gebhart/patrepeval huggingface dataset:
Structural kinetic modeling of metabolic networks (2006)

To develop and investigate detailed mathematical models of metabolic processes is one of the primary challenges in systems biology. However, despite considerable advance in the topological analysis of metabolic networks, kinetic modeling is still often severely hampered by inadequate knowledge of the enzyme-kinetic rate laws and their associated parameter values. Here we propose a method that aims to give a quantitative account of the dynamical capabilities of a metabolic system, without requiring any explicit information about the functional form of the rate equations. Our approach is based on constructing a local linear model at each point in parameter space, such that each element of the model is either directly experimentally accessible or amenable to a straightforward biochemical interpretation. This ensemble of local linear models, encompassing all possible explicit kinetic models, then allows for a statistical exploration of the comprehensive parameter space. The method is exemplified on two paradigmatic metabolic systems: the glycolytic pathway of yeast and a realistic-scale representation of the photosynthetic Calvin cycle.
Novel Nonreplicating Vaccinia Virus Vector Enhances Expression of Heterologous Genes and Suppresses Synthesis of Endogenous Viral Proteins (2017)

Viruses are used as expression vectors for protein synthesis, immunology research, vaccines, and therapeutics. Advantages of poxvirus vectors include the accommodation of large amounts of heterologous DNA, the presence of a cytoplasmic site of transcription, and high expression levels. On the other hand, competition of approximately 200 viral genes with the target gene for expression and immune recognition may be disadvantageous. We describe a vaccinia virus (VACV) vector that uses an early promoter to express the bacteriophage T7 RNA polymerase; has the A23R intermediate transcription factor gene deleted, thereby restricting virus replication to complementing cells; and has a heterologous gene regulated by a T7 promoter. In noncomplementing cells, viral early gene expression and DNA replication occurred normally but synthesis of intermediate and late proteins was prevented. Nevertheless, the progeny viral DNA provided templates for abundant expression of heterologous genes regulated by a T7 promoter. Selective expression of the <i>Escherichia coli lac</i> repressor gene from an intermediate promoter reduced transcription of the heterologous gene specifically in complementing cells, where large amounts might adversely impact VACV replication. Expression of heterologous proteins mediated by the A23R deletion vector equaled that of a replicating VACV, was higher than that of a nonreplicating modified vaccinia virus Ankara (MVA) vector used for candidate vaccines <i>in vitro</i> and <i>in vivo</i>, and was similarly immunogenic in mice. Unlike the MVA vector, the A23R deletion vector still expresses numerous early genes that can restrict immunogenicity as demonstrated here by the failure of the prototype vector to induce interferon alpha. By deleting immunomodulatory genes, we anticipate further improvements in the system.<b>IMPORTANCE</b> Vaccines provide an efficient and effective way of preventing infectious diseases. Nevertheless, new and better vaccines are needed. Vaccinia virus, which was used successfully as a live vaccine to eradicate smallpox, has been further attenuated and adapted as a recombinant vector for immunization against other pathogens. However, since the initial description of this vector system, only incremental improvements largely related to safety have been implemented. Here we described novel modifications of the platform that increased expression of the heterologous target gene and decreased expression of endogenous vaccinia virus genes while providing safety by preventing replication of the candidate vaccine except in complementing cells used for vector propagation.
Loss-of-Function of HtrA1 Abrogates All- <i>Trans</i> Retinoic Acid-Induced Osteogenic Differentiation of Mouse Adipose-Derived Stromal Cells Through Deficiencies in p70S6K Activation (2016)

