gebhart/patrepeval huggingface dataset:
Heat-Induced Changes in the Mechanics of a Collagenous Tissue: Isothermal, Isotonic Shrinkage (1998)

We present data from isothermal, isotonic-shrinkage tests wherein bovine chordae tendineae were subjected to well-defined constant temperatures (from 65 to 90 degrees C), durations of heating (from 180 to 3600 s), and isotonic uniaxial stresses during heating (from 100 to 650 kPa). Tissue response during heating and "recovery" at 37 degrees C following heating was evaluated in terms of the axial shrinkage, a gross indicator of underlying heat-induced denaturation. There were three key findings. First, scaling the heating time via temperature and load-dependent characteristic times for the denaturation process collapsed all shrinkage data to a single curve, and thereby revealed a time-temperature-load equivalency. Second, the characteristic times exhibited an Arrhenius-type behavior with temperature wherein the slopes were nearly independent of applied load--this suggested that applied loads during heating affect the activation entropy, not energy. Third, all specimens exhibited a time-dependent, partial recovery when returned to 37 degrees C following heating, but the degree of recovery decreased with increases in the load imposed during heating. These new findings on heat-induced changes in tissue behavior will aid in the design of improved clinical heating protocols and provide guidance for the requisite constitutive formulations.
Tumor necrosis factor inhibits human myogenesis in vitro. (1988)

We examined the effects of human recombinant tumor necrosis factor-alpha (TNF) on human primary myoblasts. When added to proliferating myoblasts, TNF inhibited the expression of alpha-cardiac actin, a muscle-specific gene whose expression is observed at low levels in human myoblasts. TNF also inhibited muscle differentiation as measured by several parameters, including cell fusion and the expression of other muscle-specific genes, such as alpha-skeletal actin and myosin heavy chain. Muscle cells were sensitive to TNF in a narrow temporal window of differentiation. Northern (RNA) blot and immunofluorescence analyses revealed that human muscle gene expression became unresponsive to TNF coincident with myoblast differentiation. When TNF was added to differentiated myotubes, there was no effect on muscle gene expression. In contrast, TNF-inducible mRNAs such as interferon beta-2 still responded, suggesting that the signal mediated by TNF binding to its receptor had no effect on muscle-specific genes after differentiation.
Proteasome inhibition interferes with Gag polyprotein processing, release, and maturation of HIV-1 and HIV-2 (2000)

Retrovirus assembly and maturation involve folding and transport of viral proteins to the virus assembly site followed by subsequent proteolytic cleavage of the Gag polyprotein within the nascent virion. We report that inhibiting proteasomes severely decreases the budding, maturation, and infectivity of HIV. Although processing of the Env glycoproteins is not changed, proteasome inhibitors inhibit processing of Gag polyprotein by the viral protease without affecting the activity of the HIV-1 viral protease itself, as demonstrated by in vitro processing of HIV-1 Gag polyprotein Pr55. Furthermore, this effect occurs independently of the virus release function of the HIV-1 accessory protein Vpu and is not limited to HIV-1, as proteasome inhibitors also reduce virus release and Gag processing of HIV-2. Electron microscopy analysis revealed ultrastructural changes in budding virions similar to mutants in the late assembly domain of p6(gag), a C-terminal domain of Pr55 required for efficient virus maturation and release. Proteasome inhibition reduced the level of free ubiquitin in HIV-1-infected cells and prevented monoubiquitination of p6(gag). Consistent with this, viruses with mutations in PR or p6(gag) were resistant to detrimental effects mediated by proteasome inhibitors. These results indicate the requirement for an active proteasome/ubiquitin system in release and maturation of infectious HIV particles and provide a potential pharmaceutical strategy for interfering with retrovirus replication.
Isolation, characterization and molecular cloning of Duplex-Specific Nuclease from the hepatopancreas of the Kamchatka crab (2008)

We describe a new DSN from Kamchatka crab hepatopancreas, determining its primary structure and developing a preparative method for its purification. We found that DSN had unique substrate specificity, cleaving only DNA duplexes longer than 8 base pairs, or DNA in DNA-RNA hybrids. Interestingly, the DSN primary structure is homologous to well-known Serratia-like non-specific nucleases structures, but the properties of DSN are distinct. The unique substrate specificity of DSN should prove valuable in certain molecular biology applications.
Human Tumor-Derived Exosomes Selectively Impair Lymphocyte Responses to Interleukin-2 (2007)

