gebhart/patrepeval huggingface dataset:
Orthoamide, XXXIV. Synthesen mit Vinylidendiaminen (1980)

Abstract Die Vinylidendiamine 2a, c werden aus dem 1‐Ethoxyvinylamin 4 und Dimethylamin bzw. Pyrrolidin dargestellt. Beim Erhitzen von 2a mit Formamidiniumacetat bildet sich 4‐Amino‐5‐pyrimidincarbonitril ( 7b ). Die Verbindung 2a wird mit Carbonsäurechloriden oder ‐anhydriden acyliert, wobei die Vinylidendiamine 11 entstehen. Dimethylsulfat bzw. Triethyloxonium‐tetrafluoroborat alkylieren die Vinylidendiamine 2b und 11 am Sauerstoff der Carbonylgruppe, die gebildeten Iminiumsalze 12 setzen sich mit Alkalialkoholaten zu 1,3‐Butadienen 13a, b oder vinylogen Harnstoff‐acetalen 18a, b um. Morpholin überführt 13a in das 1,3‐Butadien‐1,1,3‐triamin 19 . CH‐acide Verbindungen (Malonodinitril, Cyanessigsäure‐ethylester, p ‐Nitrobenzylcyanid und Nitromethan) reagieren mit 13a zu den „push‐pull”︁‐substituierten 1,3‐Butadienen 20 . In gleicher Weise wird aus 22 und Malonodinitril das 1,3‐Butadien 23 erhalten. Die Pyrimidine 25 und 26 werden aus 13a bzw. 18a und Amidinen oder Guanidinen dargestellt. Phenylhydrazin setzt sich mit 18a zu einem Gemisch der isomeren Pyrazole 29 und 30 um. Das 1,2‐Oxazol 31 kann durch Einwirkung von Hydroxylamin auf 18a gewonnen werden. Isocyanate und Phenylisothiocyanat ergeben bei der Umsetzung mit 13a die acylierten 1,3‐Butadiene 32 . Beim Erhitzen cyclisiert 32a zum α‐Pyridon 33 . Die Thermolyse von 32e liefert das γ‐Pyridon 37 . Methylisothiocyanat cyclisiert 13a, b zu den α‐Pyridinthionen 38 .
Regulation of Allergic Inflammation and Eosinophil Recruitment in Mice Lacking the Transcription Factor NFAT1: Role of Interleukin-4 (IL-4) and IL-5 (1998)

Transcription factors of the NFAT (nuclear factor of activated T cells) family regulate the expression of many genes encoding immunoregulatory cytokines and cell surface proteins during the immune response. The NFAT protein NFAT1 (NFATp) is expressed and functional in T cells, B cells, mast cells, and natural killer cells. Here we report a detailed analysis of the enhanced eosinophil responses of NFAT1-deficient mice, observed in an in vivo model of allergic inflammation. In addition to the pleural eosinophilia described previously, NFAT1-/- mice that have been sensitized with antigen display a significant increase, relative to wild-type mice, in the numbers of eosinophils in bone marrow and peripheral blood. After restimulation with antigen in vitro, antigen-responsive T cells from the draining lymph nodes of NFAT1-/- mice show increased expression of mRNA encoding the Th2 cytokines interleukin-4 (IL-4), IL-5, and IL-13. Consistent with this finding, there is a pronounced increase in the levels of IL-5 and IL-13 in the pleural cavities of sensitized NFAT1-/- mice after allergen challenge in vivo. Furthermore, development of eosinophilia depends on overexpression of IL-4 and IL-5, because it is strongly inhibited by administration of neutralizing antibodies to either of these cytokines. These results indicate that NFAT1-deficient mice are prone to develop a classically allergic phenotype characterized by eosinophilia and increased production of Th2 cytokines. Thus, the presence of NFAT1 might inhibit the allergic response, perhaps by interfering with the development of Th2 immune responses, and the lack or dysfunction of NFAT1 could potentially underlie certain cases of atopic disease.
An Enantioselective Ketene−Imine Cycloaddition Method for Synthesis of Substituted Ring-Fused 2-Pyridinones (2001)

