gebhart/patrepeval huggingface dataset:
Involvement of autophagy in T cell biology. (2017)

Autophagy is an essential cellular pathway that sequesters various cytoplasmic components, including accumulated proteins, damaged organelles or invading microorganisms and delivers them to lysosomes for degradation. The function of autophagy has been reported in various tissues and systems, including its role in the regulation of cellular immunity. Autophagy plays a fundamental role at various stages of T cell maturation. It regulates the thymocyte selection and the generation of T cell repertoire by presenting intracellular antigens to MHC class molecules. Autophagy is crucial for metabolic regulation of T cells, and therefore supports cell survival and homeostasis, particularly in activated mature T cells. Furthermore, deletion of specific autophagy-related genes induces several immunological alterations including differentiation of activated T cells into regulatory, memory or natural killer T cells. In this review, we emphasize the impact of autophagy on T cell development, activation and differentiation, which is pivotal for the adaptive immune system.
Polaron lattice in highly conducting polyaniline: Theoretical and optical studies (1987)

We present optical-absorption data together with band-structure calculations for the polaron lattice and bipolaron lattice for the highly conducting form of polyaniline, proton-doped polyemeraldine. We show that the polaron-lattice band structure fully accounts for the observed optical transitions. These results are in marked contrast with the electronic structure of other doped conducting polymers, in that only one single broad polaron band appears deep in the gap together with a very narrow band nearly degenerate with the conduction-band edge.
Peroxisome Proliferator-activated Receptor α-Isoform Deficiency Leads to Progressive Dyslipidemia with Sexually Dimorphic Obesity and Steatosis (1998)

The alpha-isoform of the peroxisome proliferator-activated receptor (PPARalpha) is a nuclear transcription factor activated by structurally diverse chemicals referred to as peroxisome proliferators. Activators can be endogenous molecules (fatty acids/steroids) or xenobiotics (fibrate lipid-lowering drugs). Upon pharmacological activation, PPARalpha modulates target genes encoding lipid metabolism enzymes, lipid transporters, or apolipoproteins, suggesting a role in lipid homeostasis. Transgenic mice deficient in PPARalpha were shown to lack hepatic peroxisomal proliferation and have an impaired expression and induction of several hepatic target genes. Young adult males show hypercholesterolemia but normal triglycerides. Using a long term experimental set up, we identified these mice as a model of monogenic, spontaneous, late onset obesity with stable caloric intake and a marked sexual dimorphism. Serum triglycerides, elevated in aged animals, are higher in females that develop a more pronounced obesity than males. The latter show a marked and original centrilobular-restricted steatosis and a delayed occurrence of obesity. Fat cells from their liver express substantial levels of PPARgamma2 transcripts when compared with lean cells. These studies demonstrate, in rodents, the involvement of PPARalpha nuclear receptor in lipid homeostasis, with a sexually dimorphic control of circulating lipids, fat storage, and obesity. Characterization of this pathological link may help to delineate new molecular targets for therapeutic intervention and could lead to new insights into the etiology and heritability of mammalian obesity.
Ischemia-reperfusion: Putting the pieces of the puzzle together* (2006)

Division of Intra-Abdominal Transplantation, Loyola University Medical Center, Maywood, IL The author has no financial interests to disclose.
Mutants of human insulin-like growth factor I with reduced affinity for the type 1 insulin-like growth factor receptor (1988)

Four mutants of human insulin-like growth factor I (hIGF I) have been purified from the conditioned media of yeast transformed with an expression vector containing a synthetic gene for hIGF I altered by site-directed mutagenesis. hIGF I has the sequence Phe-23-Tyr-24-Phe-25 which is homologous to a region in the B-chain of insulin. [Phe23,Phe24,Tyr25]IGF I, in which the sequence is altered to exactly correspond to the homologous sequence in insulin, is equipotent to hIGF I at the types 1 and 2 IGF and insulin receptors. [Leu24]IGF I and [Ser24]IGF I have 32- and 16-fold less affinity than hIGF I at the human placental type 1 IGF receptor, respectively. These peptides are 10- and 2-fold less potent at the placental insulin receptor, respectively. [Leu24]IGF I and [Ser24]IGF I have similarly reduced affinities for the type 1 IGF receptor of rat A10 and mouse L cells. Thus, the importance of the interaction of residue 24 with the receptor is conserved in several species. In three cell-based assays, [Leu24]IGF I and [Ser24]IGF I are full agonists with reduced efficacy compared to hIGF I. Desoctapeptide [Leu24]IGF I, in which the loss of aromaticity at position 24 is combined with the deletion of the carboxyl-terminal D region of hIGF I, has 3-fold lower affinity than [Leu24]IGF I for the type 1 receptor and 2-fold higher affinity for the insulin receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Topic segmentation with an aspect hidden Markov model (2001)