Exosomes are nanometer-sized vesicles, secreted by normal and neoplastic cells. The outcome following interaction between the cellular immune system and cancer-derived exosomes is not well understood. Interleukin-2 (IL-2) is a key factor supporting expansion and differentiation of CTL and natural killer (NK) cells but can also support regulatory T cells and their suppressive functions. Our study examined whether tumor-derived exosomes could modify lymphocyte IL-2 responses. Proliferation of healthy donor peripheral blood lymphocytes in response to IL-2 was inhibited by tumor exosomes. In unfractionated lymphocytes, this effect was seen in all cell subsets. Separating CD4(+) T cells, CD8(+) T cells, and NK cells revealed that CD8(+) T-cell proliferation was not inhibited in the absence of CD4(+) T cells and that NK cell proliferation was only slightly impaired. Other exosome effects included selective impairment of IL-2-mediated CD25 up-regulation, affecting all but the CD3(+)CD8(-) T-cell subset. IL-2-induced Foxp3 expression by CD4(+)CD25(+) cells was not inhibited by tumor exosomes, and the suppressive function of CD4(+)CD25(+) T cells was enhanced by exosomes. In contrast, exosomes directly inhibited NK cell killing function in a T-cell-independent manner. Analysis of tumor exosomes revealed membrane-associated transforming growth factor beta(1) (TGFbeta(1)), which contributed to the antiproliferative effects, shown by using neutralizing TGFbeta(1)-specific antibody. The data show an exosome-mediated mechanism of skewing IL-2 responsiveness in favor of regulatory T cells and away from cytotoxic cells. This coordinated "double hit" to cellular immunity strongly implicates the role of exosomes in tumor immune evasion.
A phase Ib trial of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor, in combination with docetaxel (2009)

3547 Background: IPI-504 is a water-soluble heat shock protein 90 (Hsp90) inhibitor. IPI-504 causes the degradation of a variety of mutated or amplified oncoproteins, including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). The combination of IPI-504 and docetaxel demonstrates additive efficacy in murine xenograft models. This Phase 1b trial was undertaken to identify the maximum tolerated dose (MTD) of IPI-504 in combination with docetaxel. Methods: Eligible patients (pts) had advanced solid tumors that were either refractory to available therapies or for which docetaxel alone was an appropriate therapy. Intravenous (IV) 75 mg/m 2 docetaxel was given once every three weeks (q 3- weekly). IPI-504 was administered IV q 3-weekly, with 3 pts per cohort and inter-cohort dose escalation. All pts were evaluated for safety, pharmacokinetics (PK), and tumor response. Results: 16 pts have been enrolled at 3 dose levels of IPI-504 (7 at 300 mg/m 2 , 6 at 450 mg/m 2 , and 3 at 550 mg/m 2 ). 6 pts had non-small cell lung cancer (NSCLC). Median age was 59 yrs (range 33–77). Median number of cycles received was 3 (1–11), with 5 pts currently on study. There have been 4 dose-limiting toxicities (DLTs): 1 at 300 mg/m 2 (Grade 3 febrile neutropenia); 1 at 450 mg/m 2 (Grade 3 fatigue); and 2 at 550 mg/m 2 (Grade 1 asymptomatic sinus bradycardia requiring hospitalization for observation, and Grade 3 elevated AST with Grade 3 acute respiratory distress syndrome). All DLTs resolved on trial. No PK interactions between docetaxel and IPI-504 have been observed. The regimen of IPI-504 450 mg/m 2 with docetaxel 75 mg/m 2 has been identified as the recommended phase 2 dose on a q 3-weekly schedule. Conclusions: In this Phase 1b trial, the MTD of IPI-504 plus docetaxel q 3-weekly was identified. Toxicities were reversible and similar to those seen with docetaxel or IPI-504 alone in this patient population. Given the activity of single-agent IPI-504 against NSCLC and the standard use of docetaxel in that disease, an expanded evaluation of this regimen in pts with previously treated NSCLC is on-going. The combination of IPI-504 and docetaxel on a weekly schedule is also being explored. [Table: see text]
Shear enhances thrombopoiesis and formation of microparticles that induce megakaryocytic differentiation of stem cells (2014)

