gebhart/patrepeval huggingface dataset:
Rapid Structure-Activity and Selectivity Analysis of Kinase Inhibitors by BioMAP Analysis in Complex Human Primary Cell-Based Models (2004)

Rapid, quantitative methods for characterizing the biological activities of kinase inhibitors in complex human cell systems could allow the biological consequences of differential target selectivity to be monitored early in development, improving the selection of drug candidates. We have previously shown that Biologically Multiplexed Activity Profiling (BioMAP) permits rapid characterization of drug function based on statistical analysis of protein expression data sets from complex primary human cellbased models of disease biology. Here, using four such model systems containing primary human endothelial cells and peripheral blood mononuclear cells in which multiple signaling pathways relevant to inflammation and immune responses are simultaneously activated, we demonstrate that BioMAP analysis can detect and distinguish a wide range of inhibitors directed against different kinase targets. Using a panel of p38 mitogen-activated protein kinase antagonists as a test set, we show further that related compounds can be distinguished by unique features of the biological responses they induce in complex systems, and can be classified according to their induction of shared (on-target) and secondary activities. Statistical comparisons of quantitative BioMAP profiles and analysis of profile features allow correlation of induced biological effects with chemical structure and mapping of biological responses to chemical series or substituents on a common scaffold. Integration of automated BioMAP analysis for prioritization of hits and for structure-activity relationship studies may improve and accelerate the design and selection of optimal therapeutic candidates.
State of the Science in Dried Blood Spots (2017)

DBS provide a wide range of potential applications that extend beyond the reach of traditional samples. Current limitations are serious but not intractable. Technological advancements will likely continue to minimize constraints around DBS adoption.
Sexual Maturity Can Double Heart Mass and Cardiac Power Output in Male Rainbow Trout (1992)

ABSTRACT Mature male rainbow trout have significantly higher relative ventricle masses (RVM, ventricle mass as a percentage of body mass) than do immature males or females. Hatchery-reared maturing male trout had a mean RVM of 0.139%, whereas females had an RVM of only 0.074%. Moreover, as males matured and their testes grew from 0.07 to 3.92% of body mass, RVM more than doubled. In female trout no such heart growth occurred; RVM remained unchanged during the period of ovary growth. Cardiac performance was assessed using an in situ perfused heart preparation. Mature male trout have larger ventricles and could generate significantly greater maximum cardiac power output per kilogram body mass than could immature males or females. This enhanced cardiac performance by the mature males was attributable to delivery of greater cardiac outputs (through larger stroke volumes) and an increased ability of the heart to work against higher output pressures. Power output per gram ventricle mass was similar in both sexes.
Replication of an Autonomous Human Parvovirus in Non-dividing Human Airway Epithelium Is Facilitated through the DNA Damage and Repair Pathways (2016)

Human bocavirus 1 (HBoV1) belongs to the genus Bocaparvovirus of the Parvoviridae family, and is an emerging human pathogenic respiratory virus. In vitro, HBoV1 infects well-differentiated/polarized primary human airway epithelium (HAE) cultured at an air-liquid interface (HAE-ALI). Although it is well known that autonomous parvovirus replication depends on the S phase of the host cells, we demonstrate here that the HBoV1 genome amplifies efficiently in mitotically quiescent airway epithelial cells of HAE-ALI cultures. Analysis of HBoV1 DNA in infected HAE-ALI revealed that HBoV1 amplifies its ssDNA genome following a typical parvovirus rolling-hairpin DNA replication mechanism. Notably, HBoV1 infection of HAE-ALI initiates a DNA damage response (DDR) with activation of all three phosphatidylinositol 3-kinase-related kinases (PI3KKs). We found that the activation of the three PI3KKs is required for HBoV1 genome amplification; and, more importantly, we identified that two Y-family DNA polymerases, Pol η and Pol κ, are involved in HBoV1 genome amplification. Overall, we have provided an example of de novo DNA synthesis (genome amplification) of an autonomous parvovirus in non-dividing cells, which is dependent on the cellular DNA damage and repair pathways.
Counter braids (2008)

