gebhart/patrepeval huggingface dataset:
Monoclonal antibodies and other biologic therapies (2001)

The treatment of systemic lupus erythematosus (SLE) presents a significant therapeutic challenge: multi-organ involvement and a variable disease course characterized by clinical exacerbations and remissions make it difficult to predict outcome. Few products have been specifically developed in this clinical indication and most accepted therapies have not been tested in randomized controlled trials in SLE. A variety of biologic agents under investigation as potential treatments for SLE are designed to interfere with specific immunologic responses, hopefully avoiding generalized immunosuppression. These include therapies to downregulate IL-10 and/or upregulate TGFb production. Agents which interfere with T cell activation and T cell-B cell collaboration, such as CTLA4-Ig and anti-CD40 ligand monoclonal antibodies, may result in long term therapeutic benefit; alone or in combination, even following brief treatment courses. Products designed to decrease production of anti-dsDNA antibodies or inhibit complement activation may prevent immune complex deposition and amerliorate organ-specific manifestations such as renal disease. More aggressive interventions include gene therapy and stem cell transplantation. As these agents enter clinical trials, efforts to develop international consensus regarding trial methodology and outcome measures will be crucial to their successful development.
Purification and characterization of a novel heparinase. (1990)

A unique heparinase was isolated from a recently discovered Gram-negative soil bacterium. The enzyme (heparinase III) was purified by hydroxylapatite chromatography, chromatofocusing, and gel permeation chromatography. The enrichment was 48x, and the specific activity of catalytically pure heparinase was 127 IU/mg of protein. Similar to the heparinase I from Flavobacterium heparinum, heparinase III also degrades heparin to mainly disaccharide fragments. It is specific for heparin and also breaks down heparan sulfate, but not hyaluronic acid and chondroitin sulfate. Heparinase III, however, differs markedly from heparinase I in several other aspects: it has a higher molecular mass (94 versus 43 kDa), pI (9.2 versus 8.5), its Km and kcat are different, and it has a higher energy of activation (15.6 versus 6.3 kcal/mol). Optimal activity was also found at higher pH (7.6 versus 6.5) and temperature (45 versus 37 degrees C). Furthermore, the amino acid composition of heparinase III is quite different from that of heparinase I.
Chemosensitivity of human pancreatic cancer cell lines serially transplanted in nude mouse. (1998)

These results reflect the low sensitivity of clinical pancreatic cancer to conventionally available antitumor agents, and suggest the possible synergistic combination antitumor activity of MMC and DDP.
Protein kinase signalling pathways involved in the up-regulation of the rat α1(I) collagen gene by transforming growth factor β1 and bone morphogenetic protein 2 in osteoblastic cells (1999)

Transforming growth factor beta (TGFbeta) family members are known for their important role in bone physiology. TGFbeta(1) and, to a smaller extent, bone morphogenetic protein 2 (BMP-2) have been reported to regulate the gene expression of different osteoblast markers in vitro. However, little is known about the molecular mechanisms involved in these actions. Here we report that BMP-2, like TGFbeta(1), up-regulated alpha1(I) collagen mRNA expression in ROS 17/2.8 osteoblastic cells. This was mediated through an increase in the transcriptional rate of the gene rather than through the stabilization of alpha1(I) collagen mRNA, and required new protein synthesis. In addition, TGFbeta(1)- and BMP-2-induced increases in alpha1(I) collagen mRNA levels were both dependent on protein kinase C and protein tyrosine kinase activities. Furthermore, the mitogen-activated protein kinase (MAPK) [MAPK/extracellular signal-regulated protein kinase kinase 1/extracellular signal-regulated protein kinase (MEK-1/ERK)] pathway participated in the up-regulation of alpha1(I) collagen gene expression by TGFbeta(1) and BMP-2. In response to either TGFbeta(1) or BMP-2, the stimulation of alpha1(I) collagen mRNA levels was paralleled by an early increase in extracellular signal-regulated kinase protein activity. Moreover, the effects of both TGFbeta(1) and BMP-2 on alpha1(I) collagen gene expression were markedly decreased in transfected ROS 17/2.8 cells expressing a dominant-negative MEK-1. Our findings therefore show that TGFbeta(1) and BMP-2, which signal through discrete cell-surface receptors, are able to trigger analogous, if not identical, protein-phosphorylation-transducing cascades leading to comparable actions on the transcription of the alpha1(I) collagen gene in osteoblastic cells.
Effect of 5‐fluoro‐2′‐deoxyuridine (FdUrd) on 5‐bromo‐2′‐deoxyuridine (BrdUrd) incorporation into DNA, measured with a monoclonal BrdUrd antibody and by the BrdUrd/hoechst quenching effect (1985)

