gebhart/patrepeval huggingface dataset:
Genome Wide Expression Profiling of Human Peripheral Blood Mononuclear Cells Stimulated With BAY 50-4798, a Novel T Cell Selective Interleukin-2 Analog (2007)

BAY 50-4798, a novel, engineered form of interleukin (IL)-2, is a selective agonist for the high-affinity IL-2 receptor and induces the proliferation of activated human T cells with potency similar to recombinant IL-2 (rIL-2), but has reduced proliferative activity on natural killer cells and is associated with a diminished secondary cytokine cascade. In the current study, the transcriptional profiles of human peripheral blood mononuclear cells (PBMCs) stimulated in vitro with BAY 50-4798 and rIL-2 were compared using Affymetrix microarray technology in combination with Ingenuity Pathway Analysis (IPA) to determine whether there are quantitative or qualitative differences in the molecular networks activated by these IL-2 analogs. A total of 299 genes were differentially expressed in response to the two IL-2 analogs, with an increase in the number of differences over time. Consistent with the fact that BAY 50-4798 interacts with fewer forms of the IL-2 receptor than rIL-2 to activate fewer cell types, 169 genes were expressed at lower levels in PBMCs cultured with BAY 50-4798 compared with IL-2. These genes were mainly categorized as cytokines and chemokines, and were used to build multiple molecular interaction networks, the most significant of which centered around a subunit of NF-kappaB, which is known to play a pivotal role in inflammation, and was associated with cell death. Of the genes induced in response to BAY 50-4798, only 25% were expressed at lower levels than those induced by rIL-2. Moreover, despite its more selective receptor targeting compared with rIL-2, BAY 50-4798 caused higher levels of expression of 130 genes, which predominantly fell into categories associated with metabolism and transcription. We interpret these results as consistent with the expected transcriptional profile of a mutein engineered and demonstrated to have diminished inflammatory effects yet fully retain selected features of IL-2 activity. In addition to demonstrating that the responses to BAY 50-4798 are characterized by differential expression of genes known to be induced by IL-2, we report for the first time the induction of a significant number of genes not previously reported in the context of IL-2 biology.
Hacia una teología latinoamericana feminista y constructiva desde un espacio eclesial (2001)

espanolEste articulo parte del presupuesto de que un locus theologicus protestante, feminista y latinoamericano brinda algunos impulsos tonificadores para la disciplina de la teologia sistematica o constructiva. Propone una teologia de sesgo trinitario, hecha con alegria y esperanza, desde el arraigo en una comunidad de fe concreta, desde una identidad como mujer en America Latina y desde la conviccion de que la fe viviente en Jesucristo, expresada en su seguimiento, puede y debe ser verdaderamente liberadora para varones y mujeres, adultos y ninos. A modo de ejemplo, se reflexiona sobre algunos ejes teologicos transversales que brotan desde la vivencia eclesial leida en la clave propuesta. EnglishThis article is based on the idea that a Protestant, feminist and Latin American locus theologicus, strengthens the systematic or constructive theology. It proposes a biased theology from a community of concrete faith, from the point of view of Latin America women and the belief in Jesus Christ. It can and should be liberating for men, women, adults and children. Reflections are also provided on transversal theological axes derived from the ecclesiastic experience. DeutschDieser Artikel geht davon aus, dass ein protestantischer, feministischer und lateinamerikanischer locus theologicus der systematischen und konstruktiven Theologie einige anregende Impulse geben kann. Er stellt eine Theologie trinitarischer Art vor, die mit Freude und Hoffnung aus der Verwurzelung in einer konkreten Glaubensgemeinschaft, aus der Identitat als Frau in Lateinamerika und aus der Uberzeugung heraus, dass der lebende Glaube an Jesus Chritsus, ausgedruckt in seiner Nachfolge, fur Manner und Frauen, Erwachsene und Kinder wirklich befreiend sein kann und muss. Es wird beispielhaft uber einige theologische transversale Achsen reflektiert, die dem kirchlichen Leben entspringen und als Vorschlag verstanden sein sollen.
Novel Nucleoside Analogue MCC-478 (LY582563) Is Effective against Wild-Type or Lamivudine-Resistant Hepatitis B Virus (2002)

