gebhart/patrepeval huggingface dataset:
Plasma cholesteryl ester transfer protein has binding sites for neutral lipids and phospholipids. (1988)

The plasma cholesteryl ester-transfer protein (CETP, Mr 74,000) promotes exchange of both neutral lipids and phospholipids (phosphatidylcholine, PC) between lipoproteins. To investigate the mechanism of facilitated lipid transfer, CETP was incubated with unilamellar egg PC vesicles containing small amounts of cholesteryl ester (CE) or triglyceride, and then analyzed by gel filtration chromatography. There was rapid transfer of radiolabeled CE or triglyceride and PC from vesicles to CETP. The CETP with bound lipids was isolated and incubated with low density lipoproteins (LDL), resulting in transfer of the lipids to LDL. The CETP bound up to 0.9 mol of CE or 0.2 mol of triglyceride and 11 mol of PC/mol of CETP. para-Chloromercuriphenylsulfonate, an inhibitor of CE and triglyceride transfer, was found to decrease the binding of radiolabeled CE and triglyceride by CETP. Under various conditions the CETP eluted either as an apparent monomer with bound lipid (Mr 75,000-93,000), or in complexes with vesicles. The distribution of CETP between these two states was influenced by the presence of apoA-I or albumin, incubation time, vesicle/CETP ratio, and buffer pH and ionic strength. The results indicate that the CETP has binding sites for CE, triglyceride, and PC which readily equilibrate with lipoprotein lipids and suggest that CETP can act as a carrier of lipid between lipoproteins.
Macrophage-Mediated Suppression of Natural Killer Cell Activity in Mice Bearing Lewis Lung Carcinoma2 (1986)

The natural killer (NK) cell cytotoxic capacity of C57BL/6 mice with implantation of Lewis lung carcinoma (LLC) was quantitated during tumor growth. The NK activity became suppressed at 1 week of tumor growth and remained suppressed. The mechanisms for the suppression during the first 3 weeks of tumor growth included secretion of prostaglandin E2 (PGE2) by both the LLC tumor and host macrophages. With tumor growth, plasma PGE2 concentrations progressively increased. Oral administration of indomethacin to tumor-bearing mice prevented the rise in serum PGE2 concentrations and the suppression of NK activity. Cultured LLC cells and splenic macrophages isolated from mice during the first 3 weeks of tumor growth secreted increased amounts of PGE2. Macrophages from tumor-bearer spleen cells were shown to suppress NK activity. Depletion of these macrophages restored the NK activity, and addition of these macrophages to normal spleen cells resulted in an indomethacin-sensitive suppression of the NK response. The mechanisms of suppression in mice bearing large tumors were different than those observed with smaller tumors. With a large tumor burden, the plasma PGE2 concentrations declined. Indomethacin treatment did not prevent the suppression of NK activity, and depletion of splenic macrophages did not restore NK cytotoxicity.
Direct fabrication of graphene on SiO2 enabled by thin film stress engineering (2014)

We demonstrate direct production of graphene on SiO2 by CVD growth of graphene at the interface between a Ni film and the SiO2 substrate, followed by dry mechanical delamination of the Ni using adhesive tape. This result is enabled by understanding of the competition between stress evolution and microstructure development upon annealing of the Ni prior to the graphene growth step. When the Ni film remains adherent after graphene growth, the balance between residual stress and adhesion governs the ability to mechanically remove the Ni after the CVD process. In this study the graphene on SiO2 comprises micron-scale domains, ranging from monolayer to multilayer. The graphene has >90% coverage across centimeter-scale dimensions, limited by the size of our CVD chamber. Further engineering of the Ni film microstructure and stress state could enable manufacturing of highly uniform interfacial graphene followed by clean mechanical delamination over practically indefinite dimensions. Moreover, our findings suggest that preferential adhesion can enable production of 2-D materials directly on application-relevant substrates. This is attractive compared to transfer methods, which can cause mechanical damage and leave residues behind.
Characterization of GD2 Peptide Mimotope DNA Vaccines Effective against Spontaneous Neuroblastoma Metastases (2006)