The purpose of this study was to improve the application of bromodeoxyuridine (BrdUrd) for the flow cytometric analysis of cell kinetics. In order to obtain a quantitative measure of the DNA synthesis rate (or the number of divided cells), BrdUrd should replace thymidine (dThd) completely in the newly synthesized DNA strands. The de novo synthesis of dThd monophosphate competing with BrdUrd incorporation was stopped by fluorodeoxyuridine (FdUrd). Cells of a human leukemic cell line (REH) were exposed to BrdUrd for either 20 min, 8 h, or 24 h. Bromodeoxyuridine incorporation was determined by a monoclonal antibody as well as by the BrdUrd/Hoechst (H) technique. Counterstaining of the DNA was performed with propidium iodide or ethidium bromide. DNA fluorescence was measured in both techniques with a two-parameter flow cytometer, the histograms being analyzed by computer. It was found that FdUrd is required in the BrdUrd/H technique for replacement of dThd at low BrdUrd concentrations and long incubation times. With short incubation periods, as used for detection by the monoclonal anti-BrdUrd antibody, FdUrd increases the incorporated BrdUrd amount when BrdUrd concentrations of 10 microM or less are applied.
Effect of Pindolol on Stress-Related Disturbances of Musical Performance: Preliminary Communication1 (1983)

The effect of 5 mg pindolol on stress-induced disturbances of performance were assessed in 30 professional musicians. An overall inverse relationship was found between anxiety and musical performance. Reduction in anxiety by administration of pindolol was associated with a subjective improvement in performance. A stress-related tachycardia and increase in systolic blood pressure were attenuated. Pindolol had no effect on peak flow measurements.
Detection of mercuric chloride by photofragment emission using a frequency-converted fiber amplifier (2007)

A real-time, noninvasive approach for detecting trace amounts of vapor-phase mercuric chloride (HgCl(2)) in combustion flue gas is demonstrated using a near-infrared pulsed fiber amplifier that is frequency converted to the ultraviolet. Excitation of the HgCl(2) ([see text]) transition at 213 nm generates 253.7 nm emission from the Hg (6(3)P(1)) photoproduct that is proportional to the concentration of HgCl(2). A measured quadratic dependence of the HgCl(2) photofragment emission (PFE) signal on the laser irradiance indicates that the photodissociation process involves two-photon excitation. Additionally, low concentrations of HgCl(2) are detected with the PFE approach in an environment characteristic of coal-fired power-plant flue gas using this compact solid-state laser source. A detection limit of 0.7 ppb is extrapolated from these results.
In vitro selection of probiotic lactobacilli: a critical appraisal. (2000)

The problem of choosing criteria for the in vitro selection of lactobacilli to be used as health-promoting, probiotic ingredients, in food and pharmaceutical preparations, was apparent even in the original works of Metchnikoff, who first proposed the therapeutic use of these bacteria. In the last decade, a consensus has been reached by scientists on some criteria, with particular attention being paid to the ecological origin of the bacteria, their tolerance to the hostile conditions of the stomach and the small intestine, and their ability to adhere to intestinal surfaces. Even though these criteria have been used to select probiotic lactobacilli, some doubts still remain about the real value of these criteria. A critical rethinking of selection criteria seems necessary in order to improve the process of developing better probiotics.
On-line data compression in a log-structured file system (1992)

We have incorporated on-line data compression into the low levels of a log-structured file system (Rosenblum's Sprite IFS). Each block of data or meta-data is compressed as it is written to the disk and decompressed as it is read. The log-structuring overcomes the problems of allocation and fragmentation for variable-sized blocks.
Nitrocellulose-RAST Analysis of Allergenic Cross-Reactivity of <i>Candida albicans</i> and <i>Saccharomyces cerevisiae</i> Mannans (1995)