The emergence of resistant hepatitis B virus (HBV) with the L528M mutation and/or the M552V and M552I mutations in the polymerase gene following long-term lamivudine treatment is becoming an important clinical problem. The aim of this study was to investigate the susceptibility of wild-type and lamivudine-resistant HBV to MCC-478 (LY582563), a novel nucleoside analogue derivative of phosphonomethoxyethyl purine. The susceptibility of wild-type HBV and lamivudine-resistant mutants (M552I, M552V, and L528M/M552V) to MCC-478 was examined by transient transfection of full-length HBV DNA into human hepatoma cells. HBV DNA replication was monitored by Southern blot hybridization, and the effective concentration required to reduce replication by 50% (EC(50)) was determined. The replicative intermediates of wild-type and lamivudine-resistant mutants were progressively diminished by treatment with increasing doses of MCC-478. The MCC-478 EC(50)s were 0.027 microM for wild-type HBV (about 20 times more efficient than lamivudine), 2.6 microM for M552I, 3.3 microM for M552V, and 2.0 microM for L528M/M552V. Wild-type HBV and lamivudine-resistant mutants are susceptible to MCC-478. MCC-478 appears to be a candidate for the treatment of HBV infection and exhibits potent activity against lamivudine-resistant HBV.
Design and Synthesis of [2-(8,9-Dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)- ethyl]phosphonic Acid (EAA-090), a Potent N-Methyl-d-aspartate Antagonist, via the Use of 3-Cyclobutene-1,2-dione as an Achiral α-Amino Acid Bioisostere (1998)

The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist. It contains the alpha-amino acid bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity. Compound 15 was as potent as CGS-19755 (5) in the [3H]CPP binding assay, the stimulated [3H]TCP binding assay, and the NMDA-induced lethality model in mice. A single bolus dose of compound 15, administered intravenously following permanent occlusion of middle cerebral artery (MCA) in the rat, reduced the size of infarcted tissue by 57%. Structure-activity relationship (SAR) studies have indicated that the six- and eight-membered ring derivatives had diminished activity and that the two-carbon side chain length was optimum for NMDA receptor affinity. Substitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the case of an H-bonding hydroxyl group. Replacement of the phosphonic acid group by either a carboxylic acid or a tetrazole group was unproductive. The potent bicyclic NMDA antagonists were synthesized efficiently by virture of their achiral nature and the ease of vinylgous amide formation from squaric acid esters. Compound 15, being a unique NMDA antagonist structural type with a favorable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma. Compound 15 is currently under clinical evaluation as a neuroprotective agent for stroke.
The A-chain of Human Relaxin Family Peptides Has Distinct Roles in the Binding and Activation of the Different Relaxin Family Peptide Receptors (2008)

The relaxin peptides are a family of hormones that share a structural fold characterized by two chains, A and B, that are cross-braced by three disulfide bonds. Relaxins signal through two different classes of G-protein-coupled receptors (GPCRs), leucine-rich repeat-containing GPCRs LGR7 and LGR8 together with GPCR135 and GPCR142, now referred to as the relaxin family peptide (RXFP) receptors 1-4, respectively. Although key binding residues have been identified in the B-chain of the relaxin peptides, the role of the A-chain in their activity is currently unknown. A recent study showed that INSL3 can be truncated at the N terminus of its A-chain by up to 9 residues without affecting the binding affinity to its receptor RXFP2 while becoming a high affinity antagonist. This suggests that the N terminus of the INSL3 A-chain contains residues essential for RXFP2 activation. In this study, we have synthesized A-chain truncated human relaxin-2 and -3 (H2 and H3) relaxin peptides, characterized their structure by both CD and NMR spectroscopy, and tested their binding and cAMP activities on RXFP1, RXFP2, and RXFP3. In stark contrast to INSL3, A-chain-truncated H2 relaxin peptides lost RXFP1 and RXFP2 binding affinity and concurrently cAMP-stimulatory activity. H3 relaxin A-chain-truncated peptides displayed similar properties on RXFP1, highlighting a similar binding mechanism for H2 and H3 relaxin. In contrast, A-chain-truncated H3 relaxin peptides showed identical activity on RXFP3, highlighting that the B-chain is the sole determinant of the H3 relaxin-RXFP3 interaction. Our results provide new insights into the action of relaxins and demonstrate that the role of the A-chain for relaxin activity is both peptide- and receptor-dependent.
Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals (2006)