Disialoganglioside GD2 is an established target for immunotherapy in neuroblastoma. We tested the hypothesis that active immunization against the glycolipid GD2 using DNA vaccines encoding for cyclic GD2-mimicking decapeptides (i.e., GD2 mimotopes) is effective against neuroblastoma. For this purpose, two GD2 peptide mimotopes (MA and MD) were selected based on docking experiments to anti-GD2 antibody ch14.18 (binding free energy: -41.23 kJ/mol for MA and -48.06 kJ/mol for MD) and Biacore analysis (K(d) = 12.3 x 10(-5) mol/L for MA and 5.3 x 10(-5) mol/L for MD), showing a higher affinity of MD over MA. These sequences were selected for DNA vaccine design based on pSecTag2-A (pSA) also including a T-cell helper epitope. GD2 mimicry was shown following transfection of CHO-1 cells with pSA-MA and pSA-MD DNA vaccines, with twice-higher signal intensity for cells expressing MD over MA. Finally, these DNA vaccines were tested for induction of tumor protective immunity in a syngeneic neuroblastoma model following oral DNA vaccine delivery with attenuated Salmonella typhimurium (SL 7207). Only mice receiving the DNA vaccines revealed a reduction of spontaneous liver metastases. The highest anti-GD2 humoral immune response and natural killer cell activation was observed in mice immunized with the pSA-MD, a finding consistent with superior calculated binding free energy, dissociation constant, and GD2 mimicry potential for GD2 mimotope MD over MA. In summary, we show that DNA immunization with pSA-MD may provide a useful strategy for active immunization against neuroblastoma.
Prediction and Optimization of Liquid Propagation in Micropillar Arrays (2010)

Prediction and optimization of liquid propagation rates in micropillar arrays are important for various lab-on-a-chip, biomedical, and thermal management applications. In this work, a semianalytical model based on the balance between capillary pressure and viscous resistance was developed to predict liquid propagation rates in micropillar arrays with height-to-period ratios greater than 1 and diameter-to-period ratios less than 0.57. These geometries represent the most useful regimes for practical applications requiring large propagation rates. The capillary pressure was obtained using an energy approach where the meniscus shape was predicted using Surface Evolver simulations and experimentally verified by interference microscopy. The combined viscous resistance of the pillars and the substrate was determined using Brinkman's equation with a numerically obtained permeability and corroborated with finite element simulations. The model shows excellent agreement with one-dimensional propagation experiments of deionized water in silicon micropillar arrays, highlighting the importance of accurately capturing the details of the meniscus shape and the viscous losses. Furthermore, an effective propagation coefficient was obtained through dimensionless analysis that is functionally dependent only on the micropillar geometry. The work offers design guidelines to obtain optimal liquid propagation rates on micropillar surfaces.
Deep Reinforcement Learning in Parameterized Action Space (2015)

Recent work has shown that deep neural networks are capable of approximating both value functions and policies in reinforcement learning domains featuring continuous state and action spaces. However, to the best of our knowledge no previous work has succeeded at using deep neural networks in structured (parameterized) continuous action spaces. To fill this gap, this paper focuses on learning within the domain of simulated RoboCup soccer, which features a small set of discrete action types, each of which is parameterized with continuous variables. The best learned agent can score goals more reliably than the 2012 RoboCup champion agent. As such, this paper represents a successful extension of deep reinforcement learning to the class of parameterized action space MDPs.
A loan pricing model : the influence of the lender's credit rating (2004)

