gebhart/patrepeval huggingface dataset:
The Role of Bloom Index of Gelatin on the Interaction with Retinal Pigment Epithelial Cells (2009)

Biocompatible materials are of considerable interest in the development of cell/drug delivery carriers for therapeutic applications. This paper investigates the effects of the Bloom index of gelatin on its interaction with retinal pigment epithelial (RPE) cells. Following two days of culture of ARPE-19 cells with gelatin samples G75-100, G175, and G300, the in vitro biocompatibility was determined by cell proliferation and viability assays, and glutamate uptake measurements, as well as cytokine expression analyses. The mitochondrial dehydrogenase activity in the G300 groups was significantly lower than that of G75-100 and G175 groups. The Live/Dead assays also showed that the gelatin samples G300 induced mild cytotoxicity. In comparison with the treatment of gelatins with low Bloom index, the exposure to high Bloom strength gelatins markedly reduced the glutamate uptake capacity of ARPE-19 cells. One possible explanation for these observations is that the presence of gelatin samples G300 with high viscosity in the medium may affect the nutrient availability to cultured cells. The analyses of pro-inflammatory cytokine IL-6 expression at both mRNA and protein levels showed that the gelatins with low Bloom index caused less cellular inflammatory reaction and had more acceptable biocompatibility than their high Bloom strength counterparts. These findings suggest that the Bloom index gives influence on cellular responses to gelatin materials.
Crystal Structure of <i>Bacillus subtilis</i> α-Amylase in Complex with Acarbose (2003)

The crystal structure of Bacillus subtilis alpha-amylase, in complex with the pseudotetrasaccharide inhibitor acarbose, revealed an hexasaccharide in the active site as a result of transglycosylation. After comparison with the known structure of the catalytic-site mutant complexed with the native substrate maltopentaose, it is suggested that the present structure represents a mimic intermediate in the initial stage of the catalytic process.
Role of Adenosine as Adjunctive Therapy in Acute Myocardial Infarction (2006)

Although early reperfusion and maintained patency is the mainstay therapy for ST elevation myocardial infarction, experimental studies demonstrate that reperfusion per se induces deleterious effects on viable ischemic cells. Thus "myocardial reperfusion injury" may compromise the full potential of reperfusion therapy and may account for unfavorable outcomes in high-risk patients. Although the mechanisms of reperfusion injury are complex and multifactorial, neutrophil-mediated microvascular injury resulting in a progressive decrease in blood flow ("no-reflow" phenomenon) likely plays an important role. Adenosine is an endogenous nucleoside found in large quantities in myocardial and endothelial cells. It activates four well-characterized receptors producing various physiological effects that attenuate many of the proposed mechanisms of reperfusion injury. The cardio-protective effects of adenosine are supported by its role as a mediator of pre- and post-conditioning. In experimental models, administration of adenosine in the peri-reperfusion period results in a marked reduction in infarct size and improvement in ventricular function. The cardioprotective effects in the canine model have a narrow time window with the drug losing its effect following three hours of ischemia. Several small clinical studies have demonstrated that administration of adenosine with reperfusion therapy reduces infarct size and improves ventricular function. In the larger AMISTAD and AMISTAD II trials a 3-h infusion of adenosine as an adjunct to reperfusion resulted in a striking reduction in infarct size (55-65%). Post hoc analysis of AMISTAD II showed that this was associated with significantly improved early and late mortality in patients treated within 3.17 h of symptoms. An intravenous infusion of adenosine for 3 h should be considered as adjunctive therapy in high risk-patients undergoing reperfusion therapy.
Vulnerability of ARID1A deficient cancer cells to pyrimidine synthesis blockade (2020)