In vivo visualization of thrombopoiesis suggests an important role for shear flow in platelet biogenesis. In vitro, shear stress was shown to accelerate proplatelet formation from mature megakaryocytes (Mks). Yet, the role of biomechanical forces on Mk biology and platelet biogenesis remains largely unexplored. In this study, we investigated the impact of shear stress on Mk maturation and formation of platelet-like particles (PLPs), pro/preplatelets (PPTs), and Mk microparticles (MkMPs), and furthermore, we explored a physiological role for MkMPs. We found that shear accelerated DNA synthesis of immature Mks in an exposure time- and shear stress level-dependent manner. Both phosphatidylserine exposure and caspase-3 activation were enhanced by shear stress. Exposure to physiological shear dramatically increased generation of PLPs/PPTs and MkMPs by up to 10.8 and 47-fold, respectively. Caspase-3 inhibition reduced shear-induced PLP/PPT and MkMP formation. PLPs generated under shear flow displayed improved functionality as assessed by CD62P exposure and fibrinogen binding. Significantly, coculture of MkMPs with hematopoietic stem and progenitor cells promoted hematopoietic stem and progenitor cell differentiation to mature Mks synthesizing α- and dense-granules, and forming PPTs without exogenous thrombopoietin, thus identifying a novel and unexplored potential physiological role for MkMPs.
Application of surface-enhanced Raman spectroscopy (SERS) for cleaning verification in pharmaceutical manufacture. (2010)

Cleaning verification is the process by which pharmaceutical manufacturing equipment is determined as sufficiently clean to allow manufacture to continue. Surface-enhanced Raman spectroscopy (SERS) is a very sensitive spectroscopic technique capable of detection at levels appropriate for cleaning verification. In this paper, commercially available Klarite SERS substrates were employed in order to obtain the necessary enhancement of signal for the identification of chemical species at concentrations of 1 to 10 ng/cm2, which are relevant to cleaning verification. The SERS approach was combined with principal component analysis in the identification of drug compounds recovered from a contaminated steel surface.
Noninvasive Prenatal Detection of Trisomy 21 by an Epigenetic–Genetic Chromosome-Dosage Approach (2009)

The epigenetic-genetic chromosome-dosage approach is a new method for noninvasive prenatal detection of T21. The epigenetic part of the analysis can be applied to all pregnancies. Because the genetic part of the analysis uses paternally inherited, fetal-specific genetic markers that are abundant in the genome, broad population coverage should be readily achievable. This approach has the potential to become a generally usable technique for noninvasive prenatal diagnosis.
HTRF: A Technology Tailored for Drug Discovery - A Review of Theoretical Aspects and Recent Applications (2009)

HTRF (Homogeneous Time Resolved Fluorescence) is the most frequently used generic assay technology to measure analytes in a homogenous format, which is the ideal platform used for drug target studies in high-throughput screening (HTS). This technology combines fluorescence resonance energy transfer technology (FRET) with time-resolved measurement (TR). In TR-FRET assays, a signal is generated through fluorescent resonance energy transfer between a donor and an acceptor molecule when in close proximity to each other. Buffer and media interference is dramatically reduced by dual-wavelength detection, and the final signal is proportional to the extent of product formation. The HTRF assay is usually sensitive and robust that can be miniaturized into the 384 and 1536-well plate formats. This assay technology has been applied to many antibody-based assays including GPCR signaling (cAMP and IP-One), kinases, cytokines and biomarkers, bioprocess (antibody and protein production), as well as the assays for protein-protein, proteinpeptide, and protein-DNA/RNA interactions.Since its introduction to the drug-screening world over ten years ago, researchers have used HTRF to expedite the study of GPCRs, kinases, new biomarkers, protein-protein interactions, and other targets of interest. HTRF has also been utilized as an alternative method for bioprocess monitoring. The first-generation HTRF technology, which uses Europium cryptate as a fluorescence donor to monitor reactions between biomolecules, was extended in 2008 through the introduction of a second-generation donor, Terbium cryptate (Tb), enhancing screening performance. Terbium cryptate possesses different photophysical properties compared to Europium, including increased quantum yield and a higher molar extinction coefficient. In addition to being compatible with the same acceptor fluorophors used with Europium, it can serve as a donor fluorophore to green-emitting fluors because it has multiple emission peaks including one at 490 nm. Moreover, all Terbium HTRF assays can be read on the same HTRF-compatible instruments as Europium HTRF assays.Overall, HTRF is a highly sensitive, robust technology for the detection of molecular interactions in vitro and is widely used for primary and secondary screening phases of drug development. This review addresses the general principles of HTRF and its current applications in drug discovery.
Additive logistic regression: a statistical view of boosting (With discussion and a rejoinder by the authors) (2000)