Fine-grained network measurement requires routers and switches to update large arrays of counters at very high link speed (e.g. 40 Gbps). A naive algorithm needs an infeasible amount of SRAM to store both the counters and a flow-to-counter association rule, so that arriving packets can update corresponding counters at link speed. This has made accurate per-flow measurement complex and expensive, and motivated approximate methods that detect and measure only the large flows.This paper revisits the problem of accurate per-flow measurement. We present a counter architecture, called Counter Braids, inspired by sparse random graph codes. In a nutshell, Counter Braids compresses while counting. It solves the central problems (counter space and flow-to-counter association) of per-flow measurement by braiding a hierarchy of counters with random graphs. Braiding results in drastic space reduction by sharing counters among flows; and using random graphs generated on-the-fly with hash functions avoids the storage of flow-to-counter association.The Counter Braids architecture is optimal (albeit with a complex decoder) as it achieves the maximum compression rate asymptotically. For implementation, we present a low-complexity message passing decoding algorithm, which can recover flow sizes with essentially zero error. Evaluation on Internet traces demonstrates that almost all flow sizes are recovered exactly with only a few bits of counter space per flow.
Intravenous Lactate Prevents Cerebral Dysfunction during Hypoglycaemia in Insulin-Dependent Diabetes Mellitus (1998)

1. Intravenous lactate prevents cerebral dysfunction during hypoglycaemia in healthy volunteers. This study examines whether this also occurs in insulin-dependent diabetes. Changes in four-choice reaction time, auditory brain stem response, and P300 latency were used as measures of cerebral function. 2. Ten subjects were studied twice at least 4 weeks apart. Blood glucose was maintained between 5 and 8 mmol/l for 1 h before starting a 60 m-unit min-1 m-2 stepped hyperinsulinaemic clamp, achieving blood glucose concentrations of 4.5, 3.3 and 2.5 mmol/l. At one visit, 40 mumol min-1 kg-1 sodium lactate was infused, and at the other, normal saline. Cerebral function was measured at each blood glucose concentration. 3. Blood lactate rose to 3.32 +/- 0.06 mmol/l during lactate infusion compared with 0.9 +/- 0.03 mmol/l during saline infusion. Compared with the results at 4.5 mmol/l there were no significant changes at 3.3 mmol/l in any measure of cerebral function at either visit. At 2.5 mmol/l a significant increase in reaction time and P300 latency occurred with saline [mean change 33.1 +/- 8.6 ms (P < 0.01) and 30.1 +/- 9.2 ms (P < 0.01) respectively] but not lactate [mean change -5.9 +/- 3.7 ms (P > 0.05) and -6 +/- 7.6 ms (P > 0.05) respectively]. No significant changes occurred in auditory brain stem response. The catecholamine response to hypoglycaemia was attenuated by lactate (P < 0.05 for adrenaline and noradrenaline). 4. Thus intravenous lactate prevents cerebral dysfunction during hypoglycaemia in insulin-dependent diabetes.
Isotopic Measurement of Glucose and Lactate Kinetics (1990)

A variety of isotopic tracers can be used to quantitate glucose kinetics in vivo. Using the standard approach to calculate the rate of appearance (Ra) of glucose from kinetic data, different rates of Ra glucose are obtained depending on the nature and position of the label in glucose. If total glucose production is considered to be all glycogen breakdown and gluconeogenesis, then that value can be calculated using the following stable isotopic tracers, or, in most cases their radioactive counterparts: 6, 6-2H-glucose; 1-13C, 6-13C; and U-13C-glucose. In the case of the 13C-labeled glucose, account must be taken of the extent of recycling of labeled carbons. If U-13C-glucose is used and recycling of isotope not quantitated, the resulting calculated value for Ra glucose will represent the rate of production from non-recycled carbons, plus some recycled carbons, due to potential dilution of 13C in the oxaloacetate pool and some loss of 13C in the PEPCK reaction. Traditional calculation of Ra glucose using 2-2H-glucose will include the rate of total glucose production and the contribution from the glucose cycle, and use of 3-2H-glucose will include the rate of total glucose production and contribution of the fructose cycle. The traditional methodology used to measure lactate production, in contrast to glucose, has a major conceptual flaw. It requires the assumption that there is no isotopic exchange between lactate and other compounds, yet experimental evidence indicates that lactate and pyruvate are in rapid equilibrium. Consequently, this approach will overestimate the true rate of net lactate production, possibly by as much as 400%.
Anti-Invasive and Metastatic Activities of Evodiamine. (2002)

