gebhart/patrepeval huggingface dataset:
Evidence suggesting a role for hydroxyl radical in glycerol-induced acute renal failure (1988)

Reactive oxygen metabolites, in particular hydroxyl radical, have been shown to be important mediators of tissue injury in several models of acute renal failure. The aim of the present study was to examine the role of hydroxyl radical in glycerol-induced acute renal failure, a model for myoglobinuric renal injury. Rats injected with glycerol alone (8 mg/kg im following dehydration for 24 h) developed significant renal failure compared with dehydrated controls. Rats treated with glycerol and a hydroxyl radical scavenger, dimethylthiourea (DMTU), had significantly lower blood urea nitrogen (BUN) and creatinine. In contrast, urea, which is chemically similar to DMTU but is not a hydroxyl radical scavenger, provided no protection. In addition, DMTU prevented the glycerol-induced rise in renal cortical malondialdehyde content (a measure of lipid peroxidation that serves as a marker of free radical-mediated tissue injury). A second hydroxyl radical scavenger, sodium benzoate, had a similar protective effect on renal function (as measured by both BUN and creatinine). Because the generation of hydroxyl radical in biological systems requires the presence of a trace metal such as iron, we also examined the effect of the iron chelator, deferoxamine on glycerol-induced renal failure. Deferoxamine was also protective. The interventional agents were also associated with a marked reduction in histological evidence of renal damage. The protective effects of two hydroxyl radical scavengers as well as an iron chelator implicate a role for hydroxyl radical in glycerol-induced acute renal failure.
Canadian Asthma Consensus Report, 1999. Canadian Asthma Consensus Group. (1999)

The recommendations were distributed to the members of the Canadian Thoracic Society Asthma and Standards Committees, as well as members of the board of the Canadian Thoracic Society. In addition, collaborating groups representing the Canadian Association of Emergency Physicians, the Canadian College of Family Physicians, the Canadian Paediatric Society and the Canadian Society of Allergy and Immunology were asked to validate the recommendations. The recommendations were discussed at regional meetings throughout Canada. They were also compared with the recommendations of other similar groups in other countries. DISSEMINATION AND IMPLEMENTATION: An implementation committee has established a strategy for disseminating these guidelines to physicians, other health professionals and patients and for developing tools and means that will help integrate the recommendations into current asthma care. The plan is outlined in this report.
Structural analysis of plasmid pSN2 in Staphylococcus aureus: no involvement in enterotoxin B production (1982)

Earlier studies have suggested the involvement of a small 1.3-kilobase plasmid, pSN2, in the production of enterotoxin D by certain Staphylococcus aureus strains. On the basis of extensive biochemical studies on pSN2, including the determination of its coding properties and its primary nucleotide sequence, we conclude that this plasmid is not in act involved in enterotoxin B production in S. aureus: although the toxin genes are apparently chromosomal, it is probable that they are part of a special genetic system such as a hitchhiking transposon.
An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers (2006)

Numerous disease-associated point mutations exert their effects by disrupting the activity of exonic splicing enhancers (ESEs). We previously derived position weight matrices to predict putative ESEs specific for four human SR proteins. The score matrices are part of ESEfinder, an online resource to identify ESEs in query sequences. We have now carried out a refined functional SELEX screen for motifs that can act as ESEs in response to the human SR protein SF2/ASF. The test BRCA1 exon under selection was internal, rather than the 3'-terminal IGHM exon used in our earlier studies. A naturally occurring heptameric ESE in BRCA1 exon 18 was replaced with two libraries of random sequences, one seven nucleotides in length, the other 14. Following three rounds of selection for in vitro splicing via internal exon inclusion, new consensus motifs and score matrices were derived. Many winner sequences were demonstrated to be functional ESEs in S100-extract-complementation assays with recombinant SF2/ASF. Motif-score threshold values were derived from both experimental and statistical analyses. Motif scores were shown to correlate with levels of exon inclusion, both in vitro and in vivo. Our results confirm and extend our earlier data, as many of the same motifs are recognized as ESEs by both the original and our new score matrix, despite the different context used for selection. Finally, we have derived an increased specificity score matrix that incorporates information from both of our SF2/ASF-specific matrices and that accurately predicts the exon-skipping phenotypes of deleterious point mutations.
Bacterial Protein Secretion Is Required for Priming of CD8+T Cells Specific for theMycobacterium tuberculosisAntigen CFP10 (2008)