ABSTRACT Here we report the discovery and preclinical validation of a novel precision medicine strategy for ARID1A -mutated cancer. Unbiased proteomics reveals for the first time that ARID1A protein (BAF250a) binds aspartate transcarbamoylase (ATCase), a key regulatory enzyme of the de novo pyrimidine synthesis pathway. Using isogenic paired ARID1A proficient/deficient cancer cell lines, we show that ARID1A protein deficiency (as occurs in ARID1A mutant cancers) leads to metabolic reprogramming and pyrimidine synthesis dependency. Pyrimidine synthesis blockade using the FDA-approved drug teriflunomide (a DHODH inhibitor) suppresses tumor growth and selectively induces DNA damage in ARID1A-deficient tumor models. Combining pyrimidine synthesis inhibition with DNA damage repair blockade, using teriflunomide and AZD6738 (an ATR inhibitor), achieves potent synergy and induces sustained tumor regression in ARID1A -mutant ovarian cancer patient-derived xenografts (PDX). These compelling preclinical data support the evaluation of this novel combination treatment in patients with ARID1A -mutated cancers. SIGNIFICANCE We identified that ARID1A-deficient cells are selectively vulnerable to pyrimidine synthesis blockade. Preclinical studies demonstrate the in vivo efficacy of a synergistic drug combination that concurrently inhibits the de novo pyrimidine synthesis pathway and DNA damage repair to induce regression in patient-derived xenograft models of ARID1A-mutated cancer.
Genotypic determination of HIV tropism - clinical and methodological recommendations to guide the therapeutic use of CCR5 antagonists. (2010)

The approval of maraviroc (Selzentri®), the first CCR5 antagonist, with specific antiviral activity against CCR5 (R5)-tropic HIV variants, has promoted the determination of HIV coreceptor usage in the clinical setting. The phenotypic assay Trofile™, which is based on recombinant virus technology, has been the most widely used diagnostic test, given that it was the only assay which provided tropism information in the pivotal maraviroc clinical trials. However, this method displays logistical and technical limitations that make it far from convenient as a diagnostic test in clinical practice. Genotypic methods based on V3 genotyping represent a more feasible alternative and progressively are replacing phenotypic assays. Even though their sensitivity to detect X4-tropic variants is lower compared to Trofile™, recent studies have demonstrated that specific genotypic tools (geno2pheno and PSSM) are comparable to Trofile™ and ES-Trofile™ in predicting virologic response to maraviroc. This review summarizes clinical and methodological recommendations for the genotypic determination of HIV tropism to guide therapeutic decisions with CCR5 antagonists in HIV therapeutics.
Improving Prediction of Protein Secondary Structure Using Structured Neural Networks and Multiple Sequence Alignments (1996)

The prediction of protein secondary structure by use of carefully structured neural networks and multiple sequence alignments has been investigated. Separate networks are used for predicting the three secondary structures alpha-helix, beta-strand, and coil. The networks are designed using a priori knowledge of amino acid properties with respect to the secondary structure and the characteristic periodicity in alpha-helices. Since these single-structure networks all have less than 600 adjustable weights, overfitting is avoided. To obtain a three-state prediction of alpha-helix, beta-strand, or coil, ensembles of single-structure networks are combined with another neural network. This method gives an overall prediction accuracy of 66.3% when using 7-fold cross-validation on a database of 126 nonhomologous globular proteins. Applying the method to multiple sequence alignments of homologous proteins increases the prediction accuracy significantly to 71.3% with corresponding Matthew's correlation coefficients C alpha = 0.59, C beta = 0.52, and Cc = 0.50. More than 72% of the residues in the database are predicted with an accuracy of 80%. It is shown that the network outputs can be interpreted as estimated probabilities of correct prediction, and, therefore, these numbers indicate which residues are predicted with high confidence.
Slow-Binding Inhibition of the Aminopeptidase from <i>Aeromonas</i> <i>proteolytica</i> by Peptide Thiols: Synthesis and Spectroscopic Characterization (1999)

