gebhart/patrepeval huggingface dataset:
Mitochondrial Profiling of Acute Myeloid Leukemia in the Assessment of Response to Apoptosis Modulating Drugs (2015)

BH3 profiling measures the propensity of transformed cells to undergo intrinsic apoptosis and is determined by exposing cells to BH3-mimicking peptides. We hypothesized that basal levels of prosurvival BCL-2 family proteins may modulate the predictive power of BH3 profiling and termed it mitochondrial profiling. We investigated the correlation between cell sensitivity to apoptogenic agents and mitochondrial profiling, using a panel of acute myeloid leukemias induced to undergo apoptosis by exposure to cytarabine, the BH3 mimetic ABT-199, the MDM2 inhibitor Nutlin-3a, or the CRM1 inhibitor KPT-330. We found that the apoptogenic efficacies of ABT-199 and cytarabine correlated well with BH3 profiling reflecting BCL2, but not BCL-XL or MCL-1 dependence. Baseline BCL-2 protein expression analysis increased the ability of BH3 profiling to predict resistance mediated by MCL-1. By utilizing engineered cells with overexpression or knockdown of BCL-2 family proteins, Ara-C was found to be independent, while ABT-199 was dependent on BCL-XL. BCL-2 and BCL-XL overexpression mediated resistance to KPT-330 which was not reflected in the BH3 profiling assay, or in baseline BCL-2 protein levels. In conclusion, mitochondrial profiling, the combination of BH3 profiling and prosurvival BCL-2 family protein analysis, represents an improved approach to predict efficacy of diverse agents in AML and may have utility in the design of more effective drug combinations.
Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17 (2007)

Abstract Recent evidence fromseveral groups indicates that IL-17-producing Th17 cells, rather than, as once was thought, IFN-γ-producing Th1 cells, can represent the key effector cells in the induction/development of several autoimmune and allergic disorders. Although Th17 cells exhibit certain phenotypic and developmental differences from Th1 cells, the extent of the differences between these two T cell subsets is still not fully understood. We found that the expression profile of cell surface molecules on Th17 cells has more similarities to that of Th1 cells than Th2 cells. However, although certain Th1-lineage markers [i.e., IL-18 receptor α, CXCR3, and T cell Ig domain, mucin-like domain-3 (TIM-3)], but not Th2-lineage markers (i.e., T1/ST2, TIM-1, and TIM-2), were expressed on Th17 cells, the intensity of expression was different between Th17 and Th1 cells. Moreover, the expression of CTLA-1, ICOS, programmed death ligand 1, CD153, Fas, and TNF-related activation-induced cytokine was greater on Th17 cells than on Th1 cells. We found that IL-23 or IL-17 can suppress Th1 cell differentiation in the presence of exogenous IL-12 in vitro. We also confirmed that IL-12 or IFN-γ can negatively regulate Th17 cell differentiation. However, these cytokines could not modulate such effects on T cell differentiation in the absence of APC.
Human Visual System Based No-Reference Objective Image Sharpness Metric (2006)

This work is motivated by the fact that existing no-reference sharpness metrics fail in predicting the correct amount of blurriness in images with different contexts. This paper presents a no-reference objective sharpness metric that can be applied to images with different contexts. The metric combines a human visual system (HVS)-based sharpness perception model as well as a local features extractor resulting in a content-invariant metric. The proposed HVS-based sharpness perception model is derived from performed subjective tests. Simulation results and comparison with existing no-reference sharpness metrics show that the proposed HVS-based sharpness metric correlates well with the perceived sharpness and is able to correctly predict the relative amount of blurriness in images with different contexts.
Two Distinct Molecular Mechanisms Underlying Cytarabine Resistance in Human Leukemic Cells (2008)

