A novel solid-phase synthesis of thalidomide and its metabolites and analogues is described. The synthetic strategy involves the coupling of hydroxymethyl polystyrene with phthalic anhydride to form the resin-linked acid. The acid is then reacted with primary amines followed by acid or base treatment to form thalidomide and its analogues with either open or closed phthalimide rings. Most of the analogues are synthesized with high yields (40.3-98.1% in three steps) and purities (92.3-98.9%).
Isolation and Characterization of Neural Crest Stem Cells Derived From In Vitro–Differentiated Human Embryonic Stem Cells (2008)

The neural crest is a transient structure of vertebrate embryos that initially generates neural crest stem cells (NCSCs) which then migrate throughout the body to produce a diverse array of mature tissue types. Due to the rarity of adult NCSCs as well as ethical and technical issues surrounding isolation of early embryonic tissues, biologic studies of human NCSCs are extremely challenging. Thus, much of what is known about human neural crest development has been inferred from model organisms. In this study, we report that functional NCSCs can be rapidly generated and isolated from in vitro-differentiated human embryonic stem cells (hESCs). Using the stromal-derived inducing activity (SDIA) of PA6 fibroblast co-culture we have induced hESCs to differentiate into neural crest. Within 1 week, migrating cells that express the early neural crest markers p75 and HNK1 as well as numerous other genes associated with neural crest induction such as SNAIL, SLUG, and SOX10 are detectable. Fluorescence-activated cell sorting (FACS)-based isolation of the p75-positive population enriches for cells with genetic, phenotypic, and functional characteristics of NCSCs. These p75-enriched cells readily form neurospheres in suspension culture, self-renew to form secondary spheres, and give rise under differentiation conditions to multiple neural crest lineages including peripheral nerves, glial, and myofibroblastic cells. Importantly, these cells differentiate into neural crest derivatives when transplanted into developing chick embryos in vivo. Thus, this SDIA protocol can be used to successfully and efficiently isolate early human NCSCs from hESCs in vitro. This renewable source of NCSCs provides an invaluable source of cells for studies of both normal and disordered human neural crest development.
Differential Functions of Growth Factor Receptor–Bound Protein 7 (GRB7) and Its Variant GRB7v in Ovarian Carcinogenesis (2010)

Our studies implicate that the overexpressed GRB7 and GRB7v are associated with high-grade tumors and exert distinct tumorigenic functions through regulating different signaling pathways in ovarian cancer cells.
Tumor Heterogeneity and Immunotherapy of Cancer (1995)

Tumor heterogeneity is the presence of intercellular differences, either from clonal origin or present within subpopulations of tumor cells. Recent advances in immuno-histology, flow cytometric analysis, molecular biological techniques, and tissue culture methods makes it possible to investigate tumor heterogeneity in detail. In this review data are presented to document that this hallmark of neoplastic disease results from DNA-instability and the interactions of tumor cells with their environment. The present inability to treat most patients effectively with immunotherapy may partly be due to the occurrence of tumor heterogeneity. Therefore, the heterogeneity of the tumor phenotype is discussed in conjunction with the various immunotherapeutic treatment modalities. In addition to local cytokine production by immune cells and tumor cells, and limited access of either antibodies or immune cells into the tumor, tumor heterogeneity is an important factor that determines the progress of immunotherapy of cancer. Therefore, accurate quantitative methods using antibodies and molecular probes to identify HLA-associated target peptides, tumor-associated antigens and accessory molecules, to predict which patients will have a high probability of responding to treatment, are needed.
The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions (2003)

Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.
PathBLAST: a tool for alignment of protein interaction networks (2004)

