gebhart/patrepeval huggingface dataset:
PI3K/Akt activation is critical for early hepatic regeneration after partial hepatectomy (2008)

Hepatic resection is associated with rapid proliferation and regeneration of the remnant liver. Phosphatidylinositol 3-kinase (PI3K), composed of a p85alpha regulatory and a p110alpha catalytic subunit, participates in multiple cellular processes, including cell growth and survival; however, the role of PI3K in liver regeneration has not been clearly delineated. In this study, we used the potent PI3K inhibitor wortmannin and small interfering RNA (siRNA) targeting the p85alpha and p110alpha subunits to determine whether total or selective PI3K inhibition would abrogate the proliferative response of the liver after partial hepatectomy in mice. Hepatic resection is associated with an induction in PI3K activity; total PI3K blockade with wortmannin and selective inhibition of p85alpha or p110alpha with siRNA resulted in a significant decrease in hepatocyte proliferation, especially at the earliest time points. Fewer macrophages and Kupffer cells were present in the regenerating liver of mice treated with wortmannin or siRNA to p85alpha or p110alpha, as reflected by a paucity of F4/80-positive cells. Additionally, PI3K inhibition led to an aberrant architecture in the regenerating hepatocytes characterized by vacuolization, lipid deposition, and glycogen accumulation; these changes were not noted in the sham livers. Our data demonstrate that PI3K/Akt pathway activation plays a critical role in the early regenerative response of the liver after resection; inhibition of this pathway markedly abrogates the normal hepatic regenerative response, most likely by inhibiting macrophage infiltration and cytokine elaboration and thus hepatocyte priming for replication.
Hybrid Solar Cells Using HgTe Nanocrystals and Nanoporous TiO2 Electrodes (2006)

Abstract HgTe nanocrystals are demonstrated to increase the photon‐harvesting efficiency of hybrid solar cells over a broad spectral region between 350 and 1500 nm. Devices combining two solar cell concepts, a solid‐state nanocrystal‐sensitized solar cell and a nanocrystal/polymer‐blend solar cell, are described. These devices give incident photon to current efficiencies up to 10 % at around 550 nm monochromatic irradiation and short‐circuit current densities of 2 mA cm –2 under simulated AM1.5 (100 mW cm –2 ) illumination (AM: air mass).
Excitotoxic loss of post‐synaptic sites is distinct temporally and mechanistically from neuronal death (2007)

Dendritic degeneration and loss of synaptic proteins are early events correlated with functional decline in neurodegenerative disease. The temporal and mechanistic relationship between synapse loss and cell death, however, remains unclear. We used confocal microscopy and image processing to count post-synaptic sites on rat hippocampal neurons by expressing post-synaptic density protein 95 fused to green fluorescent protein. Fluorescent puncta co-localized with neurotransmitter release sites, NMDA-induced Ca2+ increases and NMDA receptor immunoreactivity. During excitotoxic neurodegeneration, synaptic sites were lost and synaptic transmission impaired. These changes were mediated by NMDA receptors and required Ca2+-dependent activation of the proteasome pathway. Tracking synapses from the same cell following brief neurotoxic insult revealed transient loss followed by recovery. The time-course, concentration-dependence and mechanism for loss of post-synaptic sites were distinct from those leading to cell death. Cells expressing p14ARF, which inhibits ubiquitination of post-synaptic density protein 95 and prevents loss of synaptic sites, displayed an increased sensitivity to glutamate-induced cell death. Thus, excitotoxic synapse loss may be a disease-modifying process rather than an obligatory step leading to cell death. These results demonstrate the importance of assessing synaptic function independent of neuronal survival during neurodegeneration and indicate that this approach will be useful for identifying toxins that degrade synaptic connections and for screening for agents that protect synaptic function.
Pathogenetic relation between monoclonal gammopathies of undetermined significance and multiple myeloma. (1995)

