gebhart/patrepeval huggingface dataset:
MDM4 inhibition: a novel therapeutic strategy to reactivate p53 in hepatoblastoma (2021)

Hepatoblastoma (HB) is the most common pediatric liver malignancy. High-risk patients have poor survival, and current chemotherapies are associated with significant toxicities. Targeted therapies are needed to improve outcomes and patient quality of life. Most HB cases are TP53 wild-type; therefore, we hypothesized that targeting the p53 regulator Murine double minute 4 (MDM4) to reactivate p53 signaling may show efficacy. MDM4 expression was elevated in HB patient samples, and increased expression was strongly correlated with decreased expression of p53 target genes. Treatment with NSC207895 (XI-006), which inhibits MDM4 expression, or ATSP-7041, a stapled peptide dual inhibitor of MDM2 and MDM4, showed significant cytotoxic and antiproliferative effects in HB cells. Similar phenotypes were seen with short hairpin RNA (shRNA)-mediated inhibition of MDM4. Both NSC207895 and ATSP-7041 caused significant upregulation of p53 targets in HB cells. Knocking-down TP53 with shRNA or overexpressing MDM4 led to resistance to NSC207895-mediated cytotoxicity, suggesting that this phenotype is dependent on the MDM4-p53 axis. MDM4 inhibition also showed efficacy in a murine model of HB with significantly decreased tumor weight and increased apoptosis observed in the treatment group. This study demonstrates that inhibition of MDM4 is efficacious in HB by upregulating p53 tumor suppressor signaling.
Faculty Opinions recommendation of Electrostatic complex of neurotrophin 4 with dendrimer nanoparticles: controlled release of protein in vitro and in vivo. (2019)

Background: NT4 has been regarded as a promising therapeutic protein for treatment of damaged retinal pigment epithelium cells.Purpose: Here, we studied physicochemical parameters of an NT4-polyamidoamine (PAMAM) electrostatic complex, which can provide a sustained concentration of protein in intraocular space over an extended period after delivery.Adsorption/desorption of NT4 molecules to/from positively charged PAMAM dendrimers were precisely determined to control the concentration of bounded/unbounded protein molecules, diffusion coefficient, and size of a protein-laden dendrimer structure.We determined kinetics of NT4 desorption in PBS, vitreous, and damaged retina.Methods: Initially, adsorption of NT4 molecules on PAMAM dendrimers was studied in PBS using dynamic light scattering, electrophoresis, solution depletion, ELISA, and atomic force microscopy.This allowed us precisely to determine desorption of NT4 from nanoparticles under in situ conditions.The maximum coverage of irreversibly adsorbed NT4 determined by ELISA allowed us to devise a robust procedure for preparing stable and well-controlled coverage of NT4 on PAMAM nanoparticles.Thereafter, we studied diffusion of nanospheres containing NT4 molecules by injecting them into vitreous cavities of mice exposed to intravenous injections of sodium iodate and evaluated their intraocular desorption kinetics from drug carriers in vivo.Results: Our measurements revealed NT4-dendrimer nanoparticles can be used for continuous neurotrophic factor delivery, enhancing its distribution into mouse vitreous, as well as damaged retina over 28 days of postinjury observation.Conclusion: Understanding of polyvalent neurotrophin interactions with dendrimer nanoparticles might be useful to obtain well-ordered protein layers, targeting future development of drug-delivery systems, especially for neuroprotection of damaged retinal neurons.
Inosine-5′-Monophosphate Dehydrogenase Is a Rate-determining Factor for p53-dependent Growth Regulation (1998)

