gebhart/patrepeval huggingface dataset:
MECHANISMS OF STEROID ACTION AND RESISTANCE IN INFLAMMATION Corticosteroid-insensitive asthma: molecular mechanisms (2014)

Corticosteroids are the most potent anti-inflammatory agents used to treat chronic inflammatory diseases such as bronchial asthma. However, there are a small number (,5%) of asthmatic patients who do not respond well, or at all, to corticosteroid therapy – the corticosteroid-resistant and corticosteroid-dependent patients. Although this phenomenon is relatively uncommon, it poses a difficult therapeutic problem because few alternative therapies are available and these patients account for.50 % of the health care costs of asthma. If the mech-anisms for corticosteroid insensitivity are understood they may, in turn, provide insight into the key mechanism of corticosteroid action and allow a rational way to treat these individuals whose disease tends to be severe. Cortico-steroid insensitivity is not limited to asthma and is a feature
Single Path One-Shot Neural Architecture Search with Uniform Sampling (2019)

We revisit the one-shot Neural Architecture Search (NAS) paradigm and analyze its advantages over existing NAS approaches. Existing one-shot method, however, is hard to train and not yet effective on large scale datasets like ImageNet. This work propose a Single Path One-Shot model to address the challenge in the training. Our central idea is to construct a simplified supernet, where all architectures are single paths so that weight co-adaption problem is alleviated. Training is performed by uniform path sampling. All architectures (and their weights) are trained fully and equally. Comprehensive experiments verify that our approach is flexible and effective. It is easy to train and fast to search. It effortlessly supports complex search spaces (e.g., building blocks, channel, mixed-precision quantization) and different search constraints (e.g., FLOPs, latency). It is thus convenient to use for various needs. It achieves start-of-the-art performance on the large dataset ImageNet.
A Unified Multitask Architecture for Predicting Local Protein Properties (2012)

A variety of functionally important protein properties, such as secondary structure, transmembrane topology and solvent accessibility, can be encoded as a labeling of amino acids. Indeed, the prediction of such properties from the primary amino acid sequence is one of the core projects of computational biology. Accordingly, a panoply of approaches have been developed for predicting such properties; however, most such approaches focus on solving a single task at a time. Motivated by recent, successful work in natural language processing, we propose to use multitask learning to train a single, joint model that exploits the dependencies among these various labeling tasks. We describe a deep neural network architecture that, given a protein sequence, outputs a host of predicted local properties, including secondary structure, solvent accessibility, transmembrane topology, signal peptides and DNA-binding residues. The network is trained jointly on all these tasks in a supervised fashion, augmented with a novel form of semi-supervised learning in which the model is trained to distinguish between local patterns from natural and synthetic protein sequences. The task-independent architecture of the network obviates the need for task-specific feature engineering. We demonstrate that, for all of the tasks that we considered, our approach leads to statistically significant improvements in performance, relative to a single task neural network approach, and that the resulting model achieves state-of-the-art performance.
Characterization of Secretory Intermediates of Serratia marcescens Serine Protease Produced during Its Extracellular Secretion from Escherichia coli Cells (1993)

The Serratia marcescens serine protease (SSP; 66 kDa) is synthesized as a precursor (preproSSP; 112 kDa) composed of the NH2-terminal signal peptide of 27 amino acids, the mature protease part and a large COOH-terminal domain. When the SSP gene is expressed in Escherichia coli under the control of the tac promoter, the mature enzyme is excreted into the medium through the outer membrane, whereas preproSSP and two proteins, C-1 (40 kDa) and C-2 (38 kDa), processed from the COOH-terminal domain, are accumulated in the membrane fraction. Although treatment of the intact cells with trypsin caused slight truncation of C-1 and C-2, the main parts of C-1 and C-2, both of which are detected in the outer membrane, were resistant to trypsin, even after the cells had been osmotically shocked. Consistent with this, a high content of beta-sheet structure in C-2 was suggested by marked heat-modifiability, as determined by their electrophoretic mobilities on SDS-polyacrylamide gel. These findings suggest rigid integration of C-1 and C-2 in the outer membrane. Upon induction of the tac promoter, rapid excretion of SSP into the medium was first accompanied by the accumulation of C-1 in the outer membrane, which was followed by conversion of C-1 to C-2. PreproSSP was not detected during the accumulation of SSP in the medium, but it was gradually accumulated after the accumulation of SSP had reached a plateau. In addition, preproSSP still containing the intact NH2-terminal signal peptide was completely digested with trypsin when added to osmotically shocked cells.(ABSTRACT TRUNCATED AT 250 WORDS)
AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo , pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models (2007)

