gebhart/patrepeval huggingface dataset:
Distortion of the Active Site of Chymotrypsin Complexed with a Serpin (1996)

There is no complete understanding of how serine protease inhibitors of the serpin family inhibit their target enzymes. Structural and biochemical studies have suggested that serpins utilize a mechanism that is distinct from the standard mechanism of inhibition proposed for most small protein protease inhibitors. Proton nuclear magnetic resonance spectroscopy was used in the present study to demonstrate a fundamental difference in the atomic environment of the catalytic triad of enzyme in complex with serpins when compared to uncomplexed enzyme and enzyme in complex with standard mechanism inhibitors. This work demonstrates that the active site of chymotrypsin is distorted when complexed to a serpin and makes tenable a mechanism of inhibition in which the serpin induces a conformational change in the enzyme that dramatically reduces or completely abrogates the catalytic activity of the protease.
Electrotonic Modulation of Cardiac Impulse Conduction by Myofibroblasts (2006)

Structural remodeling of the myocardium associated with mechanical overload or cardiac infarction is accompanied by the appearance of myofibroblasts. These fibroblast-like cells express alpha-smooth muscle actin (alphaSMA) and have been shown to express connexins in tissues other than heart. The present study examined whether myofibroblasts of cardiac origin establish heterocellular gap junctional coupling with cardiomyocytes and whether ensuing electrotonic interactions affect impulse propagation. For this purpose, impulse conduction characteristics (conduction velocity [theta] and maximal upstroke velocity [dV/dtmax]) were assessed optically in cultured strands of cardiomyocytes, which were coated with fibroblasts of cardiac origin. Immunocytochemistry showed that cultured fibroblasts underwent a phenotype switch to alphaSMA-positive myofibroblasts that expressed connexin 43 and 45 both among themselves and at contact sites with cardiomyocytes. Myofibroblasts affected theta and dV/dtmax in a cell density-dependent manner; a gradual increase of myofibroblast-to-cardiomyocyte ratios up to 7:100 caused an increase of both theta and dV/dtmax, which was followed by a progressive decline at higher ratios. On full coverage of the strands with myofibroblasts (ratio >20:100), theta fell <200 mm/s. This biphasic dependence of theta and dV/dtmax on myofibroblast density is reminiscent of "supernormal conduction" and is explained by a myofibroblast density-dependent gradual depolarization of the cardiomyocyte strands from -78 mV to -50 mV as measured using microelectrode recordings. These findings suggest that myofibroblasts, apart from their role in structural remodeling, might contribute to arrhythmogenesis by direct electrotonic modulation of conduction and that prevention of their appearance might represent an antiarrhythmic therapeutic target.
Notch Pathway Inhibition Depletes Stem-like Cells and Blocks Engraftment in Embryonal Brain Tumors (2006)

The Notch signaling pathway is required in both nonneoplastic neural stem cells and embryonal brain tumors, such as medulloblastoma, which are derived from such cells. We investigated the effects of Notch pathway inhibition on medulloblastoma growth using pharmacologic inhibitors of gamma-secretase. Notch blockade suppressed expression of the pathway target Hes1 and caused cell cycle exit, apoptosis, and differentiation in medulloblastoma cell lines. Interestingly, viable populations of better-differentiated cells continued to grow when Notch activation was inhibited but were unable to efficiently form soft-agar colonies or tumor xenografts, suggesting that a cell fraction required for tumor propagation had been depleted. It has recently been hypothesized that a small population of stem-like cells within brain tumors is required for the long-term propagation of neoplastic growth and that CD133 expression and Hoechst dye exclusion (side population) can be used to prospectively identify such tumor-forming cells. We found that Notch blockade reduced the CD133-positive cell fraction almost 5-fold and totally abolished the side population, suggesting that the loss of tumor-forming capacity could be due to the depletion of stem-like cells. Notch signaling levels were higher in the stem-like cell fraction, providing a potential mechanism for their increased sensitivity to inhibition of this pathway. We also observed that apoptotic rates following Notch blockade were almost 10-fold higher in primitive nestin-positive cells as compared with nestin-negative ones. Stem-like cells in brain tumors thus seem to be selectively vulnerable to agents inhibiting the Notch pathway.
Dysfunctional teams a health and resource warning (2002)

