gebhart/patrepeval huggingface dataset:
Utilization of 1-Aryl-2,2-dibromocyclopropanes in Synthetic Approaches to Phenanthroquinolizidine and Phenanthroindolizidine Alkaloids (2004)

The 1-aryl-2,2-dibromocyclopropane 8 was treated with silver acetate in acetic acid to give the allylic acetate 19. Exposure of the derived chloride 26 to racemic 2-piperidinemethanol (7) then afforded the allylic amine 6, which engaged in a Pd(0)-catalyzed cross-coupling reaction with arylboronate 29 to provide the cis -stilbene 25. The chloride 4 (X = Cl) derived from compound 25 failed to cyclize in the presence of base to give the desired phenanthroquinolizidine alkaloid julandine 1. This outcome resulted in a re-examination of the closing stages of a previously reported synthesis of the phenanthroindolizidine alkaloid ent -septicine ( ent -3). Towards this end, chloride 26 was reacted with ( S )-2-pyrrolidinemethanol (32) to give the allylic amine 33, which was cross-coupled with boronate ester 34 to afford cis -stilbene 35. Contrary to literature reports, compound 35 was converted into the corresponding chloride 37, rather than the expected mesylate, upon reaction with methanesulfonyl chloride in the presence of pyridine. Moreover, chloride 37 was not converted into ent -septicine ( ent -3) on exposure to sodium hydride, thus calling into question a previously reported synthesis of this natural product.
The product of the Saccharomyces cerevisiae cell cycle gene DBF2 has homology with protein kinases and is periodically expressed in the cell cycle. (1990)

Several Saccharomyces cerevisiae dbf mutants defective in DNA synthesis have been described previously. In this paper, one of them, dbf2, is characterized in detail. The DBF2 gene has been cloned and mapped, and its nucleotide sequence has been determined. This process has identified an open reading frame capable of encoding a protein of molecular weight 64,883 (561 amino acids). The deduced amino acid sequence contains all 11 conserved domains found in various protein kinases. DBF2 was periodically expressed in the cell cycle at a time that clearly differed from the time of expression of either the histone H2A or DNA polymerase I gene. Its first function was completed very near to initiation of DNA synthesis. However, DNA synthesis in the mutant was only delayed at 37 degrees C, and the cells blocked in nuclear division. Consistent with this finding, the execution point occurred about 1 h after DNA synthesis, and the nuclear morphology of the mutant at the restrictive temperature was that of cells blocked in late nuclear division. DBF2 is therefore likely to encode a protein kinase that may function in initiation of DNA synthesis and also in late nuclear division.
PROMOTIF—A program to identify and analyze structural motifs in proteins (1996)

We describe a suite of programs, PROMOTIF, that analyzes a protein coordinate file and provides details about the structural motifs in the protein. The program currently analyzes the following structural features: secondary structure; beta-and gamma-turns; helical geometry and interactions; beta-strands and beta-sheet topology; beta-bulges; beta-hairpins; beta-alpha-beta units and psi-loops; disulphide bridges; and main-chain hydrogen bonding patterns. PROMOTIF creates postscript files showing the examples of each type of motif in the protein, and a summary page. The program can also be used to compare motifs in a group of related structures, such as an ensemble of NMR structures.
Protection against cyclophosphamide-induced alopecia and inhibition of mammary tumor growth by topical 1,25-dihydroxyvitamin D3 in mice (1998)

Twenty-one-day-old BALB/c mice were shaved on the back to synchronize hair growth. On day 30 or 31, when at least 90% of mice exhibited hair regrowth in the shaved area, 1,25(OH)2D3 was applied topically to the shaved area daily for 5 days. On the 6th day, cyclophosphamide (Cytoxan, CTX) was injected i.p. to induce hair loss in the shaved area. Alopecia was induced in a dose-dependent manner by CTX treatment within 1 to 2 weeks. This effect was reduced significantly if mice were pre-treated with 1,25(OH)2D3, though only slight protection was observed in female mice. Interestingly, this 1,25(OH)2D3-mediated protection against hair loss was attenuated in male mice but became more significant in female mice when they were inoculated with the EMT-6 murine mammary tumor prior to treatment. More importantly, topical treatment with 1,25(OH)2D3 alone was able to inhibit EMT-6 tumor growth in both male and female BALB/c mice. Furthermore, 1,25(OH)2D3 pre-treatment also augmented the anti-tumor effect of CTX. Our results demonstrate that topical application of 1,25(OH)2D3 can protect against CTX-induced alopecia both in tumor-free and in tumor-bearing mice in a sex-dependent manner. Moreover, 1,25(OH)2D3 was shown, either alone or in combination with CTX, to inhibit tumor growth.
SRI International FASTUS system (1992)

