gebhart/patrepeval huggingface dataset:
Nitroxyl Improves Cellular Heart Function by Directly Enhancing Cardiac Sarcoplasmic Reticulum Ca 2+ Cycling (2006)

Heart failure remains a leading cause of morbidity and mortality worldwide. Although depressed pump function is common, development of effective therapies to stimulate contraction has proven difficult. This is thought to be attributable to their frequent reliance on cAMP stimulation to increase activator Ca(2+). A potential alternative is nitroxyl (HNO), the 1-electron reduction product of nitric oxide (NO) that improves contraction and relaxation in normal and failing hearts in vivo. The mechanism for myocyte effects remains unknown. Here, we show that this activity results from a direct interaction of HNO with the sarcoplasmic reticulum Ca(2+) pump and the ryanodine receptor 2, leading to increased Ca(2+) uptake and release from the sarcoplasmic reticulum. HNO increases the open probability of isolated ryanodine-sensitive Ca(2+)-release channels and accelerates Ca(2+) reuptake into isolated sarcoplasmic reticulum by stimulating ATP-dependent Ca(2+) transport. Contraction improves with no net rise in diastolic calcium. These changes are not induced by NO, are fully reversible by addition of reducing agents (redox sensitive), and independent of both cAMP/protein kinase A and cGMP/protein kinase G signaling. Rather, the data support HNO/thiolate interactions that enhance the activity of intracellular Ca(2+) cycling proteins. These findings suggest HNO donors are attractive candidates for the pharmacological treatment of heart failure.
Parameters of Microstrip Transmission Lines and of Coupled Pairs of Microstrip Lines (1968)

A theoretical analysis is presented of microwave propagation on microstrip, with particular reference to the case of coupled pairs of microstrip lines. Data on this type of transmission line are needed for the design of directional couplers, filters, and other components in microwave integrated circuits. The inhomogeneous medium, consisting of the dielectric substrate and the vacuum above it, is treated in a rigorous manner through the use of a "dielectric Green's function" which expresses the discontinuity of the fields at the dielectric-vacuum interface. Results are presented in graphical form for substrate dielectric constants of 1, 9, and 16, and a range of values of width and spacing of the strips. Numerical tables for these and other cases are also available. The tables present capacitance, characteristic impedance, and velocity of propagation of the even and odd normal modes. The method lends itself to the treatment of other geometries which are of practical interest, such as "thick" strips, presence of an unsymmetrically located upper ground plane, etc.
Measurement of Glucose Concentration in the Presence of Coreactants with a Platinum Electrode (1982)

An implantable glucose sensor is being developed that is based on the use of a high-area platinum electrode. The sensor is operated in a controlled potential mode, in which the potential of the platinum working electrode versus an unpolarized reference electrode is periodically varied according to a preselected voltage-time regimen. The change in potential is accompanied by a flow of current between the platinum working electrode and a counter-electrode. This current serves to periodically rejuvenate the electrode surface and to provide a signal that is proportional to the glucose concentration. A method for analyzing this signal has been developed, the compensated net charge (CNC) method, that involves integration of the current over one complete potential cycle. This method significantly improves both the sensitivity and selectivity for determining glucose in the presence of the normal physiologic coreactants. For a solution containing glucose, amino acids, and urea, a change in glucose concentration from 50 to 150 mg/dl gives about a 50% change in the net charge. A change in the urea concentration from 20 to 40 mg/dl has no effect on the net charge. A change in the amino acids concentration from 35 to 65 mg/dl has little effect on the net charge above a glucose concentration of about 100 mg/dl. Negligible effects on the net charge have also been found for creatinine (0-1.5 mg/dl) and uric acid (0-4 mg/dl).
A genomic update on clostridial phylogeny: G ram‐negative spore formers and other misplaced clostridia (2013)