We have proposed that reduced activity of inosine-5'-monophosphate dehydrogenase (IMPD; IMP:NAD oxidoreductase, EC 1.2.1.14), the rate-limiting enzyme for guanine nucleotide biosynthesis, in response to wild-type p53 expression, is essential for p53-dependent growth suppression. A gene transfer strategy was used to demonstrate that under physiological conditions constitutive IMPD expression prevents p53-dependent growth suppression. In these studies, expression of bax and waf1, genes implicated in p53-dependent growth suppression in response to DNA damage, remains elevated in response to p53. These findings indicate that under physiological conditions IMPD is a rate-determining factor for p53-dependent growth regulation. In addition, they suggest that the impd gene may be epistatic to bax and waf1 in growth suppression. Because of the role of IMPD in the production and balance of GTP and ATP, essential nucleotides for signal transduction, these results suggest that p53 controls cell division signals by regulating purine ribonucleotide metabolism.
Biodegradation of acyclic isoprenoids by Pseudomonas species (1978)

The ability of various pseudomonads to utilize acyclic isoprenoids as a sole carbon source was investigated. Tests for utilization of acyclic isoprenols such as citronellol and geraniol were complicated by toxic effects of these alcohols, and most species tested were killed by exposure to citronellol or geraniol (0.1%, vol/vol) in liquid culture. In the case of Pseudomonas citronellolis, sensitivity to isoprenols is reduced by prior induction of the isoprenoid degradative pathway via either growth on succinate in the presence of citronellol or growth on citronellic acid. For this species, citronellic acid proved to be the best isoprenoid growth substrate tested. Geraniol utilization as a taxonomic indicator for different subgroups of pseudomonads is discussed. Only a few of the species tested were able to utilize acyclic isoprenoids. Two species which utilize C10 acyclic isoprenoids, P. aeruginosa and P. mendocina, were shown to contain the inducible enzyme geranyl-coenzyme A carboxylase, one of the unique enzymes in the isoprenol degradative pathway known to occur in P. citronellolis. Of the species which utilized geranitol, none showed definite growth on the homologous C15 and C20 isoprenols.
Modeling Ignition Probability for Stratified Flows (2017)

High-energy short-duration spark igniters are common in combustion devices where the discharge often occurs in a nonfueled region. This requires convection between where the spark kernel is created and where combustion can begin. Here, a reduced-order model is developed to study an ignition kernel in conditions similar to a gas turbine combustor. The kernel is generated in air and entrains ambient fluid into the reactor to model such observed fluid dynamics in a parallel set of experiments. Continuous dilution with cold reactants and endothermic fuel decomposition reactions are shown to compete with heat release in the entraining kernel. Simulation results also reveal a pressure influence on the kernel’s initial energy density and entrainment that can exceed the direct dependence of the reaction rates. A Monte Carlo perturbation approach is directly input to simulations, resulting in ignition probabilities that are directly comparable to experimental results. A computationally efficient support vector machine is trained in multiple ways with simulation results and used to quickly classify ignition success. Including the statistical variation of input parameters, the simulated ignition probabilities match the experimental results, indicating the capability of this approach for predicting ignition probability in non-premixed combustors.
VIV on Risers with Top-tensioning Buoyancy-cans. Part 2: Experimental Modelling (2003)

International audience
Improved delivery through biological membranes. 38. Brain-specific chemical delivery systems for .beta.-lactam antibiotics. Synthesis and properties of some dihydropyridine and dihydroisoquinoline derivatives of benzylpenicillin (1989)

Six chemical delivery systems (CDS) were synthesized for benzylpenicillin in order to improve its transport across the blood-brain barrier. The CDS's were based on a dihydropyridine----quaternary pyridinium ion redox system, analogous to the naturally occurring NADH----NAD+ system. Two different types of CDS's were prepared: benzylpenicillin esters of diols in which the other hydroxyl group is esterified by dihydrotrigonelline and benzylpenicillin esters of amino alcohols in which the amine group is acylated by dihydrotrigonelline, or by 1,2-dihydro-2-methyl-4-isoquinolinecarboxylic acid. Lipophilicities of the CDS's were proved to be much higher than those of benzylpenicillin by using Rm values as lipophilicity indexes. Upon oxidation, all of the CDS's gave the quaternary ion forms. Kinetic studies in buffer (pH profiles) indicated that the quaternary salts released benzylpenicillin in pH range of 5-9 via hydrolysis. The CDS's in acidic media yielded as the major reaction product 6-hydroxy-1,4,5,6-tetrahydropyridines as a result of water addition, while in basic conditions benzylpenicillin was released. The water addition reaction was dependent on the CDS's structure, being more prevalent in the case of the "amide-esters". The dihydroisoquinoline CDS was rather stable in the pH range 5-8.
Cation Exchanged Silicate Catalyst for Ethylene Polymerization (1982)