All-trans retinoic acid (ATRA) is a potent inducer of osteogenic differentiation in mouse adipose-derived stromal cells (mASCs), although the underlying mechanisms responsible for its mode of action have yet to be completely elucidated. High temperature requirement protease A1 (HtrA1) is a newly recognized modulator of human multipotent stromal cell (MSC) osteogenesis and as such, may play a role in regulating ATRA-dependent osteogenic differentiation of mASCs. In this study, we assessed the influence of small interfering RNA (siRNA)-induced repression of HtrA1 production on mASC osteogenesis and examined its effects on ATRA-mediated mammalian target of rapamycin (mTOR) signaling. Inhibition of HtrA1 production in osteogenic mASCs resulted in a significant reduction of alkaline phosphatase activity and mineralized matrix formation. Western blot analyses revealed the rapid activation of Akt (Ser473) and p70S6K (Thr389) in ATRA-treated mASCs, and that levels of phosphorylated p70S6K were noticeably reduced in HtrA1-deficient mASCs. Further studies using mTOR inhibitor rapamycin and siRNA specific for the p70S6K gene Rps6kb1 confirmed ATRA-mediated mASC osteogenesis as being dependent on p70S6K activation. Finally, transfection of cells with a constitutively active rapamycin-resistant p70S6K mutant could restore the mineralizing capacity of HtrA1-deficient mASCs. These findings therefore lend further support for HtrA1 as a positive mediator of MSC osteogenesis and provide new insights into the molecular mode of action of ATRA in regulating mASC lineage commitment.
Antidiarrheal activity of alpha-2 adrenoceptor agonist SK&F 35886. (1989)

Alpha-2 adrenoceptor agonists exhibit antidiarrheal activity in animal models and in humans. However, hypotensive and sedative side effects seriously limit the use of these agents to treat diarrhea. SK&F 35886 (2,6-dimethyl phenylamino imidazoline) is an alpha-2 adrenoceptor agonist with little central nervous system activity. In Ussing chamber preparations of rabbit ileum, SK&F 35886 produces a concentration-dependent decrease in basal short-circuit current (Isc) (EC50 0.2 microM) that is dependent on the presence of mucosal HCO3. This concentration-response curve is shifted to the right of rauwolscine, increasing the EC50 to 30 microM. Prazosin had no effect on this response. Flux studies indicate that SK&F 35886 increases net Cl absorption and enhances HCO3 absorption without altering net Na flux. After PGE2 stimulation of Isc, SK&F 35886, applied either serosally or mucosally, immediately returns the Isc to base line. This effect is due to a reversal of the PGE2-induced inhibition of Na and Cl absorption. In vivo SK&F 35886 dose-dependently inhibits PGE2-induced enteropooling when given orally (ED50 approximately 31 micrograms/kg). This effect is attenuated significantly by rauwolscine (1.0 micrograms/kg s.c.). In cecectomized rats, SK&F 35886 abolishes PGE2-induced diarrhea within 1 hr after oral administration of the drug. SK&F 35886 (500 micrograms/kg p.o.) did not alter hexobarbital sleep time or elicit piloerection or lethargy, whereas clonidine (37.3 micrograms/kg p.o.) significantly enhanced hexobarbital sleep time. These results illustrate the ability of a peripheral acting alpha-2 agonist to promote absorption and inhibit secretion and diarrhea in the mammalian intestine.
Autologous Culture-Modified Mononuclear Cells Confer Vascular Protection After Arterial Injury (2003)

These data demonstrate that delivery of CMMCs to balloon-injured arteries is associated with accelerated reendothelialization, enhanced endothelium-dependent vasoreactivity, and reduced neointimal formation. Thus, delivery of autologous CMMCs represents a novel vasculoprotective approach to attenuate the response to acute vascular injury.
α-Terpineol attenuates morphine-induced physical dependence and tolerance in mice: role of nitric oxide. (2016)

These findings indicate that α-terpineol prevents the development of dependence and tolerance to morphine probably through the influence on NO production.
Differential activation of heat shock and nuclear factor κB transcription factors in postischemic reperfused rat liver (1997)