The class Clostridia in the phylum Firmicutes (formerly low-G+C Gram-positive bacteria) includes diverse bacteria of medical, environmental and biotechnological importance. The Selenomonas-Megasphaera-Sporomusa branch, which unifies members of the Firmicutes with Gram-negative-type cell envelopes, was recently moved from Clostridia to a separate class Negativicutes. However, draft genome sequences of the spore-forming members of the Negativicutes revealed typically clostridial sets of sporulation genes. To address this and other questions in clostridial phylogeny, we have compared a phylogenetic tree for a concatenated set of 50 widespread ribosomal proteins with the trees for beta subunits of the RNA polymerase (RpoB) and DNA gyrase (GyrB) and with the 16S rRNA-based phylogeny. The results obtained by these methods showed remarkable consistency, suggesting that they reflect the true evolutionary history of these bacteria. These data put the Selenomonas-Megasphaera-Sporomusa group back within the Clostridia. They also support placement of Clostridium difficile and its close relatives within the family Peptostreptococcaceae; we suggest resolving the long-standing naming conundrum by renaming it Peptoclostridium difficile. These data also indicate the existence of a group of cellulolytic clostridia that belong to the family Ruminococcaceae. As a tentative solution to resolve the current taxonomical problems, we propose assigning 78 validly described Clostridium species that clearly fall outside the family Clostridiaceae to six new genera: Peptoclostridium, Lachnoclostridium, Ruminiclostridium, Erysipelatoclostridium, Gottschalkia and Tyzzerella. This work reaffirms that 16S rRNA and ribosomal protein sequences are better indicators of evolutionary proximity than phenotypic traits, even such key ones as the structure of the cell envelope and Gram-staining pattern.
Monocytes isolated by positive and negative magnetic sorting techniques show different molecular characteristics and immunophenotypic behaviour (2018)

<b>Background</b>: Magnetic sorting of cells, based on microbead conjugated antibodies (Abs), employs positive as well as negative immunomagnetic separation methods, for isolation of a specific cell population. These microbeads are suggested to be nontoxic, biodegradable carriers conjugated to various antibodies. Isolation of cells through positive selection involves the attachment of antibody conjugated microbeads to the cells of interest, followed by their isolation in the presence of a strong magnetic field to obtain higher purity. Negative selection involves attachment of microbead conjugated antibodies to all other cell populations except the cells of interest, which remain untagged. In the present study, we compared the two methods for their effect on functional and immunophenotypic behavior of isolated CD14+ monocytes. <b>Methods</b>: Peripheral blood mononuclear cells (PBMCs) were isolated from blood collected from healthy volunteers by density gradient centrifugation. Human blood derived monocytes were isolated through positive selection and negative selection, making use of the appropriate monocyte isolation kit. Monocytes were then stimulated with lipopolysaccharide (LPS) and their activation and proliferation capacity were examined. The degradation or dissociation of cell-bound microbeads was also investigated. <b>Results</b>: We observed an impaired LPS sensitivity as well as poor activation and proliferation capacity upon stimulation by LPS in positively sorted CD14+ monocytes as compared to negatively sorted CD14+ monocytes. The attached microbeads did not degrade and remained attached to the cells even after 6 days of culture. <b>Conclusions</b>: Our results suggest that positively sorted CD14+ cells exhibit hampered functionality and may result in inaccurate analysis and observations in downstream applications. However, these cells can be used for immediate analytical procedures.
AKT/ERK activation is associated with gastric cancer cell resistance to paclitaxel. (2014)

Paclitaxel (PTX) has shown encouraging activity in the treatment of advanced gastric cancer (GC). However, the fact that more than half of GC patients respond poorly to PTX-based chemotherapies demonstrates the urgent need for biomarkers of PTX sensitivity in GC patients. In the present work, three GC cell lines (BGC-823, HGC-27 and NCI-N87) with different sensitivities to PTX were subjected to DNA microarray analysis. The significantly differentially expressed genes and microRNAs (miRs) were identified and pathway signatures for PTX sensitivity were proposed. Ingenuity Pathway Analysis results showed that the differentially expressed genes were mainly enriched in the ErbB signaling pathway and other pathways. Additionally, the AKT/ERK signaling pathway, which is the pathway downstream of ErbB, was predicted to be active in PTX-resistant GC cell lines. ErbB3 overexpression and AKT/ERK activation in PTX-resistant cell lines were validated, respectively, by quantitative PCR and immunoblotting. Furthermore, 10 miRs were dramatically differently expressed in the three GC cell lines, and a miR-gene network was constructed from these data. Our work uncovered a reliable signature for PTX sensitivity in GC and potential therapeutic targets for GC treatments.
Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone (2004)