The system that SRI used for the MUC-4 evaluation represents a significant departure from system architectures that have been employed in the past. In MUC-2 and MUC-3, SRI used the TACITUS text processing system [1], which was based on the DIALOGIC parser and grammar, and an abudctive reasoner for horn-clause logic. In MUC-4, SRI designed a new system called FASTUS (a permutation of the initial letters in Finite State Automata-based Text Understanding System) which we feel represents a significant advance in the state of the art of text processing. The system shares certain modules with the earlier TACITUS system, namely modules for text preprocessing and standardization, spelling correction, Hispanic name recognition, and the core lexicon. However, the DIALOGIC system and abductive reasoner, which were the heart and soul of the previous system, were replaced by a system whose architecture is based on cascaded finite-state automata. Using this system we were capable of achieving a significant level of performance on the MUC-4 task with less than one month devoted to domain-specific development. In addition, the system is extremely fast, and is capable of processing texts at the rate of approximately 3,200 words per minute, measured in CPU time on a Sun SPARC-2 processor. (Measured according to elapsed real time, the system about 50% slower, but the observed time depends on the particular hardware configuration involved.)
Randomized Study of Adding Inhaled Iloprost to Existing Bosentan in Pulmonary Arterial Hypertension (2006)

Within the limitations of a relatively small sample size, results of this study demonstrate that the addition of inhaled iloprost in patients with PAH with reduced exercise capacity on bosentan monotherapy is safe and efficacious.
Critical role of nuclear factor‐κB and stress‐activated protein kinases in steroid unresponsiveness (2002)

Glucocorticoid resistance is a serious clinical problem in chronic inflammatory diseases, because many patients with rheumatoid arthritis, asthma, or Crohn's disease fail to respond to steroid treatment. The molecular mechanisms underlying this unresponsiveness, however, are completely unknown. The effects of steroids are largely mediated by the interference of the glucocorticoid receptor (GR) with proinflammatory transcription factors. In the present study, we therefore investigated the activation of the transcription factors nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and the upstream kinases p38 and c-Jun N-terminal kinase (JNK) in steroid-sensitive and steroid-resistant patients with Crohn's disease. We demonstrated that steroid-sensitive and steroid-resistant patients reveal a remarkably different cellular activation pattern of these proinflammatory mediators. In steroid-sensitive patients, activation of NF-kappaB, AP-1, p38, and JNK was mainly found in lamina propria macrophages. In contrast, steroid-resistant patients revealed activation of all these mediators mostly in epithelial cells. The functional interference of the proinflammatory mediators with the glucocorticoid response was supported by reporter gene assays. Expression of NF-kappaB and, interestingly, also JNK1 and p38 inhibited the activity of the GR. Thus, our results suggest that steroid resistance is associated with increased epithelial activation of stress-activated protein kinases and NF-kappaB, which might inhibit the anti-inflammatory action of a limited number of GRs.
Dithiocarbamates Induce Apoptosis in Thymocytes by Raising the Intracellular Level of Redox-active Copper (1995)

Dithiocarbamates are metal-chelating compounds that can exert either pro-oxidant or antioxidant effects in different situations. They have recently been found to potently inhibit apoptotic cell death, an activity attributed to their antioxidant action. However, when thymocytes were exposed to pyrrolidine dithiocarbamate, an oxidation of the glutathione pool occurred within 90 min. Longer incubation resulted in cell shrinkage, chromatin fragmentation, glutathione depletion, and eventual cell lysis, which is typical of apoptosis in these cells. These changes were inhibited by inclusion of non-permeable metal chelators in the incubation medium, suggesting that pyrrolidine dithiocarbamate exerts its toxic effect by transporting a redox-active metal into the cell. This was directly confirmed when sustained 8-fold elevations of intracellular copper were detected after addition of pyrrolidine dithiocarbamate. In agreement with this, supplementation of the incubation medium with submicromolar concentrations of copper significantly potentiated pyrrolidine dithiocarbamate toxicity. We conclude that pyrrolidine dithiocarbamate exerts a powerful pro-oxidant effect on thymocytes due to its ability to transport external redox-active copper into cells. The resulting increase in glutathione disulfide may also explain the temporary anti-apoptotic activity of this compound described in other systems.
Transforming growth factor-beta. Multiple actions and potential clinical applications (1989)