The aim of this study was to investigate the behavior of the transcription factors, heat-shock factor (HSF) and nuclear factor κB (NF-κB), in postischemic reperfused liver, with particular attention paid to possible differences in the time-course and mechanism of activation, which may help in defining their role in the response of the liver to reperfusion. Ischemia was induced by clamping the hilar pedicle of the left lateral and median liver lobes; the clamp was removed after 1 hour. Some rats were treated intraperitoneally with IL-1 receptor antagonist (IL-1RA) 30 minutes before ischemia and at the time of reperfusion. Binding of NF-κB to the corresponding consensus sequence is activated after 30 minutes of reperfusion, and is still increased 1 hour after reperfusion. Activation is suppressed in rats treated with IL-1RA; NF-κB persists in the cytosol associated with the inhibitor, IκB, and can be artifactually activated in vitro . Super-gel shift experiments revealed that the two subunits, p50 and p65, are involved in the activation of binding. In contrast, binding of HSF to the corresponding consensus sequence, heat shock element (HSE), is already activated at the end of ischemia, shows a further increase after 30 minutes of reperfusion, but declines 1 hour after reperfusion; more importantly, it is not inhibited by pretreatment of the rat with IL-1RA. In conclusion, although both HSF and NF-κB are activated by ischemia-reperfusion, there are clear differences in time-course and mechanism of activation of the two transcription factors. Activation of HSF depends directly on some events occurring during ischemia; NF-κB is activated only after reperfusion and the concurrent oxidative stress, by an indirect mechanism that can be suppressed by IL-1RA. The possibility of dissociating the activation of these two transcription factors in postischemic reperfusion can have a prospective clinical relevance.
Effects of xylanase and antibiotic supplementations on the nutritional utilisation of a wheat diet in growing chicks from genetic D+ and D− lines selected for divergent digestion efficiency (2007)

The experiment consisted of a 2 × 2 × 2 factorial design testing the two D+ and D- chicken lines selected for divergent digestion efficiency (fifth selection generation), xylanase (with or without) and ampicillin and collistin (with or without) supplementations. From 8 to 22 days, 144 chickens (18 birds per treatment) were fed a diet containing 55% wheat from a high-viscosity cultivar (Rialto). Effects of treatments were evaluated on individual growth performance (8 to 19 days), digestibilities of lipids and dry matter, dietary energy value (apparent metabolisable energy corrected to zero-nitrogen retention (AMEn)), digestive organ and breast sizes, and intestinal bile acids at 3 weeks of age. Individual variabilities were much lower in D+ than in D- birds for feed : gain ratios, digestibilities and AMEn values. In all cases, feed : gain ratios were lower in the D+ than in the D- line (P < 0.001), and D+ birds showed 22% to 86% higher values than in D- birds (P < 0.001) for digestibilities and AMEn. In D- birds, antibiotics but not xylanase supplementation had significant effects on lipid digestibility (P < 0.01) and AMEn (P < 0.05), whereas both supplements improved these parameters in D+ birds (P < 0.001 for both additives on lipids digestibility, P < 0.05 for xylanase and P < 0.01 for antibiotics on AMEn). Relative weights of gizzard and proventriculus, and gizzard : intestine weight ratio were higher in D+ than in D- birds, while relative weight of intestine was increased in D- birds compared with D+ birds. Antibiotics reduced intestine relative weight in D+ (P < 0.001) and D- (P < 0.01) lines. AMEn variations were efficiently predicted by the gizzard : intestine weight ratio. In conclusion, antibiotics were very efficient for improving growth performance, AMEn and digestibility values in both chicken lines. Xylanase was less efficient than antibiotics. Because of their low individual variabilities, D+ birds were much more efficient than D- ones for the detection of significant effects induced by xylanase supplementation. Differences between lines in feed : gain ratio, digestibilities and AMEn were reduced when xylanase and antibiotics were added together. Effects of xylanase supplementation and animal genetics on lipid digestibility could not be entirely explained in terms of intestinal bile acids. Other factors should be involved, especially for the lipid digestibility difference induced by animal genetics. The gizzard : intestine weight ratio was an efficient parameter for predicting AMEn variations due to animal genetics and additives.
Dancing About Architecture : Postmodernism and Irish Popular Music (1998)

Listening to Bono of U2 in a recent radio interview, I was struck by a comment he made. He was talking about contemporary and past musics, and how the past and the present are tied up with hopes and fears about the future. It was, he argued, a case of the difference between yesterdays tomorrow and todays tomorrow. Yesterday's tomorrow was about a confidence for the future, a belief that progress was more or less inevitable and, for music, that artistic creativity would continue to blossom and produce great works.
Differences between versions of UML diagrams (2003)

