gebhart/patrepeval huggingface dataset:
The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma (2010)

The proteasomal pathway of protein degradation involves 2 discrete steps: ubiquitination and degradation. Here, we evaluated the effects of inhibiting the ubiquitination pathway at the level of the ubiquitin-activating enzyme UBA1 (E1). By immunoblotting, leukemia cell lines and primary patient samples had increased protein ubiquitination. Therefore, we examined the effects of genetic and chemical inhibition of the E1 enzyme. Knockdown of E1 decreased the abundance of ubiquitinated proteins in leukemia and myeloma cells and induced cell death. To further investigate effects of E1 inhibition in malignancy, we discovered a novel small molecule inhibitor, 3,5-dioxopyrazolidine compound, 1-(3-chloro-4-fluorophenyl)-4-[(5-nitro-2-furyl)methylene]-3,5-pyrazolidinedione (PYZD-4409). PYZD-4409 induced cell death in malignant cells and preferentially inhibited the clonogenic growth of primary acute myeloid leukemia cells compared with normal hematopoietic cells. Mechanistically, genetic or chemical inhibition of E1 increased expression of E1 stress markers. Moreover, BI-1 overexpression blocked cell death after E1 inhibition, suggesting ER stress is functionally important for cell death after E1 inhibition. Finally, in a mouse model of leukemia, intraperitoneal administration of PYZD-4409 decreased tumor weight and volume compared with control without untoward toxicity. Thus, our work highlights the E1 enzyme as a novel target for the treatment of hematologic malignancies.
Brain-Derived Neurotrophic Factor Is Released in the Dorsal Horn by Distinctive Patterns of Afferent Fiber Stimulation (2001)

Brain-derived neurotrophic factor (BDNF) is synthesized by small neuron cell bodies in the dorsal root ganglia (DRG) and is anterogradely transported to primary afferent terminals in the dorsal horn where it is involved in the modulation of painful stimuli. Here we show that BDNF is released in the rat isolated dorsal horn after chemical stimulation by capsaicin or electrical stimulation of dorsal roots. Capsaicin superfusion (1-100 microm) induced a dose-dependent release of BDNF, measured using ELISA. The highest dose of capsaicin also induced a depletion of BDNF protein in the dorsal horn. BDNF release was also seen after electrical stimulation of the dorsal roots at C-fiber strength. This release was encoded by specific patterns of afferent fiber stimulation. Neither continuous low-frequency (480 pulses, 1 Hz) nor tetanic high-frequency (300 pulses in 3 trains, 100 Hz) stimulation evoked release of BDNF, although substance P (SP) release was observed under both of these conditions. However, BDNF was released after short bursts of high-frequency stimulation (300 pulses in 75 trains, 100 Hz) along with SP and glutamate. The NMDA antagonist d-AP-5 inhibited electrically evoked BDNF release. BDNF release was also measured after systemic or intrathecal NGF treatment. This upregulated BDNF content in the DRG and increased the capsaicin-evoked release of BDNF. Similarly, the amount of BDNF released by burst stimulation was increased after NGF treatment. This activity-dependent release continued to be encoded solely by this stimulation pattern. These experiments demonstrate that BDNF release in the dorsal horn is encoded by specific patterns of afferent fiber stimulation and is mediated by NMDA receptor activation.
Expression of VCAM‐1 and VLA‐4 dependent T‐lymphocyte adhesion to dermal fibroblasts stimulated with proinflammatory cytokines (1996)