To understand the mechanism of cellular resistance to the nucleoside analogue cytarabine (1-beta-D-arabinofuranosylcytosine, AraC), two resistant derivatives of the human leukemic line CCRF-CEM were obtained by stepwise selection in different concentrations of AraC. CEM/4xAraC cells showed low AraC resistance, whereas CEM/20xAraC cells showed high resistance. Both cell lines showed similar patterns of cross-resistance to multiple cytotoxic nucleoside analogues, with the exception that CEM/20xAraC cells remained sensitive to 5-fluorouridine and 2-deoxy-5-fluorouridine. Both cell lines were sensitive to 5-fluorouracil and to a variety of natural product drugs. Although both CEM/4xAraC and CEM/20xAraC cells displayed reduced intracellular accumulation of [(3)H]AraC, only CEM/4xAraC cells showed reduced uptake of [(3)H]uridine, which was used to assess nucleoside transport activities. Genes encoding proteins known to be involved in nucleoside transport, efflux, and metabolism were analyzed for the presence of mutations in the two cell lines. In CEM/4xAraC cells, independent mutations were identified at each allele of human equilibrative nucleoside transporter 1 (hENT1; SLC29A1), one corresponding to a single-nucleotide change in exon 4, the other being a complex intronic mutation disrupting splicing of exon 13. In contrast to CEM/20xAraC cells, CEM/4xAraC cells did not bind the hENT1/SLC29A1 ligand nitrobenzylmercaptopurine ribonucleoside and lacked detectable hENT1/SLC29A1 protein. In CEM/20xAraC cells, independent intronic mutations impairing splicing of exons 2 and 3 were found at each allele of the deoxycytidine kinase gene. These studies point to at least two distinct mechanisms of AraC resistance in leukemic cells.
Thioridazine inhibits angiogenesis and tumor growth by targeting the VEGFR-2/PI3K/mTOR pathway in ovarian cancer xenografts (2014)

Thioridazine, a member of the phenothiazine family, is a powerful anti-anxiety and anti-psychotic drug. It can also suppress the growth of several types of tumor in vitro. In the current study, we evaluated the direct anti-tumor and anti-angiogenic effects of thioridazine in vivo. The injection of thioridazine into human ovarian tumor xenografts in nude mice significantly inhibited tumor growth by ~fivefold, and also decreased tumor vascularity. In addition, thioridazine inhibited the phosphorylation of the signaling molecules downstream of phosphatidylinositol-3'-kinase (PI3K), including Akt, phosphoinositide-dependent protein kinase 1 (PDK1), and mammalian target of rapamycin (mTOR), during ovarian tumor progression via vascular endothelial growth factor receptor 2 (VEGFR-2). These results provide convincing evidence that thioridazine regulates endothelial cell function and subsequent angiogenesis by inhibiting VEGFR-2/PI3K/mTOR signal transduction. Collectively, these results strongly suggest that thioridazine might be a novel anti-tumor and anti-angiogenic agent for use in ovarian cancer.
Fluorinated phthalocyanines as molecular semiconductor thin films (2008)

Abstract Thin films of perfluorinated phthalocyanines F 16 Pc show promise as molecular semiconductors in organic field effect transistors. A review is provided of growth studies and electrical characterization of presently discussed materials. Using this state‐of‐the‐art as a starting point the synthesis and position of energy levels of partly fluorinated Zn(II) phthalocyanines is described. Growth characteristics of vapour‐deposited thin films on inorganic and organic dielectrics are studied. Possibilities to use fluorinated phthalocyanines in technical applications of OFET are discussed. (© 2008 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)
On the interaction between intragastric pH and electrical vagal stimulation in causing gastric acid secretion and intraluminal release of gastrin and somatostatin in anesthetized rats (1983)

The effect of electrical vagal stimulation (5 V, 2 ms, 2, 5 and 10 Hz) on gastric acid secretion and on the intragastric release of gastrin and somatostatin was studied in anesthetized rats. The gastric lumen was perfused with Dextrane T 70 (21 g/1) at 3 different rates (2.0, 0.15 and 0.035 ml/min). pH as well as gastrin and somatostatin levels were measured in the perfusate. At a perfusion rate of 2 ml/min electrical vagal stimulation (10 Hz) reduced pH of the perfusate from 3.8 to 2.6. Neither gastrin nor somatostatin levels were influenced. At a perfusion rate of 0.15 ml/min pH fell to 1.87 during vagal stimulation at 10 Hz. During this period the somatostatin levels in the perfusate increased approximately 7‐fold. No effect on gastrin release was observed. When the stomach was perfused with Dextrane at a rate of 0.035 ml/min. pH was lowered to 1.20 during vagal stimulation at 5 Hz. The somatostatin level increased approximately 14‐fold and the gastrin levels 6‐fold. In order to study the effect of low pH per se the stomach was perfused with 0.1 M HCl. Perfusion of the stomach with 0.1 M HCI (pH1.2) at a rate of 0.035 ml/min caused a small (3‐fold) increase in somatostatin levels. In conclusion, electrical vagal stimulation or low antral pH alone had minor effects on somatostatin or gastrin release. However, when intragastric pH was &lt;2, electrical vagal stimulation increased the intraluminal release of somatostatin and to a lesser extent that of gastrin. We suggest that both somatostatin and gastrin cells are activated by vagal stimulation at low antral pH. Less gastrin was found to be released in comparison to somatostatin, which may be due to inhibition of the gastrin cells by the somatostatin simultaneously released.
Roseburia intestinalis sp. nov., a novel saccharolytic, butyrate-producing bacterium from human faeces. (2002)