Two chemically purified mannan preparations and one affinity purified mannan preparation of Candida albicans and Saccharomyces cerevisiae were analyzed for allergenic cross-reactivity. Simultaneous IgE binding in radioallergosorbent test (RAST) was studied with all preparations and the chemically purified mannans were also used for RAST inhibitions. The yeast mannans were purified with the Peat method, using repeated ethanol precipitations and Fehling's precipitation in alkaline conditions, and the Cetavlon method, using hexadecyltrimethylammonium bromide and ethanol precipitations. Affinity purification of the mannans was performed with concanavalin A lectin bound to a Sepharose column. Mannan from Pityrosporum ovale was purified with the Cetavlon method for analysis of simultaneous RAST reactivity. Simultaneous IgE binding to all the studied yeast mannans was generally seen in all the studied sera of patients suffering from atopic dermatitis. The strongest responses were seen against C. albicans mannan, especially the Cetavlon mannan. In the RAST inhibition studies IgE binding to S. cerevisiae mannan was completely inhibited by C. albicans mannan preparations, whereas reciprocal inhibition was not complete. These results indicate that in atopic dermatitis simultaneous IgE response to yeast polysaccharides occurs and that the major sensitizer is C. albicans and IgE antibodies against S. cerevisiae mannan are cross-reacting.
Growth arrest induced by wild-type p53 protein blocks cells prior to or near the restriction point in late G1 phase. (1992)

Conditional expression of wild-type (wt) p53 protein in a glioblastoma tumor cell line has been shown to be growth inhibitory. We have now more precisely localized the position in the cell cycle where growth arrest occurs. We show that growth arrest occurs prior to or near the restriction point in late G1 phase of the cell cycle. The effect of wt p53 protein on the expression of four immediate-early genes (c-FOS, c-JUN, JUN-B, and c-MYC), one delayed-early gene (ornithine decarboxylase), and two late-G1/S-phase genes (B-MYB and DNA polymerase alpha) was also examined. Of this subset of growth response genes, only the expression of B-MYB and DNA polymerase alpha was significantly repressed. The possibility that decreased expression of B-MYB may be an important component of growth arrest mediated by wt p53 protein is discussed.
A high storage capacity neural network content-addressable memory (1991)

AbstractA new neural network design is developed and studied for error-correcting content-addressable memory (CAM). Relative to the size of the network, the design enables the storage and error-correcting retrieval of many more random patterns than has previously been possible. This increase in storage capacity is achieved by using hidden units to assist in the process of storing and retrieving patterns over the visible units. Key components of the design are the mean-field-theory learning algorithm adapted for CAM (MFT-CAM), an error-correcting retrieval algorithm for networks with hidden units, and an architecture that is not fully connected. Random pattern storage capacity appears to scale linearly with the number of hidden units, with a slope in the range 13–18, the largest networks investigated stored 4–6 bits per connection. As the ratio of the number of hidden to visible units increases, the algorithm must contend with a random-weight. Identity-map effect that creates spurious stable visible states and limits the error-correcting basins of attraction. In networks without hidden units, the error-correcting basins are found to be somewhat larger than those of the symmetric Perceptron algorithm, which has previously been shown to be a special limit of the MFT-CAM algorithm.
Controlling β-Amyloid Oligomerization by the Use of Naphthalene Sulfonates (2005)

Aggregation of proteins and peptides has been shown to be responsible for several diseases known as amyloidoses, which include Alzheimer disease (AD), prion diseases, among several others. AD is a neurodegenerative disorder caused primarily by the aggregation of beta-amyloid peptide (Abeta). Here we describe the stabilization of small oligomers of Abeta by the use of sulfonated hydrophobic molecules such as AMNS (1-amino-5-naphthalene sulfonate); 1,8-ANS (1-anilinonaphthalene-8-sulfonate) and bis-ANS (4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonate). The experiments were performed with either Abeta-1-42 or with Abeta-13-23, a shorter version of Abeta that is still able to form amyloid fibrils in vitro and contains amino acid residues 16-20, previously shown to be essential to peptide-peptide interaction and fibril formation. All sulfonated molecules tested were able to prevent Abeta aggregation in a concentration dependent fashion in the following order of efficacy: 1,8-ANS < AMNS < bis-ANS. Size exclusion chromatography revealed that in the presence of bis-ANS, Abeta forms a heterogeneous population of low molecular weight species that proved to be toxic to cell cultures. Since the ANS compounds all have apolar rings and negative charges (sulfonate groups), both hydrophobic and electrostatic interactions may contribute to interpeptide contacts that lead to aggregation. We also performed NMR experiments to investigate the structure of Abeta-13-23 in SDS micelles and found features of an alpha-helix from Lys(16) to Phe(20). 1H TOCSY spectra of Abeta-13-23 in the presence of AMNS displayed a chemical-shift dispersion quite similar to that observed in SDS, which suggests that in the presence of AMNS this peptide might adopt a conformation similar to that reported in the presence of SDS. Taken together, our studies provide evidence for the crucial role of small oligomers and their stabilization by sulfonate hydrophobic compounds.
REFLECTANCE SPECTRA OF LOW-TEMPERATURE CHLORIDE AND PERCHLORATE HYDRATES AND THEIR RELEVANCE TO THE MARTIAN SURFACE (2009)

