gebhart/patrepeval huggingface dataset:
Refined structure of the FKBP12–rapamycin–FRB ternary complex at 2.2 Å resolution (1999)

The structure of the FKBP12-rapamycin-FRB ternary complex has now been refined at 2.2 A resolution. The cell-cycle arrest agent rapamycin binds FK506-binding protein (FKBP12) and the FKBP12-rapamycin binding (FRB) domain of FKBP12-rapamycin associated protein (FRAP) simultaneously, and the inhibition of FRAP is responsible for rapamycin's biological activity. The conformation of rapamycin in the ternary complex is very similar to that observed in the FKBP12-rapamycin binary complex, with an r.m.s. difference of only 0.30 A. However, a slight (9 degrees ) rotation repositions the FRB-binding face of rapamycin in the ternary complex. There are extensive rapamycin-protein interactions and relatively few interactions between the two protein partners FKBP12 and FRB, these interactions mainly involving residues in the 40s and 80s loops of FKBP12 and alpha1 and alpha4 of FRB. The high-resolution refinement has revealed the crucial role of several buried waters in the formation of the ternary complex.
Identification of unique synergistic drug combinations associated with downexpression of survivin in a preclinical breast cancer model system (2011)

An in-vitro 72-h assay using median effect analysis and curve shift analysis was used to evaluate the utility of potentially clinically useful combinations of agents for synergism or antagonism. Six human breast cancer cell lines, both receptor rich and receptor poor, were studied.Panobinostat (LBH-589), a pan histone deacetylase inhibitor with a multitude of biological effects, exhibits time-dependent synergistic effects in breast cancer cell lines with docetaxel, doxorubicin, or gemcitabine in clinically relevant concentrations. Survivin expression was markedly downregulated in the presence of panobinostat with gemcitabine. Bortezomib, a proteasome inhibitor,markedly enhanced the cytotoxic effects of panobinostat combined with gemcitabine. Panobinostat did not demonstrate universal enhancement of cytotoxic drugs,and therefore, synergy was dependent on the second agent selected. No synergy was noted with anti-Her2 agents in Her2 overexpressing cell lines. Metformin combined with panobinostat demonstrated no synergy in this test system. These effects were confirmed by an apoptosis assay and caspase-3 production. A positive drug interaction was identified. The triplet of panobinostat with either doxorubicin/carboplatin or gemcitabine/carboplatin was especially potent in all cell lines. As all these agents are clinically available, further studies of the potent combinations are warranted.
Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. (1996)

Acquired hypogonadism is being increasingly recognized in adult men. However, the effects of long term testosterone replacement on bone density and body composition are largely unknown. We investigated 36 adult men with acquired hypogonadism (age, 22-69 yr; median, 58 yr), including 29 men with central hypogonadism and 7 men with primary hypogonadism, and 44 age-matched eugonadal controls. Baseline evaluation included body composition analysis by bioimpedance, determination of site-specific adipose area by dual energy quantitative computed tomography scan (QCT) of the lumbar spine, and measurements of spinal bone mineral density (BMD) using dual energy x-ray absortiometry, spinal trabecular BMD with QCT, and radial BMD with single photon absorptiometry. Percent body fat was significantly greater in the hypogonadal men compared to eugonadal men (mean +/- SEM, 26.4 +/- 1.1% vs. 19.2 +/- 0.8%; P < 0.01). The mean trabecular BMD determined by QCT for the hypogonadal men was 115 +/- 6 mg K2HPO4/cc. Spinal BMD was significantly lower than that in eugonadal controls (1.006 +/- 0.024 vs. 1.109 +/- 0.028 g/cm2; P = 0.02, respectively). Radial BMD was similar in both groups. Testosterone enanthate therapy was initiated in 29 hypogonadal men at a dose of 100 mg/week, and the subjects were evaluated at 6-month intervals for 18 months. During testosterone therapy, the percent body fat decreased 14 +/- 4% (P < 0.001). There was a 13 +/- 4% decrease in subcutaneous fat (P < 0.01) and a 7 +/- 2% increase in lean muscle mass (P = 0.01) during testosterone therapy. Spinal BMD and trabecular BMD increased by 5 +/- 1% (P < 0.001) and 14 +/- 3% (P < 0.001), respectively. Radial BMD did not change. Serum bone-specific alkaline phosphatase and urinary deoxypyridinoline excretion, markers of bone formation and resorption, respectively, decreased significantly over the 18 months (P = 0.003 and P = 0.04, respectively). We conclude that testosterone therapy given to adult men with acquired hypogonadism decreases sc fat and increases lean muscle mass. In addition, testosterone therapy reduces bone remodeling and increases trabecular bone density. The beneficial effects of androgen administration on body composition and bone density may provide additional indications for testosterone therapy in hypogonadal men.
What We Mean When We Say "What's the Dollar of Mexico?": Prototypes and Mapping in Concept Space (2010)