Boosting is one of the most important recent developments in classification methodology. Boosting works by sequentially applying a classification algorithm to reweighted versions of the training data and then taking a weighted majority vote of the sequence of classifiers thus produced. For many classification algorithms, this simple strategy results in dramatic improvements in performance. We show that this seemingly mysterious phenomenon can be understood in terms of well-known statistical principles, namely additive modeling and maximum likelihood. For the two-class problem, boosting can be viewed as an approximation to additive modeling on the logistic scale using maximum Bernoulli likelihood as a criterion. We develop more direct approximations and show that they exhibit nearly identical results to boosting. Direct multiclass generalizations based on multinomial likelihood are derived that exhibit performance comparable to other recently proposed multiclass generalizations of boosting in most situations, and far superior in some. We suggest a minor modification to boosting that can reduce computation, often by factors of 10 to 50. Finally, we apply these insights to produce an alternative formulation of boosting decision trees. This approach, based on best-first truncated tree induction, often leads to better performance, and can provide interpretable descriptions of the aggregate decision rule. It is also much faster computationally, making it more suitable to large-scale data mining applications.
An Experimental Study on Interactions between Imbibed Fracturing Fluid and Organic-Rich Tight Carbonate Source Rocks (2017)

Abstract Carbonate reservoirs dominate 70% of oil and 90% of gas reserves in Middle East region, and imbibition is the main mechanism for fracturing fluid up-take during hydraulic fracturing stimulation process. Due to highly heterogeneous nature of tight carbonate source rocks, it is crucial to understand effects of the imbibed fluid on the mechanical, morphological and flow properties of the carbonate rocks. While the influence of imbibed fluids on the wettability of carbonate reservoir has been studied intensively, the research on effects of imbibed fluids on the texture and mineralogy of the carbonate rocks is very limited. This paper aims to provide a conceptual approach and workflow to characterize and quantify microstructure and mineralogy changes resulting from the imbibed fluids. A thin-section of low permeability organic-rich carbonate rock sample with a dimension of 7mm × 7mm × 0.3mm (length × width × thickness) was used in the study. The sample was submerged into 2% KCl (pH = 7.1) fluid from one end to simulate the spontaneous imbibition process. Scanning Electron Microscope (SEM) was used to capture the sample’s morphological change before and after spontaneous imbibition. Energy Dispersive Spectroscopy (EDS) mapping was used to study mineralogy changes (dissolution and precipitation) before and after fluid treatment. Inductively coupled plasma (ICP) equipped with optical emission spectrometer (OES) detector has been used to quantify dissolved ion concentrations in the treatment fluid. Permeability and porosity were measured using core plugs (1" in diameter × 1.5" in length) before and after imbibition process with half-length of the sample submerged into the treatment fluid. The SEM images for the thin-section sample show three zones with distinct fluid up-take characters. In Zone I, which was submerged into the testing fluid, considerable mineral dissolution has been observed. In Zone III, which was above the testing fluid level, considerable mineral precipitation was detected. While in the transition zone (Zone II, which was between the above two zones around the water-air level), minor amount of mineral dissolution was observed. The mineralogy changes resulting from the dissolution and precipitation have been identified by EDS analysis in all three zones. Gypsum and calcite were found to be dissolved in the imbibed fluids, while gypsum was found to be deposited on the rock surface in zones above fluid level. The observed gypsum deposition might result from the dissolution of the gypsum and calcite and re-precipitaion later from the imbibition experiment due to water evaporation and/or from sample drying process. Absolute permeability and porosity measurements for core plug samples show that both increased after the imbibition process.
Inhibitors of Cyclic AMP Phosphodiesterase in Medicinal Plants (1981)