We have recently reported that evodiamine can suppress in vitro invasion and lung metastasis by colon 26-L5 carcinoma cells. To extend our study, we examine here the anti-invasive and metastatic effects of evodiamine on Lewis lung carcinoma (LLC) and B16-F10 melanoma in addition to colon 26-L5 carcinoma. Critical structures of evodiamine for the activities were also evaluated by comparison with compounds possessing structures similar to that of evodiamine. Evodiamine concentration-dependently inhibited the invasion of B16-F10, LLC and colon 26-L5 cells with IC(50) values of 2.4 micro M, 4.8 micro M and 3.7 micro M, respectively. Pre-treatment of colon 26-L5 cells with evodiamine before inoculation into mice caused significant suppression of the liver metastasis as well as the lung metastasis. Lung metastasis by LLC is also inhibited significantly by pre-exposure to evodiamine. When the anti-migratory activity of evodiamine was compared with that of evodiamine-like compounds, rutaecarpine lacking a methyl group at N-14 and a hydrogen at C-13 b exhibited much less effect than evodiamine. In addition, reserpine, having beta-configurated hydrogen at C-13 b, inhibited tumor cell migration more potently than yohimbine, having alpha-configurated hydrogen at the same position. These results suggest that evodiamine may be useful as a leading compound for agents in tumor metastasis therapy. Also, the presence of a methyl group at N-14 and the configuration of hydrogen at C-13 b may be responsible for the inhibitory activities of evodiamine.
High-affinity interleukin 2 binding by an oncogenic hybrid interleukin 2-epidermal growth factor receptor molecule. (1987)

Both interleukin 2 (IL-2) and epidermal growth factor (EGF) receptors exist in two forms that differ with respect to affinity for their ligand. Only the high-affinity receptors appear to be responsible for the proliferation signal delivered upon binding of the growth factor. Fibroblasts transfected with IL-2 receptor cDNA generate only low-affinity receptors for IL-2, but fusion of membranes from these fibroblasts with T-cell membranes converts some receptors to high affinity, indicating the involvement of a T cell-specific factor in the generation of high-affinity receptors. We have constructed a chimeric cDNA molecule containing the extracellular IL-2-binding domain of the IL-2 receptor cDNA and the transmembrane and intracellular tyrosine kinase domains of the EGF receptor cDNA. When transfected into fibroblasts, this IL-2-EGF receptor cDNA generated high-affinity receptors for IL-2. Moreover, fibroblasts transfected with the chimeric molecule were morphologically transformed and produced rapidly growing tumors in nude mice.
Resource scheduling in a high-performance multimedia server (1999)

Supporting continuous media data-such as video and audio-imposes stringent demands on the retrieval performance of a multimedia server. In this paper, we propose and evaluate a set of data placement and retrieval algorithms to exploit the full capacity of the disks in a multimedia server. The data placement algorithm declusters every object over all of the disks in the server-using a time-based declustering unit-with the aim of balancing the disk load. As for runtime retrieval, the quintessence of the algorithm is to give each disk advance notification of the blocks that have to be fetched in the impending time periods, so that the disk can optimize its service schedule accordingly. Moreover, in processing a block request for a replicated object, the server will dynamically channel the retrieval operation to the most lightly loaded disk that holds a copy of the required block. We have implemented a multimedia server based on these algorithms. Performance tests reveal that the server achieves very high disk efficiency. Specifically, each disk is able to support up to 25 MPEG-1 streams. Moreover, experiments suggest that the aggregate retrieval capacity of the server scales almost linearly with the number of disks.
Expression of TGF-β isoforms, TGF-β receptors, and SMAD molecules at different stages of human glioma (2000)