THE CURRENT excitement in research on transforming growth factor—β (TGF-β) comes from its multiple actions on almost every type of cell and its potential for therapeutic use in common clinical conditions for which there are no adequate pharmacologic agents. Although TGF-β was identified originally in an assay that measured its ability to enhance the growth of fibroblasts in soft agar (transformation), its true importance is as a mediator of normal cellular physiology, in particular during normal formation of tissues (as in embryogenesis) and during tissue response to injury (as in inflammation and repair). Almost all cells have been shown to make TGF-β in one of its molecular forms, and al— most all normal cells have receptors for TGF-β. Transforming growth factor—β1 is a highly stable peptide that consists of two identical chains, each containing 112 amino acids. It was first isolated and characterized from human platelets and placentas as well
Solid‐phase Anti‐CD3 Antibody Activation and Cryopreservation of Human Tumor‐infiltrating Lymphocytes Derived from Epithelial Ovarian Cancer (1992)

The effect of solid-phase anti-CD3 antibody activation and cryopreservation was evaluated on thirteen samples of tumor-infiltrating lymphocytes (TILs) derived from epithelial ovarian cancer. Seven preparations of TILs were cultured with or without solid-phase anti-CD3 antibody in addition to 100 units/ml of recombinant interleukin-2 (rIL-2). The proliferation rate of all of the seven TIL preparations stimulated by anti-CD3 antibody on the fourth or fifth day of culture was 3.4 to 9.8 times greater than that of lymphocytes cultured with rIL-2 alone. Furthermore, in an experiment with five TIL samples activated with anti-CD3 antibody, three of them showed augmented cytotoxic activity against autologous fresh tumor cells. The population of CD3+/CD8+ TILs was increased after 4-5 weeks of cultivation and CD8+ lymphocytes amounted to over 70% in all of seven preparations tested, whereas two of seven preparations not activated by anti-CD3 antibody were CD3+/CD4(+)-dominant. In addition, nine preparations of TILs cultured with rIL-2 were cryopreserved for several weeks; after recovery from cryopreservation, no major change was observed in cell surface markers, in growth rate or in cytotoxic activity. These results suggest that cryopreserved and/or anti-CD3 antibody-activated lymphocytes could conveniently be employed in a clinical trial of adoptive immunotherapy employing TIL.
Opposing effects of Kruppel-like factor 4 (gut-enriched Kruppel-like factor) and Kruppel-like factor 5 (intestinal-enriched Kruppel-like factor) on the promoter of the Kruppel-like factor 4 gene (2002)

KLF4 (Krüppel-like factor 4 or gut-enriched Krüppel-like factor, GKLF) and KLF5 (Krüppel-like factor 5 or intestinal-enriched Krüppel-like factor, IKLF) are two closely related members of the zinc finger-containing Krüppel-like factor family of transcription factors. Although both genes are expressed in the intestinal epithelium, their distributions are different: Klf4 is primarily expressed in the terminally differentiated villus cells while Klf5 is primarily in the proliferating crypt cells. Previous studies show that Klf4 is a negative regulator of cell proliferation and Klf5 is a positive regulator of cell proliferation. In this study, we demonstrate that Klf5 binds to a number of cis-DNA elements that have previously been shown to bind to Klf4. However, while Klf4 activates the promoter of its own gene, Klf5 suppresses the Klf4 promoter. Moreover, Klf5 abrogates the activating effect of Klf4 on the Klf4 promoter and Klf4 abrogates the inhibitory effect of Klf5 on the same promoter. An explanation of this competing effect is due to physical competition of the two proteins for binding to cognate DNA sequence. The complementary tissue localization of expression of Klf4 and Klf5 and the opposing effect of the two Klfs on the Klf4 promoter activity may provide a basis for the coordinated regulation of expression of the Klf4 gene in the intestinal epithelium.
Liposomes as carriers of enzymes or drugs: a new approach to the treatment of storage diseases (1971)

medium nor by the liver. The experiments with amyloglucosidase showed no difference in glycogen concentration in the liver nor in glucose release into the medium when compared with control per- fusions.
A 14% efficient nonaqueous semiconductor/liquid junction solar cell (1984)