Mycobacterium tuberculosis infection elicits antigen-specific CD8(+) T cells that are required to control disease. It is unknown how the major histocompatibility complex class I (MHC-I) pathway samples mycobacterial antigens. CFP10 and ESAT6 are important virulence factors secreted by M. tuberculosis, and they are immunodominant targets of the human and murine T-cell response. Here, we test the hypothesis that CFP10 secretion by M. tuberculosis is required for the priming of CD8(+) T cells in vivo. Our results reveal an explicit dependence upon the bacterial secretion of the CFP10 antigen for the induction of antigen-specific CD8(+) T cells in vivo. By using well-defined M. tuberculosis mutants and carefully controlling for virulence, we show that ESX-1 function is required for the priming of CD8(+) T cells specific for CFP10. CD4(+) and CD8(+) T-cell responses to mycobacterial antigens secreted independently of ESX-1 were unaffected, suggesting that ESX-1-dependent phagosomal escape is not required for CD8(+) T-cell priming during infection. We propose that the overrepresentation of secreted proteins as dominant targets of the CD8(+) T-cell response during M. tuberculosis infection is a consequence of their preferential sampling by the MHC-I pathway. The implications of these findings should be considered in all models of antigen presentation during M. tuberculosis infection and in vaccine development.
Navigating the protein fitness landscape with Gaussian processes (2012)

Knowing how protein sequence maps to function (the "fitness landscape") is critical for understanding protein evolution as well as for engineering proteins with new and useful properties. We demonstrate that the protein fitness landscape can be inferred from experimental data, using Gaussian processes, a Bayesian learning technique. Gaussian process landscapes can model various protein sequence properties, including functional status, thermostability, enzyme activity, and ligand binding affinity. Trained on experimental data, these models achieve unrivaled quantitative accuracy. Furthermore, the explicit representation of model uncertainty allows for efficient searches through the vast space of possible sequences. We develop and test two protein sequence design algorithms motivated by Bayesian decision theory. The first one identifies small sets of sequences that are informative about the landscape; the second one identifies optimized sequences by iteratively improving the Gaussian process model in regions of the landscape that are predicted to be optimized. We demonstrate the ability of Gaussian processes to guide the search through protein sequence space by designing, constructing, and testing chimeric cytochrome P450s. These algorithms allowed us to engineer active P450 enzymes that are more thermostable than any previously made by chimeragenesis, rational design, or directed evolution.
The Roles of Sodium Channels in Nociception: Implications for Mechanisms of Neuropathic Pain (2011)

Animal models have provided useful insights into the development and treatment of neuropathic pain. New genetic data from both human studies and transgenic mouse models suggest that specific voltage-gated sodium channel subtypes are associated with specific types of pain and, as such, may be useful analgesic drug targets for a variety of pain types including neuropathic pain. Global voltage-gated sodium channel blockers such as lidocaine have proven efficacy in treating pain but can be limited by adverse effects when administered systemically. Selective sodium channel blockers targeting channels at the periphery (Nav1.7, Nav1.8, and Nav1.9) could potentially reduce the side effect profile. Individual isoforms of voltage-gated sodium channels have been linked to particular types of pain. Nav1.7 is a useful target for ameliorating acute mechanical pain and inflammatory pain, and strong evidence also suggests that Nav1.9 could be targeted for treating inflammatory pain. Selective blockers of Nav1.8 could also have clinical benefit for visceral pain. Although there is no association between a single sodium channel isoform and neuropathic pain, combined blockade of peripherally expressed isoforms Nav1.7, Nav1.8, and Nav1.9 may prove useful.
Cox's Regression Model for Counting Processes: A Large Sample Study (1982)

The Cox regression model for censored survival data specifies that covariates have a proportional effect on the hazard function of the life-time distribution of an individual. In this paper we discuss how this model can be extended to a model where covariate processes have a proportional effect on the intensity process of a multivariate counting process. This permits a statistical regression analysis of the intensity of a recurrent event allowing for complicated censoring patterns and time dependent covariates. Furthermore, this formulation gives rise to proofs with very simple structure using martingale techniques for the asymptotic properties of the estimators from such a model. Finally an example of a statistical analysis is included.
Power wheelchair range testing and energy consumption during fatigue testing. (1995)

