gebhart/patrepeval huggingface dataset:
Effects of new 17α-hydroxylase/C17,20-lyase inhibitors on LNCaP prostate cancer cell growth in vitro and in vivo (1999)

Our laboratory has been developing new inhibitors of a key regulatory enzyme of testicular and adrenal androgen synthesis 17alpha-hydroxylase/C(17,20)-lyase (P450c17), with the aim of improving prostate cancer treatment. We designed and evaluated two groups of azolyl steroids: delta5-non-competitive inhibitors (delta5NCIs), VN/63-1, VN/85-1, VN/87-1 and their corresponding delta4 derivatives (delta4NCIs), VN/107-1, VN/108-1 and VN/109-1. The human P450c17 gene was transfected into LNCaP human prostate cancer cells, and the resultant LNCaP-CYP17 cells were utilized to evaluate the inhibitory potency of the new azolyl steroids. VN/85-1 and VN/108-1 had the lowest IC50 values of 1.25 +/- 0.44 nM and 2.96 +/- 0.78 nM respectively, which are much lower than that of the known P450 inhibitor ketoconazole (80.7 +/- 1.8 nM). To determine whether the compounds had direct actions on proliferation of wild-type LNCaP cells, cell growth studies were performed. All of the delta5NCIs and VN/108-1 blocked the growth-stimulating effects of androgens. In steroid-free media, the delta5NCIs decreased the proliferation of LNCaP cells by 35-40%, while all of the delta4NCIs stimulated LNCaP cells growth 1.5- to 2-fold. In androgen receptor (AR) binding studies, carried out to determine the mechanism of this effect, all of the delta4NCIs (5 microM) displaced 77-82% of synthetic androgen R1881 (5 nM) from the LNCaP AR. The anti-androgen flutamide and the delta5NCIs displaced 53% and 32-51% of R1881 bound to AR respectively. These results suggested that the delta5NCIs may also be acting as anti-androgens. We further evaluated our inhibitors in male severe combined immunodeficient mice bearing LNCaP tumour xenografts. In this model VN/85-1 was as effective as finasteride at inhibiting tumor growth (26% and 28% inhibition, respectively) and the inhibitory effect of VN/87-1 was similar to that of castration (33% and 36% inhibition respectively). These results suggest that VN/85-1 and VN/87-1 may be potential candidates for treatment of prostate cancer.
[Effect of Endotoxin on the expression of peroxisome proliferator-activated receptor alpha in the development of nonalcoholic steatohepatitis in rats]. (2005)

Endotoxemia can enhance hepatocellular steatosis and lead to NASH due to its downregulating the expression of PPARa mRNA.
Genome-wide RNAi screen reveals a specific sensitivity of IRES-containing RNA viruses to host translation inhibition (2005)

The widespread class of RNA viruses that utilize internal ribosome entry sites (IRESs) for translation include poliovirus and Hepatitis C virus. To identify host factors required for IRES-dependent translation and viral replication, we performed a genome-wide RNAi screen in Drosophila cells infected with Drosophila C virus (DCV). We identified 66 ribosomal proteins that, when depleted, specifically inhibit DCV growth, but not a non-IRES-containing RNA virus. Moreover, treatment of flies with a translation inhibitor is protective in vivo. Finally, this increased sensitivity to ribosome levels also holds true for poliovirus infection of human cells, demonstrating the generality of these findings.
mTOR signaling: PLD takes center stage (2008)

The mammalian target of rapamycin (mTOR) assembles a signaling network that transduces nutrient signals and various other stimuli to regulate a wide range of cellular functions. Of the two distinct mTOR complexes, mTORC1 is under the control of the TSC-Rheb pathway, which serves as an integrator of multiple upstream signals. A lipid signaling cascade involving phospholipase D (PLD) and phosphatidic acid (PA) has also been known to mediate mitogenic signals upstream of mTORC1. A new study now reveals a direct connection between these two regulatory pathways and demonstrates that PLD1 is an effector of Rheb in the activation of mTORC1. A novel role of PLD as a nutrient sensor has also been suggested. In this extra-view, we discuss the emerging importance of PA and PLD in the mTORC1 signaling network and the biological processes it governs. We also consider the implications from several recent findings and propose mechanistic models of PLD-mTOR signaling to be tested in the near future.
The effects of processing conditions on polymer photovoltaic device performance (2004)