Five strains of butyrate-producing, anaerobic, gram-positive bacteria were isolated from human faecal material. These strains were slightly curved rods that showed motility by means of multiple subterminal flagella. The DNA G + C content of the strains was 29-31 mol%. A detailed investigation of the phenotypic and phylogenetic characteristics of the strains revealed that they represent a novel species of anaerobic, low-G+C-content, butyrate-producing bacterium that shows net acetate utilization during growth on media containing carbohydrates and short-chain fatty acids. The 16S rRNA gene sequences of the five isolates were determined and they confirmed that these strains were closely related to each other. Phylogenetic analysis indicated that the most closely related species are Eubacterium rectale, Eubacterium oxidoreducens and Roseburia cecicola, members of cluster XIVa of the Clostridium subphylum of gram-positive bacteria, although they share less than 95% sequence identity with the novel strains. It is proposed that a novel species, Roseburia intestinalis sp. nov., be created, with strain L1-82T (= DSM 14610T = NCIMB 13810T) as the type strain.
Fusobacterium nucleatum Contributes to the Carcinogenesis of Colorectal Cancer by Inducing Inflammation and Suppressing Host Immunity (2019)

The presence of Fusobacterium nucleatum (F. nucleatum) in the gut is associated with the development of colorectal cancer (CRC). F. nucleatum promotes tumor development by inducing inflammation and host immune response in the CRC microenvironment. Adhesion to the intestinal epithelium by the cell surface proteins FadA, Fap2 and RadD expressed by F. nucleatum can cause the host to produce inflammatory factors and recruit inflammatory cells, creating an environment which favors tumor growth. Furthermore, F. nucleatum can induce immune suppression of gut mucosa by suppressing the function of immune cells such as macrophages, T cells and natural killer cells, contributing the progression of CRC.
Elucidating the Encapsulation of Short Interfering RNA in PEGylated Cationic Liposomes (2009)

Short interfering RNA (siRNA) holds great potential for the treatment of hard-to-cure diseases. One of the major challenges to translate siRNA into drugs is its efficient delivery to its site-of-action, namely the cytoplasm of the target cells. Cationic liposomes have been shown to do the trick, but their short circulation lifetime and potential aggregation in blood limit their applicability for intravenous administration. These hurdles might be overcome by attaching poly(ethylene glycol) (PEG) at the surface of the cationic liposomes through the use of PEGylated lipids. However, this paper reveals that the classical mixing of siRNA with preformed PEGylated cationic liposomes, as frequently done to load PEGylated liposomes with siRNA, prevents an efficient encapsulation of the siRNA in the liposomes. We show that only a minor fraction of the siRNA becomes encapsulated in the core of the PEGylated liposomes, whereas a major part of the siRNA becomes bound at the liposome's outer surface. In serum, the surface-bound siRNA is immediately released and becomes degraded by serum nucleases. By contrast, hydrating a lipid film (containing PEGylated and cationic lipids) directly with a concentrated solution of siRNA (so-called HYDRA protocol), instead of mixing the siRNA with preformed PEGylated liposomes, encapsulates almost 50% of the siRNA in the core of the PEGylated liposomes, which is the maximal encapsulation efficiency for this type of complexes. We show that the siRNA encapsulated in the core of the thus obtained "HYDRA siPLexes" remains fully encapsulated upon dispersing the PEGylated liposomes in human serum.
Stabilization of a monoclonal antibody during purification and formulation by addition of basic amino acid excipients (2011)