In chronic inflammatory conditions, mononuclear cells infiltrate the involved connective tissue and may persist, perhaps because of binding to adhesion molecules on connective tissue cells, as well as extracellular matrix. Here we investigated whether vascular cell adhesion molecule-1 (VCAM-1) may be induced on human dermal fibroblasts by proinflammatory cytokines. Expression of VCAM-1 was determined by Northern blotting, cell enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Only trace amounts of VCAM-1 mRNA or protein were constitutively expressed on dermal fibroblasts but both were rapidly (within 4 hr) upregulated by tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) and somewhat slower (20 hr) by interferon-gamma (IFN-gamma). The combination of TNF-alpha and IFN-gamma had at least an additive effect. The adhesion function of the expressed VCAM-1 was examined by studying the adhesion of the Jurkat T lymphocytes to fibroblasts. Adhesion of Jurkat cells to dermal fibroblasts was markedly increased by stimulation of fibroblasts with TNF-alpha and IFN-gamma (22% of cells adhered versus 9% on unstimulated fibroblasts). The increased adhesion was inhibited to that on unstimulated fibroblasts by monoclonal antibody (mAb) to domain 1 of VCAM-1, but not by mAb to domain 4. MAb to very late antigen-4 (VLA-4), the integrin counter-receptor on lymphocytes for VCAM-1, completely inhibited the increase in Jurkat cell adhesion to activated fibroblasts and partly also inhibited basal adhesion to unstimulated fibroblasts. These results suggest that VCAM-1 expression by dermal fibroblasts is inducible at the mRNA, protein and functional levels by proinflammatory cytokines. The VLA-4/VCAM-1 pathway maybe involved in adhesive interactions between T lymphocytes and activated fibroblasts in the skin during chronic dermal inflammatory conditions.
Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins (1997)

Human T cell leukemia/lymphotropic virus type I (HTLV-I) induces adult T cell leukemia/lymphoma (ATLL). The mechanism of HTLV-I oncogenesis in T cells remains partly elusive. In vitro, HTLV-I induces ligand-independent transformation of human CD4+ T cells, an event that correlates with acquisition of constitutive phosphorylation of Janus kinases (JAK) and signal transducers and activators of transcription (STAT) proteins. However, it is unclear whether the in vitro model of HTLV-I transformation has relevance to viral leukemogenesis in vivo. Here we tested the status of JAK/STAT phosphorylation and DNA-binding activity of STAT proteins in cell extracts of uncultured leukemic cells from 12 patients with ATLL by either DNA-binding assays, using DNA oligonucleotides specific for STAT-1 and STAT-3, STAT-5 and STAT-6 or, more directly, by immunoprecipitation and immunoblotting with anti-phosphotyrosine antibody for JAK and STAT proteins. Leukemic cells from 8 of 12 patients studied displayed constitutive DNA-binding activity of one or more STAT proteins, and the constitutive activation of the JAK/STAT pathway was found to persist over time in the 2 patients followed longitudinally. Furthermore, an association between JAK3 and STAT-1, STAT-3, and STAT-5 activation and cell-cycle progression was demonstrated by both propidium iodide staining and bromodeoxyuridine incorporation in cells of four patients tested. These results imply that JAK/STAT activation is associated with replication of leukemic cells and that therapeutic approaches aimed at JAK/STAT inhibition may be considered to halt neoplastic growth.
In vitro and in vivo evaluation and a case report of intense nanosecond pulsed electric field as a local therapy for human malignancies (2007)

When delivered to cells, very short duration, high electric field pulses (nanoelectropulses) induce primarily intracellular events. We present evidence that this emerging modality may have a role as a local cancer therapy. Five hematologic and 16 solid tumor cell lines were pulsed in vitro. Hematologic cells proved particularly sensitive to nanoelectropulses, with more than a 60% decrease in viable cells measured by MTT assay 96 hr after pulsing in 4 of 5 cell lines. In solid tumor cell lines, 10 out of 16 cell lines had more than a 10% decrease in viable cells. AsPC-1, a pancreatic cancer cell line, demonstrated the greatest in vitro sensitivity among solid tumor cell lines, with a 64% decrease in viable cells. When nanoelectropulse therapy was applied to AsPC-1 tumors in athymic nude mice, responses were seen in 4 of 6 tumors, including clinical complete responses in 3 of 6 animals. A single human subject applied nanoelectropulse therapy to his own basal cell carcinoma and had a complete pathologic response. In summary, we demonstrate that electric pulses 20 ns or less kill a wide variety of human cancer cells in vitro, induce tumor regression in vivo, and show efficacy in a single human patient. Therefore, nanoelectropulse therapy deserves further study as a potentially effective cancer therapy.
Maize glutamine synthetase cDNAs: isolation by direct genetic selection in Escherichia coli. (1988)