Team working is vital in service provision and success depends on management styles and function. Susan Major uses one example of a teamwork initiative to show how teams might work in a culture of stability, productivity and openness
The Stem Cell Pluripotency Factor NANOG Activates Transcription with Two Unusually Potent Subdomains at Its C Terminus (2004)

Embryonic stem cells are pluripotent progenitors for virtually all cell types in our body and thus possess unlimited therapeutic potentials for regenerative medicine. NANOG, an NK-2 type homeodomain gene, has been proposed to play a key role in maintaining stem cell pluripotency presumably by regulating the expression of genes critical to stem cell renewal and differentiation. Here, we provide the evidence that NANOG behaves as a transcription activator with two unusually strong activation domains embedded in its C terminus. First, we identified these two transactivators by employing the Gal4-DNA binding domain fusion and reporter system and named them WR and CD2. Whereas CD2 contains no obvious structural motif, the WR or Trp repeat contains 10 pentapeptide repeats starting with a Trp in each unit. Substitution of Trp with Ala in each repeat completely abolished its activity, whereas mutations at the conserved Ser, Gln, and Asn had relatively minor or no effect on WR activity. We then validated the activities of WR and CD2 in NANOG by constructing a reporter plasmid bearing five NANOG binding sites. Deletion of both WR and CD2 from NANOG completely eliminated its transactivation function. Paradoxically, whereas the removal of CD2 reduced NANOG activity by approximately 30-70%, the removal of WR not only did not diminish but actually enhanced its activity by approximately 50-100% depending on the cell lines analyzed. These data suggest that either WR or CD2 is sufficient for NANOG to function as a transactivator.
FIS modulates growth phase‐dependent topological transitions of DNA in Escherichia coli (1997)

The Escherichia coli DNA-binding protein FIS serves as a DNA architectural factor in two unrelated enzymatic reactions, the site-specific inversion of DNA and transcriptional activation of stable RNA promoters. In both these processes, FIS facilitates the assembly and dynamic transitions of two structurally distinct nucleoprotein complexes. We have proposed previously that, in these systems, FIS stabilizes writhed DNA microloops by binding at multiple helically phased sites in DNA. However, FIS also binds and bends DNA at many non-specific sites and, at its maximum levels in the early exponential phase, FIS could potentially occupy a considerable part of the E. coli chromosome. Here, we show that fis affects growth phase-specific alterations in the supercoiling level of DNA. Expression of fis accelerates the accumulation of moderately supercoiled plasmids in stationary phase, which are stabilized by FIS after nutritional shift-up. In accordance with such a function, FIS modulates the relaxing and supercoiling activities of topoisomerases in vitro in a way that keeps DNA in a moderately supercoiled state. Our results suggest that the primary role of FIS is to modulate chromosomal dynamics during bacterial growth.
Characterization of Angiotensin-Converting Enzyme 2 Ectodomain Shedding from Mouse Proximal Tubular Cells (2014)