Peptide-derived thiols of the general structure N-mercaptoacyl-leucyl-p-nitroanilide (1a-c) were synthesized and found to be potent, slow-binding inhibitors of the aminopeptidase from Aeromonas proteolytica (AAP). The overall potencies (K(I)) of these inhibitors against AAP range from 2.5 to 57 nM exceeding that of the natural product bestatin and approaching that of amastatin. The corresponding alcohols (2a-b) are simple competitive inhibitors of much lower potencies (K(I) = 23 and 360 microM). These data suggest that the free thiols are involved in the formation of the E. I and E.I complexes, presumably serving as a metal ligand. To investigate the nature of the interaction of the thiol-based inhibitors with the dinuclear active site of AAP, we have recorded electronic absorption and EPR spectra of Co(II)Co(II)-, Co(II)Zn(II)-, and Zn(II)Co(II)-AAP in the presence of the strongest binding inhibitor, 1c. Both [CoZn(AAP)] and [ZnCo(AAP)], in the presence of 1c, exhibited an absorption band centered at 320 nm characteristic of an S --> Co(II) ligand-metal charge-transfer band. In addition, absorption spectra recorded between 400 and 700 nm showed changes characteristic of 1c interacting with each active-site metal ion. EPR spectra recorded at high temperature (19 K) and low power (2.5 mW) indicated that in a given enzyme molecule, 1c interacts weakly with one of the metal ions in the dinuclear site and that the crystallographically identified micro-OH(H) bridge, which has been shown to mediate electronic interaction of the Co(II) ions, is likely broken upon 1c binding. EPR spectra of [CoCo(AAP)]-1c, [ZnCo(AAP)]-1c, and [CoZn(AAP)]-1c were also recorded at lower temperature (3.5-4.0 K) and high microwave power (50-553 mW). The observed signals were unusual and appeared to contain, in addition to the incompletely saturated contributions from the signals characterized at 19 K, a very sharp feature at g(eff) approximately 6.8 that is characteristic of thiolate-Co(II) interactions. These data suggest that the thiolate moiety can bind to either of the metal ions in the dinuclear active site of AAP but does not bridge the dinuclear cluster. Compounds 1a-c are readily accessible by synthesis and thus provide a novel class of potent aminopeptidase inhibitors.
Ultrastructure of the intima in WHHL and cholesterol-fed rabbit aortas prepared by ultra-rapid freezing and freeze-etching. (1989)

Intima from aortas of normal Watanabe Heritable Hyperlipidemic (WHHL) and cholesterol-fed (10 days - 3 months) rabbits were examined by ultra-rapid freezing without chemical fixation followed by rotary shadow freeze-etching. The extracellular matrix in areas devoid of cells was seen in extraordinary detail and consisted of a reticulum of thick filaments, finer branching filaments, collagen fibrils, and granules of varying sizes. No lipid deposits were seen in normal intima. However, the subendothelial region of WHHL intima was filled with collagen fibrils surrounding and entwined between clusters of discrete lipid vesicles that ranged in size from 23 to 169 nm. Approximately 80% of the lipid vesicles in the WHHL rabbit intima measured between 70 and 169 nm. The lipid particles in the WHHL intima always appeared in clusters, many of which appeared to be fusing into larger size vesicles. These aggregates were clearly linked to the matrix filaments. A similar deposition of lipid particles was seen in the extracellular matrix of cholesterol-fed rabbits but in contrast to the particle size distribution of the WHHL intima, more than 75% of the particles in the cholesterol-fed intima had a diameter between 23 and 68 nm and 51% were between 23 and 45 nm. We conclude that in cell-free areas of WHHL and after only 10 days of cholesterol feeding, lipoprotein-derived lipid is present in the intima as clusters of vesicles enmeshed in the complex extracellular matrix.
Direct correlation of 4D seismic with well activity for a clarified dynamic reservoir interpretation (2011)

ABSTRACT A method to provide an improved time‐lapse seismic attribute for dynamic interpretation is presented. This is based on the causal link between the time‐lapse seismic response and well production activity taken over time. The resultant image is obtained by computing correlation coefficients between sequences of time‐lapse seismic changes extracted over different time intervals from multiply repeated seismic and identical time sequences of cumulative fluid volumes produced or injected from the wells. Maps of these cross‐correlations show localized, spatially contiguous signals surrounding individual wells or a specific well group. These may be associated with connected regions around the selected well or well group. Application firstly to a synthetic data set reveals that hydraulic compartments may be delineated using this method. A second application to a field data set provides empirical evidence that a connected well‐centric fault block and active geobody can be detected. It is concluded that uniting well data and time‐lapse seismic using our proposed method delivers a new attribute for dynamic interpretation and potential updating of the model for the producing reservoir.
Cooling and manipulation of a levitated nanoparticle with an optical fiber trap (2015)