We assume that the brain is some kind of a computer and look at operations implied by the figurative use of language. Figurative language is pervasive, bypasses the literal meaning of what is said and is interpreted metaphorically or by analogy. Such an interpretation calls for a mapping in concept space, leading us to speculate about the nature of concept space in terms of readily computable mappings. We find that mappings of the appropriate kind are possible in high-dimensional spaces and demonstrate them with the simplest such space, namely, where the dimensions are binary. Two operations on binary vectors, one akin to addition and the other akin to multiplication, allow new representations to be composed from existing ones, and the ``multiplication'' operation is also suited for the mapping. The properties of high-dimensional spaces have been shown elsewhere to correspond to cognitive phenomena such as memory recall. The present ideas further suggest the suitability of high-dimensional representation for cognitive modeling.
Siderurgia româneasca în perspectiva aderarii la UE (2004)

The paper presents the analysis of the Romanian steel sector. The aim is to emphasize the steel industry perspectives, now, when the Romanian integration within EU is near. Steel industry keeps on being a strategic sector of any industrialized country. Romania's integration within EU means a major challenge for the national steel industry. Although, at present time, most part of Romanian steel enterprises are private-owned, the role of the state in future evolution of this sector is not negligible.
Astrocytes Modulate Neural Network Activity by Ca 2+ -Dependent Uptake of Extracellular K + (2012)

Astrocytes are electrically nonexcitable cells that display increases in cytosolic calcium ion (Ca²+) in response to various neurotransmitters and neuromodulators. However, the physiological role of astrocytic Ca²+ signaling remains controversial. We show here that astrocytic Ca²+ signaling ex vivo and in vivo stimulated the Na+,K+-ATPase (Na+- and K+-dependent adenosine triphosphatase), leading to a transient decrease in the extracellular potassium ion (K+) concentration. This in turn led to neuronal hyperpolarization and suppressed baseline excitatory synaptic activity, detected as a reduced frequency of excitatory postsynaptic currents. Synaptic failures decreased in parallel, leading to an increase in synaptic fidelity. The net result was that astrocytes, through active uptake of K+, improved the signal-to-noise ratio of synaptic transmission. Active control of the extracellular K+ concentration thus provides astrocytes with a simple yet powerful mechanism to rapidly modulate network activity.
Production Forecast after Hydraulic Fracturing in Naturally Fractured Reservoirs: Coupling a Complex Fracturing Simulator and a Semi-Analytical Production Model (2012)

Abstract The growing interest in exploiting shale resources is generating new technologies in fracture modeling and reservoir simulation. In the presence of pre-existing natural fractures, hydraulic fracture propagation and proppant distribution can be very complex. Developing the tools to understand fracture propagation and its link to production in shale reservoirs is one of the major technological challenges that the industry is facing today. These challenges are being addressed with new hydraulic fracture simulators and production models for complex hydraulic fracture networks in shale reservoirs. However, the coupling between these two technologies is not mature yet. This paper presents a simple automated workflow from simulating hydraulic fracture propagation in naturally fractured reservoirs to the subsequent production. This work documents the coupling of an existing complex fracturing simulator with a new production model. The complex fracture model considers interactions with natural fractures, stress shadow effects and proppant placement. The production model is based on a semi-analytical approach applied to the discrete hydraulic fracture network. The analytical solution used to simulate the flow from the matrix into the fracture network is simple and well known, but it relies on the assumption of constant pressure in the fracture which can only be obtained with infinite fracture conductivity. An original feature of this model is an algorithm to extend the validity of the analytical solution to all fracture conductivities, by calculating a local "time delay" based on mass balance. The validity of this approach is illustrated by a comparison with results from a standard reservoir simulator. The simple automated workflow that combines the two simulators gives the opportunity to investigate the relation between production and fracture treatment design in naturally fractured reservoirs. This paper illustrates the application of the workflow to realistic cases and the sensitivity of several design parameters that affect well performance.
Optimumin vitroexpansion of human antigen-specific CD8+ T cells for adoptive transfer therapy (2005)