We describe the most efficient semiconductor/liquid junction solar cell reported to date. Under W-halogen (ELH) illumination, the device is a 14% efficient two-electrode solar cell fabricated from an n-type silicon photoanode in contact with a nonaqueous electrolyte solution. The cell′s central feature is an ultrathin electrolyte layer which simultaneously reduces losses which result from electrode polarization, electrolyte light absorption, and electrolyte resistance. The thin electrolyte layer also eliminates the need for forced convection of the redox couple and allows for precise control over the amount of water (and other electrolyte impurities) exposed to the semiconductor. After one month of continuous operation under ELH light at 100 mW/cm2, which corresponds to the passage of over 70 000 C/cm2, thin-layer cells retained over 90% of their efficiency. In addition, when made with Wacker Silso cast polycrystalline Si, cells yield an efficiency of 9.8% under simulated AMl illumination. The thin-layer cells employ no external compensation yet surpass their corresponding experimental (three-electrode) predecessors in efficiency.
The ampa glutamate receptor GluR3 is enriched in oxytocinergic magnocellular neurons and is localized at synapses (1995)

The cellular localization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptor, GluR3, was identified using antibodies that recognize the N-terminus of the predicted polypeptide sequence of GluR3. Regional immunoblot analysis of monkey brain homogenates identified a protein of approximately 102,000 mol. wt that was enriched in hypothalamus. Immunocytochemistry demonstrated that GluR3 was enriched within the hypothalamic magnocellular neurosecretory nuclei and axons of the hypothalamo-neurohypophysial tract in rat and monkey. GluR3 immunoreactivity co-localized to oxytocin-containing, but not vasopressin-containing, neurons of the hypothalamic paraventricular nucleus, supraoptic nucleus and accessory magnocellular nuclei. Ultrastructurally, GluR3 immunoreactivity was enriched throughout cytoplasm of the somatodendritic compartment and was associated with postsynaptic and presynaptic structures. GluR3 immunoreactivity was frequently observed to be clustered at the plasma membrane of the somatodendritic compartment, consistent with the predicted localization of a membrane-bound ion channel. Additionally, GluR3-immunoreactive axon terminals in synaptic contact with unlabeled dendrites within the retrochiasmatic area and bed nucleus of the stria terminalis were observed, providing morphological evidence for a presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor. By immunoblot analysis and immunocytochemistry using antibodies directed against a specific alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor in rat and monkey brain, our findings suggest a highly selective hypothalamic distribution of the GluR3 subunit that may have functional significance in the glutamatergic regulation of oxytocinergic neurons.
Neurotrophin receptor expression during development of the chick spinal sensory ganglion (1995)

The expression of mRNA for the trk neurotrophin receptors was studied in developing chicken dorsal root ganglion neurones using in situ hybridization histochemistry. trkC mRNA is expressed first, followed by trkB mRNA and finally trkA mRNA. The expression of each receptor begins very early during neurogenesis, and although initially quite widespread throughout the ganglion, the proportion of neurones expressing each receptor reduces as development proceeds. Expression patterns for each receptor become specifically restricted within the ganglion during this time, but during subsequent development the neurones migrate to their final site within the ganglion. From an assessment of the ganglion's ability to respond to neurotrophins in vitro, and from the results of earlier studies, both on the expression of receptors and gene targeting experiments, it is apparent that DRG neurones are dependent on these factors at very early stages of development and not, as previously thought, only after target innervation.
[Postoperative analgesia in abdominal surgery: a new look at an old problem]. (2004)