Introduction: Chlorides and perchlorates present on Mars can form aqueous solutions because of low temperature eutectics and related lower evaporation rates [1]. The recent discovery of chlorides and perchlorates on Mars by NASA’s Phoenix Lander [2] reinforced the potential for chlorides on Mars. Chlorides present in databases lack spectral features (absorption bands) in the near-infrared. Most spectral libraries contain only high temperature “Earthrelevant” chlorides, such as NaCl or KCl. However, at typical Martian relevant temperatures, hydrates are more stable [1]. Similarly, not much is really known about perchlorate spectral features. Experimental: The following salts and their lowtemperature hydrates were synthesized and measured: KCl, NaCl, CaCl2, MgCl2, FeCl2, FeCl3, NH4Cl, NaClO4, KClO4, and Mg(ClO4)2. We also measured eutectic mixtures of ice and salt. Reflectance spectra were taken using a Nicolet 6700 FTIR Spectrometer to allow analysis in the range 1.0-2.5 m. For comparison reasons, chlorides and perchlorates stable at ambient temperature were also measured. In the case of eutectic mixtures, we corrected for ice content using KCl + ice as a control sample since it does not form any hydrate. Results: Chlorides. After correcting the spectra for water ice, we see KCl does not exhibit any significant features, nor does anhydrous NaCl (Fig. 1). However, other anhydrous chlorides (e.g. CaCl2), as well as their hydrated forms, clearly show evidence of additional absorption bands. The most significant bands are located at 1.19, 1.44 and 1.97, the latter two due to hydration. Also, notice that the absorption band depth increases with increasing hydration state.
Swift: Fast, Reliable, Loosely Coupled Parallel Computation (2007)

We present Swift, a system that combines a novel scripting language called SwiftScript with a powerful runtime system based on CoG Karajan, Falkon, and Globus to allow for the concise specification, and reliable and efficient execution, of large loosely coupled computations. Swift adopts and adapts ideas first explored in the GriPhyN virtual data system, improving on that system in many regards. We describe the SwiftScript language and its use of XDTM to describe the logical structure of complex file system structures. We also present the Swift runtime system and its use of CoG Karajan, Falkon, and Globus services to dispatch and manage the execution of many tasks in parallel and grid environments. We describe application experiences and performance experiments that quantify the cost of Swift operations.
Ethylene Response Factor 1 Mediates Arabidopsis Resistance to the Soilborne Fungus Fusarium oxysporum (2004)

Ethylene response factor 1 (ERF1) is a transcriptional factor from Arabidopsis thaliana that regulates plant resistance to the necrotrophic fungi Botrytis cinerea and Plectosphaerella cucumerina and whose overexpression enhances resistance to these fungi. Here, we show that ERF1 also mediates Arabidopsis resistance to the soilborne fungi Fusarium oxysporum sp. conglutinans and F. oxysporum f. sp. lycopersici, because its constitutive expression in Arabidopsis confers enhanced resistance to these pathogens. Expression of ERF1 was upregulated after inoculation with F. oxysporum f. sp. conglutinans, and this response was blocked in ein2-5 and coi1-1 mutants, impaired in the ethylene (ET) and jasmonic acid (JA) signal pathways, respectively, which further indicates that ERF1 is a downstream component of ET and JA defense responses. The signal transduction network controlling resistance to F. oxysporum fungi was explored using signaling-defective mutants in ET (ein2-5), JA (jar1-1), and salicylic acid (SA) (NahG, sid2-1, eds5-1, npr1-1, pad4-1, eds1-1, and pad2-1) transduction pathways. This analysis revealed that Arabidopsis resistance to F. oxysporum requires the ET, JA, and SA signaling pathways and the NPR1 gene, although it is independent of the PAD4 and EDS1 functions.
Validation and Structural Characterization of the LEDGF/p75–MLL Interface as a New Target for the Treatment of MLL-Dependent Leukemia (2014)