Previously, a method for the stereoselective synthesis of beta-lactams, starting from 2H-Delta(2)-thiazolines and Meldrum's acid derivatives, has been reported from our laboratory. We now report a new method for the synthesis of optically active, highly substituted ring-fused 2-pyridinones. This was discovered when 2-alkyl-Delta(2)-thiazolines and Meldrum's acid derivatives were treated with HCl(g) in benzene at 5 --> 78 degrees C. Further refinement of the synthetic protocol revealed that use of 1,2-dichloroethane as solvent at 0 --> 64 degrees C led to the desired 2-pyridinones in good yields and with excellent enantioselectivity. Use of these conditions allowed preparation of 2-pyridinones from several different Delta(2)-thiazolines and Meldrum's acid derivatives and may be a general route to 2-pyridinones.
Cell culture media for recombinant protein expression in Chinese hamster ovary (CHO) cells: History, key components, and optimization strategies (2018)

The culture of Chinese Hamster Ovary (CHO) cells for modern industrial applications, such as expression of recombinant proteins, requires media that support growth and production. Such media must support high viable cell densities while also stimulating the synthesis and extracellular transport of biologic products. Early media development efforts in this area yielded basic formulations to sustain growth, viability, and cellular function, albeit comprising animal sourced components, and complex constituents used in batch culture mode. Subsequent improvements included the development of serum-free and chemically defined (CD) media, the identification of critical nutrients, growth factors, and potentially inhibitory or toxic cellular metabolites, and the use of fed-batch and perfusion culture techniques to optimize nutrient delivery while minimizing accumulation of unwanted waste products. This review is comprised of sections covering milestones in the evolution of mammalian cell culture media, nutrient composition and formulation requirements, optimization strategies, consistency and scalability of powder and liquid media preparation for industrial applications, and key recent advances driving progress in CHO cell culture medium design and development. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1407-1426, 2018.
Direct comparison of infrared and ultraviolet wavelength matrix-assisted laser desorption/ionization mass spectrometry of proteins (1998)

In an effort to gain an understanding of the processes governing matrix-assisted laser desorption/ionization (MALDI), we made a direct comparison of ultraviolet (UV)- and infrared (IR)-MALDI linear time-of-flight mass spectra of proteins obtained from the same samples and matrices (on the same sample surface), using two different lasers, each having short duration (< 10-ns) pulses, i.e., a tunable wavelength Nd:yttrium aluminum garnet (YAG) pumped optical parametric oscillator laser operating at 2.94 microns and a Nd:YAG laser operating at 355 nm. We observed that (1) the IR-MALDI and UV-MALDI spectra of a given protein from the same matrix were strikingly similar; (2) protein ions produced by IR-MALDI experienced less fragmentation than those produced by UV-MALDI; and (3) photochemical adducts produced during UV-MALDI were absent in IR-MALDI. These results lead us to speculate on the mechanisms for the ionization process in UV- and IR-MALDI. Because photons with a wavelength of approximately 3 microns are unlikely to effect electronic excitation of the matrix at the irradiance used for MALDI we propose that ionization in IR-MALDI occurs as a natural consequence of the solid-to-gas phase transition induced by the IR irradiation, and involves proton transfer reactions in the intermediate phase between solid and gas. The strikingly similar UV- and IR-MALDI mass spectra leads us to the additional proposal that ionization in UV-MALDI may also be a natural consequence of the phase transition and that electronic excitation may not play a primary role in the ionization process.
Annual Report to the Nation on the Status of Cancer, 1975–2005, Featuring Trends in Lung Cancer, Tobacco Use, and Tobacco Control (2008)

Although the decrease in overall cancer incidence and death rates is encouraging, large state and regional differences in lung cancer trends among women underscore the need to maintain and strengthen many state tobacco control programs.
Near-infrared photoconductive and photovoltaic devices using single-wall carbon nanotubes in conductive polymer films (2005)

We have fabricated prototypical Al/single-wall carbon nanotube (SWNT)-polymer/indium tin oxide thin-film devices that exhibit promising photoconductive and photovoltaic responses in a broad spectral range, typically from 300to1600nm. This achievement was made possible by finely dispersed SWNT powders in polymer matrices such as poly-phenylene-vinylene and poly-thiophene. These devices utilize (i) the intrinsic near-infrared light harvesting properties of semiconducting SWNTs, (ii) the electronic transport properties of both semiconducting and metallic SWNTs in combination with those of the polymer matrices, and (iii) probably charge/energy transfer processes between SWNTs and the polymers. By selecting different sources of SWNTs and polymers, we have shown that the optoelectronic properties of these devices are potentially tunable. To support our investigation, several techniques including spectrally resolved photoconductivity, optical absorption, and photoluminescence spectroscopy were utilized.
Making the Connection (2008)