Human gliomas express TGF-beta but, so far the expression of downstream mediators has been investigated in only a few cell lines. We have examined tissue specimens of 23 gliomas: 3 astrocytomas grade II (AST), 8 anaplastic astrocytomas grade III (AAST), and 12 glioblastoma multiforme grade IV (GBM). We analyzed the mRNA expression of TGF-beta1, TGF-beta2, TGF-beta3, the TGF-beta receptors type I (TbetaR-I) and type II (TbetaR-II), Smad2, Smad3, and Smad4. mRNA expression of IL-10 and CD95 (FAS/APO-1) were also studied. We detected increased mRNA levels of the 3 TGF-beta isoforms, correlating with the degree of malignancy. TGF-beta3 mRNA was increased, particularly in AST and AAST, while TGF-beta1 and TGF-beta2 mRNAs were strongly expressed in GBM. TGF-beta normally up-regulates the TGF-beta receptors, and TbetaR-I and TbetaR-II showed stronger expression in all gliomas when compared to normal tissues. However, the mRNA expression of Smad2, Smad3, and Smad4 was decreased in GBM. IL-10 mRNA expression was detected in glioma tissues but not in glioma cell lines. No marked increase in the expression of soluble CD95 splicing variants was found in the gliomas compared with normal tissue. However, total CD95 mRNA was elevated among GBM tissues.
Reversal of increased lymphocyte PC-1 activity in patients with Type 2 diabetes treated with metformin (1999)

This study has shown an increased activity of lymphocyte PC-1 in Type 2 diabetes and its reversal by 3-month metformin treatment, corresponding to the improvement of insulin sensitivity. Data obtained are consistent with a role of PC-1 in insulin resistance and suggest a new mechanism of action for metformin via PC-1 inhibition.
Nonvolatile memory based on solid electrolytes (2005)

Programmable metallization cell (PMC) memory utilizes electrochemical control of nanoscale quantities of metal in thin films of solid electrolyte. A silver or copper layer and an inert electrode formed in contact with a Ag/sup +/or Cu/sup 2+/-containing electrolyte film creates a device in which information is stored using large nonvolatile resistance change caused by the reduction of the metal ions. Key attributes are low voltage, low current, rapid write and erase, good retention and endurance, and the ability for the storage cells to be physically scaled to a few tens of nm. This work describes the principle of operation of PMC devices and presents representative results from cells with diameters ranging from micron scale to nanoscale dimensions based on Ag-Ge-Se, Ag-Ge-S, and Cu-WO/sub 3/ solid electrolytes.
Toxicities associated with monoclonal antibody infusions in cancer patients. (1988)

The toxicity during and following 291 infusions of 19 murine and three human monoclonal antibodies (MoAB) in 177 cancer patients with 10 different malignancies was assessed. Doses ranged from 0.5 to 500 mg administered over 0.25 to 24 hours. Various reactions in varying degrees were observed in 45 (28%) patients during their first MoAb infusion. Nine additional patients experienced toxicity following a subsequent antibody infusion. Antibodies that reacted with circulating cells were associated with toxicity in 20 of 28 (71%) of the first infusions, compared to 24 of 127 (19%) for patients receiving antibodies that did not react with circulating cells. Fevers, rigors, chills, and diaphoresis were observed in 10% to 12% of the patients and were associated with binding to circulating cells. Presumed hypersensitivity reactions, including urticaria, pruritus, bronchospasm, and anaphylaxis occurred in 20 patients (11%). There were five episodes of bronchospasm and a single episode of anaphylaxis. Liver transaminases were elevated in 14%. There was no correlation between dose or infusion rate and toxicity. Murine monoclonal antibodies that are not conjugated to cytotoxic agents can be given with an acceptable frequency of side effects and serious allergic reactions. There is a small risk of anaphylaxis, and one should avoid rapid infusion of high antibody doses in the presence of circulating target cells and/or circulating free antigen.
Directly modeling voiced and unvoiced components in speech waveforms by neural networks (2016)

This paper proposes a novel acoustic model based on neural networks for statistical parametric speech synthesis. The neural network outputs parameters of a non-zero mean Gaussian process, which defines a probability density function of a speech waveform given linguistic features. The mean and covariance functions of the Gaussian process represent deterministic (voiced) and stochastic (unvoiced) components of a speech waveform, whereas the previous approach considered the unvoiced component only. Experimental results show that the proposed approach can generate speech waveforms approximating natural speech waveforms.
Localization of lens intrinsic membrane protein MP19 and mutant protein MP19(To3) using fluorescent expression vectors. (2002)