Angiotensin-converting enzyme 2 (ACE2) is highly expressed in the kidney proximal tubule, where it cleaves angiotensin (Ang) II to Ang-(1-7). Urinary ACE2 levels increase in diabetes, suggesting that ACE2 may be shed from tubular cells. The aim of this study was to determine if ACE2 is shed from proximal tubular cells, to characterize ACE2 fragments, and to study pathways for shedding. Studies involved primary cultures of mouse proximal tubular cells, with ACE2 activity measured using a synthetic substrate, and analysis of ACE2 fragments by immunoblots and mass spectrometry. The culture media from mouse proximal tubular cells demonstrated a time-dependent increase in ACE2 activity, suggesting constitutive ACE2 shedding. ACE2 was detected in media as two bands at ∼ 90 kDa and ∼ 70 kDa on immunoblots. By contrast, full-length ACE2 appeared at ∼ 100 kDa in cell lysates or mouse kidney cortex. Mass spectrometry of the two deglycosylated fragments identified peptides matching mouse ACE2 at positions 18-706 and 18-577, respectively. The C-terminus of the 18-706 peptide fragment contained a non-tryptic site, suggesting that Met(706) is a candidate ACE2 cleavage site. Incubation of cells in high D-glucose (25 mM) (and to a lesser extent Ang II) for 48-72 h increased ACE2 activity in the media (p<0.001), an effect blocked by inhibition of a disintegrin and metalloproteinase (ADAM)17. High D-glucose increased ADAM17 activity in cell lysates (p<0.05). These data indicate that two glycosylated ACE2 fragments are constitutively shed from mouse proximal tubular cells. ACE2 shedding is stimulated by high D-glucose, at least partly via an ADAM17-mediated pathway. The results suggest that proximal tubular shedding of ACE2 may increase in diabetes, which could enhance degradation of Ang II in the tubular lumen, and increase levels of Ang-(1-7).
Rearrangement of l-2-Hydroxyglutarate to l-threo-3-Methylmalate Catalyzed by Adenosylcobalamin-Dependent Glutamate Mutase (2000)

Adenosylcobalamin-dependent enzymes catalyze a variety of chemically difficult isomerizations in which a nonacidic hydrogen on one carbon is interchanged with an electron-withdrawing group on an adjacent carbon. We describe a new isomerization, that of L-2-hydroxyglutarate to L-threo-3-methylmalate, involving the migration of the carbinol carbon. This reaction is catalyzed by glutamate mutase, but k(cat) = 0.05 s(-)(1) is much lower than that for the natural substrate, L-glutamate (k(cat) = 5.6 s(-)(1)). EPR spectroscopy confirms that the major organic radical that accumulates on the enzyme is the C-4 radical of L-2-hydroxyglutarate. Pre-steady-state kinetic measurements revealed that L-2-hydroxyglutarate-induced homolysis of AdoCbl occurs very rapidly, with a rate constant approaching those measured previously with glutamate and methylaspartate as substrates. These observations are consistent with the rearrangement of the 2-hydroxyglutaryl radical being the rate-determining step in the reaction. The slow rearrangement of the 2-hydroxyglutaryl radical can be attributed to the poor stabilization by the hydroxyl group of the migrating glycolyl moiety of the radical transiently formed on the migrating carbon. In contrast, with the normal substrate the migrating carbon atom bears a nitrogen substituent that better stabilizes the analogous glycyl moiety. These studies point to the importance of the functional groups attached to the migrating carbon in facilitating the carbon skeleton rearrangement.
Fast saving and restoring virtual machines with page compression (2011)

More and more enterprises are moving beyond server virtualization to desktop virtualization in recent years. In virtualization environments, centralized shared storage systems are generally used to take advantage of virtualization features such as VM migration. Network file system (NFS) is considered to be the best choice in small or medium sized LANs due to its flexibility and low cost. But it becomes the bottleneck when many clients access the server simultaneously, especially when multiple virtual machines access a large amount of data at the same time, such as operation save and restore. In this paper, we present a new method named ComIO to quickly save and restore virtual machines using page compression. Based on the analysis of virtual machines' memory characteristics, we design a fast enhanced characteristic-based compression (ECBC) algorithm. Combined with multi-threaded techniques, the compression tasks are parallelized for significantly shortened compresssion time. Page boundary alignment is proposed to enable wanted page data to be directly extracted from the compressed block. The experimental results demonstrate that compared with Xen, our method ComIO not only greatly reduces the time spent on saving and restoring virtual machines on average, but also indirectly augments the effective storage space.
Semi-automatic test suite generation from Estelle (1992)

Overviews of the standard formal specfication language Estelle and test suite specification language TTCN are provided. Steps involved in semi-automatic generation of TTCN test suites from Estelle are introduced. Details of TTCN test step generation from Estelle transitions are explained. Test cases are obtained from these test steps by way of ordering them using the control flow graph. The implementation of a software tool called TTCNGEN, which largely automates the methodology, is explained and examples are provided from the LAP-D protocol of the integrated services digital network. Related research is discussed, and various ideas are highlighted for future research.
Minor Structural Modifications Convert the Dual TP/CRTH2 Antagonist Ramatroban into a Highly Selective and Potent CRTH2 Antagonist (2005)