The chapters in this volume convey insights from mathematics education research that have direct implications for anyone interested in improving teaching and learning in undergraduate mathematics. This synthesis of research on learning and teaching mathematics provides relevant information for any mathematics department or any individual faculty member who is working to improve introductory proof courses, the longitudinal coherence of precalculus through differential equations, students' mathematical thinking and problem solving abilities, and students' understanding of fundamental ideas such as variable, and rate of change. Other chapters include information about programs that have been successful in supporting students' continued study of mathematics. The authors provide many examples and ideas to help the reader infuse the knowledge from mathematics education research into mathematics teaching practice.
Rap1A antagonizes the ability of Ras and Ras-Gap to inhibit muscarinic K+ channels. (1991)

Rap1A is a Ras-related GTP binding protein which has an amino acid sequence identical to that of Ras in the putative "effector" domain (amino acids 32-40). The binding of Rap1A to Ras-GTPase activating protein (GAP) through this domain is a potential mechanism for explaining the observation that Rap1A can antagonize the ability of oncogenic Ras to transform cells. It was recently shown (Yatani, A., Okabe, K., Polakis, P., Halenbeck, R., McCormick, F., and Brown, A. M. (1990) Cell 61, 769-776) that the activation of M2-muscarinic receptor-coupled K+ channels in heart is inhibited by the addition of exogenous Ras and Ras-GAP. We have made use of this system in the present paper to show that Rap1A is able to effectively block this inhibitory action of Ras-GAP. We observed that both Rap1A-GDP and Rap1A-guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) were able to block the inhibitory effect of Ras-GAP upon channel activation. This effect occurred at picomolar concentrations of Rap1A, and the GTP gamma S-bound form of the protein was consistently found to be more potent than the GDP form. A Rap1A Thr35----Ala mutation which bound GTP gamma S did not prevent K+ channel inhibition by Ras-GAP, suggesting that the antagonism by wild type Rap1A involves an interaction with GAP in the effector domain. The effectiveness of Rap1A to inhibit Ras-GAP is dependent upon the amount of Ras-GAP present in the assay and can also be overcome by the addition of GTP-bound N-Ras (GC-43), suggesting a competitive mechanism is operative. Finally, a truncated form of Ras-GAP (GAP32) which is no longer dependent upon Ras for inhibition of the M2-activated K+ channel is also no longer sensitive to blockade by added Rap1A. These data support the concept of GAP as an effector of Ras action and indicate that Rap1A can serve as an inhibitor of Ras action in a system distinct from cell transformation by a competitive mechanism involving the GAP binding domain of Rap1A.
Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus (2010)

Double-stranded (ds) DNA, DNA- or RNA-associated nucleoproteins are the primary autoimmune targets in SLE, yet their relative inability to trigger similar autoimmune responses in experimental animals has fascinated scientists for decades. While many cellular proteins bind non-specifically negatively charged nucleic acids, it was discovered only recently that several intracellular proteins are involved directly in innate recognition of exogenous DNA or RNA, or cytosol-residing DNA or RNA viruses. Thus, endosomal Toll-like receptors (TLR) mediate responses to double-stranded RNA (TLR-3), single-stranded RNA (TLR-7/8) or unmethylated bacterial cytosine (phosphodiester) guanine (CpG)-DNA (TLR-9), while DNA-dependent activator of IRFs/Z-DNA binding protein 1 (DAI/ZBP1), haematopoietic IFN-inducible nuclear protein-200 (p202), absent in melanoma 2 (AIM2), RNA polymerase III, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) mediate responses to cytosolic dsDNA or dsRNA, respectively. TLR-induced responses are more robust than those induced by cytosolic DNA- or RNA- sensors, the later usually being limited to interferon regulatory factor 3 (IRF3)-dependent type I interferon (IFN) induction and nuclear factor (NF)-kappaB activation. Interestingly, AIM2 is not capable of inducing type I IFN, but rather plays a role in caspase I activation. DNA- or RNA-like synthetic inhibitory oligonucleotides (INH-ODN) have been developed that antagonize TLR-7- and/or TLR-9-induced activation in autoimmune B cells and in type I IFN-producing dendritic cells at low nanomolar concentrations. It is not known whether these INH-ODNs have any agonistic or antagonistic effects on cytosolic DNA or RNA sensors. While this remains to be determined in the future, in vivo studies have already shown their potential for preventing spontaneous lupus in various animal models of lupus. Several groups are exploring the possibility of translating these INH-ODNs into human therapeutics for treating SLE and bacterial DNA-induced sepsis.
Loss of beta-catenin expression associated with disease progression in malignant melanoma (2001)