Hot aqueous extracts of medicinal plants used in oriental medicine were tested for their inhibitory effect on beef heart phosphodiesterase to detect biologically active compounds present therein. Of 222 samples tested 22 showed reproducible inhibition. cAMP phosphodiesterase inhibitors contained in Anemarrhena asphodeloides were identified as norlignans and their structure activity relationship was investigated; cis-hinokiresinol, the main inhibitor exhibited a prolongation effect on hexobarbital sleeping time in mice.
Nanofiber-Based in Vitro System for High Myogenic Differentiation of Human Embryonic Stem Cells (2013)

Myogenic progenitor cells derived from human embryonic stem cells (hESCs) can provide unlimited sources of cells in muscle regeneration but their clinical uses are largely hindered by the lack of efficient methods to induce differentiation of stem cells into myogenic cells. We present a novel approach to effectively enhance myogenic differentiation of human embryonic stem cells using aligned chitosan-polycaprolactone (C-PCL) nanofibers constructed to resemble the microenvironment of the native muscle extracellular matrix (ECM) in concert with Wnt3a protein. The myogenic differentiation was assessed by cell morphology, gene activities, and protein expression. hESCs grown on C-PCL uniaxially aligned nanofibers in media containing Wnt3a displayed an elongated morphology uniformly aligned in the direction of fiber orientation, with increased expressions of marker genes and proteins associated with myogenic differentiation as compared to control substrates. The combination of Wnt3a signaling and aligned C-PCL nanofibers resulted in high percentages of myogenic-protein expressing cells over total treated hESCs (83% My5, 91% Myf6, 83% myogenin, and 63% MHC) after 2 days of cell culture. Significantly, this unprecedented high-level and fast myogenic differentiation of hESC was demonstrated in a culture medium containing no feeder cells. This study suggests that chitosan-based aligned nanofibers combined with Wnt3a can potentially act as a model system for embryonic myogenesis and muscle regeneration.
Thromboembolism and antithrombotic therapy for heart failure in sinus rhythm (2012)

Chronic heart failure (HF) with either reduced or preserved left ventricular (LV) ejection fraction is common and remains an extremely serious disorder with a high mortality and morbidity. Many complications related to heart failure can be related to thrombosis. Epidemiological and pathophysiological data also link HF to an increased risk of thrombosis, leading to the clinical consequences of sudden death, stroke, systemic thromboembolism and/or venous thromboembolism. This executive summary of a joint consensus document of the Heart Failure Association (EHFA) of the European Society of Cardiology (ESC) and the ESC Working Group on Thrombosis reviews the published evidence, summarises 'best practice', and puts forward consensus statements that may help to define evidence gaps and assist management decisions in everyday clinical practice. In HF patients with atrial fibrillation, oral anticoagulation is clearly recommended, and the CHA2DS2-VASc and HAS-BLED scores should be used to determine the likely risk-benefit ratio (thromboembolism prevention versus risk of bleeding) of oral anticoagulation. In HF patients with reduced LV ejection fraction who are in sinus rhythm there is no evidence of an overall benefit of vitamin K antagonists (e.g. warfarin) on mortality, with risk of major bleeding. Whilst there is the potential for a reduction in ischaemic stroke, there is currently no compelling reason to routinely use warfarin for these patients. Risk factors associated with increased risk of thromboembolic events should be identified and decisions regarding use of anticoagulation individualised. Patient values and preferences are important determinants when balancing the risk of thromboembolism against bleeding risk. Novel oral anticoagulants that offer a different risk-benefit profile compared with warfarin may appear as an attractive therapeutic option, but this would need to be confirmed in clinical trials.
A New Synthesis of Glutathione via the Thiazoline Peptide (1980)

Abstract A convenient synthesis of glutathione (GSH) by the use of minimal protecting groups was investigated. N-Formyl-l-2-amino-4-cyanobutyric acid ethyl ester was condensed with ethyl l-cysteinylglycinate to give (4R)-2-[(3S)-3-ethoxycarbonyl-3-(formylamino)propyl]-4-(ethoxycarbonylmethylcarbamoyl)-2-thiazoline. This compound was saponified in aqueous acetone at −15–−20 °C and subsequently treated with dilute H2SO4 (pH 4) to yield formylglutathione, whose formyl group was then hydrolyzed with 0.5 M (1 M=1 mol dm−3) H2SO4 to give free GSH. For purification, this was changed to a copper thiolate, which was then decomposed with H2S to afford pure GSH.