Within the context of a banking institution, economic capital is a statistical measure of the amount of resources required to meet unexpected losses over a specified time period and specified level of certainty. The amount of economic capital held by banks is thus a function of their target insolvency rate (the probability that losses will exceed a certain threshold) and is linked to an implied credit rating. In Australia, for example, the top four banks maintain sufficient economic capital to achieve a target credit rating of AA, which is equivalent to a 0.03% probability of insolvency. The benefits that accrue to banks from a high credit rating, in general, are access to lower cost funds in debt markets and low counterparty margins in swap and foreign exchange markets. However, as banks increase their economic capital to achieve a higher credit rating, the breakeven price on their asset portfolios will rise to the extent that the bank prices these assets to achieve a minimum return on economic capital. Ceteris paribus, the increase in loan rates may make the bank uncompetitive in specific asset markets, depending on the extent to which loan rates and other asset prices are market driven. Thus an increase in the solvency standard for a bank has two opposing effects on bank asset prices. To the extent that a bank prices its assets to achieve a target return on economic capital, an increase in economic capital will increase the net income that the bank needs to earn on its assets, resulting in higher asset prices. Offset against this, is the impact of a higher solvency standard on the cost of funds and market credit spreads for the bank. We propose that a bank that carries a large proportion of its funding book in retail funds may not benefit by targeting a high credit rating, depending on the sensitivity of retail depositors to incremental changes in credit rating. We model this relationship to ascertain an optimal economic capital requirement, varying the relative proportion of retail funds in the funding book. We compare the results of our model to empirical data on bank credit spreads in capital to markets to assess the extent to which an upgrade in the credit rating of a bank will be beneficial to the bank.
Easy Access to Both Enantiomers of C7-C12 Segment of Epothilones (1999)

AbstractBoth enantiomers of the C7-C12 segment (5 and 6) of epothilones A and B (1 and 2) were effectively synthesized starting from the methyl (R)- and (S)-hydroxy-2-methylpropionates (3 and 4) using the Grignard cross-coupling reaction mediated by cuprous (I) salts in three steps.
Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. (1999)

Epidermal growth factor (EGF)-related proteins such as transforming growth factor alpha (TGF-alpha) control cancer cell growth through autocrine and paracrine pathways. Overexpression of TGF-alpha and/or its receptor (EGFR) has been associated with a more aggressive disease and a poor prognosis. The blockade of EGFR activation has been proposed as a target for anticancer therapy. Monoclonal antibody (MAb) C225 is an anti-EGFR humanized chimeric mouse MAb that is presently in Phase II clinical trials in cancer patients. Previous studies have suggested the potentiation of the antitumor activity of certain cytotoxic drugs, such as cisplatin and doxorubicin, in human cancer cell lines by treatment with anti-EGFR antibodies. We have evaluated in human ovarian, breast, and colon cancer cell lines, which express functional EGFR, the antiproliferative activity of MAb C225 in combination with topotecan, a cytotoxic drug that specifically inhibits topoisomerase I and that has shown antitumor activity in these malignancies. A dose-dependent supraadditive increase of growth inhibition in vitro was observed when cancer cells were treated with topotecan and MAb C225 in a sequential schedule. In this respect, the cooperativity quotient, defined as the ratio between the actual growth inhibition obtained by treatment with topotecan followed by MAb C225 and the sum of the growth inhibition achieved by each agent, ranged from 1.2 to 3, depending on drug concentration and cancer cell line. Treatment with MAb C225 also markedly enhanced apoptotic cell death induced by topotecan. For example, in GEO colon cancer cells, 5 nM topotecan, followed by 0.5 microg/ml MAb C225, induced apoptosis in 45% cells as compared with untreated cells (6%) or to 5 nM topotecan-treated cells (22%). Treatment of mice bearing established human GEO colon cancer xenografts with topotecan or with MAb C225 determined a transient inhibition of tumor growth because GEO tumors resumed the growth rate of untreated tumors at the end of the treatment period. In contrast, an almost complete tumor regression was observed in all mice treated with the two agents in combination. This determined a prolonged life span of the mice that was significantly different as compared with controls (P < 0.001), to MAb C225-treated group (P < 0.001), or to the topotecan-treated group (P < 0.001). All mice of the topotecan plus MAb C225 group were the only animals alive 14 weeks after tumor cell injection. Furthermore, 20% of mice in this group were still alive after 19 weeks. The combined treatment with MAb C225 and topotecan was well tolerated by mice with no signs of acute or delayed toxicity. These results provide a rationale for the evaluation of the anticancer activity of the combination of topoisomerase I inhibitors and anti-EGFR blocking MAbs in clinical trials.
A New Approach to the Adoptive Immunotherapy of Cancer with Tumor-Infiltrating Lymphocytes (1986)