We will discuss recent results for the NREL polymer photovoltaics group. The work reported here explores the impact of polymer morphology on the physics and performance of polymer-based photovoltaic devices. By varying both the annealing temperatures and the solvent used for polymer deposition, we can alter the polymer chain morphology, thus shifting the absorption onset and shape and improving the charge transport properties of the resulting devices. The higher degree of order in the films results in increased photovoltaic performance.
Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models (2004)

Curcumin is a polyphenolic diketone from turmeric. Because of its anti-oxidant and anti-inflammatory effects, it was tested in animal models of Alzheimer's disease, reducing levels of amyloid and oxidized proteins and preventing cognitive deficits. An alternative mechanism of these effects is metal chelation, which may reduce amyloid aggregation or oxidative neurotoxicity. Metals can induce Abeta aggregation and toxicity, and are concentrated in AD brain. Chelators desferrioxamine and clioquinol have exhibited anti-AD effects. Using spectrophotometry, we quantified curcumin affinity for copper, zinc, and iron ions. Zn2+ showed little binding, but each Cu2+ or Fe2+ ion appeared to bind at least two curcumin molecules. The interaction of curcumin with copper reached half-maximum at approximately 3-12 microM copper and exhibited positive cooperativity, with Kd1 approximately 10-60 microM and Kd2 approximately 1.3 microM (for binding of the first and second curcumin molecules, respectively). Curcumin-iron interaction reached half-maximum at approximately 2.5-5 microM iron and exhibited negative cooperativity, with Kd1 approximately 0.5-1.6 microM and Kd2 approximately 50-100 microM. Curcumin and its metabolites can attain these levels in vivo, suggesting physiological relevance. Since curcumin more readily binds the redox-active metals iron and copper than redox-inactive zinc, curcumin might exert a net protective effect against Abeta toxicity or might suppress inflammatory damage by preventing metal induction of NF-kappaB.
Tapping-mode tuning fork force sensing for near-field scanning optical microscopy (1998)

A tapping-mode tuning fork force-sensing method for near-field scanning optical microscope is reported. Use of the tapping-mode tuning fork with mechanically asymmetric excitation generates better stability and sensitivity than in the shear force mode. Comparison of force curves for the two methods demonstrate that the tapping-mode tuning fork method provides a simpler and more sensitive method for near-field measurements. The method is demonstrated by imaging a sample consisting of 500 nm standard polystyrene spheres on silica in both air and water.
Diet and colorectal adenomas: A case‐control study in majorca (1993)

A case-control study on dietary factors and colorectal adenomas was conducted in the island of Majorca, Spain, from April 1987 to February 1990. Subjects were interviewed using a food frequency questionnaire. Nutrient and caloric intake was estimated using local food composition tables. The risk of colorectal adenomas was related to the consumption of sugar and pastries. Consumption of vegetables was highly protective, irrespective of the cooking procedures. Analyses by nutrients identified as protective factors fiber from fruits and vegetables, magnesium and zinc, and vitamins C, B6 and folic acid. No excess risk was found for alcohol drinking, intake of saturated fats or animal protein. Of the non-dietary factors, sedentariness in the work-place and urban residence were the only risk factors identified.
Trafficking of Porin-Deficient Salmonella typhimurium Mutants inside HeLa Cells: ompR and envZ Mutants Are Defective for the Formation of Salmonella -Induced Filaments (1998)

Outer membrane porin genes of Salmonella typhimurium, including ompC, ompF, and tppB, are regulated by the products of ompB, a two-component regulatory locus encoding OmpR and EnvZ. S. typhimurium ompR mutants are attenuated in mice, but to date no one has studied the intracellular trafficking of S. typhimurium porin-deficient mutants. In this study, isogenic transposon mutants of S. typhimurium with insertions in ompR, envZ, ompF, ompC, ompD, osmZ, and tppB were compared with wild-type SL1344 for trafficking in the human epithelial cell line HeLa. We found that ompR and envZ mutants were reduced or completely inhibited for the formation of Salmonella-induced filaments (Sifs). This result was confirmed with an ompB deletion mutant. Sifs are tubular structures containing lysosomal glycoprotein which are induced specifically by intracellular Salmonella. Genetic analysis showed that the ompR mutation could be complemented in trans by cloned ompR to restore its ability to induce Sifs. In contrast, mutations in the known ompR-regulated genes ompF, ompC, and tppB (as well as the ompR-independent porin gene, ompD) had no effect on Sif formation relative to that of wild-type SL1344, thus indicating that OmpR does not exert its role on these genes to induce Sif formation. The omp mutants studied were able to invade and replicate in HeLa cells at levels comparable to those in wild-type SL1344. We conclude that OmpR and EnvZ appear to regulate Sif formation triggered by intracellular S. typhimurium.
Discovery of Vibegron: A Potent and Selective β3Adrenergic Receptor Agonist for the Treatment of Overactive Bladder (2015)