Accurate delivery of small targets in high vacuum is a pivotal task in many branches of science and technology. Beyond the different strategies developed for atoms, proteins, macroscopic clusters, and pellets, the manipulation of neutral particles over macroscopic distances still poses a formidable challenge. Here, we report an approach based on a mobile optical trap operated under feedback control that enables cooling and long range 3D manipulation of a silica nanoparticle in high vacuum. We apply this technique to load a single nanoparticle into a high-finesse optical cavity through a load-lock vacuum system. We foresee our scheme to benefit the field of optomechanics with levitating nano-objects as well as ultrasensitive detection and monitoring.
Dihydroartemisinin Potentiates the Cytotoxic Effect of Temozolomide in Rat C6 Glioma Cells (2008)

Gliomas are the most common primary brain tumor in adults, but the efficacy of chemotherapy is limited. Artemisinin and its analogs, such as dihydroartemisinin (DHA), can kill cancer cells via generating free radicals. In the present study, we determined whether DHA at low concentrations potentiates the cytotoxic effect of temozolomide in rat glioma C6 cells. We found that the IC50 values of DHA and temozolomide for cell viability were 23.4 and 560 micromol/l, respectively. The cytotoxic effect of temozolomide was enhanced by 177% at a nontoxic DHA concentration (1 micromol/l), and by 321% at a low-toxic DHA concentration (5 micromol/l). DHA substantially increased temozolomide-induced apoptosis and necrosis. The generation of intracellular reactive oxygen species (ROS) was increased by temozolomide combined with DHA at noneffective concentrations of both agents. Edaravone (20 micromol/l), a ROS scavenger, reversed the effects of temozolomide/DHA on both ROS generation and cell viability reduction. These results indicate that DHA at low concentrations potentiates the cytotoxic effects of temozolomide in C6 cells partly via generating ROS, suggesting a beneficial combination for the chemotherapy of gliomas.
A two-stage sequential linear programming approach to IMRT dose optimization (2010)

The conventional IMRT planning process involves two stages in which the first stage consists of fast but approximate idealized pencil beam dose calculations and dose optimization and the second stage consists of discretization of the intensity maps followed by intensity map segmentation and a more accurate final dose calculation corresponding to physical beam apertures. Consequently, there can be differences between the presumed dose distribution corresponding to pencil beam calculations and optimization and a more accurately computed dose distribution corresponding to beam segments that takes into account collimator-specific effects. IMRT optimization is computationally expensive and has therefore led to the use of heuristic (e.g., simulated annealing and genetic algorithms) approaches that do not encompass a global view of the solution space. We modify the traditional two-stage IMRT optimization process by augmenting the second stage via an accurate Monte Carlo-based kernel-superposition dose calculations corresponding to beam apertures combined with an exact mathematical programming-based sequential optimization approach that uses linear programming (SLP). Our approach was tested on three challenging clinical test cases with multileaf collimator constraints corresponding to two vendors. We compared our approach to the conventional IMRT planning approach, a direct-aperture approach and a segment weight optimization approach. Our results in all three cases indicate that the SLP approach outperformed the other approaches, achieving superior critical structure sparing. Convergence of our approach is also demonstrated. Finally, our approach has also been integrated with a commercial treatment planning system and may be utilized clinically.
A Low Power System-on-Chip with Memory Stacked on Top of Logic (2014)

This work introduces a low-power Cortex-M0+ based computing platform for battery-powered, embedded applications. Voltage stacking is used to save power by recycling charge through a power domain between 0V and Vdd, and a power domain stacked on top of it between Vdd and 2Vdd. The technique enables connecting chips of the future directly to the main power source. This increases the power efficiency and the power density of the power delivery scheme. The needed special circuitry components like level shifters and voltage regulators have been designed and integrated into a standard digital SoC flow to demonstrate that voltage stacking can be used for any digital system. For comparison and also functional purposes, the designed system is reconfigurable between the conventional, high throughput, flat mode where all the power- and ground rails are common, and the low power, stacked mode where the power domains are stacked on top of each other. A 1.44µm2 test chip has been fully designed and is to be fabricated in a 40nm CMOS process to evaluate the concept. Pre tape-out simulations show that the power efficiency of the system improves by 15% from 79.5% in the flat mode to 95% in stacked mode, while running a typical benchmark program in the Cortex-M0+ core at 80MHz clock frequency. The system power density for the same test case improves from 10.5mW/mm2 to 34.9mW/mm2. The research has been carried out at NXP Semiconductors in Eindhoven.
Specific Neurotrophic Factors Support the Survival of Cortical Projection Neurons at Distinct Stages of Development (2001)

