gebhart/patrepeval huggingface dataset:
Role of Residue 99 at the S2 Subsite of Factor Xa and Activated Protein C in Enzyme Specificity (1996)

It is thought that only a limited number of residues in the extended binding pocket of coagulation proteases are critical for substrate and inhibitor specificity. A candidate residue from the crystal structures of thrombin and factor Xa (FXa) that may be critical for specificity at the S2 subsite is residue 99. Residue 99 is Tyr in FXa and Thr in activated protein C (APC). To determine the role of residue 99 in S2 specificity, a Gla-domainless mutant of protein C (GDPC) was prepared in which Thr99 was replaced with Tyr of FXa. GDPC T99Y bound Ca2+ and was activated by the thrombin-thrombomodulin complex normally. The T99Y mutant, similar to FXa, hydrolyzed the chromogenic substrates with a Gly at the P2 positions. This mutant was also inhibited by antithrombin (AT) (k2 = 4.2 +/- 0.2 x 10(1) M-1 s-1), and heparin accelerated the reaction >350-fold (k2 = 1.5 +/- 0.1 x 10(4) M-1 s-1). The T99Y mutant, however, did not activate prothrombin but inactivated factor Va approximately 2-fold better than wild type. To try to switch the specificity of FXa, both Tyr99 and Gln192 of FXa were replaced with those of APC in the Gla-domainless factor X (GDFX Y99T/Q192E). This mutant was folded correctly as it bound Ca2+ with a similar affinity as GDFX and was also activated by the Russell's viper venom at similar rate, but it cleaved the chromogenic substrates with a Gly at the P2 positions poorly. The mutant, instead, cleaved the APC-specific chromogenic substrates efficiently. The Y99T/Q192E mutant became resistant to inhibition by AT in the absence of heparin but was inhibited by AT almost normally in the presence of heparin (k2 = 3.4 +/- 0.5 x 10(5) M-1 s-1). The Y99T/Q192E mutant did not inactivate factor Va, and prothrombin activation by this mutant was impaired. These results indicate that 1) residue 99 is critical for enzyme specificity at the S2 subsite, 2) a role for heparin in acceleration of FXa inhibition by AT may involve the S2-P2 modulation, and 3) the exchange of residues 99 and 192 in FXa and APC may switch the enzyme specificity with the chromogenic substrates and inhibitors but not with the natural substrates.
A Preconditioned Conjugate Gradient Based Algorithm for Coupling Geomechanical-Reservoir Simulations (2002)

In this article, we introduce a new coupling algorithm between the reservoir multiphase Darcy flow simulator and the geomechanical code accounting for the compaction of the porous medium. The coupling is defined on time periods in such a way that the reservoir unknowns are computed for time steps which are small enough subdivisions of the time period whereas the mechanical problem is solved at the end of the period. Our new approach is based on a nonlinear preconditioned conjugate gradient method which is applied to the mechanical displacement variable. This algorithm is compared, on a one dimensional example, to the staggered coupling algorithm with a porous medium compressibility as relaxation parameter. The main conclusion is that the preconditioned conjugate gradient method is much more robust and converge much faster than the staggered algorithm, while the additional cost per iteration should remain in practical situations very small.
Online Detection of High-Resistance Connections in the Incoming Electrical Circuit for Induction Motors (2009)

A high-resistance (R) connection in an induction-motor electrical circuit results in localized overheating and supply-voltage unbalance, which leads to a decreased efficiency and reliability and an increased fire hazard in the electrical distribution system and motor. Therefore, it is important to monitor and correct high-R connections for a reliable, efficient, and safe operation of the industrial facility. This paper focuses on the development of an online technique for detecting poor connections based on monitoring the asymmetry in the voltage and current measurement. The development of the technique begins with the derivation of the dynamic model of an induction motor with high-R connections. Based on the analysis of the model, two approaches for detecting poor contacts using the negative-sequence current and zero-sequence voltage are proposed. In addition to detecting the existence of faults, the location and severity of the fault can also be determined using the proposed method. An experimental study on a 10-hp induction machine under simulated and realistic high-R conditions shows that the proposed techniques provide a simple low-cost solution for reliably detecting poor contact problems at an early stage. It is also shown that the severity and location of the high-R contact fault can be assessed with high accuracy.
Basement membrane procollagen IV and its specialized carboxyl domain are conserved in Drosophila, mouse, and human. (1987)