A series of antisense oligonucleotides (ASOs) containing either 2'-O-methoxyethylribose (MOE) or locked nucleic acid (LNA) modifications were designed to investigate whether LNA antisense oligonucleotides (ASOs) have the potential to improve upon MOE based ASO therapeutics. Some, but not all, LNA containing oligonucleotides increased potency for reducing target mRNA in mouse liver up to 5-fold relative to the corresponding MOE containing ASOs. However, they also showed profound hepatotoxicity as measured by serum transaminases, organ weights and body weights. This toxicity was evident for multiple sequences targeting three different biological targets, as well as in mismatch control sequences having no known mRNA targets. Histopathological evaluation of tissues from LNA treated animals confirmed the hepatocellular involvement. Toxicity was observed as early as 4 days after a single administration. In contrast, the corresponding MOE ASOs showed no evidence for toxicity while maintaining the ability to reduce target mRNA. These studies suggest that while LNA ASOs have the potential to improve potency, they impose a significant risk of hepatotoxicity.
Therapeutic potential of peptides in allergic disease. (1993)

Immunotherapy with crude allergens prevents allergic symptoms in many patients, but its effects are temporary and variable. This type of intervention provokes a transient increase in IgE antibody synthesis that may produce untoward side effects. Recent research has suggested that such immunotherapy downregulates T-cell activity, indicating that regulation of proinflammatory T cells may be a critical mechanism of the therapeutic response. Animal studies have shown that T cells can be rendered anergic by the administration of nonimmunogenic, T-cell-active peptides. Peptides prepared by urea denaturation of purified allergens and by pepsin digestion of crude allergens have been evaluated in humans. Although evidence of specific immunosuppression was noted, allergic reactions occurred as well. Subsequently, researchers synthesized peptides representing short sequences from the protein chains of principal allergens, such as Amb a I of ragweed and Fel d I of cat. Assays of proliferation of T-cell lines from ragweed- and cat-sensitive patients have shown that relatively short sequences from these proteins are responsible for a major portion of the activity of the whole protein. One such cat peptide has shown no reactivity with human IgE. The characteristics of these peptides suggest they should be evaluated further in clinical trials of allergic patients. The anticipated outcome would be prolonged T-cell downregulation, which might result in suppression of late-phase allergic inflammation and IgE antibody synthesis. The question whether such changes will reduce clinical reactivity sufficiently to be clinically useful remains to be answered in future studies.
Electronic Versus Traditional Data Collection: A Multicenter Randomized Controlled Perioperative Pain Trial (2019)

<b>Background</b>: Electronic data collection is increasingly available as a means to collect pain-related clinical trial data; however, effectiveness and costs relative to traditional data collection are uncertain. <b>Aims</b>: The aim of this study was to evaluate data quality, protocol adherence, satisfaction, and resource requirements of electronic data collection (i.e., Internet-based electronic submission) compared to traditional data collection methods (i.e., paper-based diaries and telephone interviews) in a perioperative factorial randomized controlled trial. <b>Methods</b>: This study was an open-label two-arm parallel randomized controlled trial. Women (18-75 years) undergoing breast cancer surgery were allocated to either electronic or traditional data collection and completed pain-related questionnaires at baseline, postoperative period, and 3-month follow-up (NCT02240199). <b>Results</b>: We acquired outcome data at all time points from 78 randomized patients, 38 in the electronic group and 40 in the traditional group. The number of data queries (e.g., erroneously entered data) per patient was higher in the electronic data group (4.92 [SD = 4.67] vs. 1.88 [SD = 1.51]; <i>P</i> < 0.001). No between-group differences were observed for compliance with medications, data completeness, loss to follow-up, or patient or research assistant satisfaction. More research assistant time per patient was spent collecting data in the traditional group (42.6 min [SD = 12.8] vs. 9.92 min [SD = 7.6]; <i>P</i> < 0.001); however, costs per patient were higher in the electronic group ($176.85 [SD = 2.90] vs. $16.33 [SD = 4.90]; <i>P</i> < 0.001). <b>Conclusion</b>: Electronic data collection is feasible for perioperative pain clinical trials. Additional trials, including different surgical populations, are needed to confirm our findings and optimize use of electronic data capture methods.
Protein and lipid kinase inhibitors as targeted anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways (2008)