PathBLAST is a network alignment and search tool for comparing protein interaction networks across species to identify protein pathways and complexes that have been conserved by evolution. The basic method searches for high-scoring alignments between pairs of protein interaction paths, for which proteins of the first path are paired with putative orthologs occurring in the same order in the second path. This technique discriminates between true- and false-positive interactions and allows for functional annotation of protein interaction pathways based on similarity to the network of another, well-characterized species. PathBLAST is now available at http://www.pathblast.org/ as a web-based query. In this implementation, the user specifies a short protein interaction path for query against a target protein-protein interaction network selected from a network database. PathBLAST returns a ranked list of matching paths from the target network along with a graphical view of these paths and the overlap among them. Target protein-protein interaction networks are currently available for Helicobacter pylori, Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. Just as BLAST enables rapid comparison of protein sequences between genomes, tools such as PathBLAST are enabling comparative genomics at the network level.
Triple quantum sodium imaging of articular cartilage (1997)

Triple quantum (TQ) sodium imaging of bovine articular cartilage is presented. True triple quantum imaging sequence was modified to incorporate asymmetric echo acquisition. Triple quantum signal expression in the presence of residual quadrupolar interaction is presented. The filtering capability of the sequence is first demonstrated on an agarose phantom. Both single and triple quantum images of articular cartilage are compared. The TQ image shows non-zero signal intensity solely from cartilage, indicating complete suppression of signals from bone marrow and saline. The advantages of TQ imaging of articular cartilage, its feasibility in in vivo situations and further improvements in SNR are described.
Frequency and Domain Specificity of Toxin-Neutralizing Paratopes in the Human Antibody Response to Anthrax Vaccine Adsorbed (2009)

Protective antigen (PA) is the cell surface recognition unit of the binary anthrax toxin system and the primary immunogenic component in both the current and proposed "next-generation" anthrax vaccines. Several studies utilizing animal models have indicated that PA-specific antibodies, acquired by either active or passive immunization, are sufficient to protect against infection with Bacillus anthracis. To investigate the human antibody response to anthrax immunization, we have established a large panel of human PA-specific monoclonal antibodies derived from multiple individuals vaccinated with the currently approved anthrax vaccine BioThrax. We have determined that although these antibodies bind PA in standard binding assays such as enzyme-linked immunosorbent assay, Western blotting, capture assays, and dot blots, less than 25% are capable of neutralizing lethal toxin (LT) in vitro. Nonneutralizing antibodies also fail to neutralize toxin when present in combination with other nonneutralizing paratopes. Although neutralizing antibodies recognize determinants throughout the PA monomer, they are significantly less common among those paratopes that bind to the immunodominant amino-terminal portion of the molecule. These findings demonstrate that PA binding alone is not sufficient to neutralize LT and suggest that for an antibody to effectively block PA-mediated toxicity, it must bind to PA such that one of the requisite toxin functions is disrupted. A vaccine design strategy that directed a higher percentage of the antibody response toward neutralizing epitopes may result in a more efficacious vaccine for the prevention of anthrax infection.
Detection of T cells that secrete molecules which share determinants with antigen-specific T-cell factors. (1981)

A single-cell secretion assay was used to detect cells that secrete products which react with an antiserum that binds T cell antigen-binding polypeptides. The antiserum (R11), which was produced by immunization of rabbits with a murine trinitrophenyl-specific suppressor factor, reacts with T cells and their products and with a suppressor T-cell clone but not with B cells or their products. The secretory cells this antiserum detected were found to be unevenly distributed among various organs (spleen, lymph node, and thymus) and, to different degrees, in spleens of various strains of mice. In unimmunized CBA/J mice, approximately 1-3% of spleen cells secreted macromolecules precipitable by R11. The majority of the secretory cells could be removed by panning with a mixture of Ly 1 and Ly 2 antibodies but not with either antibody alone. This is consistent with the cells having low surface antigen densities as a result of being either "pre-T" cells or mature secretory cells analogous to B-lineage plasma cells. In agreement with the latter possibility was our finding that the secretory activity of cells detected with antisuppressor factor was comparable to that of Ig-secretory cells as detected with an anti-Ig antiserum. However, higher numbers of R11+ secretory cells were seen in the immunoglobulin-negative fraction of spleen cells from nude mice, which could be interpreted to favor the first possibility. In either case this study shows that the single-cell assay technique is well suited for the detection and characterization of molecules released by immunoregulatory T cells.
Large Involuntary Forces Consistent with Plateau-Like Behavior of Human Motoneurons (2001)