The range of a power wheelchair depends on many factors including: battery type, battery state, wheelchair/rider weight, terrain, the efficiency of the drive train, and driving behavior. The purpose of this study was to evaluate the feasibility of three methods of estimating power wheelchair range. Another significant purpose was to compare the current draw on pavement to current draw on an International Standards Organization (ISO) Double Drum tester at one m/sec. Tests were performed on seven different power wheelchairs unloaded, and loaded with an ISO 100 kg test dummy. Each chair was configured according to the manufacturer's specifications, and tires were properly inflated. Experienced test technicians were used for the tennis court tests, and treadmill tests. An ISO 100 kg test dummy was used for the ISO Double Drum test. Energy consumption was measured over a distance of 1500 m for each of the three test conditions. The rolling surface was level in all cases. Repeated measure analysis of variance (ANOVA) revealed a significant difference (p = 0.0001) between the predicted range at maximum speed for the three tests. Post hoc analysis demonstrated a significant difference (p < 0.01) in estimated range at maximum speed between the Double Drum test and the treadmill test, as well as between the Double Drum test and the tennis court test. Our results indicate no significant difference (p > 0.05) between the predicted range at maximal speed between the treadmill and tennis court tests. A simple relationship does not exist between the results of range testing with the Double Drum tester and the tennis court. An alternative would be to permit the use of a treadmill for range testing as simple relationships between all pertinent treadmill and tennis court range data were found. For the Double Drum tester used, the current demand is higher than under normal usage. This presents a problem as current is related to load torque in a power wheelchair. Hence, the Double Drum tester friction must be reduced. The predicted range for the tennis court test at maximum speed ranges from a low of 23.6 km to a high of 57.7 km. The range of the power wheelchair can be improved by the use of wet lead acid batteries in place of gel lead acid batteries.
Substrate stabilization of lysozyme to thermal and guanidine hydrochloride denaturation. (1980)

The thermal and guanidine hydrochloride (GdnHCl) denaturation of lysozyme has been investigated at various concentrations of tri-N-acetylglucosamine ((GlcNAc)3), a trisaccharide which binds specifically at the active site of native lysozyme. The presence of (GlcNAc)3 leads to a readily observable stabilization of the protein to thermal and GdnHCl denaturation. An analysis of guanidine hydrochloride denaturation curves shows that the stability of lysozyme is increased by 495 cal/mol by the presence of 3 x 10(-4) M (GlcNAc)3. The midpoint of the thermal denaturation curve, T 1/2, is increased 1.6 and 5.3 degrees C by 2.02 x 10(-4) M and 1.38 x 10(-3) M (GlcNAc)3, respectively. This corresponds to an increase in the stability of lysozyme of 385 and 1275 cal/mol. These results are in excellent agreement with predictions based on an equation derived by Schellman ((1975) Biopolymers 14, 999-1018) to take into account the effect of ligand binding on the melting temperature of a protein. delta T 1/2 = TT0R divided by delta HD ln (1 + KB[S]) where T and T0 are T1/2 values in the presence and absence of (GlcNAc)3, delta HD is the enthalpy of denaturation in the presence of (GlcNAc)3, KB in the equilibrium constant for the binding of (GlcNAc)3 to lysozyme, and [S] is the free concentration of (GlcNAc)3. Thus, the increased stability of an enzyme in the presence of its substrate, coenzyme, or any small molecule that it binds specifically results because binding to the native state shifts the unfolding equilibrium and decreases the concentration of unfolded states of the enzyme. It is suggested that this may be a more important factor than substrate-induced conformational changes in acccounting for the decreased rates of protein catabolism frequently observed in vivo at elevated substrate concentrations.
Temperature‐Gradient gel electrophoresis of nucleic acids: Analysis of conformational transitions, sequence variations, and protein‐nucleic acid interactions (1989)

Temperature-gradient gel electrophoresis (TGGE) is applied to analyze conformational transitions and sequence variations of nucleic acids and protein-nucleic acid interactions. A linear and highly reproducible temperature-gradient is established perpendicular or parallel to the direction of the electrophoresis. The instrument consists of an electrically insulated metal plate, which is heated at one edge and cooled at the other edge by two thermostating baths and is used as an ancillary device for commercial horizontal gel electrophoresis instruments. Biopolymers are separated in TGGE according to size, shape and thermal stability of their conformational transitions. If the temperature-gradient is established perpendicular to the electrophoresis, monomolecular conformational transitions of nucleic acids show up as continuous transition curves; strand-separation leads to discontinuous transitions. In the studies on viroid RNA it was shown that natural circular viroid RNA undergoes one highly cooperative transition detected by TGGE as a drastic retardation in mobility. Oligomeric replication intermediates of viroids exhibit coexisting structures which could not be detected by any other technique. Double-stranded satellite RNA from cucumber mosaic virus is a mixture of sequence variants, all of which have the identical length of 335 nucleotides. In TGGE six different strains were resolved. Sequence variants of viroids were analyzed by hybridizing viroid RNA to (-)strand viroid RNA transcripts from viroid cDNA clones. Sequence variations lead to mismatches in the double strands and thereby to a shift of the transition curve to lower temperature. Mutations in plasmids, particularly in cloned inserts, were detected by mixing plasmids of two different clones, linearizing, denaturing, renaturing, and searching for shifts in the transition curves, which are generated by mismatch-formation during the renaturation of (+)- and (-)strands from different clones. Examples are given for different viroid clones and HIV-clones from one and the same patient. In another example, clones with point mutations from site-directed mutagenesis are analyzed and selected by TGGE. TGGE is also applied to study the effect of amino acid exchanges in the Tet repressor from E. coli on the thermal stability of the repressor and on the mode of binding of the repressor to the operator DNA. The results are discussed under the aspect that TGGE may be applied as routine analytical laboratory procedure.
Role of the Trans-activation Response Element in Dimerization of HIV-1 RNA (2004)

