gebhart/patrepeval huggingface dataset:
Roles of c-FLIP in Apoptosis, Necroptosis, and Autophagy (2013)

Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major antiapoptotic protein and an important cytokine and chemotherapy resistance factor that suppresses cytokine- and chemotherapy-induced apoptosis. c-FLIP is expressed as long (c-FLIPL), short (c-FLIPS), and c-FLIPR splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 and TRAIL receptor 5 (DR5). This interaction in turn prevents Death-Inducing Signaling Complex (DISC) formation and subsequent activation of the caspase cascade. c-FLIPL and c-FLIPS are also known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective and pro-survival signaling proteins including Akt, ERK, and NF-κB. In addition to its role in apoptosis, c-FLIP is involved in programmed necroptosis (necrosis) and autophagy. Necroptosis is regulated by the Ripoptosome, which is a signaling intracellular cell death platform complex. The Ripoptosome contains receptor-interacting protein-1/Receptor-Interacting Protein-3 (RIP1), caspase-8, caspase-10, FADD, and c-FLIP isoforms involved in switching apoptotic and necroptotic cell death. c-FLIP regulates the Ripoptosome; in addition to its role in apoptosis, it is therefore also involved in necrosis. c-FLIPL attenuates autophagy by direct acting on the autophagy machinery by competing with Atg3 binding to LC3, thereby decreasing LC3 processing and inhibiting autophagosome formation. Upregulation of c-FLIP has been found in various tumor types, and its silencing has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. This review focuses on (1) the anti-apoptotic role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and chemotherapy drug resistance, as well as its roles in necrosis and autophagy, and (2) modulation of c-FLIP expression as a means to enhance apoptosis and modulate necrosis and autophagy in cancer cells.
Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency (1998)

Two children with acute lymphoblastic leukaemia (ALL) were found to be thiopurine methyltransferase (TPMT)-deficient by both genotype and phenotype. They were monitored with haematological parameters and red blood cell concentrations of 6-thioguanine nucleotides (E-6TGN) and methotrexate (E-MTX, including MTX polyglutamates), in relation to the doses of 6-mercaptopurine (6MP) and methotrexate (MTX), during their maintenance chemotherapy. Both patients developed severe pancytopenia at the standard protocol dose of 6MP. Even at 25% and 5%, respectively, of the protocol dose of 6MP, they achieved E-6TGN values several-fold above the population median, but without unacceptable bone-marrow toxicity. Their high E-6TGN values had only a minor influence on their E-MTX values and their tolerance to oral MTX, but severe pancytopenia followed high-dose MTX infusions. Due to the risk of fatal myelosuppression we recommend up-front determination of TPMT activity in patients treated with 6MP or azathioprine.
Quantification of Alzheimer pathology in ageing and dementia: age‐related accumulation of amyloid‐β(42) peptide in vascular dementia (2006)

Clinicopathological observations suggest there is considerable overlap between vascular dementia (VaD) and Alzheimer's disease (AD). We used immunochemical methods to compare quantities of amyloid-beta (Abeta) peptides in post mortem brain samples from VaD, AD subjects and nondemented ageing controls. Total Abeta peptides extracted from temporal and frontal cortices were quantified using a previously characterized sensitive homogenous time-resolved fluorescence (HTRF) assay. The HTRF assays and immunocapture mass spectrometric analyses revealed that the Abeta(42) species were by far the predominant form of extractable peptide compared with Abeta(40) peptide in VaD brains. The strong signal intensity for the peak representing Abeta(4-42) peptide confirmed that these N-terminally truncated species are relatively abundant. Absolute quantification by HTRF assay showed that the mean amount of total Abeta(42) recovered from VaD samples was approximately 50% of that in AD, and twice that in the age-matched controls. Linear correlation analysis further revealed an increased accumulation with age of both Abeta peptides in brains of VaD subjects and controls. Interestingly, VaD patients surviving beyond 80 years of age exhibited comparable Abeta(42) concentrations with those in AD in the temporal cortex. Our findings suggest that brain Abeta accumulates increasingly with age in VaD subjects more so than in elderly without cerebrovascular disease and support the notion that they acquire Alzheimer-like pathology in older age.
Human fur gene encodes a yeast KEX2-like endoprotease that cleaves pro-beta-NGF in vivo. (1990)