Ramatroban, a thromboxane A(2) receptor (TP) antagonist with clinical efficacy in asthma and allergic rhinitis, was recently shown to also antagonize the prostaglandin D(2) receptor CRTH2. Here we report that minor structural changes to ramatroban result in a compound (13) with complete lack of activity on TP but sub-nanomolar potency toward CRTH2. This is the first selective CRTH2 antagonist described to date, and should prove highly valuable in further elucidating the biological significance of CRTH2.
Mechanism of selenium-glutathione peroxidase and its inhibition by mercaptocarboxylic acids and other mercaptans. (1984)

In a systematic search for effectors of glutathione peroxidase, a number of mercaptocarboxylic acids and tertiary mercaptans were found to be strong and specific inhibitors of the enzyme glutathione peroxidase. Assessment of various models was made by linear and nonlinear least squares fitting techniques. The results support the formation of reversible enzyme-inhibitor complexes. The active site selenium is trapped by the rapid binding of the inhibitor in competition with GSH. Data are consistent with the formation of thioselenenate adducts of the active site. The kinetic model which best describes the observed inhibition by the very strong inhibitor mercaptosuccinate implies that a selenenic acid with a kinetically significant lifetime is not formed when hydroperoxide is reduced. A noncovalent binding site for GSH or the presence of a cysteine residue at the active site of the enzyme provides a mechanistic rationale for the observed kinetics. Three of the most potent inhibitors found in this study, mercaptosuccinate, penicillamine, and alpha-mercaptopropionylglycine, are currently used as slow-acting drugs in the treatment of rheumatoid arthritis. Overall, the evidence suggests that glutathione peroxidase may be involved in the etiology of this disease.
Branch site haplotypes that control alternative splicing (2004)

We show that the allele-dependent expression of transcripts encoding soluble HLA-DQbeta chains is determined by branchpoint sequence (BPS) haplotypes in DQB1 intron 3. BPS RNAs associated with low inclusion of the transmembrane exon in mature transcripts showed impaired binding to splicing factor 1 (SF1), indicating that alternative splicing of DQB1 is controlled by differential BPS recognition early during spliceosome assembly. We also demonstrate that naturally occurring human BPS point mutations that alter splicing and lead to recognizable phenotypes cluster in BP and in position -2 relative to BP, implicating impaired SF1-BPS interactions in disease-associated BPS substitutions. Coding DNA variants produced smaller fluctuations of exon inclusion levels than random exonic substitutions, consistent with a selection against coding mutations that alter their own exonization. Finally, proximal splicing in this multi-allelic reporter system was promoted by at least seven SR proteins and repressed by hnRNPs F, H and I, supporting an extensive antagonism of factors balancing the splice site selection. These results provide the molecular basis for the haplotype-specific expression of soluble DQbeta, improve prediction of intronic point mutations and indicate how extraordinary, selection-driven DNA variability in HLA affects pre-mRNA splicing.
Living Radical Polymerization of Acrylates by Organocobalt Porphyrin Complexes (1994)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTLiving Radical Polymerization of Acrylates by Organocobalt Porphyrin ComplexesBradford B. Wayland, George Poszmik, Shakti L. Mukerjee, and Michael FrydCite this: J. Am. Chem. Soc. 1994, 116, 17, 7943–7944Publication Date (Print):August 1, 1994Publication History Published online1 May 2002Published inissue 1 August 1994https://pubs.acs.org/doi/10.1021/ja00096a080https://doi.org/10.1021/ja00096a080research-articleACS PublicationsRequest reuse permissionsArticle Views2175Altmetric-Citations479LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Modeling and evaluation of control flow prediction schemes using complete system simulation and Java workloads (2003)