The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.
Expression and Function of the Leucine Zipper Protein Par-4 in Apoptosis (1997)

The prostate apoptosis response-4 (par-4) gene was identified by differential screening for genes that are upregulated when prostate cancer cells are induced to undergo apoptosis. The par-4 gene is induced by apoptotic signals but not by growth-arresting, necrotic, or growth-stimulatory signals. The deduced amino acid sequence of par-4 predicts a protein with a leucine zipper domain at its carboxy terminus. We have recently shown that the Par-4 protein binds, via its leucine zipper domain, to the zinc finger domain of Wilms' tumor protein WT1 (R. W. Johnstone et al., Mol. Cell. Biol. 16:6945-6956, 1996). In experiments aimed at determining the functional role of par-4 in apoptosis, an antisense par-4 oligomer abrogated par-4 expression and activator-driven apoptosis in rat prostate cancer cell line AT-3, suggesting that par-4 is required for apoptosis in these cells. Consistent with a functional role for par-4 in apoptosis, ectopic overexpression of par-4 in prostate cancer cell line PC-3 and melanoma cell line A375-C6 conferred supersensitivity to apoptotic stimuli. Transfection studies with deletion mutants of Par-4 revealed that full-length Par-4, but not mutants that lacked the leucine zipper domain of Par-4, conferred enhanced sensitivity to apoptotic stimuli. Most importantly, ectopic coexpression of the leucine zipper domain of Par-4 inhibited the ability of Par-4 to enhance apoptosis. Finally, ectopic expression of WT1 attenuated apoptosis, and coexpression of Par-4 but not a leucine zipperless mutant of Par-4 rescued the cells from the antiapoptotic effect of WT1. These findings suggest that the leucine zipper domain is required for the Par-4 protein to function in apoptosis.
Traction stress in focal adhesions correlates biphasically with actin retrograde flow speed (2008)

How focal adhesions (FAs) convert retrograde filamentous actin (F-actin) flow into traction stress on the extracellular matrix to drive cell migration is unknown. Using combined traction force and fluorescent speckle microscopy, we observed a robust biphasic relationship between F-actin speed and traction force. F-actin speed is inversely related to traction stress near the cell edge where FAs are formed and F-actin motion is rapid. In contrast, larger FAs where the F-actin speed is low are marked by a direct relationship between F-actin speed and traction stress. We found that the biphasic switch is determined by a threshold F-actin speed of 8-10 nm/s, independent of changes in FA protein density, age, stress magnitude, assembly/disassembly status, or subcellular position induced by pleiotropic perturbations to Rho family guanosine triphosphatase signaling and myosin II activity. Thus, F-actin speed is a fundamental regulator of traction force at FAs during cell migration.
Scaffold mesh size affects the osteoblastic differentiation of seeded marrow stromal cells cultured in a flow perfusion bioreactor (2005)

In this study, we cultured marrow stromal cells on titanium fiber meshes in a flow perfusion bioreactor and examined the effect of altering scaffold mesh size on cell behavior in an effort to develop a bone tissue construct composed of a scaffold, osteogenic cells, and extracellular matrix. Scaffolds of differing mesh size, that is, distance between fibers, were created by altering the diameter of the mesh fibers (20 or 40 microm) while maintaining a constant porosity. These scaffolds had a porosity of 80% and mesh sizes of 65 microm (20-microm fibers) or 119 microm (40-microm fibers). Cell/scaffold constructs were grown in static culture or under flow for up to 16 days and assayed for osteoblastic differentiation. Cellularity was higher at early time points and Ca2+ deposition was higher at later time points for flow constructs over static controls. The 20-microm mesh had reduced cellularity in static culture. Under flow conditions, mass transport limitations are mitigated allowing uniform cell growth throughout the scaffold, and there was no difference in cellularity between mesh types. There was greater alkaline phosphatase (ALP) activity, osteopontin levels, and calcium under flow at 8 days for the 40-microm mesh compared to the 20-microm mesh. However, by day 16, the trend was reversed, suggesting the time course of differentiation was dependent on scaffold mesh size under flow conditions. However, this dependence was not linear with respect to time; larger mesh size was conducive to early osteoblast differentiation while smaller mesh size was conducive to later differentiation and matrix deposition.
Effects of alternate RNA splicing on glucokinase isoform activities in the pancreatic islet, liver, and pituitary. (1991)