Extracts from BSC-40 cells infected with vaccinia recombinants expressing either the yeast KEX2 prohormone endoprotease or a human structural homologue (fur gene product) contained an elevated level of a membrane-associated endoproteolytic activity that could cleave at pairs of basic amino acids (-LysArg- and -ArgArg-). The fur-directed activity (furin) shared many properties with Kex2p including activity at pH 7.3 and a requirement for calcium. By using antifurin antibodies, immunoblot analysis detected two furin translation products (90 and 96 kD), while immunofluorescence indicated localization to the Golgi apparatus. Coexpression of either Kex2p or furin with the mouse beta-nerve growth factor precursor (pro-beta-NGF) resulted in greatly enhanced conversion of the precursor to mature nerve growth factor. Thus, the sequence homology shared by furin and the yeast KEX2 prohormone processing enzyme is reflected by significant functional homology both in vitro and in vivo.
Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers. (1989)

A class of high molecular weight iron chelators has been prepared by covalently attaching deferoxamine (DFO), by its amino group, to a variety of biocompatible polymers such as dextran and hydroxyethyl-starch. The iron-binding properties of DFO are virtually unchanged after the attachment procedure, but the toxicity and circulatory half-life are profoundly altered. Competitive iron-binding experiments indicate that the conjugates retain a high affinity for ferric iron. In addition, the derivatives inhibit iron-driven lipid peroxidation as effectively as the parent drug. However, the LD50 in mice (based on DFO equivalents) is approximately 4000 mg/kg for dextran-DFO as compared to 250 mg/kg for free DFO. Consistent with the greatly decreased LD50, intravenous administration of the conjugates in dogs at a dose of 100 mg/kg (body weight) does not cause the severe hypotension associated with intravenous administration of DFO. The plasma half-lives of these adducts are increased greater than 10-fold for dextran-DFO and hydroxyethyl-starch-DFO compared to the free drug. Finally, and most importantly, the conjugates are effective in mediating in vivo iron mobilization and excretion. Because recent evidence implicates iron as an important component of tissue injury in many disease states, these high molecular weight iron chelators may have potential for improved therapy, allowing higher sustained plasma concentrations of the active drug.
Selective Stimulation by Ceramide of the Expression of the α Isoform of Retinoic Acid and Retinoid X Receptors in Osteoblastic Cells (2000)

Recent studies have demonstrated that sphingosine 1-phosphate (SPP) plays a functional role as a signaling molecule in gene expression in several kinds of cells. The present study demonstrates selective expression by ceramide of retinoic acid receptor-alpha (RAR-alpha) and retinoic X receptor-alpha (RXR-alpha) in osteoblastic MC3T3-E1 cells and a functional role of SPP-mediated AP-1 in the signaling mechanism of ligand-dependent transcriptional activity of heterodimers of these receptors in the cells. C(2)- and C(6)-ceramides selectively stimulated the expression of RAR-alpha and RXR-alpha genes, but not that of beta and gamma isoform genes of RAR and RXR, in the cells. The C(2)-ceramide-induced stimulation was clearly inhibited by dl-threo-dihydrosphingosine, an inhibitor of sphingosine kinase. SPP also selectively stimulated the expression of both receptors and increased the specific binding of the nuclear proteins to direct repeat 5 (DR-5), a consensus sequence of RAR-RXR. In addition, SPP markedly stimulated transient chloramphenicol acetyltransferase (CAT) activity of retinoic acid-dependent transcriptional activity in the cells transfected with a DR-5-CAT reporter gene. The SPP stimulation was activation protein-1 (AP-1)-dependent, because the SPP stimulatory action toward these nuclear gene expressions and the transient CAT activity were inhibited by antisense c-fos and c-jun oligonucleotides. We observed that SPP actually stimulated AP-1 transcriptional activity in the cells. This study suggests an important role of SPP-mediated AP-1 in the selective expression of RAR-alpha and RXR-alpha in osteoblastic cells via the sphingosine pathway.
Differential dependence of store‐operated and excitation‐coupled Ca 2+ entry in skeletal muscle on STIM1 and Orai1 (2008)