Constitutive activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway in human cancers is often associated with mutational activation of BRAF or RAS. MAPK/ERK kinase 1/2 kinases lie downstream of RAS and BRAF and are the only acknowledged activators of ERK1/2, making them attractive targets for therapeutic intervention. AZD6244 (ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of MAPK/ERK kinase 1/2. In vitro cell viability inhibition screening of a tumor cell line panel found that lines harboring BRAF or RAS mutations were more likely to be sensitive to AZD6244. The in vivo mechanisms by which AZD6244 inhibits tumor growth were investigated. Chronic dosing with 25 mg/kg AZD6244 bd resulted in suppression of growth of Colo-205, Calu-6, and SW-620 xenografts, whereas an acute dose resulted in significant inhibition of ERK1/2 phosphorylation. Increased cleaved caspase-3, a marker of apoptosis, was detected in Colo-205 and Calu-6 but not in SW-620 tumors where a significant decrease in cell proliferation was detected. Chronic dosing of AZD6244 induced a morphologic change in SW-620 tumors to a more differentiated phenotype. The potential of AZD6244 in combination with cytotoxic drugs was evaluated in mice bearing SW-620 xenografts. Treatment with tolerated doses of AZD6244 and either irinotecan or docetaxel resulted in significantly enhanced antitumor efficacy relative to that of either agent alone. These results indicate that AZD6244 has potential to inhibit proliferation and induce apoptosis and differentiation, but the response varies between different xenografts. Moreover, enhanced antitumor efficacy can be obtained by combining AZD6244 with the cytotoxic drugs irinotecan or docetaxel.
Agricultural and Food Chemistry: 50 Years of Synergy between AGFD andJAFC (2009)

The Division of Agricultural and Food Chemistry (AGFD) and the American Chemical Society had the foresight to launch the Journal of Agricultural and Food Chemistry in 1953. JAFC, still closely connected with the Division, has grown to be the premier international journal in the field, providing an outlet for publishing original research articles, reviews, perspectives, and editorials, for agricultural and food chemists from many nations. JAFC has expanded coverage of current areas of intense interest, such as bioactive constituents of foods, biotechnology, and biobased products and biofuels, as well as continuing strong coverage of such mainstream categories as food chemistry/biochemistry, analytical methods, safety and toxicology, and agrochemistry. In 2008 alone, JAFC published over 1650 peer-reviewed manuscripts, several symposia (largely from AGFD symposia at ACS National Meetings), and a number of reviews. The synergy between AGFD and JAFC offers many benefits and exciting opportunities for advancing the science of agricultural and food chemistry for the future.
Estrogen and progesterone receptors in the normal female breast. (1991)

We have studied estrogen receptor (ER) and progesterone receptor (PR) in normal breast by immunocytochemistry using tissue biopsies and fine needle aspirates (FNA) and, in the case of ER, by enzyme immunoassay. For ER we found a high degree of reproducibility for biopsies taken from the upper outer quadrant: FNA, r = 0.56 (P less than 0.002); tissue section immunocytochemistry, r = 0.89 (P less than 0.0001); and enzyme immunoassay, r = 0.76 (P less than 0.0001). For PR, FNA (r = 0.56, P less than 0.002) and tissue section (r = 0.97, P less than 0.0001) were also found to be reproducible techniques. Using enzyme immunoassay, we were able to measure ER accurately in normal breast tissue. In 59 samples we found a range of 0-37 fmol/mg cytosol protein (mean, 4 fmol/mg). In an age-matched group of 126 women with breast cancer, we found a significantly higher ER [range, 0-139 fmol/mg; mean, 37 fmol/mg (P less than 0.001)]. We then analyzed the ER and PR content of FNAs obtained from the upper outer quadrant of the normal breast in 143 normal women. We found that in only 23 of 143 samples (16%) were greater than or equal to 50% epithelial cells stained. There was a relationship between ER and PR (P = 0.03) and a higher ER content in European women than in non-European women (P less than 0.03). The PR content was related to high body mass index (P less than 0.02) and family history of breast cancer (P = 0.04). Samples tended to be more frequently ER positive by FNA if taken in the follicular phase of the menstrual cycle. We conclude that, although the levels of ER and PR are low in normal breast, they can be accurately measured. There is significant variation of ER and PR with several clinical parameters.
Survey of glucosinolate variation in leaves of Brassica rapa crops (2010)