Abstract BACKGROUND: Protein stability of therapeutic monoclonal antibodies during processing and final storage is imperative for the commercial success of the product. Amino acid addition is one of the options for stabilization of proteins that can be employed during the manufacturing process and storage. RESULTS: Use of arginine in the elution buffer during Protein A purification and subsequent neutralization doubled the yield of antibody compared with the original glycine‐based elution buffer. The role of amino acids in stabilizing monoclonal antibody liquid formulations was then studied using differential scanning calorimetry. Increase in the unfolding transition temperatures ( T m ) of immunoglobulin G (IgG) was measured after supplementing a glycine buffer with a range of amino acids. The basic amino acids histidine, lysine, and arginine stabilized all three domains of IgG. The neutral amino acids serine and alanine provided less stabilization; glutamine, proline, and the acidic amino acids provided negligible stabilization. CONCLUSION: The positive charge on the side‐chain of histidine, lysine, and arginine appears to be the most important factor affecting the IgG stabilization. It is probable that the mechanism for IgG stabilisation is the same for all of the basic amino acids and that it binds transiently to IgG side chains, altering water populations in the solvation shell, making unfolding and aggregation less energetically favourable. Copyright © 2011 Society of Chemical Industry
<title>Four-color beam smoothing irradiation system for laser-plasma interaction experiments at LLNL</title> (1995)

A novel four-color beam smoothing scheme with a capability similar to that planned for the proposed National Ignition Facility has been deployed on the Nova laser, and has been successfully used for laser fusion experiments. Wavefront aberrations in high power laser systems produce nonuniformities in the energy distribution of the focal spot that can significantly degrade the coupling of energy into a fusion target, driving various plasma instabilities. The introduction of temporal and spatial incoherence over the face of the beam using techniques such as smoothing by spectral dispersion (SSD) can reduce these variations in the focal irradiance when averaged over a finite time interval. One of the limitations of beam smoothing techniques used to date with solid state laser systems has been the inability to efficiently frequency convert broadband pulses to the third harmonic (351 nm). To obtain high conversion efficiency, we developed a multiple frequency source that is spatially separated into four quadrants, each containing a different central frequency. Each quadrant is independently converted to the third harmonic in a four-segment Type I/Type II KDP crystal array with independent phase-matching for efficient frequency conversion. Up to 2.3 kJ of third harmonic light is generated in a 1 ns pulse, corresponding to up to 65% intrinsic conversion efficiency. SSD is implemented by adding limited frequency modulated bandwidth to each frequency component. This improves smoothing without significant impact on the frequency conversion process. The measured far field irradiance shows 25% rms intensity variation with four colors alone, and is calculated to reach this level within 3 ps. Smoothing by spectral dispersion is implemented during the spatial separation of the FM modulated beams to provide additional smoothing, reaching a 16% rms intensity variation level. Following activation the four-color system was successfully used to probe NIF-like plasmas, producing less than 1% SBS backscatter at greater than 2 multiplied by 10<SUP>15</SUP> W/cm<SUP>2</SUP>. This paper discusses the detailed implementation and performance of the segmented four-color system on the Nova laser system.
Protein damage and degradation by oxygen radicals. I. general aspects. (1987)

Aggregation, fragmentation, amino acid modification, and proteolytic susceptibility have been studied following exposure of 17 proteins to oxygen radicals. The hydroxyl radical (.OH) produced covalently bound protein aggregates, but few or no fragmentation products. Extensive changes in net electrical charge (both + and -) were observed. Tryptophan was rapidly lost with .OH exposure, and significant production of bityrosine biphenol occurred. When incubated with cell-free extracts of human and rabbit erythrocytes, rabbit reticulocytes, or Escherichia coli, most .OH-modified proteins were proteolytically degraded up to 50 times faster than untreated proteins. The exceptions were alpha-casein and globin, which were rapidly degraded without .OH modification. ATP did not stimulate the degradation of .OH-modified proteins, but alpha-casein was more rapidly degraded. Leupeptin had little effect under any condition, and degradation was maximal at pH 7.8. The data indicate that proteins which have been denatured by .OH can be recognized and degraded rapidly and selectively by intracellular proteolytic systems. In both red blood cells and E. coli, the degradation appears to be conducted by soluble, ATP-independent (nonlysosomal) proteolytic enzymes. In contrast with the above results, superoxide (O2-) did not cause aggregation or fragmentation, tryptophan loss, or bityrosine production. The combination of .OH + O2- (+O2), which may mimic biological exposure to oxygen radicals, induced charge changes, tryptophan loss, and bityrosine production. The pattern of such changes was similar to that seen with .OH alone, although the extent was generally less severe. In contrast with .OH alone, however, .OH + O2- (+O2) caused extensive protein fragmentation and little or no aggregation. More than 98% of the protein fragments had molecular weights greater than 5000 and formed clusters of ionic and hydrophobic bonds which could be dispersed by denaturing agents. The results indicate a general sensitivity of proteins to oxygen radicals. Oxidative modification can involve direct fragmentation or may provide denatured substrates for intracellular proteolysis.
Transcription factor AP2 and its role in epidermal-specific gene expression. (1991)