The adoptive transfer of tumor-infiltrating lymphocytes (TIL) expanded in interleukin-2 (IL-2) to mice bearing micrometastases from various types of tumors showed that TIL are 50 to 100 times more effective in their therapeutic potency than are lymphokine-activated killer (LAK) cells. Therefore the use of TIL was explored for the treatment of mice with large pulmonary and hepatic metastatic tumors that do not respond to LAK cell therapy. Although treatment of animals with TIL alone or cyclophosphamide alone had little impact, these two modalities together mediated the elimination of large metastatic cancer deposits in the liver and lung. The combination of TIL and cyclophosphamide was further potentiated by the simultaneous administration of IL-2. With the combination of cyclophosphamide, TIL, and IL-2, 100% of mice (n = 12) bearing the MC-38 colon adenocarcinoma were cured of advanced hepatic metastases, and up to 50% of mice were cured of advanced pulmonary metastases. Techniques have been developed to isolate TIL from human tumors. These experiments provide a rationale for the use of TIL in the treatment of humans with advanced cancer.
The Vascular Dementia of Fabry's Disease (1997)

Fabry's disease, a rare X-linked disorder of glycosphingolipid metabolism, can present as an insidious dementia in middle or later life. This genetic disorder produces a deficiency of alpha-galactosidase A which results in the deposition of glycosphingolipids in blood vessel walls in the brain as well as in the kidney, heart, peripheral nerves, and other organs. Among the cerebrovascular manifestations of this disorder is a vascular dementia from involvement of multiple small penetrating blood vessels. Fabry's disease is a consideration in the workup of an otherwise unexplained vascular dementia, particularly in males less than 65 years of age.
Asthma and atopy – a total genome scan for susceptibility genes (2002)

We found evidence for two new asthma and atopy loci, 1p36 and 3q21-q22, and supported linkage in the Danish population to seven previously reported candidate regions.
Three-dimensional structure and molecular mechanism of novel enzymes of spore-forming bacteria. (2002)

Bacillus and Clostridium species are spore-forming bacilli that cause serious diseases in livestock and in humans. An important pathogen in this group of organisms is Bacillus anthracis is which is the causative agent of anthrax. The biochemical properties, structure, function, and mechanism of catalysis of the novel spore germination protease (GPR) that degrades small, acid soluble proteins (SASP) protecting spore's DNA against damage and a novel, cofactor independent phosphoglycerate mutase (iPGM) are described. A coat created from SASP synthesized during sporulation protects DNA in spores and later in the germination this protective coat is removal by a novel GPR protease. GPR does not resemble in its structure any other known protein and functionally likely belongs to a novel class of proteases utilizing glutamic acid residue in its catalysis in order to degrade SASP. This process provides amino acids necessary for synthesis of other proteins or enzymes necessary in vegetative state. In addition during the spore creation process energy is stored in the form of 3-phosphoglycerate by downregulating a novel, diphosphoglycerate independent iPGM. These depots of energy are utilized later by the germinating spore in addition to the above source of amino acids. The two above enzymes are inherently involved in the processes of sporulation, spore germination and outgrowth. A combination of structural investigations and site-directed mutagenesis studies that were used to characterize the functional properties and the active sites of these novel proteins will be discussed. The understanding of functional properties of these enzymes contributes to a better understanding of spore-forming organisms.
Bioprocess decision support tool for scalable manufacture of extracellular vesicles (2018)

Newly recognized as natural nanocarriers that deliver biological information between cells, extracellular vesicles (EVs), including exosomes and microvesicles, provide unprecedented therapeutic opportunities. Large-scale and cost-effective manufacturing is imperative for EV products to meet commercial and clinical demands; successful translation requires careful decisions that minimize financial and technological risks. Here, we develop a decision support tool (DST) that computes the most cost-effective technologies for manufacturing EVs at different scales, by examining the costs of goods associated with using published protocols. The DST identifies costs of labor and consumables during EV harvest as key cost drivers, substantiating a need for larger-scale, higher-throughput, and automated technologies for harvesting EVs. Importantly, we highlight a lack of appropriate technologies for meeting clinical demands, and propose a potentially cost-effective solution. This DST can facilitate decision-making very early on in development and be used to predict, and better manage, the risk of process changes when commercializing EV products.
Transcutaneous Auricular Vagus Nerve Stimulation Protects Endotoxemic Rat from Lipopolysaccharide-Induced Inflammation (2012)