This paper addresses the problem of how to detect and visualise differences between versions of UML documents such as class or object diagrams. Our basic approach for showing the differences between two documents is to use a unified document which contains the common and specific parts of both base documents; the specific parts are highlighted. The main problems are (a) how to abstract from modifications done to the layout and other (document type-specific) details which are considered irrelevant; (b) how to deal with structural changes such as the shifting of an operation from one class to another; (c) how to reduce the amount of highlighted information. Our approach is based on the assumption that software documents are modelled in a fine-grained way, i.e. they are stored as syntax trees in XML files or in a repository system, and that the version management system supports fine-grained data. Our difference computation algorithm detects structural changes and enables their appropriate visualisation. Highlighting can be restricted on the basis of the types of the elements and on the basis of the revision history, e.g. only changes which occurred during a particular editing session are highlighted.
Internal Preload Control of redundantly actuated Parallel Manipulators – Backlash avoiding Control (2006)

Redundant actuation of parallel manipulators admits internal forces without generating end-effector forces (preload). Preload can be controlled in order to prevent backlash during the manipulator motion. Such controlis based on the inverse dynamics. The general solution of the inverse dynamics of redundantly actuated parallel manipulators is given. For the special case of simple over actuation an explicit solution is derived in terms of a single preload parameter. With this formulation a computational effcient open-loop preload control is developed and applied to the elimination of backlash. Its simplicity makes it applicable in real-time applications. The approach is exemplified for a planar 4RRR manipulator.
Integrated Effects of Genetic Resistance and Prothioconazole + Tebuconazole Application Timing on Fusarium Head Blight in Wheat (2018)

Integrated Fusarium head blight (FHB) management programs consisting of different combinations of cultivar resistance class and an application of the fungicide prothioconazole + tebuconazole at or after 50% early anthesis were evaluated for efficacy against FHB incidence (INC; percentage of diseased spikes), index (IND; percentage of diseased spikelets per spike), Fusarium damaged kernel (FDK), deoxynivalenol (DON) toxin contamination, grain yield, and test weight (TW) in inoculated field trials conducted in 11 U.S. states in 2014 and 2015. Mean log response ratios and corresponding percent control values for INC, IND, FDK, and DON, and mean differences in yield and TW relative to a nontreated, inoculated susceptible check (S_CK), were estimated through network meta-analyses as measures of efficacy. Results from the analyses were then used to estimate the economic benefit of each management program for a range of grain prices and fungicide applications costs. Management programs consisting of a moderately resistant (MR) cultivar treated with the fungicide were the most efficacious, reducing INC by 60 to 69%, IND by 71 to 76%, FDK by 66 to 72%, and DON by 60 to 64% relative to S_CK, compared with 56 to 62% for INC, 68 to 72% for IND, 66 to 68% for FDK, and 58 to 61% for DON for programs with a moderately susceptible (MS) cultivar. The least efficacious programs were those with a fungicide application to a susceptible (S) cultivar, with less than a 45% reduction of INC, IND, FDK, or DON. All programs were more efficacious under conditions favorable for FHB compared with less favorable conditions, with applications made at 50% early anthesis being of comparable efficacy to those made 2 to 7 days later. Programs with an MS cultivar resulted in the highest mean yield increases relative to S_CK (541 to 753 kg/ha), followed by programs with an S cultivar (386 to 498 kg/ha) and programs with an MR cultivar (250 to 337 kg/ha). Integrated management programs with an MS or MR cultivar treated with the fungicide at or after 50% early anthesis were the most likely to result in a 50 or 75% control of IND, FDK, or DON in a future trial. At a fixed fungicide application cost, these programs were $4 to $319/MT more economically beneficial than corresponding fungicide-only programs, depending on the cultivar and grain price. These findings demonstrate the benefits of combining genetic resistance with a prothioconazole + tebuconazole treatment to manage FHB, even if that treatment is applied a few days after 50% early anthesis.
Inhibition of growth of estrogen receptor positive and estrogen receptor negative breast cancer cells in culture by AA-etherA, a stable 2-5A derivative. (1996)