In non-excitable cells, agonist-induced depletion of intracellular Ca(2+) stores triggers Ca(2+) influx via a process termed store-operated Ca(2+) entry (SOCE). In T-lymphocytes, stromal interaction molecule 1 (STIM1) acts as the intra-store Ca(2+) sensor and Orai1 functions as the Ca(2+)-permeable SOCE channel activated by STIM1 following store depletion. Two functionally distinct Ca(2+) entry pathways exist in skeletal muscle; one activated by store depletion (SOCE) and a second by sustained/repetitive depolarization that does not require store depletion (excitation-coupled Ca(2+) entry, ECCE). However, the role of STIM1 and Orai1 in coordinating SOCE and ECCE activity in skeletal muscle and whether these two Ca(2+) entry pathways represent distinct molecular entities or two different activation mechanisms of the same channel complex is unknown. Here we address these issues using siRNA-mediated STIM1 knockdown, dominant-negative Orai1, and permeation-defective Orai1 to determine the role of STIM1 and Orai1 in store-operated and excitation-coupled Ca(2+) entry in skeletal myotubes. SOCE and ECCE activity were quantified from both intracellular Ca(2+) measurements and Mn(2+) quench assays. We found that STIM1 siRNA reduced STIM1 protein by more than 90% and abolished SOCE activity, while expression of siRNA-resistant hSTIM1 fully restored SOCE. SOCE was also abolished by dominant-negative Orai1 (E106Q) and markedly reduced by expression of a permeation-defective Orai1 (E190Q). In contrast, ECCE was unaffected by STIM1 knockdown, E106Q expression or E190Q expression. These results are the first to demonstrate that SOCE in skeletal muscle requires both STIM1 and Orai1 and that SOCE and ECCE represent two distinct molecular entities.
Monoacylglycerol lipase – a target for drug development? (2012)

The endocannabinoid (eCB) system is involved in processes as diverse as control of appetite, perception of pain and the limitation of cancer cell growth and invasion. The enzymes responsible for eCB breakdown are attractive pharmacological targets, and fatty acid amide hydrolase inhibitors, which potentiate the levels of the eCB anandamide, are now undergoing pharmaceutical development. 'Drugable' selective inhibitors of monoacylglycerol lipase, a key enzyme regulating the levels of the other main eCB, 2-arachidonoylglycerol, were however not identified until very recently. Their availability has resulted in a large expansion of our knowledge concerning the pharmacological consequences of monoacylglycerol lipase inhibition and hence the role(s) played by the enzyme in the body. In this review, the pharmacology of monoacylglycerol lipase will be discussed, together with an analysis of the therapeutic potential of monoacylglycerol lipase inhibitors as analgesics and anticancer agents.
Acute Renal Failure (1996)

Acute renal failure is characterized by a deterioration of renal function over a period of hours to days, resulting in the failure of the kidney to excrete nitrogenous waste products and to maintain fluid and electrolyte homeostasis. In the past five decades, several important causes of acute renal failure and the pathophysiologic mechanisms that underlie renal dysfunction have come to be understood. In this article we highlight the epidemiology, general causes, and evaluation of acute renal failure in adults. We then expand on the pathophysiology of ischemic acute renal failure and discuss the rationale for both current and future therapies. . . .
The Reservoir for HIV-1 in Human Peripheral Blood Is a T Cell That Maintains Expression of CD4 (1989)