Several cation exchanged-layer silicate catalysts were prepared from acid clay mainly consisted of montmorillonite, and their catalytic activities for the ethylene polymerization were studied at room temperature. It was found that over -Mont, dimerization of ethylene to n-butene proceeded selectively. -Mont was activated by evacuation at elevated temperature, giving a maximum temperature, 150C . The variations in catalytic activities were closely correlated to the acidity of the catalysts. -Mont exhibited a high activity for the polymerization, showing, a maximum at the evacuation temperature of 450. The active site in -Mont was considered to be ion.
Gallium phosphide solar cells for multi-juntion systems (2009)

Gallium Phosphide (GaP) is a good candidate for a high band gap solar cell in a multi-junction solar cell system due to its proper band gap (2.26ev), well developed technology, and high carrier mobility. High energy gap solar cell plays a very important role in multi-junction systems. In this paper, theoretical simulation work has been done for GaP solar cells by PC-1D software. High quality GaP epitaxial layers have been grown on GaP (100) and (111) substrates via liquid phase epitaxial (LPE) method. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) have been used to characterize the surface morphology and quality of the growth layer, respectively. I-V measurement has been used to test the performance of GaP solar cells. The open circuit voltage, which is the most important feature of GaP solar cells, is 1.33V under simulated one sun illumination in our lab.
A high energy, short pulse CO<inf>2</inf>laser system (1973)

A high power, short pulse CO <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> laser system has been constructed for target irradiation and materials damage studies at 10.6 µm. The system consists of a low energy short pulse CO <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> oscillator followed by a series of high gain amplifiers. Output energies of 30 J in a nanosecond pulse have been achieved.
Improving ATR performance by incorporating virtual negative examples (2003)

One common problem in learning from examples is the insufficient size of the training set. Many researchers have proposed methods to counteract this shortcoming, such as the noisy interpolation theory, hints, new distance measure (tangent distance), virtual examples, etc. This paper presents the idea of creating virtual negative examples as severe distortions of the known class patterns. Two classifiers are studied, a perceptron and a support vector machine trained to recognize objects in synthetic aperture radar (SAR) images. They utilize the training set (positive examples) to create the discriminant function of each class in the conventional way. On the other hand, the virtual negative examples will help determine the regions where the discriminant function should yield a low value. The experimental results show that incorporating the negative examples improves greatly (up to 50 percent improvement) the confuser rejection rates.
Microphysiological Modeling of the Structure and Function of Neuromuscular Transmitter Release Sites (2022)

The general mechanism of calcium-triggered chemical transmitter release from neuronal synapses has been intensely studied, is well-known, and highly conserved between species and synapses across the nervous system. However, the structural and functional details within each transmitter release site (or active zone) are difficult to study in living tissue using current experimental approaches owing to the small spatial compartment within the synapse where exocytosis occurs with a very rapid time course. Therefore, computer simulations offer the opportunity to explore these microphysiological environments of the synapse at nanometer spatial scales and on a sub-microsecond timescale. Because biological reactions and physiological processes at synapses occur under conditions where stochastic behavior is dominant, simulation approaches must be driven by such stochastic processes. MCell provides a powerful simulation approach that employs particle-based stochastic simulation tools to study presynaptic processes in realistic and complex (3D) geometries using optimized Monte Carlo algorithms to track finite numbers of molecules as they diffuse and interact in a complex cellular space with other molecules in solution and on surfaces (representing membranes, channels and binding sites). In this review we discuss MCell-based spatially realistic models of the mammalian and frog neuromuscular active zones that were developed to study presynaptic mechanisms that control transmitter release. In particular, these models focus on the role of presynaptic voltage-gated calcium channels, calcium sensors that control the probability of synaptic vesicle fusion, and the effects of action potential waveform shape on presynaptic calcium entry. With the development of these models, they can now be used in the future to predict disease-induced changes to the active zone, and the effects of candidate therapeutic approaches.
Metal Dependence of Oxalate Decarboxylase Activity (2009)