The design, chemical synthesis and biological activities of a nuclease-resistant, nontoxic bioactive 2-5A derivative, AA-etherA [i.e., adenylyl-(2'-5')-adenylyl-(2'-2")-9-[(2'-hydroxyethoxy)-methyl]adenine], are described as a new approach to the inhibition of breast cancer cell growth. AA-etherA inhibits DNA replication and cell division of both estrogen receptor positive (MCF-7) and estrogen receptor negative (BT-20) breast cancer cells in culture in a dose-dependent manner. Maximal inhibition in MCF-7 and BT-20 cells was obtained with 100 microM AA-etherA after four days of treatment, with an GI50 of 58 and 37 microM, respectively. AA-etherA is stable in the cytoplasm. Treated cells accumulate within the late G1/early S phase of the cell cycle and then progress only very slowly through S phase. AA-etherA does not activate RNase L, as do 2-5A and other 2-5A derivatives, nor does it increase p68 kinase (PKR) content of the cells. High resolution, two-dimensional protein gel electrophoresis reveals twofold or greater inhibition of synthesis of 92 proteins out of 682 proteins that were reproducibly detected as high quality spots with average rates of synthesis of > or = 20 p.p.m. in untreated cells. The specificity of the effects of AA-etherA on select proteins and its failure to activate RNase L indicate that AA-etherA does not act through a general effect on mRNA translation or stability, but rather inhibits cell proliferation through a block to DNA replication, with a concommitant reduction in the synthesis of specific proteins, some of which may be required for cell cycle transit. Two likely targets to account for the AA-etherA inhibition of DNA replication are DNA topoisomerase I, which is inhibited by AA-etherA in other cell lines, and thymidine kinase, which could be inhibited in a manner similar to the effect of acyclovir. These data indicate that 2-5A analogs, particularly bifunctional 2-5A analogs like AA-etherA, will be useful for controlling cancer cell growth. Further development of such 2-5A analogs may provide highly specific compounds for chemotherapy and chemoprevention.
Cortical event-related potentials in preclinical familial Alzheimer disease (2009)

Auditory sensory and cognitive cortical potentials in persons with familial Alzheimer disease (FAD) mutations are abnormal approximately 10 years before dementia will be manifest. Longer event-related potential latencies suggest slowing of cortical information processing in FAD mutation carriers.
Big Data Application in Biomedical Research and Health Care: A Literature Review (2016)

Big data technologies are increasingly used for biomedical and health-care informatics research. Large amounts of biological and clinical data have been generated and collected at an unprecedented speed and scale. For example, the new generation of sequencing technologies enables the processing of billions of DNA sequence data per day, and the application of electronic health records (EHRs) is documenting large amounts of patient data. The cost of acquiring and analyzing biomedical data is expected to decrease dramatically with the help of technology upgrades, such as the emergence of new sequencing machines, the development of novel hardware and software for parallel computing, and the extensive expansion of EHRs. Big data applications present new opportunities to discover new knowledge and create novel methods to improve the quality of health care. The application of big data in health care is a fast-growing field, with many new discoveries and methodologies published in the last five years. In this paper, we review and discuss big data application in four major biomedical subdisciplines: (1) bioinformatics, (2) clinical informatics, (3) imaging informatics, and (4) public health informatics. Specifically, in bioinformatics, high-throughput experiments facilitate the research of new genome-wide association studies of diseases, and with clinical informatics, the clinical field benefits from the vast amount of collected patient data for making intelligent decisions. Imaging informatics is now more rapidly integrated with cloud platforms to share medical image data and workflows, and public health informatics leverages big data techniques for predicting and monitoring infectious disease outbreaks, such as Ebola. In this paper, we review the recent progress and breakthroughs of big data applications in these health-care domains and summarize the challenges, gaps, and opportunities to improve and advance big data applications in health care.