When electrical stimulation is applied over human muscle, the evoked force is generally considered to be of peripheral origin. However, in relaxed humans, stimulation (1 msec pulses, 100 Hz) over the muscles that plantarflex the ankle produced more than five times more force than could be accounted for by peripheral properties. This additional force was superimposed on the direct response to motor axon stimulation, produced up to 40% of the force generated during a maximal voluntary contraction, and was abolished during anesthesia of the tibial nerve proximal to the stimulation site. It therefore must have resulted from the activation of motoneurons within the spinal cord. The additional force could be initiated by stimulation of low-threshold afferents, distorted the classical relationship between force and stimulus frequency, and often outlasted the stimulation. The mean firing rate of 27 soleus motor units recorded during the sustained involuntary activity after the stimulation was 5.8 +/- 0.2 Hz. The additional force increments were not attributable to voluntary intervention because they were present in three sleeping subjects and in two subjects with lesions of the thoracic spinal cord. The phenomenon is consistent with activation of plateau potentials within motoneurons and, if so, the present findings imply that plateau potentials can make a large contribution to forces produced by the human nervous system.
Cover Picture: Angew. Chem. Int. Ed. 15/2002 (2002)

The cover picture shows the interior of a red-figure kylix (440–430 BC, British Museum London) which shows the brilliant exploits of Theseus, the Greek mythology hero. In the center, Theseus is shown defeating the infamous Minataur within the labyrinth. On the right, the hero raises his hand against Sciron, below whom the turtle is visible. Next clockwise, are shown the bull of Marathon, the punishment of Sinis, the slaying of the sow Phaea, the battle of Cercyon, and finally the punishment of Procrustes. The labors of Theseus are no different from the accomplishments of today's synthetic chemists working in total synthesis. One such endeavor, the total synthesis of the CP molecules with its challenges, twists and turns, and dead-ends, but also its rewards, is compared to the conquest of the Minotaur by Theseus in the Review by K. C. Nicolaou and P. S. Baran on p. 2678 ff.
A Long-Acting Human Growth Hormone With Delayed Clearance (VRS-317): Results of a Double-Blind, Placebo-Controlled, Single Ascending Dose Study in Growth Hormone–Deficient Adults (2013)

The elimination half-life for VRS-317 is 30- to 60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of overexposure to high IGF-I levels. The pharmacokinetics and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing.
Expansion of Hepatic and Hematopoietic Stem Cells Utilizing Mouse Embryonic Liver Explants (2001)

Ex vivo embryonic liver explant culture is a novel and attractive approach to obtain abundant hepatic and hematopoietic stem cells. Gene therapy of autologous hepatic and hematopoietic stem cells represents an alternative therapeutic approach to liver transplantation for genetic and metabolic disorders. In this study we characterize the growth and differentiation of hepatic stem cells utilizing embryonic liver cultures. Day 9.5 liver buds are microdissected and cultured under specific conditions. Modulation of growth conditions by addition of hepatocyte growth factor, Flt-3 ligand, and stem cell factor leads to enrichment of hepatic progenitor cells in embryonic liver explants. Under these conditions, we also demonstrate the role of a novel marker PRAJA-1 to identify hepatic stem cells and transitional hepatocytes. Utilization of dexamethasone enhanced pseudolobule formation with increased hepatocytic and biliary differentiation. Transforming growth factor-beta leads to enrichment of biliary cells in the culture. Gut formation is enhanced in the presence of interleukin-3 and blood formation by increasing the mesodermal tissue in these cultures. We also show increased retroviral-mediated expression of the green fluorescent protein expression in the expanded hepatic and hematopoietic stem cells under different culture conditions. Thus, the embryonic liver explant culture is an attractive source for hepatic progenitors and is a possible step towards generating nontumorigenic immortalized hepatocytes with possible transplantation applications.