We present a novel probabilistic method for topic segmentation on unstructured text. One previous approach to this problem utilizes the hidden Markov model (HMM) method for probabilistically modeling sequence data [7]. The HMM treats a document as mutually independent sets of words generated by a latent topic variable in a time series. We extend this idea by embedding Hofmann's aspect model for text [5] into the segmenting HMM to form an aspect HMM (AHMM). In doing so, we provide an intuitive topical dependency between words and a cohesive segmentation model. We apply this method to segment unbroken streams of New York Times articles as well as noisy transcripts of radio programs on SpeechBot, an online audio archive indexed by an automatic speech recognition engine. We provide experimental comparisons which show that the AHMM outperforms the HMM for this task.
Peroxynitrite-mediated nitration of tyrosine residues in Escherichia coli glutamine synthetase mimics adenylylation: relevance to signal transduction. (1996)

Treatment of Escherichia coli glutamine synthetase (GS) with peroxynitrite leads to nitration of some tyrosine residues and conversion of some methionine residues to methionine sulfoxide (MSOX) residues. Nitration, but not MSOX formation, is stimulated by Fe-EDTA. In the absence of Fe-EDTA, nitration of only one tyrosine residue per subunit of unadenylylated GS leads to changes in divalent cation requirement, pH-activity profile, affinity for ADP, and susceptibility to feedback inhibition by end products (tryptophan, AMP, CTP), whereas nitration of one tyrosine residue per subunit in the adenylylated GS leads to complete loss of catalytic activity. In the presence of Fe-EDTA, nitration is a more random process: nitration of five to six tyrosine residues per subunit is needed to convert unadenylylated GS to the adenylylated configuration. These results and the fact that nitration of tyrosine residues is an irreversible process serve notice that the regulatory function of proteins that undergo phosphorylation or adenylylation in signal transduction cascades might be seriously compromised by peroxynitrite-promoted nitration.
An IL-4/IL-13 Dual Antagonist Reduces Lung Inflammation, Airway Hyperresponsiveness, and IgE Production in Mice (2013)

IL-4 and IL-13 comprise promising targets for therapeutic interventions in asthma and other Th2-associated diseases, but agents targeting either IL-4 or IL-13 alone have shown limited efficacy in human clinical studies. Because these cytokines may involve redundant function, dual targeting holds promise for achieving greater efficacy. We describe a bifunctional therapeutic targeting IL-4 and IL-13, developed by a combination of specific binding domains. IL-4-targeted and IL-13-targeted single chain variable fragments were joined in an optimal configuration, using appropriate linker regions on a novel protein scaffold. The bifunctional IL-4/IL-13 antagonist displayed high affinity for both cytokines. It was a potent and efficient neutralizer of both murine IL-4 and murine IL-13 bioactivity in cytokine-responsive Ba/F3 cells, and exhibited a half-life of approximately 4.7 days in mice. In a murine model of ovalbumin-induced ear swelling, the bifunctional molecule blocked both the IL-4/IL-13-dependent early-phase response and the IL-4-dependent late-phase response. In the ovalbumin-induced lung inflammation model, the bifunctional IL-4/IL-13 antagonist reduced the IL-4-dependent rise in serum IgE titers, and reduced IL-13-dependent airway hyperresponsiveness, lung inflammation, mucin gene expression, and serum chitinase responses. Taken together, these findings demonstrate the effective dual blockade of IL-4 and IL-13 with a single agent, which resulted in the modulation of a more extensive range of endpoints than could be achieved by targeting either cytokine alone.
First in human phase I study of MK-2461, a small molecule inhibitor of c-Met, for patients with advanced solid tumors (2008)