Program control flow transfer (branch) prediction is considered to be a performance hurdle and a key design issue for current and future microprocessors. Branch prediction schemes with high prediction accuracy have been proposed to support longer processor pipelines with higher frequency clocks. In the previously published literature, the design and evaluation of branch predictors have been based heavily on the simulation of only user instructions from scientific and commercial workloads written in programming languages such as C or C++. To complement the existing research, the paper presents a case study of the modeling and evaluation of advanced branch predictors using full-system simulation of Java workloads running on a commercial operating system. The contributions of the paper are: (1) the presentation of a full system simulation framework to model, simulate and evaluate the performance of a set of advanced prediction schemes on emerging Java workloads; (2) an analysis of the performance and design complexity of advanced branch predictors in the presence of full system code; (3) an accurate modeling of user/kernel branch aliasing on a wide range of branch predictors.
Self-Assembly of Silk-Collagen-like Triblock Copolymers Resembles a Supramolecular Living Polymerization (2011)

We produced several pH-responsive silk-collagen-like triblocks, one acidic and two alkaline. At pH values where the silk-like block is uncharged the triblocks self-assemble into filaments. The pH-induced self-assembly was examined by atomic force microscopy, light scattering, and circular dichroism. The populations of filaments were found to be very monodisperse, indicating that the filaments start to grow from already present nuclei in the sample. The growth then follows pseudo-first-order kinetics for all examined triblocks. When normalized to the initial concentration, the growth curves of each type of triblock overlap, showing that the self-assembly is a generic process for silk-collagen-silk triblocks, regardless of the nature of their chargeable groups. The elongation speed of the filaments is slow, due to the presence of repulsive collagen-like blocks and the limited number of possibilities for an approaching triblock to successfully attach to a growing end. The formation of filaments is fully reversible. Already present filaments can start growing again by addition of new triblocks. The structure of all filaments is very rich in β-turns, leading to β-rolls. The triblocks attain this structure only when attaching to a growing filament.
High dynamic range imaging: spatially varying pixel exposures (2002)

While real scenes produce a wide range of brightness variations, vision systems use low dynamic range image detectors that typically provide 8 bits of brightness data at each pixel. The resulting low quality images greatly limit what vision can accomplish today. This paper proposes a very simple method for significantly enhancing the dynamic range of virtually any imaging system. The basic principle is to simultaneously sample the spatial and exposure dimensions of image irradiance. One of several ways to achieve this is by placing an optical mask adjacent to a conventional image detector array. The mask has a pattern with spatially varying transmittance, thereby giving adjacent pixels on the detector different exposures to the scene. The captured image is mapped to a high dynamic range image using an efficient image reconstruction algorithm. The end result is an imaging system that can measure a very wide range of scene radiance and produce a substantially larger number of brightness levels, with a slight reduction in spatial resolution. We conclude with several examples of high dynamic range images computed using spatially varying pixel exposures.
Human P40/IL-9. Expression in activated CD4+ T cells, genomic organization, and comparison with the mouse gene. (1990)

P40 is a cytokine that was originally identified in the mouse as a T cell growth factor, but whose spectrum of potential targets was recently shown to include mast cells as well as megakaryoblastic leukemic cells. Given these multiple activities, it was proposed that the protein be renamed IL-9. The analysis of P40 genomic clones reported here shows that the human and mouse P40 genes consist of 5 exons spread over approximately 4 kb of DNA and organized in a similar fashion in both species. The two genes exhibit a high degree of identity in the coding sequence and in the 5' untranslated regions, which contain, among other consensus motifs, a conserved sequence for the binding of AP-1. Expression of human P40 was studied in PBMC. Treatment of the cells with PMA and a calcium ionophore induced strong expression of a 0.7-kb P40 mRNA. No message was detected in unstimulated cells or in cells stimulated with LPS or Staphylococcus aureus, indicating that P40 expression is not constitutive and suggesting that the gene is not easily activated in B lymphocytes and in monocytes. By contrast, T cell mitogens such as PHA or anti-CD3 antibodies induced a substantial P40 expression that was further enhanced in the presence of PMA. Cell fractionation experiments indicated that, under these conditions, the protein is preferentially induced in CD4+ T cells. The induction of P40 by anti-CD3 antibodies suggests that P40 production is part of the normal T cell response to antigenic stimulation.