Plasma cell atypia and cell proliferation changes which occur during the progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are accompanied by critical changes in neoplastic plasma cells and marrow stromal cells. Key elements include paracrine secretion of interleukin 6 (IL-6) by marrow stromal cells resulting from interleukin 1 beta (IL-1 beta) secreted by myeloma cells. In addition, there are stable elevated levels of serum soluble IL-6 receptor (sIL-6R) in MM and MGUS. They are higher than levels seen in normals. Oncogenes such as c-myc and ras probably play a major role as do cell adhesion molecules and loss of apoptosis. Immune regulatory cells may also play a role. A key element yet to be clearly defined is delineating the role of circulating plasma cells and their precursors in spreading the disease.
RNAi-Mediated Targeting of Heterochromatin by the RITS Complex (2004)

RNA interference (RNAi) is a widespread silencing mechanism that acts at both the posttranscriptional and transcriptional levels. Here, we describe the purification of an RNAi effector complex termed RITS (RNA-induced initiation of transcriptional gene silencing) that is required for heterochromatin assembly in fission yeast. The RITS complex contains Ago1 (the fission yeast Argonaute homolog), Chp1 (a heterochromatin-associated chromodomain protein), and Tas3 (a novel protein). In addition, the complex contains small RNAs that require the Dicer ribonuclease for their production. These small RNAs are homologous to centromeric repeats and are required for the localization of RITS to heterochromatic domains. The results suggest a mechanism for the role of the RNAi machinery and small RNAs in targeting of heterochromatin complexes and epigenetic gene silencing at specific chromosomal loci.
Adaptation to tRNA acceptor stem structure by flexible adjustment in the catalytic domain of class I tRNA synthetases (2011)

Class I aminoacyl-tRNA synthetases (aaRSs) use a Rossmann-fold domain to catalyze the synthesis of aminoacyl-tRNAs required for decoding genetic information. While the Rossmann-fold domain is conserved in evolution, the acceptor stem near the aminoacylation site varies among tRNA substrates, raising the question of how the conserved protein fold adapts to RNA sequence variations. Of interest is the existence of an unpaired C-A mismatch at the 1-72 position unique to bacterial initiator tRNA(fMet) and absent from elongator tRNAs. Here we show that the class I methionyl-tRNA synthetase (MetRS) of Escherichia coli and its close structural homolog cysteinyl-tRNA synthetase (CysRS) display distinct patterns of recognition of the 1-72 base pair. While the structural homology of the two enzymes in the Rossmann-fold domain is manifested in a common burst feature of aminoacylation kinetics, CysRS discriminates against unpaired 1-72, whereas MetRS lacks such discrimination. A structure-based alignment of the Rossmann fold identifies the insertion of an α-helical motif, specific to CysRS but absent from MetRS, which docks on 1-72 and may discriminate against mismatches. Indeed, substitutions of the CysRS helical motif abolish the discrimination against unpaired 1-72. Additional structural alignments reveal that with the exception of MetRS, class I tRNA synthetases contain a structural motif that docks on 1-72. This work demonstrates that by flexible insertion of a structural motif to dock on 1-72, the catalytic domain of class I tRNA synthetases can acquire structural plasticity to adapt to changes at the end of the tRNA acceptor stem.
Non-degenerate nanomechanical parametric amplifier (2002)

We present a nanomechanical parametric amplifier system, which consists of two electrostatically coupled resonators, and operates using 3 frequencies (non-degenerate amplifier). The use of 3 frequencies eliminates phase sensitivity between the signal and pump voltage. We observed the amplification of small signals by up to 43 dB. The width of the response of the resonator is tuned by varying the pump voltage. The resonant frequencies of the individual oscillators can be slightly tuned by adjusting the bias voltages. To our knowledge, this is the first reported mechanical parametric amplification scheme using two separate resonators.
Rapid, Controlled and Intensive Lentiviral Vector-Based RNAi (2009)