14657 Background: MK-2461 is a potent small molecule inhibitor of c-Met, a receptor tyrosine kinase involved in tumor cell proliferation and motility. Over-expression of c-Met or Met gene amplification has been associated with poorer prognosis in several tumor types. Methods: Multicenter, open-label, phase I dose escalation study in patients with advanced solid tumors refractory to standard therapy. Drug was administered by mouth daily or twice daily (BID) for 28 days followed by a 14 day rest period during cycle 1. Patients received continuous dosing subsequently for 28-day cycles. Maximum tolerated dose (MTD) was determined using a standard 3+3 dosing design. PK analyses were performed on days 1 and 28 of cycle 1. Results: Fourteen patients (10 M/ 4 F), mean age 54 (range 19–76), have received 31 cycles (range 1–6). Dose levels tested include 60mg daily, 60mg BID, 120mg BID, and 180 mg BID. Toxicity data are available for 11 patients treated at the 60mg daily-120mg BID dosing cohorts. Ten patients (91%) have not experienced > Grade 1 drug-related toxicity. Dose limiting toxicity has not been reached and no objective antitumor responses have been observed. One patient with mucinous carcinoma of the appendix had stable disease for 6 cycles. Common drug related toxicities are outlined in the table below. Four patients experienced serious adverse experiences that were considered not related to MK-2461. PK analysis revealed a rapid Tmax (1–3 hr) across all dosing cohorts with a terminal half life of 6.3 hr following the final day of dosing for the QD dosing cohort. Conclusions: Twice daily administration of MK-2461 at the doses tested is well tolerated. Terminal t1/2 suggests acceptable drug plasma concentrations expected at BID dosing. Dose escalation continues. Toxicity Grade 1 (%) Grade 2 (%) Anorexia 2(18%) 0 Fatigue 1(9%) 1(9%) Nausea 1(9%) 0 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Merck Merck Exelixis, Merck
Controlled delivery of the heparan sulfate/FGF‐2 complex by a polyelectrolyte scaffold promotes maximal hMSC proliferation and differentiation (2010)

Growth factors and other regulatory molecules are required to direct differentiation of bone marrow-derived human mesenchymal stem cells (hMSC) along specific lineages. However, the therapeutic use of growth factors is limited by their susceptibility to degradation, and the need to maintain prolonged local release of growth factor at levels sufficient to stimulate hMSC. The aim of this study was to investigate whether a device containing heparan sulfate (HS), which is a co-factor in growth factor-mediated cell proliferation and differentiation, could potentiate and prolong the delivery of fibroblast growth factor-2 (FGF-2) and thus enhance hMSC stimulation. To this aim, we synthesized cationic polyelectrolyte polymers covalently and non-covalently anchored to HS and evaluated their effect on hMSC proliferation. Polymers non-covalently bound to HS resulted in the release of an HS/FGF-2 complex rather than FGF-2 alone. The release of this complex significantly restored hMSC proliferation, which was abolished in serum-free medium and only partially restored by the release of FGF-2 alone as occurred with polymer covalently bound to HS. We also demonstrate that exposure to HS/FGF-2 during early growth but not during post-confluence is essential for hMSC differentiation down the fibroblast lineage, which suggests that both factors are required to establish the correct stem cell commitment that is necessary to support subsequent differentiation. In conclusion, the delivery platform described here is a step towards the development of a new class of biomaterial that enables the prolonged, non-covalent binding and controlled delivery of growth factors and cofactors without altering their potency.
Reversal of acute coagulopathy during hypotensive resuscitation using small-volume 7.5% NaCl adenocaine and Mg2+ in the rat model of severe hemorrhagic shock* (2012)

Plasma activated partial thromboplastin time and prothrombin time increased over 10-fold during the bleed and shock periods prior to resuscitation, and a small-volume (~1 mL/kg) IV bolus of 7.5% NaCl AL/Mg²⁺ was the only treatment group that raised mean arterial pressure into the permissive range and returned activated partial thromboplastin time and prothrombin time clotting times to baseline at 60 mins.
pH-dependent binding of immunoglobulins to intestinal cells of the neonatal rat. (1976)