Maize glutamine synthetase cDNA clones were isolated by genetic selection for functional rescue of an Escherichia coli delta glnA mutant growing on medium lacking glutamine. The Black Mexican Sweet cDNA library used in this study was constructed in pUC13 such that cDNA sense strands were transcribed under the control of the lac promoter. E. coli delta glnA cells were transformed with cDNA library plasmid DNA, grown briefly in rich medium to allow phenotypic expression of the cDNAs and the pUC13 ampr gene, and challenged to grow on agar medium lacking glutamine. Large numbers of glutamine synthetase cDNA clones have been identified in individual 150-mm Petri dishes; all characterized cDNA clones carry complete coding sequences. Two cDNAs identical except for different 5' and 3' termini have been sequenced. The major open reading frame predicts a protein with an amino acid sequence that exhibits striking similarity to the amino acid sequences of the predicted products of previously sequenced eukaryotic glutamine synthetase cDNAs and genes. In addition, the maize glutamine synthetase cDNAs were shown to contain a 5' mini-ORF of 29 codons separated by 37 nucleotide pairs from the major ORF. This mini-ORF was shown not to be essential for the functional rescue of the E. coli delta glnA mutant. Expression of the cDNAs in E. coli is presumed to be due to the function of a polycistronic hybrid lac messenger RNA or translational fusions encoded by the pUC plasmids. Proteins of the expected sizes encoded by two different pUC clones were shown to react with antibodies to tobacco glutamine synthetase.
Similar differential for total polyglutamylation and cytotoxicity among various folate analogues in human and murine tumor cells in vitro. (1985)

Four folate analogues, methotrexate, aminopterin, 10-deazaminopterin, and 10-ethyl-10-deazaaminopterin were assessed for their ability to be metabolized to poly-gamma-glutamyl derivatives in three tumor lines which vary in their sensitivity to these agents. Cytotoxicity of the four analogues against the murine L1210 leukemia and the human Manca B cell leukemia, as determined by a 3-h clonogenic assay, showed aminopterin and the two 10-deazaaminopterin compounds to be approximately equivalent for each cell type and were 3- to 10- (L1210) and 7- to 14-fold (Manca) more potent than methotrexate. In murine Sarcoma 180 cells, 10-ethyl-10-deazaaminopterin and aminopterin were similarly potent but were 5- to 10-fold more potent than 10-deazaaminopterin and 40- to 80-fold more potent than methotrexate. These results could be explained in part by the differences in transport properties and substrate activities for polyglutamylation for each analogue in these cell types. Initial rates of polyglutamate accumulation of the four analogues, which were determined under conditions of comparable rates of drug entry into the three tumor cell lines, were 7- to 18-fold less than drug entry rates. In L1210 and Sarcoma 180 cells, the relative rates of polyglutamylation were in the order aminopterin greater than 10-ethyl-10-deazaaminopterin greater than methotrexate greater than 10-deazaaminopterin. In contrast, the relative rates of polyglutamylation in Manca cells were in the order 10-ethyl-10-deazaaminopterin approximately equal to aminopterin greater than 10-deazaaminopterin greater than methotrexate, suggesting that folylpolyglutamyl synthetase may have varying substrate preferences in different cell types. The maximum relative extents of total polyglutamate accumulation in L1210 cells were 85 to 95% of the total drug at 24 h. In Manca cells, the maximum polyglutamate accumulation was also 85 to 95%, but this was obtained by 6 h. However, in Sarcoma 180 cells, only aminopterin polyglutamates reached a similar maximum percentage of accumulation, while lower relative polyglutamate levels were achieved with the other analogues. Accumulation of individual polyglutamates in each cell line was similar for all analogues except aminopterin. For methotrexate and the two 10-deazaaminopterins, accumulation occurred mainly as the tetraglutamate or as higher polyglutamates. Aminopterin was accumulated mainly as the diglutamate, particularly in Manca cells where 70% of total drug was in the diglutamate form within the first 3 h and remained the predominant form for 24 h.(ABSTRACT TRUNCATED AT 400 WORDS)
Characterization and study of a single TiO_{2}-coated optical fiber reactor (2006)