RNA interference (RNAi) is a powerful technology for studying the functional significance of genes. The technique is more accessible than gene knockout methods, and is directly applicable to diverse human cells. However, inadequate reductions in target mRNAs can reduce the utility of RNAi and insufficiently rigorous controls can lead to spurious conclusions. Optimally combining pol III promoters to drive short hairpin RNA expression with the gene transfer capabilities of lentiviral vectors has led to ways to perform especially effective and convincing RNAi, which we review here. We detail practical methods, including one-step vector construction. Deep, stable knockdowns to trace mRNA levels are readily achieved in T cell lines, which can then be subjected to comprehensive HIV challenge studies. Rescue of preknockdown phenotype by RNAi-resistant gene re-expression is a critical validating step. The methods can also be applied to primary T cells and macrophages. The time from thinking of a target to initial data read-out can be a few weeks.
Oxygenated Hydrocarbon Ionic Surfactants Exhibit CO2 Solubility (2005)

Several oxygenated hydrocarbons, including acetylated sugars, poly(propylene glycol), and oligo(vinyl acetate), have been used to generate CO2-soluble ionic surfactants. Surfactants with vinyl acetate tails yielded the most promising results, exhibiting levels of CO2 solubility comparable to those associated with fluorinated ionic surfactants. For example, a sodium sulfate with single, oligomeric vinyl acetate (VAc) tails consisting of 10 VAc repeat units was 7 wt % soluble in CO2 at 25 degrees C and 48 MPa. Upon introduction of water to these systems, only surfactants with the oligomeric vinyl acetate tails exhibited spectroscopic evidence of a polar environment that was capable of solubilizing the methyl orange into the CO2-rich phase. For example, a single-phase solution of CO2, 0.15 wt % sodium bis(vinyl acetate)8 sulfosuccinate, and water, at water loading (W) values ranging from 10 to 40 at 25 degrees C and 34.5 MPa, exhibited a methyl orange peak at 423 nm. This result indicated that the core of a reverse micelle provided a microenvironment with a polarity similar to that of methanol. Quantum chemical calculations indicate that the acetylated sugars may be too hydrophilic to readily form reverse micelles, whereas the VAc-based surfactants appear to have the correct balance of hydrophilic and hydrophobic forces necessary to form reverse micelles.
Thrombus imaging with a technetium-99m-labeled activated platelet receptor-binding peptide. (1996)

The combination of high in vitro receptor-binding affinity and specificity, in vivo thrombus imaging and fast clearance support the evaluation of 99mTc-280 as a clinical imaging agent.
Preclinical absorption, distribution, metabolism, excretion, and pharmacokinetic–pharmacodynamic modelling ofN-(4-(3-((3S,4R)-1-ethyl-3-fluoropiperidine-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, a novel MET kinase inhibitor (2010)

GNE-A (AR00451896; N-(4-(3-((3S,4R)-1-ethyl-3-fluoropiperidine-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide) is a potent, selective MET kinase inhibitor being developed as a potential drug for the treatment of human cancers. Plasma clearance was low in mice and dogs (15.8 and 2.44 mL/min/kg, respectively) and moderate in rats and monkeys (36.6 and 13.9 mL/min/kg, respectively). The volume of distribution ranged from 2.1 to 9.0 L/kg. The mean terminal elimination half-life ranged from 1.67 h in rats to 16.3 h in dogs. Oral bioavailability in rats, mice, monkeys, and dogs were 11.2%, 88.0%, 72.4%, and 55.8%, respectively. Allometric scaling predicted a clearance of 1.3-7.4 mL/min/kg and a volume of distribution of 4.8-11 L/kg in human. Plasma protein binding was high (96.7-99.0% bound). Blood-to-plasma concentration ratios (0.78-1.46) indicated that GNE-A did not preferentially distribute into red blood cells. Transporter studies in MDCKI-MDR1 and MDCKII-Bcrp1 cells suggested that GNE-A is likely a substrate for MDR1 and BCRP. Pharmacokinetic-pharmacodynamic modelling of tumour growth inhibition in MET-amplified EBC-1 human non-small cell lung carcinoma tumour xenograft mice projected oral doses of 5.6 and 13 mg/kg/day for 50% and 90% tumour growth inhibition, respectively. Overall, GNE-A exhibited favourable preclinical properties and projected human dose estimates.
Endothelium‐derived nitric oxide: actions and properties (1989)