Increasing evidence suggests that adoptive transfer of antigen-specific CD8(+) T cells could represent an effective strategy in the fight against chronic viral infections and malignancies such as melanoma. None the less, a major limitation in the implementation of such therapy resides in the difficulties associated with achieving rapid and efficient expansion of functional T cells in culture necessary to obtain the large numbers required for intravenous infusion. Recently, the critical role of the cytokines interleukin (IL)-2, IL-7 and IL-15 in driving T cell proliferation has been emphasized, thus suggesting their use in the optimization of expansion protocols. We have used major histocompatibility complex (MHC) class I/peptide multimers to monitor the expansion of antigen-specific CD8 T lymphocytes from whole blood, exploring the effect of antigenic peptide dose, IL-2, IL-7 and IL-15 concentrations on the magnitude and functional characteristics of the antigen-specific CD8(+) T cells generated. We show here that significant expansions of antigen-specific T cells, up to 50% of the CD8(+) T cell population, can be obtained after a single round of antigen/cytokine (IL-2 or IL-15) stimulation, and that these cells display good cytolytic and interferon (IFN)-gamma secretion capabilities. Our results provide an important basis for the rapid in vitro expansion of autologous T cells from the circulating lymphocyte pool using a simple procedure, which is necessary for the development of adoptive transfer therapies.
Biological Relevance of Tissue Liquidity and Viscoelasticity (2004)

An emerging theme in developmental biology is the interplay of genetic and generic (i.e. physical) mechanisms[2, 15]. As the embryo grows its cells progressively organize into tissues with vastly differing physical properties extending from liquid (e.g. blood) to solid (e.g. bone). In more biological terms, different tissues are the consequence of cell differentiation. It is the particular differentiated state that gives rise to the specific physical-material properties of the cell. On the other hand the emerging physical characteristics feed back into development and restrict its outcomes[2].The embryonic state is particularly convenient for the study of this interplay because at this stage the organism is in a state of constant change involving active cell movement, it has not yet rigidified into more or less permanent structures and thus the effects of physical processes are more conspicuous.
Formation of Bimolecular Membranes from Lipid Monolayers and a Study of Their Electrical Properties (1972)

Bimolecular membranes are formed from two lipid monolayers at an air-water interface by the apposition of their hydrocarbon chains when an aperture in a Teflon partition separating two aqueous phases is lowered through the interface. Formation of the membrane is monitored by an increase of the electrical capacity, as measured with a voltage clamp. Electrical resistance of the unmodified membrane is analogous to that of conventional planar bilayers (black lipid membranes) prepared in the presence of a hydrocarbon solvent, i.e., 10(6)-10(8) ohm cm(2); the resistance can be lowered to values of 10(3) ohm cm(2) by gramicidin, an antibiotic that modifies the conductance only when the membranes are of biomolecular thickness. In contrast to the resistance, there is a significant difference between the capacity of bilayers made from mono-layers and that of hydrocarbon-containing bilayers made by phase transition; the average values are 0.9 and 0.45 muF cm(-2), respectively. The value of 0.9 muF cm(-2) approximates that of biological membranes. Assuming a dielectric constant of 2.1 for the hydrocarbon region, the dielectric thickness, as calculated from a capacity of 0.9 muF cm(-2), is 22 A. This value is 6-10 A smaller than the actual thickness of the hydrocarbon region of bilayers and cell membranes, as determined by x-ray diffraction. The difference may be due to a limited penetration of water into the hydrocarbon region near the ester groups that would lower the electrical resistance of this region and reduce the dielectric thickness. Asymmetric membranes have been formed by adjoining two lipid monolayers of different chemical composition.
Acquired Ultrastructural Alterations of Respiratory Cilia and Clinical Disease (1988)