The epidermis is a stratified squamous epithelium whose major differentiation-specific products are keratins. To elucidate factors controlling keratinocyte-specific gene expression, we previously identified proximal and distal regulatory elements that act synergistically to drive keratinocyte-specific expression of the gene encoding human epidermal keratin K14. Control by the proximal element is mediated by a transcription factor, KER1, which is more abundant in nuclear extracts of keratinocytes than in extracts of other cell types, including fibroblasts, lymphocytes, and simple epithelial cells. In this report, we identify this factor as transcription factor AP2, shown to be transcribed in cells of epidermal and neural crest lineages. Furthermore, we demonstrate functional AP2 binding sites upstream from three additional epidermal genes, suggesting that AP2 may be generally involved in epidermal gene regulation. Finally, although AP2 is necessary, it is not sufficient for epidermal gene expression: a distal element contributes to tissue-specific expression of the human keratin K14 gene as judged by its ability to enhance expression of a heterologous promoter in keratinocytes but not in hepatoma cells. These results imply that a combination of factors is likely to contribute to epidermal-specific expression of the human keratin K14 gene.
The effect of fibrinogen concentrate administration on coagulation abnormalities in a rat sepsis model (2004)

Disseminated intravascular coagulation is a disorder that affects the function of the clotting system and is frequently associated with sepsis or septic shock. One of its leading symptoms is the decrease in circulating fibrinogen. We investigated the effect of fibrinogen concentrate (Haemocomplettan P) on fibrinogen plasma levels, coagulation parameters and mortality in a rat model of sepsis-induced disseminated intravascular coagulation. The disseminated intravascular coagulation was characterized by elevated thrombin-antithrombin complex and a sharp drop in circulating fibrinogen. Coagulation abnormalities were evaluated by thrombelastography. Plasma fibrinogen levels decreased from 2.06 +/- 0.2 to 0.16 +/- 0.1 g/l following administration of bacterial lipopolysaccharide. Thrombelastographic measurements revealed a concurrent decrease in maximum amplitude and an increase in reaction time. Treatment with fibrinogen concentrate (Haemocomplettan P, 25-200 mg/kg body weight intravenously) resulted in a statistically significant dose-dependent increase in fibrinogen plasma levels and amelioration of the measured coagulation abnormalities. Fibrinogen plasma concentrations were restored to normal levels when 200 mg/kg body weight fibrinogen concentrate was administered. A significant decrease in sepsis-induced mortality was observed in animals treated with Haemocomplettan P.
Precise insertion of antibiotic resistance determinants into Tn21-like transposons: nucleotide sequence of the OXA-1 beta-lactamase gene. (1987)

Several plasmid-encoded beta-lactamases are on multiresistance transposable elements. The OXA-1 beta-lactamase gene is part of Tn2603, which is borne on the R plasmid RGN238. We report here the complete nucleotide sequence of the OXA-1 beta-lactamase gene and flanking sequences. The OXA-1 gene shows a greater than 50% sequence divergence from the OXA-2 gene, yet there is significant functional similarity at the peptide level. Analysis of 5' and 3' flanking sequences shows that Tn2603 differs from its probable precursor, Tn21, by a precise 1004-base-pair insertion, containing the OXA-1 structural gene, at the target sequence AAAGTT, which is located between the Tn21 streptomycin/spectinomycin (aadA) promoter and its structural gene. A 5- for 6-base repeat of the target sequence is found at the end of the insertion. The same precise insertion and repeat of the target sequence are found for the OXA-2 gene from R46. The 5' flanking regions of two other genes, the trimethoprim-resistance gene from R388 and the gentamicin resistance (aadB) gene from pDGO100, are greater than 98% homologous to the 5' flanking sequences of the OXA-1, OXA-2, and aadA genes until they diverge at the target sequence. From the available sequence data a recombinational hot spot is defined at the nucleotide level 5' of the aadA gene of Tn21, and a second potential hot spot is proposed 3' of this gene.