Cytochromes P450 (P450s) metabolize a wide range of endogenous compounds and xenobiotics, such as pollutants, environmental compounds, and drug molecules. The microsomal, membrane-associated, P450 isoforms CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1, and CYP1A2 are responsible for the oxidative metabolism of more than 90% of marketed drugs. Cytochrome P450 3A4 (CYP3A4) metabolizes more drug molecules than all other isoforms combined. Here we report three crystal structures of CYP3A4: unliganded, bound to the inhibitor metyrapone, and bound to the substrate progesterone. The structures revealed a surprisingly small active site, with little conformational change associated with the binding of either compound. An unexpected peripheral binding site is identified, located above a phenylalanine cluster, which may be involved in the initial recognition of substrates or allosteric effectors.
AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014)

We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented.
What Use is a Cotton Crop Simulation Model (1992)

The relevance of computer simulation of cotton cropping systems for achieving a sustainable Australian cotton industry is examined. The OZCOT and CERCOT cotton crop models are presented. Model structure is briefly described and the types of applications best suited to crop models are discussed. The past, present and potential future applications of the models are considered.
alpha-(3,4-dimethyoxyphenyl)-3,4-dihydro-6,7-dimethoxy-alpha- [(4-methylphenyl)thio]-2(1H)-isoquinolineheptanenitrile (CL 329,753): a novel chemosensitizing agent for P-glycoprotein-mediated resistance with improved biological properties compared with verapamil and cyclosporine A. (1996)

Agents that inhibit P-glycoprotein may restore sensitivity to some antitumor drugs in cancer patients. Optimization of the specificity and potency of one class of chemosensitizing agents related to verapamil has led to the identification of alpha-(3,4-dimethyoxyphenyl)-3,4-dihydro-6, 7-dimethoxy-alpha-[(4-methylphenyl) thio]-2(1H)-isoquinolineheptanenitrile, designated CL 329,753. In vitro, 0.1 to 2.0 microM CL 329,753 restored sensitivity to drugs in the multidrug resistance (MDR) phenotype in cell lines that overexpress P-glycoprotein. CL 329,753 was greater than 10-fold more potent and efficacious than cyclosporine A or verapamil in vitro, particularly in cells that express high levels of P-glycoprotein. The enhanced activity of CL 329,753 may be related to its inability to be transported by P-glycoprotein, since low drug accumulation of cyclosporine or verapamil but not CL 329,753 was found in P-glycoprotein-containing cells, yet all three agents inhibited vinblastine binding to membranes containing P-glycoprotein and inhibited photoaffinity labeling of P-glycoprotein. In vivo, CL 329,753 resensitized drug-resistant tumors to vinblastine or doxorubicin in an ascitic or solid tumor model, respectively. No alteration in the plasma pharmacokinetic profile of doxorubicin by CL 329,753 has been found. Furthermore, the compound had 70-fold less calcium channel antagonistic activity compared with verapamil.
Structure/function analysis of interleukin-2-toxin (DAB486-IL-2). Fragment B sequences required for the delivery of fragment A to the cytosol of target cells. (1990)