Interaction with the extracellular matrix is important for the proliferation and differentiation of cells during development. A specialized extracellular matrix, basement membrane, is built around a scaffold of procollagen IV molecules. We report the sequence of a 2.5-kilobase cDNA which contains the carboxyl end of a Drosophila melanogaster procollagen IV. The amino acid sequence of the carboxyl-terminal domain, which forms an essential intermolecular linkage between procollagen IV molecules, is 59% identical in Drosophila and vertebrate procollagens IV, and an additional 17% of residues are conservatively substituted. This implies that the nature of the linkage is also conserved. We suggest that intermolecular junctions through procollagen IV carboxyl domains are fundamental elements of the molecular architecture of Metazoan basement membranes and have been conserved during evolution. The isolation and identification of this basement membrane collagen gene of Drosophila will help in deducing the function of procollagen IV in basement membranes.
Imeglimin, a novel glimin oral antidiabetic, exhibits a good efficacy and safety profile in type 2 diabetic patients (2012)

The results from both studies confirm that imeglimin displays a superior benefit : risk profile compared with metformin in type 2 diabetes patients. The encouraging tolerability profile of imeglimin could make it suitable for combination with other classes of antidiabetic agents and may increase availability to a wider patient population.
trans-Targeting of the Phage Mu Repressor Is Promoted by Conformational Changes That Expose Its ClpX Recognition Determinant (2003)

Dominant negative forms of the phage Mu repressor, including the mutant Vir repressors, are not only rapidly degraded by the ClpXP protease but also promote degradation of the unmodified, wild-type repressor. This trans-targeting of the wild-type repressor depends upon a determinant within its C-terminal domain, which is needed for recognition by ClpX. An environmentally sensitive fluorescent probe (2-(4'-maleimidylanilino)naphthalene-6-sulfonic acid (MIANS)) attached to the C terminus of the full-length repressor indicated that Vir induces the movement of this domain into a more exposed configuration. Vir also promoted attachment of MIANS to the C terminus of the repressor at an accelerated rate, and it greatly increased the rate of phosphorylation of a cAMP-dependent protein kinase motif attached to the repressor C terminus. While an excess of Vir was needed to promote repressor phosphorylation at maximal rates, the presence of ClpX could increase phosphorylation rates at lower Vir levels. trans-Targeting of the Mu repressor is therefore promoted by exposing its ClpX recognition determinant, and the action of ClpX can assist Vir in exposing these determinants.
Levitation Polymerization to Fabricate a Large Polymer Sphere (2002)

ADVERTISEMENT RETURN TO ISSUEPREVNoteNEXTLevitation Polymerization to Fabricate a Large Polymer SphereMasafumi Yamato, Haruka Nakazawa, and Tsunehisa KimuraView Author Information Department of Applied Chemistry, Tokyo Metropolitan University, 1-1 Minami-ohsawa, Hachioji, Tokyo 192-0397, Japan Cite this: Langmuir 2002, 18, 24, 9609–9610Publication Date (Web):September 11, 2002Publication History Received3 April 2002Revised1 July 2002Published online11 September 2002Published inissue 1 November 2002https://pubs.acs.org/doi/10.1021/la020316fhttps://doi.org/10.1021/la020316fbrief-reportACS PublicationsCopyright © 2002 American Chemical SocietyRequest reuse permissionsArticle Views224Altmetric-Citations20LEARN 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 SUBJECTS:Atmospheric chemistry,Energy,Liquids,Polymers,Suspensions Get e-Alerts
Antibiotics in the clinical pipeline in 2013 (2013)

The continued emergence of multi-drug-resistant bacteria is a major public health concern. The identification and development of new antibiotics, especially those with new modes of action, is imperative to help treat these infections. This review lists the 22 new antibiotics launched since 2000 and details the two first-in-class antibiotics, fidaxomicin (1) and bedaquiline (2), launched in 2011 and 2012, respectively. The development status, mode of action, spectra of activity, historical discovery and origin of the drug pharmacophore (natural product, natural product derived, synthetic or protein/mammalian peptide) of the 49 compounds and 6 β-lactamase/β-lactam combinations in active clinical development are discussed, as well as compounds that have been discontinued from clinical development since 2011. New antibacterial pharmacophore templates are also reviewed and analyzed.
Metabolic clearance of recombinant human growth hormone in health and chronic renal failure. (1994)