Different glucokinase isoforms are produced by tissue-specific alternative RNA splicing in the liver and pancreatic islet, the only tissues in which glucokinase activity has been detected. To determine whether differences in protein structure brought about by alternative RNA splicing have an effect on glucose phosphorylating activity, we expressed cDNAs encoding four different hepatic and islet glucokinase isoforms and determined the Km and Vmax of each. When the glucokinase B1 and L1 isoforms were expressed in eukaryotic cells, both high Km glucose phosphorylating activity and immunoreactive protein were detected. However, when the glucokinase B2 and L2 isoforms were expressed, both of which differ by deletion of 17 amino acids in a region between the putative glucose and ATP-binding domains, no high Km glucose phosphorylating activity and much less immunoreactive protein were detected. When the glucokinase B1 and B2 isoforms were expressed in Escherichia coli as fusion proteins with glutathione S-transferase, affinity-purified B1 fusion protein was able to phosphorylate glucose whereas the B2 fusion protein was not, thus indicating that the lack of glucose phosphorylating activity from both the B2 and L2 isoforms is due to lack of intrinsic activity in addition to accumulation of less protein. The Km values of the B1 and L1 isoforms, which differ from each other by 15 amino acids at the NH2 terminus, were similar, but the Vmax of the B1 isoform was 2.8-fold higher than that of the L1 isoform. Mutagenesis of the first two potential initiation codons in the glucokinase B1 cDNA from ATG to GTC (methionine to valine) indicated that the first ATG was crucial for activity and is, therefore, the likely translation initiation codon. Messenger RNAs encoding both the B2 and L2 isoforms of glucokinase were detected in islet and liver by polymerase chain reaction amplification of total cDNA, indicating that mRNAs utilizing this weak alternate splice acceptor site in the fourth exon are normally present in both the liver and islet but as minor components. A regulatory role for weak alternate splice acceptor and donor sites in the glucokinase gene was suggested by examining the expression of the gene in the pituitary and in AtT-20 cells. Interestingly, although glucokinase mRNAs of appropriate sizes were detected in both the AtT-20 cells and rat pituitaries, neither exhibited any detectable high Km glucose phosphorylating activity.(ABSTRACT TRUNCATED AT 400 WORDS)
A robust and scalable microfluidic metering method that allows protein crystal growth by free interface diffusion (2002)

Producing robust and scalable fluid metering in a microfluidic device is a challenging problem. We developed a scheme for metering fluids on the picoliter scale that is scalable to highly integrated parallel architectures and is independent of the properties of the working fluid. We demonstrated the power of this method by fabricating and testing a microfluidic chip for rapid screening of protein crystallization conditions, a major hurdle in structural biology efforts. The chip has 480 active valves and performs 144 parallel reactions, each of which uses only 10 nl of protein sample. The properties of microfluidic mixing allow an efficient kinetic trajectory for crystallization, and the microfluidic device outperforms conventional techniques by detecting more crystallization conditions while using 2 orders of magnitude less protein sample. We demonstrate that diffraction-quality crystals may be grown and harvested from such nanoliter-volume reactions.
Predictors of Systolic Augmentation From Left Ventricular Preexcitation in Patients With Dilated Cardiomyopathy and Intraventricular Conduction Delay (2000)