Vascular smooth muscle relaxation in response to chemically diverse naturally occurring neurotransmitters and autacoids has been attributed to the formation and/or release of one or more vascular endothelium-derived relaxing factors (EDRFs) distinct from prostacyclin. The chemical, biochemical, and pharmacological properties of one such EDRF resemble closely the properties of nitric oxide (NO). Thus, both arterial and venous EDRFs as well as authentic NO cause heme-dependent activation of soluble guanylate cyclase, endothelium-independent vascular and nonvascular smooth muscle relaxation accompanied by tissue cyclic GMP formation, and inhibition of platelet aggregation and adhesion to endothelial cell surfaces. EDRF from artery, vein, and freshly harvested and cultured aortic endothelial cells was recently identified as NO or a labile nitroso species as assessed by chemical assay and bioassay. Endothelium-derived NO (EDNO) has an ultrashort half-life of 3-5 s due to spontaneous oxidation to nitrite and nitrate, both of which have only weak biological activity. EDNO can be synthesized from L-arginine and possibly other basic amino acids and polypeptides, perhaps by oxidative metabolic pathways that could involve polyunsaturated fatty acid-derived oxygen radicals. Inorganic nitrite could serve as both a stored precursor and an inactivation product of EDNO. EDNO and related EDRFs may serve physiological and/or pathophysiological roles in the regulation of local blood flow and platelet function.
The properties of solid dispersions of indomethacin, ketoprofen and flurbiprofen in phosphatidylcholine. (1988)

Solid dispersions in which the carriers were water-soluble agents have been investigated with the aim of improving the solubilities and dissolution rates of poorly water-soluble drugs. We have now examined the utility of barely soluble, but hydrophilic, phosphatidylcholine (PC) purified from hydrogenated soybean phospholipids as a carrier. As poorly water-soluble drugs, infomethacin (IM), flurbiprofen (FP) and ketoprofen (KP) were used.The X-ray diffraction patterns suggested an a amorphous state of IM when the molar ratio of IM was under 0.75.From the infrared spectra, it was considered that IM and PC had only a weak interaction with the carrier. The phase transition temperature of PC was depressed by IM and the degree of depression became larger with increasing molar ratio of IM. The solubility of IM in pH 7.0 buffer solution became 4.0mg/ml (5 times that of IM powder), when the PC solid dispersion with an IM molar ratio in the range of 0.50-0.75 was used. However, the IM concentration decreased with time and became 2mg/ml after 30h.FP and KP also had a weak interaction with PC and were present in the amorphous state, but this state was stable only when the molar ratio was under 0.50, which was lower that than in the case of IM. The solubilities of FP and KP from the PC solid dispersions were each about 1.5 times that from the powder.PC dissolved in water to the extent of 0.1-0.5mg/ml from the solid dispersions with IM, but the dissolution showed poor reproducibility, and no dissolution of PC was observed from FP and KP solid dispersions. Thus, the increased drug solubilities were considered to be due to the amorphous state of the drugs in the PC solid dispersions.
Comparison of effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on plasma lipids and lipoproteins in man. (1985)