Background. Transcutaneous auricular vagus nerve stimulation (ta-VNS) could evoke parasympathetic activities via activating the brainstem autonomic nuclei, similar to the effects that are produced after vagus nerve stimulation (VNS). VNS modulates immune function through activating the cholinergic anti-inflammatory pathway. Methods. VNS, ta-VNS, or transcutaneous electrical acupoint stimulation (TEAS) on ST36 was performed to modulate the inflammatory response. The concentration of serum proinflammatory cytokines and tissue NF-kappa B p65 (NF-κB p65) were detected in endotoxaemia affected anesthetized rats. Results. Similar to the effect of VNS, ta-VNS suppressed the serum proinflammatory cytokines levels, such as tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) as well as NF-kappa B p65 expressions of lung tissues. ST36 stimulation also decreases LPS-induced high TNF-α level and NF-κB signal, but it did not restrain proinflammatory cytokine IL-1β and IL-6. Neither ta-VNS nor ST36 stimulation could suppress LPS-induced TNF-α and NF-κB after vagotomy or with α7nAChR antagonist injection. Conclusions. The present paper demonstrated that ta-VNS could be utilized to suppress LPS-induced inflammatory responses via α7nAChR-mediated cholinergic anti-inflammatory pathway.
TP53Mutation is an Independent Prognostic Marker for Poor Outcome in Both Node-negative and Node-positive Breast Cancer (2000)

TP53 gene-mutation and protein expression of p53 are described as being of prognostic importance for the outcome of breast cancer. The present study was therefore carried out to evaluate whether TP53 mutation would be a feasible prognostic marker in the routine diagnostic evaluation of breast cancer, and, in particular, to analyse the relationship between TP53 mutation and nodal status. Tumour material was obtained from women with sporadic early breast cancer. Gene mutations in exon 2-11 were identified using denaturing gradient gel electrophoresis (DGGE) as the initial scanning procedure and characterized by sequencing. All patients were treated according to the guidelines of the Danish Breast Cancer Cooperative Group for the DBCG 89 protocols. The results were correlated with clinico-pathological parameters and the prognosis evaluated by uni- and multivariate analysis using local control, freedom from distant metastasis, disease-free survival, and overall survival as endpoints. The study included 294 patients. TP53 mutations were found in 23% of cases. Mutations were significantly more frequent in tumours from patients who were node-positive and with tumours characterized as being ductal, large of size, with a high degree of anaplasia, and oestrogen receptor negative. Using univariate analysis, it was found that distant metastasis, disease-free, and overall survival were correlated to tumour size, nodal status, degree of anaplasia, oestrogen receptor status, and TP53 mutation. In addition, overall survival was also correlated to age and menopausal status. When analysed according to nodal status, TP53 mutation was found to have a significantly poor survival probability in each of the subgroups. A Cox proportional hazard analysis, including all 294 patients, demonstrated that positive nodal status and TP53 mutation were the only parameters that had an independent poor influence on the risk of developing distant metastasis and reduced recurrence-free survival. The same factors together with postmenopausal status were found to be significantly associated with increased risk of death. TP53 mutation is a strong marker for the prediction of overall and disease-free survival in breast cancer, irrespective of nodal status. A better understanding of the role of the p53 pathway, including analysis of different types of TP53 mutations, is required in order further to investigate the prognostic potential of this marker.
The Neural Basis of the Psychomotor Vigilance Task (2005)

Optimal performance on the PVT appears to rely on activation both within the sustained attention system and within the motor system. Poor performance following TSD may result from a disengagement from the task and related inattention, and brain regions responsible for this localize within midline structures shown to be involved in the brain's "default mode." Finally, particularly poor performance after TSD may elicit a subsequent attentional recovery that manifests as greater activation within the same regions normally responsible for fast reaction times.