We have used cassette and deletion mutagenesis to analyze the structural features of fragment B-related sequences in the fusion toxin DAB486-IL-2 (where IL-2 represents interleukin-2) that are necessary for the efficient delivery of fragment A to the cytosol of target cells. We demonstrate that whereas an intact disulfide bond between Cys461 and Cys471 may be required for the cytotoxic action of native diphtheria toxin, this bond is not required for the cytotoxic action of DAB486-IL-2. The in-frame deletion of the 97 amino acids from Thr387 to His485 of DAB486-IL-2 increases both the potency and the apparent dissociation constant (Kd) of the resulting fusion toxin for high affinity interleukin-2 receptor-bearing target cells. In contrast, the inframe deletion of either the 191 amino acids between Asp291 and Gly483 or the 85 amino acids between Asn204 and Ile290 results in a 1000-fold loss in potency. These regions contain the putative membrane-spanning regions and the amphipathic membrane surface-associating regions of fragment B, respectively. These results indicate that the efficient delivery of the ADP-ribosyltransferase from DAB486-IL-2 to the cytosol requires the membrane-associating domains of fragment B. This function has been postulated to play a role in the diphtherial intoxication of eukaryotic cells. However, unlike native diphtheria toxin, fragment B sequences distal to Thr387 do not enhance the potency of DAB486-IL-2.
Antisense oligodeoxynucleotide inhibition as a potent strategy in plant biology: identification of SUSIBA2 as a transcriptional activator in plant sugar signalling (2005)

Sugar signalling cascades are important components of regulatory networks in cells. Compared with the situation in bacteria, yeast and animals, participants of the sugar signalling pathways in plants are poorly understood. Several genes involved in starch synthesis are known to be sugar inducible, although the signal transduction pathways remain undisclosed. We reported recently the isolation of SUSIBA2, a transcription factor involved in sugar-mediated regulation of starch synthesis. Here, we used antisense oligodeoxynucleotide (ODN) inhibition, a powerful approach in medical sciences, to block the effects of SUSIBA2 in sugar-treated barley leaves. The uptake and intracellular trafficking of an 18-mer susiba2 antisense ODN in leaves were followed by confocal microscopy. Administration of the antisense ODN to the leaves impeded susiba2 expression by RNase H activation. This dramatically diminished the ectopic expression of the iso1 and sbeIIb genes and resulted in altered starch synthesis. This study illustrates the successful exploitation of the antisense ODN technology in plant biology, e.g. as a rapid antecedent to time-consuming transgenic studies, and identifies SUSIBA2 as a transcriptional activator in plant sugar signalling. Based on our findings, we propose a model for sugar-signalling control of starch synthesis.
Determination of defect size distributions based on electrical measurements at a novel harp test structure (2002)

To improve accuracy of electrically based measurements of defect densities and defect size distributions, we present a novel harp test structure. There, horizontal and vertical parallel lines will be placed inside a given boundary pad frame without using any additional active semiconductor devices. The enhanced 2D-permutation sequence provides that all neighborhood relationships of adjacent test structure lines are unique. This is the key to disentangle even multiple faults detected by fast digital measurements. For this reason, the number and size of individual defects will be extracted anywhere inside or in-between layers.
Versican Is Upregulated in CNS Injury and Is a Product of Oligodendrocyte Lineage Cells (2002)

Chondroitin sulfate proteoglycan (CS-PG) expression is increased in response to CNS injury and limits the capacity for axonal regeneration. Previously we have shown that neurocan is one of the CS-PGs that is upregulated (Asher et al., 2000). Here we show that another member of the aggrecan family, versican, is also upregulated in response to CNS injury. Labeling of frozen sections 7 d after a unilateral knife lesion to the cerebral cortex revealed a clear increase in versican immunoreactivity around the lesion. Western blot analysis of extracts prepared from injured and uninjured tissue also revealed considerably more versican in the injured tissue extract. In vitro studies revealed versican to be a product of oligodendrocyte lineage cells (OLCs). Labeling was seen between the late A2B5-positive stage and the O1-positive pre-oligodendrocyte stage. Neither immature, bipolar A2B5-positive cells, nor differentiated, myelin-forming oligodendrocytes were labeled. The amount of versican in conditioned medium increased as these cells differentiated. Versican and tenascin-R colocalized in OLCs, and coimmunoprecipitation indicated that the two exist as a complex in oligodendrocyte-conditioned medium. Treatment of pre-oligodendrocytes with hyaluronidase led to the release of versican, indicating that its retention at the cell surface is dependent on hyaluronate (HA). In rat brain, approximately half of the versican is bound to hyaluronate. We also provide evidence of a role for CS-PGs in the axon growth-inhibitory properties of oligodendrocytes. Because large numbers of OLCs are recruited to CNS lesions, these results suggest that OLC-derived versican contributes to the inhospitable environment of the injured CNS.
Knowledge-Based Design of Target-Focused Libraries Using Protein−Ligand Interaction Constraints (2005)