The identification and characterization of the components of individual signal transduction cascades, and advances in our understanding on how these biological signals are integrated in cancer initiation and progression, have provided new strategies for therapeutic intervention in solid tumors and hematological malignancies. To this end, pharmaceutical efforts have been directed to target different components of the Ras/Raf/MEK and PI3K/PKB pathways. This review article covers recent salient achievements in the identification and development of Raf, MEK, and PI3K inhibitors.
High-Throughput FACS Method for Directed Evolution of Substrate Specificity (2003)

Directed evolution is a powerful technology for the isolation of enzyme variants with enhanced properties such as organic solvent tolerance (), thermostability (), glutaraldehyde resistance (), and altered substrate specificity (,). Typically, enzyme variants are isolated using low throughput screening techniques such as agar plate or microtiter well plate assays. Recently, Fluorescence Activated Cell Sorting (FACS) has emerged as a tool offering significant promise for the high-throughput screening of very large libraries of mutants with single cell resolution (). Arising from the simultaneous collection of multiple parameters, FACS is inherently capable of rapidly evaluating libraries for several different catalytic activities simultaneously with no increase in time required for library screening. We have exclusively used a Becton Dickinson FACSCaliber instrument, perhaps the most popular low-end sorter commercially available.
Seeding Neural Stem Cells on Scaffolds of PGA, PLA, and Their Copolymers (2003)

Tissue engineering has arisen to address the extreme shortage of tissues and organs for transplantation and repair. One of the most successful techniques has been the seeding and culturing of cells on three-dimensional biodegradable scaffolds in vitro followed by implantation in vivo (1,2). This technique has been used to treat bladder conditions (3) and cartilage (4) and skin (5) defects, and is being studied for a variety of other applications. While matrices have been made from a host of natural and synthetic materials, there has been particular interest in the biodegradable polymers of poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and their copolymers poly(lactic-co-glycolic acid) (PLGA) Fig. 1). This particular family of degradable esters is very attractive for tissue engineering because the members are readily available and can be easily processed into a variety of structures, their degradation can be controlled through the ratio of glycolic acid to lactic acid subunits, and the polymers have already been approved for use in a number of applications by the FDA. Furthermore, recent research has shown this family of polymers to be biocompatible in the brain (6) and spinal cord (7).
A Feasibility Study on Noninvasive Blood Glucose Measurement Using Photoacoustic Method (2010)

Diabetes is a disease of concern, which affects vital organs of body. In order to prevent complications, frequent glucose measurement is necessary. This paper presents a possible methodology for noninvasive blood glucose measurement using photoacoustic (PA) method. Although encouraging results have been obtained using the developed system, certain other error sources like melanin content of skin, tissue and skin profiles, variation of blood flow due to pressure changes, should also be considered and investigated.
Nuclear mRNA accumulation causes nucleolar fragmentation in yeast mtr2 mutant. (1994)

We have identified a set of genes that affect mRNA transport (mtr) from the nucleus to the cytoplasm of Saccharomyces cerevisiae. One of these genes, MTR2, has been cloned and shown to encode a novel 21-kDa nuclear protein that is essential for vegetative growth. MTR2 shows limited homology to a protein implicated in plasmid DNA transfer in Escherichia coli. PolyA+RNA accumulates within the nucleus of mtr2-1 in two to three foci at 37 degrees C. mRNA, tRNA, and rRNA synthesis continue as do pre-mRNA splicing, tRNA processing, and rRNA export at 37 degrees C. Under these conditions the polyA tail length increases, and protein synthesis is progressively inhibited. Nucleolar antigens also redistribute to two to three nuclear foci at 37 degrees C, and this redistribution depends on ongoing transcription by RNA polymerase II. Surprisingly, these foci coincide with the sites of polyA+RNA accumulation. Comparable colocalization and dependance on RNA polymerase II transcription is seen for the mtr1-1 mutant. The disorganization of the nucleolus thus depends on mRNA accumulation in these mutants. We discuss the possible functions of MTR2 and the yeast nucleolus in mRNA export.
HIV type 1 Tat protein enhances activation-but not Fas (CD95)-induced peripheral blood T cell apoptosis in healthy individuals (1997)