The breakdown products of glucosinolates (gsl) are biologically active secondary metabolites involved in plant defense and human nutrition. We identified and quantified 14 different gsl present in the young leaves of 82 different varieties of Brassica rapa, including the following crops: Chinese cabbage, broccoleto, Pak choi and other leafy vegetables, turnip, sarson and rapeseed. We did not find crop specific gsl, but their quantity varied extensively among varieties and crops, except that the Chinese cabbage accessions tended to have similar gsl profile and amount. Gluconapin, glucobrassicanapin (aliphatic), neoglucobrassicin, glucobrassicin (indolic), and gluconaturtiin (aromatic) are the predominant gsl in most of the varieties surveyed. We also found two gsl not commonly found in B. rapa, 2-methyl-2-propenyl and n-butyl. Their identities were confirmed by HPLC-MS. Most of the Chinese cabbages contain lower amount of aliphatic than indolic gsl, whereas broccoleto, turnip and rapeseed all have much higher aliphatic gsl content than indolic gsl content. The predominant aliphatic gsl in most of the varieties contain 4-carbon side-chains. The lack of significant correlation observed between the conversion of 3- to 4-carbon side-chain gsl and the conversion of 4- to 5-carbon side-chain gsl suggests that these two elongation cycles are probably under the control of two independent genes in B. rapa. The absence of glucoraphanin in all accessions indicates that only functional Brgsl-Alk alleles are present in B. rapa.
Hidden Killers: Human Fungal Infections (2012)

Although fungal infections contribute substantially to human morbidity and mortality, the impact of these diseases on human health is not widely appreciated. Moreover, despite the urgent need for efficient diagnostic tests and safe and effective new drugs and vaccines, research into the pathophysiology of human fungal infections lags behind that of diseases caused by other pathogens. In this Review, we highlight the importance of fungi as human pathogens and discuss the challenges we face in combating the devastating invasive infections caused by these microorganisms, in particular in immunocompromised individuals.
Characterization of mesenchymal stem cells isolated from the human umbilical cord (2008)

Numerous papers have reported that mesenchymal stem cells (MSCs) can be isolated from various sources such as bone marrow, adipose tissue and others. Nonetheless it is an open question whether MSCs isolated from different sources represent a single cell lineage or if cells residing in different organs are separate members of a family of MSCs. Subendothelial tissue of the umbilical cord vein has been shown to be a promising source of MSCs. The aim of this study was to isolate and characterize cells derived from the subendothelial layer of umbilical cord veins as regards their clonogenicity and differentiation potential. The results from these experiments show that cells isolated from the umbilical cord vein displayed fibroblast-like morphology and grew into colonies. Immunophenotyping by flow cytometry revealed that the isolated cells were negative for the hematopoietic line markers HLA-DR and CD34 but were positive for CD29, CD90 and CD73. The isolated cells were also positive for survivin, Bcl-2, vimentin and endoglin, as confirmed by RT-PCR and immunofluorescence. These cells can be induced to differentiate into osteogenic and adipogenic cells, but a new finding is that these cells can be induced to differentiate into endothelial cells expressing CD31, vWF and KDR-2, and also form vessel-like structures in Matrigel. The differentiated cells stopped expressing survivin, thus showing a diminished proliferative potential. It can be assumed that the subendothelial layer of the umbilical cord vein contains a population of cells with the overall characteristics of MSCs, with the additional capability to transform into endothelial cells.
Optimal range and Doppler centroid estimation for a ScanSAR system (1996)