Twenty patients consumed a liquid diet in which the predominant fatty acids were either saturated (Sat), monounsaturated (Mono), or polyunsaturated (Poly). The fats in these three diets comprised 40% of total calories and consisted of palm oil, high-oleic safflower oil, and high-linoleic safflower oil, respectively. During the third and fourth week of each dietary period, multiple samples of blood were taken and were analyzed for plasma total cholesterol (TC), triglycerides (TG), and cholesterol in lipoprotein fractions (VLDL-C, LDL-C, and HDL-C). Twelve of the patients had normal TG levels; in these patients, both Mono and Poly diets caused statistically significant and equal lowerings of plasma LDL-C, but the Poly diet lowered HDL-C levels more frequently than did the Mono diet. Neither diet changed the level of plasma TG. The proportions of total protein and the various lipid components in isolated fractions (VLDL, IDL, LDL, HDL) were not altered by the two diets. Eight patients had hypertriglyceridemia; these individuals showed considerable variability in response to Mono and Poly diets. Although there was a trend towards reductions in TC and LDL-C levels by both types of unsaturated fats, the changes were inconsistent; furthermore, HDL-C concentrations were low on the Sat diet and were unaffected by either the Mono or the Poly diet. The results of this study show that oleic acid is as effective as linoleic acid in lowering LDL-C levels in normo-triglyceridemic patients, and oleic acid seemingly reduces HDL-C levels less frequently than does linoleic acid. Neither type of unsaturated fat had striking effects on lipoprotein levels of hypertriglyceridemic patients.
Novel Approach to Meta-Analysis of Microarray Datasets Reveals Muscle Remodeling-related Drug Targets and Biomarkers in Duchenne Muscular Dystrophy (2012)

Elucidation of new biomarkers and potential drug targets from high-throughput profiling data is a challenging task due to a limited number of available biological samples and questionable reproducibility of differential changes in cross-dataset comparisons. In this paper we propose a novel computational approach for drug and biomarkers discovery using comprehensive analysis of multiple expression profiling datasets.The new method relies on aggregation of individual profiling experiments combined with leave-one-dataset-out validation approach. Aggregated datasets were studied using Sub-Network Enrichment Analysis algorithm (SNEA) to find consistent statistically significant key regulators within the global literature-extracted expression regulation network. These regulators were linked to the consistent differentially expressed genes.We have applied our approach to several publicly available human muscle gene expression profiling datasets related to Duchenne muscular dystrophy (DMD). In order to detect both enhanced and repressed processes we considered up- and down-regulated genes separately. Applying the proposed approach to the regulators search we discovered the disturbance in the activity of several muscle-related transcription factors (e.g. MYOG and MYOD1), regulators of inflammation, regeneration, and fibrosis. Almost all SNEA-derived regulators of down-regulated genes (e.g. AMPK, TORC2, PPARGC1A) correspond to a single common pathway important for fast-to-slow twitch fiber type transition. We hypothesize that this process can affect the severity of DMD symptoms, making corresponding regulators and downstream genes valuable candidates for being potential drug targets and exploratory biomarkers.
Local Fisher Discriminant Analysis for Pedestrian Re-identification (2013)

Metric learning methods, for person re-identification, estimate a scaling for distances in a vector space that is optimized for picking out observations of the same individual. This paper presents a novel approach to the pedestrian re-identification problem that uses metric learning to improve the state-of-the-art performance on standard public datasets. Very high dimensional features are extracted from the source color image. A first processing stage performs unsupervised PCA dimensionality reduction, constrained to maintain the redundancy in color-space representation. A second stage further reduces the dimensionality, using a Local Fisher Discriminant Analysis defined by a training set. A regularization step is introduced to avoid singular matrices during this stage. The experiments conducted on three publicly available datasets confirm that the proposed method outperforms the state-of-the-art performance, including all other known metric learning methods. Further-more, the method is an effective way to process observations comprising multiple shots, and is non-iterative: the computation times are relatively modest. Finally, a novel statistic is derived to characterize the Match Characteristic: the normalized entropy reduction can be used to define the 'Proportion of Uncertainty Removed' (PUR). This measure is invariant to test set size and provides an intuitive indication of performance.