Rat and rabbit IgG immunoglobulins conjugated to horseradiah peroxidase as a histochemical marker bind at 0 degrees C to the luminal surface of absorptive cells in isolated segments of jejunum from 10-12-day old rats. Binding is observed at pH 6.0, near the normal luminal pH of the duodenum and jejunum at this age, but not at pH 7.4. Furthermore, no binding occurs when cells are exposed at pH 6.0 to either free peroxidase or peroxidase conjugated to chicken or sheep IgG immunoglobulins or bovine serum albumin. The sensitivity of binding to pH suggests a means whereby immunoglobulins which are selectively absorbed by the cells can be released efficiently at the abluminal surface.
Flavonols from Saffron Flower:  Tyrosinase Inhibitory Activity and Inhibition Mechanism (1999)

A common flavonol, kaempferol, isolated from the fresh flower petals of Crocus sativus L. (Iridaceae) was found to inhibit the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) catalyzed by mushroom tyrosinase with an ID(50) of 67 microgram/mL (0.23 mM). Interestingly, its 3-O-glycoside derivatives did not inhibit this oxidation. The inhibition kinetics analyzed by a Lineweaver-Burk plot found kaempferol to be a competitive inhibitor, and this inhibitory activity presumably comes from its ability to chelate copper in the enzyme. This copper chelation mechanism can be applicable for all of the flavonols as long as their 3-hydroxyl group is free. However, quercetin, kaempferol, and galangin each affect the oxidation of L-tyrosine in somewhat different ways.
4 High-Performance Tangential Flow Filtration for Protein Separations (2000)

High-performance tangential flow filtration (HPTFF) is an emerging technology that uses semipermeable membranes for the separation of proteins without limit to their relative size (1). HPTFF can be used throughout the purification process to remove specific impurities (e.g., proteins, DNA, or endotoxins), clear viruses, and/or eliminate protein oligomers or degradation products. In addition, HPTFF can effect simultaneous purification, concentration, and buffer exchange, providing the unique capability of combining several different separation steps into a single scalable unit operation.
3D Ultrasound Measurement of Change in Carotid Plaque Volume (2005)

3D plaque volume measurement can show large effects of therapy on atherosclerosis in 3 months in sample sizes of approximately 20 patients per group. Sample sizes of 22 per group would be sufficient to show an effect size of 25% that of atorvastatin in 6 months. This technology promises to be very useful in evaluation of new therapies.
Behavioral despair in mice: a primary screening test for antidepressants. (1977)

A depressed state can be induced in mice by forcing them to swim in a narrow cylinder from which they cannot escape. After a brief period of vigorous activity the mice adopt a characteristic immobile posture which is readily identifiable. Immobility was reduced by tricyclic antidepressants, monoamine oxidase inhibitors and atypical antidepressants, as well as by electroconvulsive shock. Psychostimulants also reduced immobility but in contrast to antidepressants caused marked motor stimulation. Immobility was not affected by minor or major tranquilisers. These findings, closely parallel to those we have previously reported in rats, suggest that the procedure is selectively sensitive to antidepressant treatments. The mouse procedure is, however, more rapid and less costly than that with rats and is thus more suitable for the primary screening of antidepressant drugs.
Secondary prophylaxis of hepatic encephalopathy in cirrhosis of liver: a double-blind randomized controlled trial of l-ornithine l-aspartate versus placebo (2018)