A TiO _{2} -coated optical fiber photoreactor was built and studied in order to optimize different parameters before the development of a multi-optical fiber reactor. The physico-chemical properties of the TiO _{2} film prepared by a sol-gel method on an optical fiber were first determined. A thickness of about 30 nm per layer and a roughness of 2 nm were estimated by ESEM and AFM, respectively. The refractive index of the TiO _{2} coating was determined by a simulation method. Then, the influences of the film thickness, coating length and coating volume on the light transmission within the fiber were investigated. The intensity of transmitted light was found to decrease exponentially as the volume of TiO _{2} increased. Afterward, the dependence of the photocatalytic degradation of hydroxybutanedioic acid on the incident light intensity, the TiO _{2} coating thickness and the coating volume was studied and modelized. The photocatalytic degradation was found to be stabilized above a TiO _{2} volume of 200 μ m ^{3} for a fiber of 1 mm and 100 μ m ^{3} for a fiber of 0.6 mm. Finally, a multi-fiber reactor was built and its degradation rate of hydroxybutanedioic acid was compared to that obtained in a single optical fiber reactor.
Efficacy of cilofungin alone and in combination with amphotericin B in a murine model of disseminated aspergillosis (1991)

Cilofungin, amphotericin B, and a combination of the two drugs were compared in a model of aspergillosis in immunocompetent mice in three experiments. Cilofungin was equivalent to amphotericin B in preventing death and eradicating cerebral aspergillosis, but it did not sterilize the kidneys. This is the first demonstration of the in vivo activity of cilofungin against any fungus other than Candida albicans. The mortality with combination therapy was higher than those with amphotericin B alone (P = 0.003) and cilofungin alone (P = 0.054), as was weight loss after infection, indicating antagonism between cilofungin and amphotericin B in this model. The mechanisms of action and antagonism remain to be explained.
Physics at Surfaces (1988)

Physics at Surfaces is a unique graduate-level introduction to the physics and chemical physics of solid surfaces, and atoms and molecules that interact with solid surfaces. A subject of keen scientific inquiry since the last century, surface physics emerged as an independent discipline only in the late 1960s as a result of the development of ultra-high vacuum technology and high speed digital computers. With these tools, reliable experimental measurements and theoretical calculations could at last be compared. Progress in the last decade has been truly striking. This volume provides a synthesis of the entire field of surface physics from the perspective of a modern condensed matter physicist with a healthy interest in chemical physics. The exposition intertwines experiment and theory whenever possible, although there is little detailed discussion of technique. This much-needed text will be invaluable to graduate students and researchers in condensed matter physics, physical chemistry and materials science working in, or taking graduate courses in, surface science.
Identification and isolation of glucose dehydrogenase genes of Bacillus megaterium M1286 and their expression in Escherichia coli (1988)

A gene encoding glucose dehydrogenase of Bacillus megaterium M1286 was isolated from a lambda-EMBL3 phage library. It is transcribed and translated in cells of the heterologous organism Escherichia coli by own control regions. The gene is located on a 1126-bp HindIII fragment. Its nucleotide sequence contains 220 bp in the 5' non-coding region, 783 bp in the coding region and 123 bp in the 3' non-coding region. The amino acid sequence, as deduced from the coding region, consists of 261 amino acids and is different from the known protein sequence of glucose dehydrogenase from B. megaterium M1286. [Jany, K. D., Ulmer, W., Fröschle, M. & Pfleiderer, G. (1984) FEBS Lett. 165, 6-10]. By using this gene as a hybridization probe a second glucose dehydrogenase gene was isolated, which was also directly expressed in E. coli. Additionally a DNA region with extended sequence homology to the hybridization probe was identified. This work indicates the existence of at least two independent glucose dehydrogenase genes in B. megaterium M1286. Homologies in the primary structures of the two different glucose dehydrogenases of B. megaterium M1286 and of the corresponding Bacillus subtilis enzyme are discussed.
Segmentation and Tracking Multiple Objects Under Occlusion From Multiview Video (2011)