Analgesia in abdominal surgery is a sufficiently complicated problem. The extensive surgeries in the abdominal cavity are concomitant with massive tissue damages and are associated the systematic tissue inflammatory response to an intensity of the pain syndrome and of other postoperative complications. The modern understanding of surgical-trauma pathophysiology is indicative of the necessity to modulate the systemic inflammatory response whose severity is preconditioned not only by postoperative pain intensity but also by surgical results. With respect to the above stated, multi-model analgesia can be regarded as an optimal technique since it presupposes the long-term administration of local anesthetics (preferably 0.2% ropivakain) concurrently with non-steroid anti-inflammatory drugs used preoperatively (the most effective one is lornoxicam).
Activation of nuclear factor-κB during doxorubicin-induced apoptosis in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen peroxide (2002)

Doxorubicin (DOX) is a widely used anti-tumour drug. Cardiotoxicity is a major toxic side effect of DOX therapy. Although recent studies implicated an apoptotic pathway in DOX-induced cardiotoxicity, the mechanism of DOX-induced apoptosis remains unclear. In the present study, we investigated the role of reactive oxygen species and the nuclear transcription factor nuclear factor kappaB (NF-kappaB) during apoptosis induced by DOX in bovine aortic endothelial cells (BAECs) and adult rat cardiomyocytes. DOX-induced NF-kappaB activation is both dose- and time-dependent, as demonstrated using electrophoretic mobility-shift assay and luciferase and p65 (Rel A) nuclear-translocation assays. Addition of a cell-permeant iron metalloporphyrin significantly suppressed NF-kappaB activation and apoptosis induced by DOX. Overexpression of glutathione peroxidase, which detoxifies cellular H(2)O(2), significantly decreased DOX-induced NF-kappaB activation and apoptosis. Inhibition of DOX-induced NF-kappaB activation by a cell-permeant peptide SN50 that blocks translocation of the NF-kappaB complex into the nucleus greatly diminished DOX-induced apoptosis. Apoptosis was inhibited when IkappaB mutant vector, another NF-kappaB inhibitor, was added to DOX-treated BAECs. These results suggest that NF-kappaB activation in DOX-treated endothelial cells and myocytes is pro-apoptotic, in contrast with DOX-treated cancer cells, where NF-kappaB activation is anti-apoptotic. Removal of intracellular H(2)O(2) protects endothelial cells and myocytes from DOX-induced apoptosis, possibly by inhibiting NF-kappaB activation. These findings suggest a novel mechanism for enhancing the therapeutic efficacy of DOX.
Severe Human Bocavirus Infection, Germany (2011)

Human bocavirus (HBoV), discovered in 2005, can cause respiratory disease or no symptoms at all. We confirmed HBoV infection in an 8-month-old girl with hypoxia, respiratory distress, wheezing, cough, and fever. This case demonstrates that lower respiratory tract infection caused by HBoV can lead to severe and life-threatening disease.
Identification and Biological Characterization of Heterocyclic Inhibitors of the Hepatitis C Virus RNA-dependent RNA Polymerase (2002)

The hepatitis C virus (HCV) NS5B protein encodes an RNA-dependent RNA polymerase (RdRp), the primary catalytic enzyme of the HCV replicase complex. We established a biochemical RNA synthesis assay, using purified recombinant NS5B lacking the C-terminal 21 amino acid residues, to identify potential polymerase inhibitors from a high throughput screen of the GlaxoSmithKline proprietary compound collection. The benzo-1,2,4-thiadiazine compound 1 was found to be a potent, highly specific inhibitor of NS5B. This agent interacts directly with the viral polymerase and inhibits RNA synthesis in a manner noncompetitive with respect to GTP. Furthermore, in the absence of an in vitro-reconstituted HCV replicase assay employing viral and host proteins, the ability of compound 1 to inhibit NS5B-directed viral RNA replication was determined using the Huh7 cell-based HCV replicon system. Compound 1 reduced viral RNA in replicon cells with an IC(50) of approximately 0.5 microm, suggesting that the inhibitor was able to access the perinuclear membrane and inhibit the polymerase activity in the context of a replicase complex. Preliminary structure-activity studies on compound 1 led to the identification of a modified inhibitor, compound 4, showing an improvement in both biochemical and cell-based potency. Lastly, data are presented suggesting that these compounds interfere with the formation of negative and positive strand progeny RNA by a similar mode of action. Investigations are ongoing to assess the potential utility of such agents in the treatment of chronic HCV disease.