Bacillus subtilis oxalate decarboxylase (OxDC) catalyzes the conversion of oxalate into CO(2) and formate. The enzyme is composed of two cupin domains, each of which contains a Mn(II) ion. Although there is general agreement that Mn(II) in the N-terminal domain mediates OxDC-catalyzed decarboxylation, legitimate questions have been raised concerning the function (if any) of the Mn(II) bound in the C-terminal cupin domain. We have investigated this problem using a series of OxDC mutants in which Mn(II) binding is perturbed by mutagenesis of Glu-101 and Glu-280, which coordinate the metal in the N-terminal and C-terminal domains, respectively. We now demonstrate that decarboxylase activity and total manganese content are sensitive to modifications in either metal-binding glutamate residue. These findings, in combination with EPR measurements, raise the possibility that the C-terminal Mn(II) center can catalyze the decarboxylation reaction. Further support for this conclusion has been provided from a combination of in vivo and in vitro strategies for preparing wild-type OxDC in which Mn(II) is incorporated to a variety of extents. Kinetic characterization of these variants shows that OxDC activity is linearly correlated with manganese content, as might be expected if both sites can catalyze the breakdown of oxalate into formate and CO(2). These studies also represent the first unequivocal demonstration that OxDC activity is uniquely mediated by manganese.
Abstract A35: DNA microarray analysis of the effect of fusarochromanone on human malignant bladder cancer cells. (2011)

Abstract Fusarochromanone (FC-101a) has been identified as a potential, novel anti-cancer compound. Several studies revealed that FC-101a is an inhibitor of many human cancer cell lines, increases apoptosis of melanoma cell lines and significantly reduces tumor growth in mice. The long-term goal of this project is to elucidate how FC-101a inhibits cancer cell growth by identifying its molecular target(s). In this study, we used DNA microarray analysis and realtime PCR to identify genes that are differentially-expressed in response to FC-101a treatment in yeast and human bladder cancer cells. We hypothesize that changes in gene expression in response to FC-101a treatment will elucidate cellular mechanisms by which FC-101a inhibits cancer cell growth. Our study includes human cancer cell lines as a model system and budding yeast as a model organism to identify cellular pathways that are responsive to FC-101a treatment in multiple eukaryotic cell types. In this study, we have determined that among human skin, breast, prostate and bladder cancer cell lines, bladder cancer cells are the most sensitive to FC-101a treatment. Thus, we performed DNA microarray analysis using human bladder carcinoma cells treated with FC-101a for 24, 48 and 72 hours and yeast cells treated with FC-101a for 20 minutes. We identified hundreds of genes that are highly expressed and greater than two-fold up-regulated or down-regulated in FC-101a-treated cells compared with untreated cells. Of these FC-101a-responsive genes common to yeast and human bladder cancer cells, a majority of these genes regulate apoptosis, metabolic pathways, cell cycle progression, DNA replication, cell signaling and DNA recombination and repair. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A35.
Comparative genomic analyses of trace element utilization and evolution (2009)

Trace elements are needed in minute quantities for proper growth, development, and physiology of organisms. Although many trace element‐containing proteins are well characterized, little is known about the global trends in trace element utilization. We carried out comparative genomic analyses to examine occurrence and evolution of the utilization of five trace elements, including copper (Cu), molybdenum (Mo), nickel (Ni), cobalt (Co) and selenium (Se), in more than 700 sequenced prokaryotes and eukaryotes at the level of (i) transport and/or utilization traits, and (ii) trace element‐dependent proteins. Only few organisms were found to utilize all five elements whereas most intracellular symbionts and parasites lacked the ability to use any of them. Cu and Mo were the most frequently used elements in bacteria and archaea, respectively. The presence of metal transporters generally matched the occurrence of corresponding utilization traits. Se utilization was detected in less about 25% prokaryotes, revealing a scattered and reduced usage of this metalloid. In eukaryotes, the utilization of Cu, Mo and Se was found in at least half of sequenced species, whereas that of Ni and Co was limited. Investigation of the metalloproteomes and selenoproteomes suggested increased utilization of trace elements in some organisms. Finally, environmental factors appeared to affect the utilization of trace elements.
Attempts to Localize and Identify the Gravity-sensing Device of Plant Seedlings (1985)