Here we present a new strategy for designing and filtering potentially massive combinatorial libraries using structural information of a binding site. We have developed a variation of the structural interaction fingerprint (SIFt) named r-SIFt, which incorporates the binding interactions of variable fragments in a combinatorial library. This method takes into account the 3D structure of the active site of the target molecule and translates desirable ligand-target binding interactions into library filtering constraints. We show using the MAP kinase p38 as a test case that we can efficiently analyze and classify compounds on the basis of their abilities to interact with the target in the desired binding mode. On the basis of these classifications, decision tree models were generated using the molecular descriptors of the compounds as predictor variables. Our results suggest that r-SIFt coupled with the classification models should be a valuable tool for structure-based focusing of combinatorial chemical libraries.
Using a large area CMOS APS for direct chemiluminescence detection in Western blotting electrophoresis (2012)

Western blotting electrophoretic sequencing is an analytical technique widely used in Functional Proteomics to detect, recognize and quantify specific labelled proteins in biological samples. A commonly used label for western blotting is Enhanced ChemiLuminescence (ECL) reagents based on fluorescent light emission of Luminol at 425nm. Film emulsion is the conventional detection medium, but is characterized by non-linear response and limited dynamic range. Several western blotting digital imaging systems have being developed, mainly based on the use of cooled Charge Coupled Devices (CCDs) and single avalanche diodes that address these issues. Even so these systems present key drawbacks, such as a low frame rate and require operation at low temperature. Direct optical detection using Complementary Metal Oxide Semiconductor (CMOS) Active Pixel Sensors (APS)could represent a suitable digital alternative for this application. In this paper the authors demonstrate the viability of direct chemiluminescent light detection in western blotting electrophoresis using a CMOS APS at room temperature. Furthermore, in recent years, improvements in fabrication techniques have made available reliable processes for very large imagers, which can be now scaled up to wafer size, allowing direct contact imaging of full size western blotting samples. We propose using a novel wafer scale APS (12.8 cm×13.2 cm), with an array architecture using two different pixel geometries that can deliver an inherently low noise and high dynamic range image at the same time representing a dramatic improvement with respect to the current western blotting imaging systems.
lmmunodetection of Lipoprotein Lipase: Antibody Production, Immunoprecipitation, and Western Blotting Techniques (2003)

Lipoprotein lipase (LPL) is an N-inked glycoprotein of approximately 57 kDa that is synthesized by a numbel of tissues, including white and brown adipose tissue, heart, skeletal muscle, neonatal liver and brain (1,2). In these tissues, LPL is synthesized by parenchymal cells and secreted to the surface of endothelial cells where it is bound by heparan sulfate proteoglycans. Endothelial-bound LPL hydrolyzes triglycerides from the core lipids of chylomicrons and very low density lipoproteins, liberating free fatty acids that can be utilized by the subjacent tissue for storage or oxidation.
Chalk sounds (2011)

Awareness of other people's activity is an important part of shared-workspace collaboration, and is typically supported using visual awareness displays such as radar views. These visual presentations are limited in that the user must be able to see and attend to the view in order to gather awareness information. Using audio to convey awareness information does not suffer from these limitations, and previous research has shown that audio can provide valuable awareness in distributed settings. In this paper we evaluate the effectiveness of synthesized dynamic audio information, both on its own and as an adjunct to a visual radar view. We developed a granular-synthesis engine that produces realistic chalk sounds for off-screen activity in a groupware workspace, and tested the audio awareness in two ways. First, we measured people's ability to identify off-screen activities using only sound, and found that people are almost as accurate with synthesized sounds as with real sounds. Second, we tested dynamic audio awareness in a realistic groupware scenario, and found that adding audio to a radar view significantly improved awareness of off-screen activities in situations where it was difficult to see or attend to the visual display. Our work provides new empirical evidence about the value of dynamic synthesized audio in distributed groupware.