Twenty-two DCM patients with conduction delay were studied by cardiac catheterization with a dual-sensor micromanometer to measure LV and aortic pressures during sinus rhythm and LV free-wall pacing. Pacing enhanced isovolumetric (dP/dt(max)) and ejection-phase (pulse pressure, PP) systolic function by 35+/-21% and 16.4+/-11%, respectively, and these changes correlated directly (r=0.7, P=0.001). %DeltadP/dt(max) was weakly predicted by baseline QRS (r=0.6, P<0.02), more strongly by baseline dP/dt(max) (r=0.7, P=0.001), and best by bidiscriminate analysis combining baseline dP/dt(max) < or =700 mm Hg/s and QRS > or =155 ms to predict %DeltadP/dt(max) > or =25% and %DeltaPP > or =10% (P<0.0005, chi(2)), with no false-positives. Benefit could not be predicted by %DeltaQRS. To test whether basal mechanical dyssynchrony predicted responsiveness to LV pacing, circumferential strains were determined at approximately 80 sites throughout the LV by tagged MRI in 8 DCM patients and 7 additional control subjects. Strain variance at time of maximal shortening indexed dyssynchrony, averaging 28.0+/-7.1% in normal subjects versus 201.4+/-84.3% in DCM patients (P=0.001). Mechanical dyssynchrony also correlated directly with %DeltadP/dt(max) (r=0.85, P=0.008). Conclusions-These results show that although mechanical dyssynchrony is a key predictor for pacing efficacy in DCM patients with conduction delay, combining information about QRS and basal dP/dt(max) provides an excellent tool to identify maximal responders.
Insoluble Poly [2‐(2′‐ethylhexyloxy)‐5‐methoxy‐1,4‐phenylenevinylene] for Use in Multilayer Light‐Emitting Diodes (1997)

Both soluble and insoluble conjugated polymers have advantages and disadvantages for the construction of light‐emitting diodes (LEDs). A route is reported fo the formation of optical quality films of insoluble (I) MEHPV, a poly(phenylenevinylene) derivative whose soluble form is widely used in single‐layer devices. The incorporation of 1‐MEHPPV into a multilayer device is described, in which the electron‐transport/holeblocking layer was deposited on top of the 1‐MEHPPV layer from a solvent in which the standard soluble MEHPPV should dissolve.
Bone Deformation Recorded in vivo from Strain Gauges Attached to the Human Tibial Shaft (1975)

A strain gauge rosette was attached to the midshaft of a man's tibia. This demonstrated that during every stride the bone surface was subjected to a number of discrete deformation cycles. During each cycle the bone was deformed from a particular direction, released at least partially and then deformed from another direction. This feature has been observed from a number of sites in experimental animals. The largest deformation occurred while the subject was running; the principal tension then reached 850 microstrain applied in line with the bone's long axis at 13 times 10-3 microstrain per second. When walking the largest deformation occurred prior to 'toe off'; compression was then the larger principal strain about minus 400 microstrain applied at 37 degrees to the bone's long axis at minus 4 times 10-3 microstrain per second. These strain values are the same order of size as those recorded from the long bones of sheep and pigs during their locomotion.
Novel sulfobetaine‐sulfonic acid‐contained superswelling hydrogels (2005)

Abstract Novel hydrogels based on zwitterionic monomer [3‐(methacrylamido)propyl] dimethyl (3‐sulfopropyl) ammonium hydroxide (MPDSAH) and a strong acid monomer (2‐acrylamido‐2‐methylpropane sulfonic acid, AMPS) were synthesized through solution polymerization under normal conditions to achieve nearly quantitative gel yield. The structure of the gels was confirmed using infrared spectroscopy. Thermal properties were simultaneously studied by differential scanning calorimetry and thermogravimetric analysis (DSC/TGA). The effects of the polymerization variables on the swelling capacity of the products were investigated. It was found that, in a certain range of the monomers mol ratio, increase of AMPS content was surprisingly accompanied with swelling reduction. The swelling exhibited lower sensitivity to the crosslinker concentration (range 0.6–1.2 wt%) compared with the conventional superabsorbents. However, in contrast with the conventional acrylic acid‐based superabsorbents, the neutralization degree of AMPS part of the new gels had only a small enhancing effect on their swelling capacity. The effect of total monomer concentration on the hydrogel absorbency was also studied. The fully ionic hydrogels showed an unusual pH‐independency behavior, so that their absorbency was nearly unchanged in a wide range of pH. Such unexpected behavior was also observed for the swelling in the ionic environments with various ionic strengths. Copyright © 2005 John Wiley &amp; Sons, Ltd.