Despite the increasing therapeutic use of recombinant human growth hormone (rhGH), its metabolic clearance has not been investigated in detail. To evaluate the kinetics of rhGH as a possible function of GH plasma concentration and glomerular filtration rate (GFR), we investigated the steady state metabolic clearance rate (MCR), disappearance half-life, and apparent volume of distribution of rhGH at low and high physiological as well as supraphysiological plasma GH levels during pharmacological suppression of endogenous GH secretion in human subjects with normal and reduced renal function. GH in plasma and urine was determined by an immunoradiometric assay, and GFR by inulin clearance. In all subjects MCR decreased and plasma half-life increased with increasing plasma GH concentrations (P < 0.001). MCR of rhGH was approximately half in patients with chronic renal failure at each GH level and plasma half-life was increased by 25-50%. Allowing for the linear dependence of MCR on GFR and assuming single-compartment distribution, the estimated renal fraction of total MCR was 25-53 and 4-15% in controls and patients, respectively. Saturation of extrarenal disposal of GH was suggested by an inverse hyperbolic relationship between extrarenal MCR and plasma GH concentrations in all subjects. Fractional GH excretion was up to 1,000-fold higher in patients than in controls. We conclude that MCR of hGH is a function of plasma GH concentrations and GFR. Extrarenal elimination is saturable in the upper physiological range of GH concentrations, whereas renal MCR is independent of plasma GH levels. The kidney handles GH like a microprotein involving glomerular filtration, tubular reabsorption, and urinary excretion.
Cloning and Expression of Human Steroid-sulfatase (1989)

A 2.4-kilobase cDNA clone for human steroid-sulfatase (STS) was isolated and sequenced, which encoded an enzymatically active protein. The deduced amino acid sequence comprises 583 amino acids with an N-terminal signal peptide of 21 or 23 residues and four potential N-glycosylation sites. Two of the N-glycosylation sites are utilized and were localized to the asparagine residues 47 and 259. STS has the solubility properties of an integral membrane protein. The resistance of STS toward proteinase K after translocation into microsomes suggests that most, if not all, sequences of STS are exposed at the luminal side of microsomes. The deduced amino acid sequence predicts two membrane-spanning domains (amino acids 185-211 and 213-237) separated by a helix-breaking proline residue. We propose for STS a three-domain model. Two glycosylated luminally oriented domains of 161 and 346 residues are separated by a hydrophobic domain spanning the membrane twice in opposite directions. STS expressed in BHK-21 cells is located predominantly in the endoplasmic reticulum; smaller fractions are found in the Golgi, at the cell surface, multivesicular endosomes, as well as in lysosomes. The stability of STS in lysosomes may be related to the high homology of the two luminal domains of STS with the lysosomal sulfatases, arylsulfatase A, and arylsulfatase B. In spite of its similarity with these two lysosomal sulfatases, STS does not contain mannose 6-phosphate residues and is transported to lysosomes by a mannose 6-phosphate receptor-independent mechanism.
Inheritance of Resistance to Beet Western Yellows Virus in Lactuca virosa L. (1991)

Beet western yellows virus (BWYV), a member of the Luteovirus group, causes severe losses in many lettuce-growing areas. Attempts to identify complete resistance to BWYV in lettuce cultivars (Lactuca sativa L.) or in L. serriola L. and L. saligna L. were unsuccessful. Among three accessions of L. virosa tested, one, IVT 280, appeared to be extremely resistant to BWYV. Heredity of this resistance was studied in crosses with susceptible L. virosa IVT 1398. The results were compatible with the hypothesis of one gene, with resistance being dominant. The symbol Bw for Beet western is proposed for this gene.
Structure and Mechanism of the Lactose Permease of Escherichia coli (2003)