The distribution of MP19 and MP19To3 in the cell appeared to be quite distinct. MP19 was observed to distribute to the cell membrane while MP19To3 did not. The fact that the MP19To3 did not traffic to the membrane, instead appearing to be trapped within a subcellular compartment within the cell sheds further light on the cause of the cataract and microphthalmia observed in the MP19To3 mutation, and further sheds information on the pathway of MP19 transport to the cell membrane.
Engineering Studies of Protein Secretion in Recombinant Saccharomyces cerevisiae (1991)

A recombinant model system consisting of either the MFα1 (α-factor) or the SUC2 promoter/signal-sequence fused to the SUC2 structural gene (codes for the yeast enzyme invertase) was used to study secreted protein localization and kinetics in the yeast Saccharomyces cerevisiae. The MFα1 and SUC2-directed secretion transported similar amounts of total specific invertase activity out of the cytoplasm. Multiple copies of the SUC2 gene on a 2µm based plasmid resulted in a four fold increase in total invertase produced over the wild type, and a five fold increase in invertase secreted to the medium. Derepression of the SUC2 promoter showed rapid expression and secretion of invertase into the periplasm, with slow passage through the cell wall to the fermentation broth.
Identification of a Human Cancer Related Organ‐Specific Neoantigen (1993)

Human cancers express organ-specific neoantigens (OSNs) which elicit specific cellular immune responses in the cancer patient, as demonstrated by leukocyte adherence inhibition (LAI), an in vitro immune response assay. A purified protein of MW 40,000 (p40) exhibiting OSN (colon specific) activity was cleaved into specific peptide fragments and their partial amino acid sequences determined. This information was used in the polymerase chain reaction (PCR) to obtain a 992 bp cDNA clone (PCR-992) from a human colon adenocarcinoma cell line (LS-180). By comparison of the predicted amino acid sequence of PCR-992 with the known sequence of p40 peptides, PCR-992 was shown to correspond to almost the entire coding region of p40. Nucleotide sequence analysis suggested that the protein was mycoplasmal in origin due to its high A+T content (76%) and the presence of five in frame TGA termination codons; at least two of the latter are actually read as tryptophan, a known feature of mycoplasma translation. We have confirmed this origin by direct isolation of a contaminating mycoplasma species from the LS-180 cell line and demonstration that it could be hybridized with the PCR-992 probe. Northern and PCR analysis of RNA preparations from the contaminated LS-180 cell line showed that p40 was part of the high affinity transport system operon of Mycoplasma hyorhinis (Dudler et al, EMBO J., 7: 3963-3970, 1988). Total protein lysates of Mycoplasma hyorhinis cultivated without animal cells could elicit positive LAI responses when incubated with cancer patient leukocytes but not with normal patient leukocytes. The organ-specific nature of the response was, however, not observed indicating that host cell-mycoplasmal interactions may play a role in determining the organ-specific nature of p40 seen with the LAI. The significance of these findings will be discussed in the context of previous thinking regarding the origin of OSNs.
Muscle and neuronal nicotinic acetylcholine receptors (2007)

Nicotinic acetylcholine receptors (nAChRs) are integral membrane proteins and prototypic members of the ligand-gated ion-channel superfamily, which has precursors in the prokaryotic world. They are formed by the assembly of five transmembrane subunits, selected from a pool of 17 homologous polypeptides (alpha1-10, beta1-4, gamma, delta, and epsilon). There are many nAChR subtypes, each consisting of a specific combination of subunits, which mediate diverse physiological functions. They are widely expressed in the central nervous system, while, in the periphery, they mediate synaptic transmission at the neuromuscular junction and ganglia. nAChRs are also found in non-neuronal/nonmuscle cells (keratinocytes, epithelia, macrophages, etc.). Extensive research has determined the specific function of several nAChR subtypes. nAChRs are now important therapeutic targets for various diseases, including myasthenia gravis, Alzheimer's and Parkinson's diseases, and schizophrenia, as well as for the cessation of smoking. However, knowledge is still incomplete, largely because of a lack of high-resolution X-ray structures for these molecules. Nevertheless, electron microscopy studies on 2D crystals of nAChR from fish electric organs and the determination of the high-resolution X-ray structure of the acetylcholine binding protein (AChBP) from snails, a homolog of the extracellular domain of the nAChR, have been major steps forward and the data obtained have important implications for the design of subtype-specific drugs. Here, we review some of the latest advances in our understanding of nAChRs and their involvement in physiology and pathology.