The HIV-1 genome consists of two identical RNA strands that are linked together through non-covalent interactions. A major determinant for efficient dimerization of the two RNA strands is the interaction between palindromic sequences in the dimerization initiation site. Here we use an interplay of bioinformatics, biochemistry, and atomic force microscopy to describe another conserved palindrome in the trans-activation response element (TAR) that functions as a strong dimerization site when transiently exposed to the viral nucleocapsid protein. In conjunction with the DIS interaction, the TAR dimerization induces the formation of a 65-nm higher-order circular structure in the dimeric HIV-1 RNA. Our results provide a molecular model for the role of TAR in packaging and reverse transcription of the viral genome. The unique structure of the TAR-TAR dimer renders it an intriguing therapeutic target for the treatment of HIV-1 infection.
Receptor-dependent internalization of platelet-activating factor. (1994)

A human neutrophil platelet-activating factor (PAF) receptor expressed in transfected cells was utilized to study receptor-dependent interactions with the ligand. This receptor displays ligand-binding properties comparable with those observed with naturally occurring receptor-positive cells when binding experiments are performed using COS-7 cells at 4 degrees C. The ligand-receptor interaction is markedly temperature dependent, with approximately 10-fold more [3H]PAF specifically associated with the cells at 37 degrees C than at 4 degrees C. Such temperature dependence is not observed with other ligand-receptor pairs. At 37 degrees C essentially all the cell-associated PAF appears to be internalized and incorporated into a phospholipid pool. In the absence of transfected receptor no specific binding is detected in COS-7 cells at 4 degrees C, and at 37 degrees C, no significant ligand internalization is observed. The epitope-tagged fusion protein, Flag-PAF receptor, was used to track the receptor independently of ligand binding, and showed that the receptor protein expressed on the cell surface is not influenced by temperature alone. Incubation with PAF at 37 degrees C resulted in the disappearance of approximately 20% of the Flag-PAF receptor epitope from the cell surface relative to cells incubated without PAF or cells preincubated with or without PAF at 4 degrees C. Ligand internalization in PAF receptor-transfected cells is inhibited by the receptor antagonist, WEB 2086, further supporting the receptor-dependence of this action. Stimulation of untransfected cells with phorbol ester, or C5a receptor-transfected cells with C5a, shows minimal increase in PAF internalization relative to PAF receptor-transfected cells, another feature that distinguishes the receptor-dependent pathway. These data suggest that in the COS-7 cell system PAF internalization is dependent on expression of the PAF receptor, and that the apparently nonspecific uptake observed in human neutrophils and other cells may involve receptor-independent mechanisms.
Distributed Text Classification With an Ensemble Kernel-Based Learning Approach (2010)

<para xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> Constructing a single text classifier that excels in any given application is a rather inviable goal. As a result, ensemble systems are becoming an important resource, since they permit the use of simpler classifiers and the integration of different knowledge in the learning process. However, many text-classification ensemble approaches have an extremely high computational burden, which poses limitations in applications in real environments. Moreover, state-of-the-art kernel-based classifiers, such as support vector machines and relevance vector machines, demand large resources when applied to large databases. Therefore, we propose the use of a new systematic distributed ensemble framework to tackle these challenges, based on a generic deployment strategy in a cluster distributed environment. We employ a combination of both task and data decomposition of the text-classification system, based on partitioning, communication, agglomeration, and mapping to define and optimize a graph of dependent tasks. Additionally, the framework includes an ensemble system where we exploit diverse patterns of errors and gain from the synergies between the ensemble classifiers. The ensemble data partitioning strategy used is shown to improve the performance of baseline state-of-the-art kernel-based machines. The experimental results show that the performance of the proposed framework outperforms standard methods both in speed and classification. </para>
Efficiency analysis and application of uncovered background prediction in a low bit rate image coder (1990)

A fast algorithm for gaining scene background information from a TV sequence is presented. This picture information is used by an uncovered background predictor in a motion-compensating predictive coder for videoconference or picture telephone applications. In uncovered background regions, prediction error entropy is reduced close to the value of the frame difference entropy in static regions, which is regarded as a practical lower bound. Almost all these picture elements can therefore be reconstructed without transmission. A motion-compensating hybrid differential pulse-code modulation (hybrid-DPCM)/transform coder is supplemented by uncovered background prediction. The maximum bit rate reduction achieved in the experiments is 9% for a picture where 14% of the picture elements of temporally changed regions belong to uncovered background regions.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>