The growth hormone asymmetry develops within three minutes following the initiation of the gravitational asymmetry and radio-labeled compounds being transported from the seed to the shoot also show asymmetric distribution. It is found that the target of the gravity stimulus resides primarily in the permability of the vascular tissue that regulates the supply of hormone to the surrounding tissues. It is hypothesized that the gravitational stimulus induces an asymmetric change in the rate of secretion of the growth hormone, IAA, from the vascular tissue into the surrounding cortical cells. More hormone would be secreted from the vascular stele proximal to the lower side of a horizontally placed plant shoot than from the upper side. This results in more growth hormone in the lower cortical (plus epidermal) cells, and ultimately more growth, such that the plant grows asymmetrically and, ultimately attain its normal vertical orientation. A theory was developed of how plants respond to the gravitational stimulus. The theory is based upon the analytical results concerning the effects of gravity on the distribution of the plant growth hormone, IAA, in both its free and conjugated forms, and upon the effect of the growth stimulis on the distribution of externally applied radio-labeled compounds. Its advantage is that it is testable and that it is built upon solid knowledge of the effects of the gravitational stimulus upon the endogenous growth hormone, IAA, and upon the distribution of externally applied radio-labeled compounds.
Facile synthesis of composition-tuned ZnO/Zn x Cd1-x Se nanowires for photovoltaic applications (2015)

ZnO/Zn x Cd1-x Se coaxial nanowires (NWs) have been successfully synthesized by combining chemical vapor deposition with a facile alternant physical deposition method. The shell composition x can be precisely tuned in the whole region (0 ≤ x ≤ 1) by adjusting growth time ratio of ZnSe to CdSe. As a result, the effective bandgaps of coaxial nanowires were conveniently modified from 1.85 eV to 2.58 eV, almost covering the entire visible spectrum. It was also found that annealing treatment was in favor of forming the mixed crystal and improving crystal quality. An optimal temperature of 350°C was obtained according to our experimental results. Additionally, time resolved photo-luminescence spectra revealed the longest carrier lifetime in ZnO/CdSe coaxial nanowires. As a result, the ZnO/CdSe nanowire cell acquired the maximal conversion efficiency of 2.01%. This work shall pave a way towards facile synthesis of ternary alloys for photovoltaic applications.
Intermittent lipid nanoparticle mRNA administration prevents cortical dysmyelination associated with arginase deficiency (2022)

Arginase deficiency is associated with prominent neuromotor features, including spastic diplegia, clonus, and hyperreflexia; intellectual disability and progressive neurological decline are other signs. In a constitutive murine model, we recently described leukodystrophy as a significant component of the central nervous system features of arginase deficiency. In the present studies, we sought to examine if the administration of a lipid nanoparticle carrying human <i>ARG1</i> mRNA to constitutive knockout mice could prevent abnormalities in myelination associated with arginase deficiency. Imaging of the cingulum, striatum, and cervical segments of the corticospinal tract revealed a drastic reduction of myelinated axons; signs of degenerating axons were also present with thin myelin layers. Lipid nanoparticle/<i>ARG1</i> mRNA administration resulted in both light and electron microscopic evidence of a dramatic recovery of myelin density compared with age-matched controls; oligodendrocytes were seen to be extending processes to wrap many axons. Abnormally thin myelin layers, when myelination was present, were resolved with intermittent mRNA administration, indicative of not only a greater density of myelinated axons but also an increase in the thickness of the myelin sheath. In conclusion, lipid nanoparticle/<i>ARG1</i> mRNA administration in arginase deficiency prevents the associated leukodystrophy and restores normal oligodendrocyte function.