Human immunodeficiency virus type 1 (HIV-1) selectively infects cells expressing the CD4 molecule, resulting in substantial quantitative and qualitative defects in CD4+ T lymphocyte function in patients with acquired immunodeficiency syndrome (AIDS). However, only a very small number of cells in the peripheral blood of HIV-1-infected individuals are expressing virus at any given time. Previous studies have demonstrated that in vitro infection of CD4+ T cells with HIV-1 results in downregulation of CD4 expression such that CD4 protein is no longer detectable on the surface of the infected cells. In the present study, highly purified subpopulations of peripheral blood mononuclear cells (PBMCs) from AIDS patients were obtained and purified by fluorescence-automated cell sorting. They were examined with the methodologies of virus isolation by limiting dilution analysis, in situ hybridization, immunofluorescence, and gene amplification. Within PBMCs, HIV-1 was expressed in vivo predominantly in the T cell subpopulation which, in contrast to the in vitro observations, continued to express CD4. The precursor frequency of these HIV-1-expressing cells was about 1/1000 CD4+ T cells. The CD4+ T cell population contained HIV-1 DNA in all HIV-1-infected individuals studied and the frequency in AIDS patients was at least 1/100 cells. This high level of infection may be the primary cause for the progressive decline in number and function of CD4+ T cells in patients with AIDS.
Accurate microcrystallography using electron back-scattering patterns (1977)

Abstract A method for precise determination of the orientation of mierocrystals is described. Electron back-scattering patterns are observed on a fluorescent screen in a scanning electron microscope, and high precision is obtained by casting geo metrical shadows onto the screen to determine the point from which the back-scattered electrons are emitted. Orientational accuracy around ±0.5° can be routinely obtained. The geometrical constructions used for evaluating the crystal orientation, and the errors in this orientation, are described. Some experimental examples are given.
A Redox Fuel Cell That Operates with Methane as Fuel at 120°C (1994)

Platinum black efficiently catalyzes the oxidation of methane by iron(III) to generate carbon dioxide and eight equivalents of iron(II) in solutions of sulfuric acid in water. The rate of oxidation increases over 4 hours to reach approximately 4.83 x 10(-2) moles of iron(II) per gram atom of surface platinum per second. A redox fuel cell was assembled that used this reaction in a liquid reformer to generate soluble reducing equivalents of iron(II) from methane, which was electrochemically oxidized to iron(III) in the cell. A vanadium(V)-(IV)-nitric acid-O(2) redox system catalyzed the electrochemical reduction of O(2). The open-circuit voltage of the cell was 0.48 volt, and the maximum power output of the cell was 8.1 milliwatts per cubic centimeter of graphite felt electrode.
Human Mesenchymal Progenitor Cell-Based Tissue Engineering of a Single-Unit Osteochondral Construct (2004)

A desirable strategy for articular cartilage repair is to surgically replace the damaged area with an in vitro-engineered osteochondral plug. We report here the development of a novel osteochondral construct using human trabecular bone-derived mesenchymal progenitor cells and a biodegradable poly-D,L-lactic acid scaffold. The cartilage layer was fabricated by press-coating a chondrifying high-density cell pellet onto the scaffold, which was then loaded with cells previously initiated to undergo osteogenesis. The composite was then cultured in a cocktail medium formulated to maintain both chondrogenesis and osteogenesis. Macroscopically, the construct consisted of a cartilage-like layer adherent to, and overlying, a dense bone-like component. RT-PCR, immunohistochemistry, and histology revealed hyaline-like cartilage and bone with an interface resembling the native osteochondral junction. All parameters, including mechanical properties, improved with increased culture time. The single-cell source nature of the construct, which minimizes handling while maximizing biocompatibility, suggests applicability for articular cartilage repair.
Decoding fidelity at the ribosomal A and P sites: influence of mutations in three different regions of the decoding domain in 16S rRNA (1997)

The involvement of defined regions of Escherichia coli 16S rRNA in the fidelity of decoding has been examined by analyzing the effects of rRNA mutations on misreading errors at the ribosomal A and P sites. Mutations in the 1400-1500 region, the 530 loop and in the 1050/1200 region (helix 34) all caused readthrough of stop codons and frameshifting during elongation and stimulated initiation from non-AUG codons at the initiation of protein synthesis. These results indicate the involvement of all three regions of 16S rRNA in decoding functions at both the A and P sites. The functional similarity of all three mutant classes are consistent with close physical proximity of the 1400- 1500 region, the 530 loop and helix 34 and suggest that all three regions of rRNA comprise a decoding domain in the ribosome.
Combined Active Capping/Wetland Demonstration in the Chicago River (2007)