These results suggest that loss or downregulation of beta-catenin expression in melanoma cells plays a significant role in progression of the disease.
Deployme: Tellme's Package Management and Deployment System (2000)

Many administrators use a central software repository because managing distributed packages is difficult. Deployme is our solution to manage the package update lifecycle across a large number of independently configured hosts.Deployme is highly flexible and has been extended to handle many different types of packages. Deployme packages include standard UNIX tools, local applications, web site content, and voice site content. Most packages require fast, frequent deployment.Deployme has a web-based user interface that allows less technical users to deploy on their own. Deployme also restarts appropriate server processes, a feature which was much more difficult than we expected.We discuss other lessons learned from the first implementation and planned improvements for the future.
4E10-Resistant Variants in a Human Immunodeficiency Virus Type 1 Subtype C-Infected Individual with an Anti-Membrane-Proximal External Region-Neutralizing Antibody Response (2007)

The broadly neutralizing monoclonal antibody (MAb) 4E10 recognizes a linear epitope in the C terminus of the membrane-proximal external region (MPER) of gp41. This epitope is particularly attractive for vaccine design because it is highly conserved among human immunodeficiency virus type 1 (HIV-1) strains and neutralization escape in vivo has not been observed. Multiple env genes were cloned from an HIV-1 subtype C virus isolated from a 7-year-old perinatally infected child who had anti-MPER neutralizing antibodies. One clone (TM20.13) was resistant to 4E10 neutralization as a result of an F673L substitution in the MPER. Frequency analysis showed that F673L was present in 33% of the viral variants and in all cases was linked to the presence of an intact 2F5 epitope. Two other envelope clones were sensitive to 4E10 neutralization, but TM20.5 was 10-fold less sensitive than TM20.6. Substitutions at positions 674 and 677 within the MPER rendered TM20.5 more sensitive to 4E10 but had no effect on TM20.6. Using chimeric and mutant constructs of these two variants, we further demonstrated that the lentivirus lytic peptide-2 domain in the cytoplasmic tail affected the accessibility of the 4E10 epitope, as well as virus infectivity. Collectively, these genetic changes in the face of a neutralizing antibody response to the MPER strongly suggested immune escape from antibody responses targeting this region.
Targeted activation of melanoma differentiation-associated protein 5 (MDA5) for immunotherapy of pancreatic carcinoma (2015)

The RIG-I-like helicase melanoma differentiation-associated protein 5 (MDA5) is an innate immune receptor for double-stranded viral RNA (dsRNA) that, upon activation, induces a Type I interferon (IFN)-driven immune response. In the present study, we demonstrate that human und murine pancreatic cancer cells express functional MDA5 and are highly sensitive to MDA5-induced cell death. Activation of MDA5 by cytosolic delivery of the synthetic dsRNA analog poly(I:C) led to phosphorylation of the transcription factor IRF3, IFNβ production and upregulation of MHC-I expression. MDA5 signaling also induced tumor cell apoptosis via the intrinsic pathway and sensitized tumor cells toward extrinsic, Fas-mediated apoptosis. Systemic treatment of orthotopic pancreatic cancer-bearing mice with the MDA5 ligand resulted in activated CD8<sup>+</sup> T cell tumor infiltration, an increased frequency of tumor antigen-specific CD8<sup>+</sup> T cells and an immunogenic cytokine milieu in the tumor microenvironment. These effects were paralleled by MDA5-induced pronounced tumor cell death <i>in situ</i> and significantly prolonged survival in two different mouse models for pancreatic cancer, an immunotherapeutic response dependent on CD8<sup>+</sup> T cells. Treated mice were further protected from subsequent tumor challenge. In summary, we identified MDA5 as a novel therapeutic target for overcoming apoptosis resistance and tumor-mediated immunosuppression in pancreatic cancer. MDA5 ligands link innate with adaptive immune mechanisms for effective tumor control.
Engineered β-Lactoglobulin Produced in E. coli: Purification, Biophysical and Structural Characterisation (2016)