T cell apoptosis may play an important role in the depletion and functional defects of T cells in HIV disease. A number of investigators have shown that peripheral blood T cells in HIV disease undergo spontaneous and activation-induced apoptosis. We found recently that peripheral blood T cells from HIV+ individuals undergo apoptosis when stimulated through Fas. Also, a number of investigators have shown that Tat protein from HIV-1 can increase spontaneous and activation-induced apoptosis. In the present study we examined the effect of HIV type 1 Tat protein on spontaneous, activation-induced and Fas-induced apoptosis of peripheral blood T cells from HIV- individuals. We find that Tat protein has no effect on spontaneous apoptosis but does enhance activation-induced apoptosis of both CD4+ and CD8+ T cells. Tat, however, failed to enhance Fas-induced apoptosis of CD4+ and CD8+ T cells. Examining the mechanisms by which Tat induces apoptosis, we found that inhibitors of reactive oxygen intermediate (ROI) generation or neutralizers of ROI, such as rotenone, a potent inhibitor of mitochondrial complex I of the respiratory chain, and 3,3,5,5-tetramethylpyrroline N-oxide (TMPO), an electron spin trap, could both enhance the spontaneous apoptosis induced by Tat. This enhancement of Tat-induced apoptosis by rotenone and TMPO was independent of ICE activation as it could not be inhibited by the tripeptide z-VAD-fmk, an irreversible inhibitor of ICE/ced-3 protease homologs. These findings suggest that Tat induced enhancement of activation-induced cell death may involve complex mechanisms, some of which are ROI independent. These results indicate that a HIV-specific mechanism other than Tat is responsible for the previously observed increased susceptibility of peripheral blood T cells from HIV-infected individuals to undergo apoptosis in response to Fas stimulation.
Identities and Phylogenetic Comparisons of Posttranscriptional Modifications in 16 S Ribosomal RNA from Haloferax volcanii (2000)

Small subunit (16 S) rRNA from the archaeon<i>Haloferax volcanii</i>, for which sites of modification were previously reported, was examined using mass spectrometry. A census of all modified residues was taken by liquid chromatography/electrospray ionization-mass spectrometry analysis of a total nucleoside digest of the rRNA. Following rRNA hydrolysis by RNase T<sub>1</sub>, accurate molecular mass values of oligonucleotide products were measured using liquid chromatography/electrospray ionization-mass spectrometry and compared with values predicted from the corresponding gene sequence. Three modified nucleosides, distributed over four conserved sites in the decoding region of the molecule, were characterized: 3-(3-amino-3-carboxypropyl)uridine-966,<i>N</i><sup>6</sup>-methyladenosine-1501, and<i>N</i><sup>6</sup>,<i>N</i><sup>6</sup>-dimethyladenosine-1518 and -1519 (all <i>Escherichia coli</i> numbering). Nucleoside 3-(3-amino-3-carboxypropyl)uridine, previously unknown in rRNA, occurs at a highly conserved site of modification in all three evolutionary domains but for which no structural assignment in archaea has been previously reported. Nucleoside<i>N</i><sup>6</sup>-methyladenosine, not previously placed in archaeal rRNAs, frequently occurs at the analogous location in eukaryotic small subunit rRNA but not in bacteria.<i>H. volcanii</i> small subunit rRNA appears to reflect the phenotypically low modification level in the Crenarchaeota kingdom and is the only cytoplasmic small subunit rRNA shown to lack pseudouridine.
CMOS-Based Biosensor Arrays (2005)

CMOS-based sensor array chips provide new and attractive features as compared to today's standard tools for medical, diagnostic, and biotechnical applications. Examples for molecule- and cell-based approaches and related circuit design issues are discussed.
Probing unnatural amino acid integration into enhanced green fluorescent protein by genetic code expansion with a high-throughput screening platform (2016)

The developed HTMS is powerful tool for parallelized and rapid screening. In light of uAA integration, future applications may include parallelized screening of different PylRS/tRNA<sup>Pyl</sup><sub>CUA</sub> pairs as well as further optimization of culture conditions.