Repair of specific neuronal circuitry in the neocortex may be possible via neural precursor transplantation or manipulation of endogenous precursors in situ. These approaches will almost certainly require a detailed understanding of the mechanisms that control survival and differentiation of specific neuronal lineages. Such analysis has been hampered by the overwhelming diversity of neuronal types intermixed in neocortex and the inability to isolate individual lineages. To elucidate stage-specific controls over the survival of individual lineages of cortical neurons, we purified immature callosal projection neurons (CPN) at distinct stages of development from embryonic and postnatal mouse cortex by retrograde fluorescence labeling, followed by fluorescence-activated cell sorting. Purified CPN survive well in culture, acquire stage-specific projection neuron morphologies, and express appropriate neurotransmitters and growth factor receptors. Purified CPN are dependent on exogenous trophic support for survival in a stage-specific manner. Survival of postnatal day 2 (P2) to P3 and P6-P7 CPN is promoted by overlapping but distinct sets of neurotrophic factors, whereas embryonic day 19 CPN show less specificity of dependence on peptide factors. These studies demonstrate for the first time the stage-specific control by peptide growth factors over the survival of a specific cortical neuronal lineage. Such information may be critical for the future goal of directed differentiation of transplanted or endogenous precursors toward cellular repair of complex cortical circuitry.
Streptokinase Treatment of Deep Venous Thrombosis and the Postthrombotic Syndrome (1981)

The conditions of 35 patients with deep venous thrombosis treated with streptokinase were reevaluated after a mean of 29 months with clinical examination, venous plethysmography, foot volumetry, phlebography (28 patients) and femoral vein pressure measurement (24 patients). At follow-up, 25 patients (71%) had symptoms and 22 (63%) had signs of venous insufficiency. Plethysmography was abnormal in 29 patients (83%) and foot volumetry in 25 (72%). Only two (6%) of the patients had normal plethysmography and foot volumetry and were free from symptoms and signs. No leg ulcer or severe postthrombotic syndrome was found. Phlebography showed that no patient had a normal deep venous system. Six of earlier thrombotic iliac veins (38%) and femoral veins 14 (48%), respectively, remained occluded. Increased femoral venous pressure, more pronounced during and after exercise, was found when iliac vein was diseased. Our results emphasize the importance of functional evaluation of the patient with a postthrombotic leg.
Streptozotocin-induced diabetes in rats is associated with impaired metabolic availability of vitamin A (retinol) (1996)

Using streptozotocin-induced diabetic Wistar rats, studies were carried out to examine the metabolic availability of vitamin A in the plasma, liver and the retina of the eye. Control and diabetic rats were fed ad lib. on a semi-purified diet either with or without (basal) vitamin A supplementation, or pair-fed on the basal diet for 4 weeks. Despite the fact that diabetic rats consumed 48% more feed, they had lower plasma concentrations of retinol (P < 0.003). The decrease in plasma retinol concentration was a response to diabetes (or diabetes-induced trauma), since neither pair-feeding (P < 0.01) nor vitamin A supplementation altered this effect (P < 0.05). Furthermore, the hepatic concentrations of the vitamin in these animals remained elevated and this increase was greater in the supplemented diabetic group (P < 0.001). Decreases in 11-cis retinal (a component of rhodopsin) concentrations in the retina were also observed in diabetic animals. The increased hepatic and the decreased plasma and retina vitamin A levels suggest a defect in the transport of the vitamin from the liver.
Revealing common ground (1999)

At the center of an intellectual community, members draw upon their knowledge of shared assumptions to have nuanced discussions about complex ideas. Newcomers to the conversation, who are on the edge of this "interpretive community," do not partake in the common ground necessary to join these discussions and can find themselves in a trapped state. We are designing a new kind of computationally-generated augmentation that jumpstarts the search for meaningful common ground ñ both for people trying to join an established interpretive community, and for people trying to form a new one. This paper discusses the application of this type of augmentation, called the μ -cue, to both face-to-face and on-line communities.