Our group is collaborating with the Metropolitan Water Reclamation Dis- trict of Greater Chicago, the Wetlands Initiative, and Patrick Engineering to install field scale active capping demonstration projects in Collateral Channel and in the Chicago River. The Collateral Channel site is a channel terminating at a combined sewage outfall dating to the late 1800s. Bubbly Creek is a 6800 ft (2000 m) creek termi- nating at the Racine Avenue pumping station (RAPS), the largest sewage pumping station in the world. During large storm events, the RAPS can discharge up to 6000 ft 3 /s (175 m 3 /s) into the creek. These high flow rates result in large shear flows on the sediment. The capping will be carried out in conjunction with overlaying wetlands to remove nutrients from the river and pollutants from combined sewage outflows. Active cap amendments will be evaluated in the one acre Collateral Channel site and the four acre Bubbly Creek site. Amendments will include metal sequestration agents and hydrophobic organic contaminant sequestration agents, as well as nitrate salts (to stimu- late anaerobic oxidation) and a sand reference cap. Extensive sampling of Collateral Channel and the Turning Basin of Bubbly Creek was performed to get a background dataset. Levels of toxic heavy metals, polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls were compared to those at the same location from previous sampling events. In Collateral Channel, organic pollutant levels were high throughout core samples dating back to the 1800s. Contaminants were not significantly changed since 1995, suggesting natural attenuation is not occurring. Based on our results, we are focusing our active capping design in Collateral Channel on the very high levels of PAHs suggesting the importance of organic sequestration. In Bubbly Creek, the focus of the design is on combined treatment for metals, hydrophobic organics and high sulfide levels. Predicted gas ebullition rates of these sediments suggest the need for collection, particularly in the summer months in Collateral Channel. The wetland will overlay a sloped sand layer to bring biogenically-produced gas to shoreline collectors through an innovative support grid. The capping design is innovative by inclusion of an overlaying wetland to remove nutrients from the adjoining Chicago River and provide a public
Gel-Silica Optics (1988)

The processing and properties of Types I and II fused quartz optics and Types III and IV synthetic fused silica optics are compared with new organometallic sol-gel derived (Types V and VI) gel-silica optics. Type V gel-silica has excellent transmission from 165 nm to 4200 nm with no OH absorption peaks. Other physical properties and structural characteristics of Type V gel-silica are similar to high grade fused silica but offer the advantages of near net shape cast4ng, including internal cavities, and a lower coefficient of thermal expansion of 0.2 x 10-6 cm/cm compared with 0.55 x 10-6 cm/cm. Optically transparent porous gel silica (Type VI) has a UV cut-off ranging from 250-300 nm. Type VI gel-silica optics has a density as low as 60% of Types I-V silica and can be impregnated with up to 30 to 40% by volume of a second phase optically active organic or inorganic compound.
Reduced variation in transgene expression from a binary vector with selectable markers at the right and left T‐DNA borders (1994)

Summary A new binary vector for Agrobacterium ‐mediated plant transformation was constructed, in which two selectable markers, for kanamycin and hygromycin resistance, were placed next to the right and left T‐DNA borders, respectively, and a CaMV 35S promoter‐driven β‐glucuronidase (GUS) gene was placed between these markers as a reporter gene (transgene). Using double antibiotic selection, all transgenic tobacco plants carrying at least one intact copy of the T‐DNA expressed the transgene, and this population exhibited reduced variability in transgene expression as compared with that obtained from the parent vector pBI121. Absence of the intact transgene was the major reason for transgenic plants with little or no transgene expression. Integration of truncated T‐DNAs was also observed among transgenic plants that expressed the transgene and carried multiple T‐DNA inserts. The copy number of fully integrated T‐DNAs was positively associated with transgene expression levels in R 0 plants and R 1 progeny populations. Variability due to position effect was determined among 17 plants carrying a single T‐DNA insert. The coefficient of variability among these plants was only 35.5%, indicating a minor role for position effects in causing transgene variability. The new binary vector reported here can therefore be used to obtain transgenic populations with reduced variability in transgene expression.