This paper presents a new range and Doppler centroid estimation algorithm for a ScanSAR system. This algorithm is based on processing the image data in the overlapped region of two bursts of the same beam or adjacent beams. It leads to highly accurate radar pointing angles that are paramount to achieving good radiometric performance in ScanSAR imagery. The achievable accuracy is derived theoretically and verified by tests performed using SIR-C ScanSAR data and ERS data. This algorithm is computationally efficient and easy to implement. The proposed Doppler centroid estimation algorithm is also an excellent candidate for a strip mode SAR system.
On relating apparent stress to the stress causing earthquake fault slip (1999)

Apparent stress τ a is defined as , where is the average shear stress loading the fault plane to cause slip and η is the seismic efficiency, defined as E a / W , where E a is the energy radiated seismically and W is the total energy released by the earthquake. The results of a recent study in which apparent stresses of mining‐induced earthquakes were compared to those measured for laboratory stick‐slip friction events led to the hypothesis that . This hypothesis is tested here against a substantially augmented data set of earthquakes for which can be estimated, mostly from in situ stress measurements, for comparison with τ a . The expanded data set, which includes earthquakes artificially triggered at a depth of 9 km in the German Kontinentales Tiefbohrprogramm der Bundesrepublik Deutschland (KTB) borehole and natural tectonic earthquakes, covers a broad range of hypocentral depths, rock types, pore pressures, and tectonic settings. Nonetheless, over ∼14 orders of magnitude in seismic moment, apparent stresses exhibit distinct upper bounds defined by a maximum seismic efficiency of ∼0.06, consistent with the hypothesis proposed before. This behavior of τ a and η can be expressed in terms of two parameters measured for stick‐slip friction events in the laboratory: the ratio of the static to the dynamic coefficient of friction and the fault slip overshoot. Typical values for these two parameters yield seismic efficiencies of ∼0.06. In contrast to efficiencies for laboratory events for which η is always near 0.06, those for earthquakes tend to be less than this bounding value because E a for earthquakes is usually underestimated due to factors such as band‐limited recording. Thus upper bounds on appear to be controlled by just a few fundamental aspects of frictional stick‐slip behavior that are common to shallow earthquakes everywhere. Estimates of from measurements of τ a for suites of earthquakes, using , are found to be comparable in magnitude to estimates of shear stress on the basis of extrapolating in situ stress data to seismogenic depths.
The role of cell maturation in the generation of phenotypic heterogeneity in B-cell chronic lymphocytic leukaemia. (1989)

B-chronic lymphocytic leukaemia (B-CLL) patients can be ranked along a progression of phenotypes characterized by a decreasing surface expression of CD20, CD21, CD22 and membrane immunoglobulin and a gradual replacement of the high molecular weight (MW) glycoproteins of the leucocyte-common antigen (LC) CD45RA by the lower MW components, including the CD45RO determinant. As CD20, CD21, CD22 and membrane immunoglobulin change during or after B-cell activation, and the CD45RA/CD45RO inversion is implicated in T-cell maturation, the possibility that the phenotypic differences are generated by a maturational diversity of the CLL clones has been investigated by testing the effects of TPA treatment of the leukaemic cells. TPA reduces the level of expression of CD20, CD21, mIg and CD45RA and increases CD45RO binding, thereby minimizing the phenotypic heterogeneity of the CLL clones and causing them to converge towards one end of the natural range. We propose that the phenotypic diversity in CLL is, at least in part, a consequence of maturational diversity where lymphocyte development is disrupted at different stages in different patients.
Fasting Induces a Large, Leptin-Dependent Increase in the Intrinsic Action Potential Frequency of Orexigenic Arcuate Nucleus Neuropeptide Y/Agouti-Related Protein Neurons (2005)

The neuropeptide Y (NPY)/Agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus are thought to promote feeding. Here, we demonstrate that feeding state in vivo, through a leptin-dependent process, induces large and persistent changes in the electrophysiological activity of these neurons as measured extracellularly in vitro. Consistent with an orexigenic role, fasting induced a 4-fold increase in the basal action potential frequency of NPY/AgRP neurons. Leptin, when injected into fasted wild-type mice, induced a dose- and time-dependent decrease in spike frequency, which approached fed levels 2-3 h post treatment. In leptin-deficient (lep(ob)/lep(ob)) and leptin receptor-deficient (lepr(db)/lepr(db)) mice, NPY/AgRP spike frequency was not significantly increased by fasting, and even in mutant mice fed ad libitum, spike frequency was at least as high as in fasted wild-type mice. All recordings included GABA(A) and ionotropic glutamate receptor antagonists, suggesting that expression of this modulation is potentially intrinsic and not synaptically dependent. Recorded neurons were unambiguously identified using NPY-Sapphire transgenic mice. This is a remarkably straightforward example of a very robust in vitro electrophysiogical effect produced by a simple behavioral manipulation, food restriction.
Cyclodextrin overcomes deficient lysosome-to-endoplasmic reticulum transport of cholesterol in Niemann-Pick type C cells (2009)