Functional recombinant bovine β-lactoglobulin has been produced by expression in E. coli using an engineered protein gene and purified to homogeneity by applying a new protocol. Mutations L1A/I2S introduced into the protein sequence greatly facilitate in vivo cleavage of the N-terminal methionine, allowing correctly folded and soluble protein suitable for biochemical, biophysical and structural studies to be obtained. The use of gel filtration on Sephadex G75 at the last purification step enables protein without endogenous ligand to be obtained. The physicochemical properties of recombinant β-lactoglobulin such as CD spectra, ligand binding (n, K a, ΔH, TΔS, ΔG), chemical and thermal stability (ΔG D, C mid) and crystal structure confirmed that the protein obtained is almost identical to the natural one. The substitutions of N-terminal residues did not influence the binding properties of the recombinant protein so that the lactoglobulin produced and purified according to our protocol is a good candidate for further engineering and potential use in pharmacology and medicine.
Control and Characterization of a Multistep Unimolecular Reaction (2000)

Electrons from a scanning tunneling microscope were used to break a C-H bond in a single acetylene (HCCH) molecule adsorbed on Cu(001) at 9 K. The product ethynyl (CCH) was characterized by imaging, inelastic electron tunneling spectroscopy, and variable temperature measurements of the rotation rate. Significant changes in the vibrational spectra and bonding geometry accompanied HCCH dissociation. The ethynyl was further dehydrogenated to form dicarbon (CC). Dissociation studies of the isotopes HCCD and DCCD permitted unambiguous identification of the reaction products.
Abstract 4405: Immune modulation and Treg suppression with metronomic cyclophosphamide enhances the anti-tumor effect of a therapeutic peptide vaccine in a murine model (2012)

Abstract In order to be optimally effective therapeutic cancer vaccines must be combined with immune modulatory approaches, particularly in advanced cancer where several different pathways of cancer induced immune suppression may be active. We have developed a potent cancer vaccine enhancement formulation named DepoVaxTM (DPX) that is particularly well suited for the delivery of peptide antigens. DPX is a novel vaccine platform comprised of liposomes in oil that is formulated with a TLR adjuvant, universal T-helper peptide and specific tumor peptide antigens. We have shown that DPX generates better immune responses than Montanide based emulsion formulations. A major obstacle to any cancer vaccine, however, is tumor induced immune suppression. Regulatory T cell (Treg) mediated immune suppression is an important mechanism of tumor immune evasion in many types of cancer including ovarian cancer. We sought to determine if combining a DPX-based peptide vaccine approach with immune modulation in the form of Treg suppression could enhance the anti-tumor effect of the vaccine. Metronomic cyclophosphamide (mCPA) treatment has been reported to selectively sustain reduced regulatory T cell numbers and activity. Using a murine tumor model (C3) we tested the benefit of combining mCPA and DPX vaccination for controlling well established subcutaneous solid tumors in vivo. We found that neither mCPA or DPX treatments alone were sufficient to eradicate advanced C3 tumors. However, combining mCPA with DPX vaccination provided effective tumor control. We further characterized the immune response by isolating and phenotyping tumor infiltrating lymphocytes and testing their immunogenicity by IFN-γ ELISPOT assay. Our results indicate that the DPX vaccine can increase the levels of antigen-specific CD8+ T cells and mCPA treatment reduces the CD4+FoxP3+ T regulatory cells. We conclude that immune responses generated by the DPX vaccine were more effective at controlling advanced tumors together with reduced Treg-mediated immune suppression. We have designed and initiated a phase I/II clinical trial to test a DPX vaccine targeting Survivin (DPX-Survivac), in combination with mCPA in ovarian cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4405. doi:1538-7445.AM2012-4405