LOLA is effective in the secondary prophylaxis of HE and is associated with significant improvements in psychometric hepatic encephalopathy score, ammonia level, critical flicker frequency scores, and health-related quality of life.
Subcellular localization and purification of a p-hydroxyphenylpyruvate dioxygenase from cultured carrot cells and characterization of the corresponding cDNA (1997)

p-Hydroxyphenylpyruvate dioxygenase catalyses the transformation of p-hydroxyphenylpyruvate into homogentisate. In plants this enzyme has a crucial role because homogentisate is the aromatic precursor of all prenylquinones. Furthermore this enzyme was recently identified as the molecular target for new families of potent herbicides. In this study we examine precisely the localization of p-hydroxyphenylpyruvate dioxygenase activity within carrot cells. Our results provide evidence that, in cultured carrot cells, p-hydroxyphenylpyruvate dioxygenase is associated with the cytosol. Purification and SDS/PAGE analysis of this enzyme revealed that its activity is associated with a polypeptide of 45–46 kDa. This protein specifically cross-reacts with an antiserum raised against the p-hydroxyphenylpyruvate dioxygenase of Pseudomonas fluorescens. Gel-filtration chromatography indicates that the enzyme behaves as a homodimer. We also report the isolation and nucleotide sequence of a cDNA encoding a carrot p-hydroxyphenylpyruvate dioxygenase. The nucleotide sequence (1684 bp) encodes a protein of 442 amino acid residues with a molecular mass of 48094 Da and shows specific C-terminal regions of similarity with other p-hydroxyphenylpyruvate dioxygenases. This cDNA encodes a functional p-hydroxyphenylpyruvate dioxygenase, as evidenced by expression studies with transformed Escherichia coli cells. Comparison of the N-terminal sequence of the 45–46 kDa polypeptide purified from carrot cells with the deduced peptide sequence of the cDNA confirms that this polypeptide supports p-hydroxyphenylpyruvate dioxygenase activity. Immunodetection studies of the native enzyme in carrot cellular extracts reveal that N-terminal proteolysis occurs during the process of purification. This proteolysis explains the difference in molecular masses between the purified protein and the deduced polypeptide.
An Inorganic Microsphere Composite for the Selective Removal of137Cesium from Acidic Nuclear Waste Solutions. 2: Bench‐Scale Column Experiments, Modeling, and Preliminary Process Design (2009)

A new inorganic ion exchange composite for removing radioactive cesium from acidic waste streams has been developed. The new material consists of ammonium molybdophosphate, (NH4)3P(Mo3O10)4·3H2O (AMP), synthesized within hollow aluminosilicate microspheres (AMP‐C), which are produced as a by‐product from coal combustion. The selective cesium exchange capacity of this inorganic composite was evaluated in bench‐scale column tests using simulated sodium bearing waste solution as a surrogate for the acidic tank waste currently stored at the Idaho National Laboratory (INL). Total cesium loading on the columns at saturation agreed very well with equilibrium values predicted from isotherm experiments performed previously. A numerical algorithm for solving the governing partial differential equations (PDE) for cesium uptake was developed using the intraparticle mass transfer coefficient obtained from previous batch kinetic experiments. Solutions to the governing equations were generated to obtain the cesium concentration at the column effluent as a function of throughput volume using the same conditions as those used for the actual column experiments. The numerical solutions of the PDE fit the column break through data quite well for all the experimental conditions in the study. The model should therefore provide a reliable prediction of column performance at larger scales.
Effects of a herbal medicine, Hippophae rhamnoides, on cardiovascular functions and coronary microvessels in the spontaneously hypertensive stroke-prone rat (2009)

The dry fruits of Hippophae rhamnoides (so-called "Saji" or "Sea buckthorn") are used in China as a herbal medicine. The present work studied the effects on microvessels in the left ventricular wall, hematological parameters, cardiovascular performance and plasma constituents in spontaneously hypertensive stroke-prone rats (SHRSP/EZO) treated with Hippophae for 60 days. Analyses showed that the powder made of dry Hippophae fruits contains the vitamins C, B1, B2 and E, provitamin A, rutin, serotonin, cytosterol, selenium and zinc, among other constituents. The experimental rats were fed ad libitum with blocks of rat chow supplemented with Hippophae powder at a concentration of 0.7 g/kg in rat powder chow, while control rats were unsupplemented chow. The mean arterial blood pressure, heart rate, total plasma cholesterol, triglycerides, and glycated hemoglobin were significantly decreased by the Hippophae treatment. The arteriolar capillary portions of microvessels expressing alkaline phosphatase decreased, but there was a trend for an increase in the total capillary density. It was concluded that Hippophae fruits improved the metabolic processes accompanied by reduction of hypertensive stress on the ventricular microvessels.