In this paper, we present a multiview approach to segment the foreground objects consisting of a group of people into individual human objects and track them across the video sequence. Depth and occlusion information recovered from multiple views of the scene is integrated into the object detection, segmentation, and tracking processes. Adaptive background penalty with occlusion reasoning is proposed to separate the foreground regions from the background in the initial frame. Multiple cues are employed to segment individual human objects from the group. To propagate the segmentation through video, each object region is independently tracked by motion compensation and uncertainty refinement, and the motion occlusion is tackled as layer transition. The experimental results implemented on both our sequences and other's sequence have demonstrated the algorithm's efficiency in terms of subjective performance. Objective comparison with a state-of-the-art algorithm validates the superior performance of our method quantitatively.
Serotonin reuptake inhibitors are associated with reduced severity of ictal hypoxemia in medically refractory partial epilepsy (2010)

Ictal respiratory dysfunction occurs in patients with epilepsy and may contribute to sudden unexplained death in epilepsy (SUDEP). Fluoxetine reverses respiratory arrest in a mouse model of epilepsy, suggesting that selective serotonin reuptake inhibitors (SSRIs) may reduce ictal respiratory dysfunction. Video–electroencephalography (EEG) and pulse oximetry data from 496 seizures in 73 consecutive patients with partial epilepsy was reviewed, including 87 seizures in 16 patients taking SSRIs (SSRI+) and 409 seizures in 57 patients not taking SSRIs (SSRI)). The proportion of ictal-related oxygen desaturation <85% with partial seizures without secondary convulsions in SSRI+ patients was reduced relative to SSRI) patients (p = 0.011). There was no statistically significant difference in ictal oxygen desaturation for secondarily generalized convulsions. SSRIs are associated with reduced likelihood of ictal oxygen desaturation in patients with partial seizures.
Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A (2000)

Charcot-Marie-Tooth disease type 1A (CMT1A), the most frequent form of CMT, is caused by a 1.5 Mb duplication on the short arm of chromosome 17. Patients with CMT1A typically have slowed nerve conduction velocities (NCVs), reduced compound motor and sensory nerve action potentials (CMAPs and SNAPs), distal weakness, sensory loss and decreased reflexes. In order to understand further the molecular pathogenesis of CMT1A, as well as to determine which features correlate with neurological dysfunction and might thus be amenable to treatment, we evaluated the clinical and electrophysiological phenotype in 42 patients with CMT1A. In these patients, muscle weakness, CMAP amplitudes and motor unit number estimates correlated with clinical disability, while motor NCV did not. In addition, loss of joint position sense and reduction in SNAP amplitudes also correlated with clinical disability, while sensory NCV did not. Taken together, these data strongly support the hypothesis that neurological dysfunction and clinical disability in CMT1A are caused by loss or damage to large calibre motor and sensory axons. Therapeutic approaches to ameliorate disability in CMT1A, as in amyotrophic lateral sclerosis and other neurodegenerative diseases, should thus be directed towards preventing axonal degeneration and/or promoting axonal regeneration.
Recent advances in the design of bioconjugates from controlled/living radical polymerization (2010)

Since its discovery, controlled/living radical polymerization (CLRP) has proven to be a mature technology for building tailor-made (block) copolymers, functional polymers and polymers with a wide range of biological recognition. Due to these considerable advantages over other synthetic approaches, CLRP techniques have been successfully exploited to construct novel polymer-protein/peptide bioconjugates with a high level of structural control and varied interesting, somehow unexpected, features. A comprehensive review of the recent advances in the rapidly expanding field of bioconjugation is presented and outlines work up to early 2010.
Role of the Bacillus subtilis gsiA gene in regulation of early sporulation gene expression (1992)

The Bacillus subtilis gsiA operon was induced rapidly, but transiently, as cells entered the stationary phase in nutrient broth medium. A mutation at the gsiC locus caused sporulation to be defective and expression of gsiA to be elevated and prolonged. The sporulation defect in this strain was apparently due to persistent expression of gsiA, since a gsiA null mutation restored sporulation to wild-type levels. Detailed mapping experiments revealed that the gsiC82 mutation lies within the kinA gene, which encodes the histidine protein kinase member of a two-component regulatory system. Since mutations in this gene caused a substantial blockage in expression of spoIIA, spoIIG, and spoIID genes, it seems that accumulation of a product of the gsiA operon interferes with sporulation by blocking the completion of stage II. It apparently does so by inhibiting or counteracting the activity of KinA.