Efficient cleansing of the upper and lower respiratory surfaces by the mucociliary apparatus is essential to health. Failure of the cleansing allows contaminants prolonged residence on the mucosal respiratory surfaces and thus penetration into the mucosa and possibly inauguration of disease. For some years, genetic ultrastructural ciliary alterations have been recognized, with symptoms dating from early life. It is only in recent years, however, that evidence has shown that ultrastructural ciliary alterations can be acquired later in life and that these alterations in turn lead to a deterioration of efficient ciliary cleansing. A discussion of the ultrastructure of the normal mammalian cilium will be given, as well as a listing of the genetic ciliary disease and their characteristic morphologic alterations. A more complete review will be made in regard to acquired ciliary defects, their cause, the ultrastructural changes, and the relation to clinical disease.
Atomic Structure of Salutaridine Reductase from the Opium Poppy (Papaver somniferum) (2010)

The opium poppy (Papaver somniferum L.) is one of the oldest known medicinal plants. In the biosynthetic pathway for morphine and codeine, salutaridine is reduced to salutaridinol by salutaridine reductase (SalR; EC 1.1.1.248) using NADPH as coenzyme. Here, we report the atomic structure of SalR to a resolution of ∼1.9 Å in the presence of NADPH. The core structure is highly homologous to other members of the short chain dehydrogenase/reductase family. The major difference is that the nicotinamide moiety and the substrate-binding pocket are covered by a loop (residues 265-279), on top of which lies a large "flap"-like domain (residues 105-140). This configuration appears to be a combination of the two common structural themes found in other members of the short chain dehydrogenase/reductase family. Previous modeling studies suggested that substrate inhibition is due to mutually exclusive productive and nonproductive modes of substrate binding in the active site. This model was tested via site-directed mutagenesis, and a number of these mutations abrogated substrate inhibition. However, the atomic structure of SalR shows that these mutated residues are instead distributed over a wide area of the enzyme, and many are not in the active site. To explain how residues distal to the active site might affect catalysis, a model is presented whereby SalR may undergo significant conformational changes during catalytic turnover.
A Metal-Chelating Pluronic for Immobilization of Histidine-Tagged Proteins at Interfaces:  Immobilization of Firefly Luciferase on Polystyrene Beads (1998)

Pluronic is a surface-active poly(ethylene oxide)−poly(propylene oxide)−poly(ethylene oxide) (PEO−PPO−PEO) triblock copolymer. The PEO chains of the triblock form a hydrophilic, protein-repelling interface at hydrophobic surfaces. The protein-repelling property of Pluronic surfactants was used as an activity-preserving foundation on which to develop a scheme for specific protein immobilization at hydrophobic interfaces through immobilized metal affinity. A nitrilotriacetic acid (NTA) group was coupled to the terminal hydroxyl groups of the PEO chains of Pluronic F108 to create a metal-chelating Pluronic (F108-NTA). Recombinant firefly luciferase (FFL) with C-terminal histidine tags was used as a test protein. Histidine-tagged FFL adsorbed strongly to untreated polystyrene beads but retained much less than 1% of its bioluminescence activity. An equivalent amount of histidine-tagged FFL bound to polystyrene beads treated with the chelating Pluronic, but only in the presence of Ni2+ ions. The firefly luciferase immobilized on the chelating Pluronic retained at least 93% of its bioluminescence activity. The results demonstrate that the chelating Pluronic is a simple and versatile reagent for specific, oriented immobilization of histidine-tagged proteins on hydrophobic interfaces.
Privacy-preserving remote diagnostics (2007)

We present an efficient protocol for privacy-preserving evaluation of diagnostic programs, represented as binary decision trees or branching programs. The protocol applies a branching diagnostic program with classification labels in the leaves to the user's attribute vector. The user learns only the label assigned by the program to his vector; the diagnostic program itself remains secret. The program's owner does not learn anything. Our construction is significantly more efficient than those obtained by direct application of generic secure multi-party computation techniques.
Real-Time Optical Hough Transform for Industrial Inspection (1990)