A handoff model has been proposed to explain the egress from lysosomes of cholesterol derived from receptor-mediated endocytosis of LDL. Cholesterol is first bound by soluble Niemann-Pick C2 (NPC2) protein, which hands off the cholesterol to the N-terminal domain of membrane-bound NPC1. Cells lacking NPC1 or NPC2 accumulate LDL-derived cholesterol in lysosomes and fail to deliver LDL cholesterol to the endoplasmic reticulum (ER) for esterification by acyl-CoA acyltransferase (ACAT) and for inhibition of sterol regulatory element-binding protein cleavage. Here, we support this model by showing that the cholesterol transport defect in NPC1 mutant cells is restricted to lysosomal export. Other cholesterol transport pathways appear normal, including the movement of cholesterol from the plasma membrane to the ER after treatment of cells with 25-hydroxycholesterol or sphingomyelinase. The NPC1 or NPC2 block in cholesterol delivery to the ER can be overcome by 2-hydroxypropyl-beta-cyclodextrin, which leads to a marked increase in ACAT-mediated cholesterol esterification. The buildup of cholesteryl esters in the cytosol is expected to be much less toxic than the buildup of free cholesterol in the lysosomes of patients with mutations in NPC1 or NPC2.
Current-Induced Magnetization Switching Probability in MgO-Based Magnetic Tunnel Junctions (2007)

We report the results of current-induced magnetization switching (CIMS) for MgO-based magnetic tunnel junctions (MTJs) with a tunneling magnetoresistance (TMR) ratio of about 66% and a critical current density of 4.45times10 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">6</sup> A/cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> . The stable switching probability related to CIMS over 1times10 <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">4</sup> cycles is observed up to 90%. The influence between the switching current and the pulse duration is discussed
Effect of Small-Dose Dopamine on Mesenteric Blood Flow and Renal Function in a Pig Model of Cardiopulmonary Resuscitation with Vasopressin (1999)

Vasopressin (antidiuretic hormone) seems a promising alternative to epinephrine for cardiopulmonary resuscitation (CPR) in cardiac arrest victims, mediating a pronounced blood flow shift toward vital organs. We evaluated the effects of small-dose dopamine on splanchnic blood flow and renal function after successful resuscitation with this potent vasoconstrictor in an established porcine CPR model. After 4 min of cardiac arrest and 3 min of CPR, animals received 0.4 U/kg vasopressin and were continuously infused with either dopamine 4 μg · kg−1 · min−1 (n = 6), or saline placebo (n = 6). Defibrillation was performed 5 min after drug administration; all animals were observed for 6 h after return of spontaneous circulation. During the postresuscitation phase, average mean ± SD superior mesenteric artery blood flow was significantly (P = 0.002) higher in the dopamine group compared with the placebo group (1185 ± 130 vs 740 ± 235 mL/min), whereas renal blood flow was comparable between groups (255 ± 40 vs 250 ± 85 mL/min). The median calculated glomerular filtration rate had higher values in the dopamine group (70–120 mL/min) than in the placebo group (40–70 mL/min; P = 0.1 at 0 min and P = 0.08 at 360 min). We conclude that small-dose dopamine administration may be useful in improving superior mesenteric artery blood flow and renal function after successful resuscitation with vasopressin. Implications Long-term survival after cardiac arrest may be determined by the ability to ensure adequate organ perfusion during cardiopulmonary resuscitation and in the postresuscitation phase. In this regard, small-dose dopamine improved postresuscitation blood flow to the mesenteric bed when vasopressin was used as an alternative vasopressor in an animal model of cardiac arrest.