Mixed lineage leukemia (MLL) fusion-driven acute leukemias represent a genetically distinct subset of leukemias with poor prognosis. MLL forms a ternary complex with the lens epithelium-derived growth factor (LEDGF/p75) and MENIN. LEDGF/p75, a chromatin reader recognizing H3K36me3 marks, contributes to the association of the MLL multiprotein complex to chromatin. Formation of this complex is critical for the development of MLL leukemia. Available X-ray data represent only a partial structure of the LEDGF/p75-MLL-MENIN complex. Using nuclear magnetic resonance spectroscopy, we identified an additional LEDGF/p75-MLL interface, which overlaps with the binding site of known LEDGF/p75 interactors-HIV-1 integrase, PogZ, and JPO2. Binding of these proteins or MLL to LEDGF/p75 is mutually exclusive. The resolved structure, as well as mutational analysis, shows that the interaction is primarily sustained via two aromatic residues of MLL (F148 and F151). Colony-forming assays in MLL-AF9(+) leukemic cells expressing MLL interaction-defective LEDGF/p75 mutants revealed that this interaction is essential for transformation. Finally, we show that the clonogenic growth of primary murine MLL-AF9-expressing leukemic blasts is selectively impaired upon overexpression of a LEDGF/p75-binding cyclic peptide CP65, originally developed to inhibit the LEDGF/p75-HIV-1 integrase interaction. The newly defined protein-protein interface therefore represents a new target for the development of therapeutics against LEDGF/p75-dependent MLL fusion-driven leukemic disorders. Cancer Res; 74(18); 5139-51. ©2014 AACR.
The Achilles Heel of ErbB-2/HER2: Regulation by the Hsp90 Chaperone Machine and Potential for Pharmacological Intervention (2004)

Signal transduction mediated by ErbB/HER receptor tyrosine kinases is crucial for the development and maintenance of epithelial tissues, and aberrant signaling is frequently associated with malignancies of epithelial origin. This review focuses on the roles played by the Hsp90 chaperone machinery in the regulation of signaling through the ErbB/HER network, and discusses potential therapeutic strategies that disrupt chaperone functions. Hsp90 and its associated cochaperones regulate ErbB signal transduction through multiple mechanisms. The chaperone system controls the stability of the nascent forms of both ErbB-1 (EGF-receptor) and ErbB-2/HER2, while regulation of the mature form is restricted to ErbB-2. Regulation by the Hsp90 complex extends to downstream effectors of ErbB signaling, namely Raf-1, Pdk-1 and Akt/PKB. Disrupting the function of Hsp90 results in the degradation of both the receptors and their effectors, thereby inhibiting tumor cell growth. The importance of an Hsp90-recognition motif located within the kinase domain of ErbB-2 is discussed, as well as a direct role for Hsp90 in regulating tyrosine kinase activity. In light of recent observations, we emphasize the ability of specific tyrosine kinase inhibitors to selectively target ErbB-2 to the chaperone-mediated degradation pathway. ErbB-specific drugs are already used to treat cancers, and clinical trials are underway for additional compounds that intercept ErbB signaling, including drugs that target Hsp90. Hence, the dependence of ErbB-2 upon Hsp90 reveals an Achilles heel, which opens a window of opportunity for combating cancers driven by the ErbB/HER signaling network.
Acid-catalyzed hydrolysis of 4-diazo-isothiochroman-3-one. Comparison with the acyclic analog and the corresponding oxygen system (1997)

The acid-catalyzed hydrolysis of the cyclic diazothiolactone, 4-diazoisochroman-3-one (3) was found to occur with the hydronium-ion isotope effect, [Formula: see text] and to give the ring-contracted product, 1,3-dihydrobenzo[c]thiophene-1-carboxylic acid (4). This shows that protonation of the diazo carbon atom occurs in the rate-determining step and that the reaction also involves migration of the thio group. The hydronium-ion catalytic coefficient for this reaction, [Formula: see text], is 45 times less than that for hydrolysis of its acyclic thio ester analog, S-methyl phenyldiazothioacetate (5). Semiempirical AM1 molecular orbital calculations support the idea that this difference in reactivity is the result of increased delocalization of negative charge into the aromatic ring in the case of the cyclic substrate, which reduces the negative charge on the diazo carbon atom and makes it less susceptible to protonation. Key words: hydrolysis, diazoalkanes, charge delocalization, AM1 calculations, thio group migration.