We describe a real-time optical Hough transform (HT) inspection system and show quantitative inspection results using an industrial inspection application. The HT architecture uses an electronically addressed liquid crystal television (LCTV) as the real-time spatial light modulator, a novel selective edge-enhancement filtering technique, and realizes multiple slices of the HT with a computer generated hologram. The industrial case study of the inspection of cigarette packages is used to benchmark the HT processor. A test set of 100 packages is presented to the processor to qualify its effectiveness. The statistical significance of these finite test set results is also examined.
Effect of siRNA-mediated knockdown of eIF3c gene on survival of colon cancer cells (2013)

Eukaryotic initiation factor subunit c (eIF3c) has been identified as an oncogene that is over-expressed in tumor cells and, therefore, is a potential therapeutic target for gene-based cancer treatment. This study was focused on investigating the effect of small interfering RNA (siRNA)-mediated eIF3c gene knockdown on colon cancer cell survival. The eIF3c gene was observed to be highly expressed in colon cancer cell models. The expression levels of the gene in eIF3c siRNA infected and control siRNA infected cells were compared via real-time polymerase chain reaction (PCR) and western blotting analysis. Cell proliferation levels were analyzed employing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. Furthermore, the effects of eIF3c gene knockdown on the cell cycle and apoptosis were analyzed using flow cytometry. The results showed that suppression of eIF3c expression significantly (P<0.001) reduced cell proliferation and colony formation of RKO colon cancer cells. The cell cycle was arrested by decreasing the number of cells entering S phase. Further, apoptosis was induced as a result of eIF3c knockdown. Collectively, eIF3c deletion effectively reduced the survival of colon cancer cells and could be used as a therapeutic tool for colon cancer therapy.
Fibroblast and neutrophil collagenases cleave at two sites in the cartilage aggrecan interglobular domain (1993)

The actions of recombinant human fibroblast collagenase (MMP1), purified polymorphonuclear leucocyte collagenase (MMP8) and their N-terminal catalytic domain fragments against cartilage aggrecan and an aggrecan G1-G2 fragment have been investigated in vitro. After activation with recombinant human stromelysin and typsin, both collagenases were able to degrade human and porcine aggrecans to a similar extent. An N-terminal G1-G2 fragment (150 kDa) was used to identify specific cleavage sites occurring within the proteinase-sensitive interglobular domain between G1 and G2. Two specific sites were found; one at an Asn341-Phe342 bond and another at Asp441-Leu442 (human sequence). This specificity of the collagenases for aggrecan G1-G2 was identical with that of the truncated metalloproteinase matrilysin (MMP7), but different from those of stromelysin (MMP3) and the gelatinases (MMP2 or gelatinase A; MMP9 or gelatinase B) which cleave at the Asn-Phe site, but not the Asp-Leu site. In addition, collagenase catalytic fragments lacking C-terminal hemopexin-like domains were tested and shown to exhibit the same specificities for the G1-G2 fragment as the full-length enzymes. Thus the specificity of the collagenases for cartilage aggrecan was not influenced by the presence or absence of the C-terminal domain. Together with our previous findings, the results show that stromelysin-1, matrilysin, gelatinases A and B and fibroblast and neutrophil collagenases cleave at a common, preferred site in the aggrecan interglobular domain, and additionally that both fibroblast and neutrophil collagenases cleave at a second site in the interglobular domain that is not available to stromelysin or gelatinases.
fMRI Evidence for a Dual Process Account of the Speed-Accuracy Tradeoff in Decision-Making (2008)

The speed and accuracy of decision-making have a well-known trading relationship: hasty decisions are more prone to errors while careful, accurate judgments take more time. Despite the pervasiveness of this speed-accuracy tradeoff (SAT) in decision-making, its neural basis is still unknown.
El pont de la Reforma (Manresa) (1993)

EL PONTEl projecte de construcci d'un pont entre I'estaci i la Reforma en els rimers anys 40 venia ja d'a E ans.L'article no en qestiona la necessitat, sin I'oportvnitat d'un proiecte farcit del monumentalisme feixista en un mornent en que les rioritats de la ciutat enmig de midria de la postguerra eren molt ms rimaries.L'analisi de P 'abast del projecte i de I'estil que el caracteritza corrobora la seva adscripci en I'exaltaci propia del nacionalcatolicisme, el seu fi propagandistic, i el fracas d'uns resultats qualificats de bunyol per molts ciutadans de I'epoca.