Membrane transport proteins that transduce free energy stored in electrochemical ion gradients into a concentration gradient are a major class of membrane proteins. We report the crystal structure at 3.5 angstroms of the Escherichia coli lactose permease, an intensively studied member of the major facilitator superfamily of transporters. The molecule is composed of N- and C-terminal domains, each with six transmembrane helices, symmetrically positioned within the permease. A large internal hydrophilic cavity open to the cytoplasmic side represents the inward-facing conformation of the transporter. The structure with a bound lactose homolog, β-D-galactopyranosyl-1-thio-β-D-galactopyranoside, reveals the sugar-binding site in the cavity, and residues that play major roles in substrate recognition and proton translocation are identified. We propose a possible mechanism for lactose/proton symport (co-transport) consistent with both the structure and a large body of experimental data.
The liberation of CD44 (2003)

CD44 was once thought to simply be a transmembrane adhesion molecule that also played a role in the metabolism of its principal ligand hyaluronan. Investigations of CD44 over the past ∼20 yr have established additional functions for CD44, including its capacity to mediate inflammatory cell function and tumor growth and metastasis. It has also become evident that intricate posttranslational modifications of CD44 regulate the affinity of the receptor for its ligands. In this review, we focus on emerging evidence that functional fragments of the cytoplasmic and ectodomain of CD44 can be liberated by enzymatic modification of cell surfaces as well as of cell-associated matrix. Based on the evidence discussed, we propose that CD44 exists in three phases, as a transmembrane receptor, as an integral component of the matrix, and as a soluble protein found in body fluids, each with biologically significant functions of which some are shared and some distinct. Thus, CD44 represents a model for understanding posttranslational processing and its emerging role as a general mechanism for regulating cell behavior.
Molecular Dynamics Simulations Highlight the Structural Differences among DNA:DNA, RNA:RNA, and DNA:RNA Hybrid Duplexes (1997)

Nanosecond length simulations applying the particle mesh Ewald method within AMBER 4.1 on canonical A-form and B-form geometries of d[CCAACGTTGG]2, r[CCAACGUUGG]2, and d[CCAACGTTGG]−r[CCAACGUUGG] duplexes in aqueous solution are reported. DNA duplexes only adopt a stable B-DNA geometry, in contrast to RNA duplexes which adopt both a stable A-RNA and “B-RNA” geometry. The observation of a stable “B-RNA” structure is somewhat surprising and suggests significant kinetic barriers to structural conversion in RNA structures on a nanosecond time scale. The “B-RNA” can be converted to A-RNA by forcing a concerted flip in the sugar puckers from C2‘-endo to C3‘-endo. The A-RNA structure displays features similar to A-form crystal structures, specifically interstrand purine stacking at the central pyrimidine−purine step is observed. When started in a canonical A-form geometry, DNA:RNA hybrid duplexes converge to a structure that is characteristic of experimental solution structures; specifically, a minor groove width intermediate between A-form and B-form geometries, the RNA strand in an A-form geometry, a mixture of C2‘-endo and C3‘-endo sugar puckers in the DNA strand, expected distribution of backbone angles and reasonable agreement with the helicoidal parameters are observed. In all of the simulations reported, A-form geometries appear to be less flexible than B-form geometries. There are also significant differences in the patterns of hydration and counterion association between A-form and B-form duplexes. In A-RNA, sodium counterions tend to associate into “pockets” in the major groove whereas these counterions tend to associate into the minor groove in B-form structures.
Hepatic intra-arterial injection of 3-bromopyruvate in rabbit vx2 tumor (2006)

A single session of intra-arterial injection of 3-BrPA showed no better results in terms of tumor necrosis than that of saline injection in a rabbit VX2 tumor model.
Context-awareness on mobile devices - the hydrogen approach (2003)

Information about the user's environment offers new opportunities and exposes new challenges in terms of time-aware, location-aware, device-aware and personalized applications. Such applications constantly need to monitor the environment - called context - to allow the application to react accordingly to this context. Context-awareness is especially interesting in mobile scenarios where the context of the application is highly dynamic and allows the application to deal with the constraints of mobile devices in terms of presentation and interaction abilities and communication restrictions. Current context-aware applications often realize sensing of context information in an ad hoc manner. The application programmer needs to deal with the supply of the context information including the sensing of the environment, its interpretation and its disposal for further processing in addition to the primary purpose of the application. The close interweavement of device specific context handling with the application obstructs its reuse with other hardware configurations. Recently, architectures providing support for context-aware applications have been developed. Up to now such architectures are not trimmed to the special requirements of mobile devices regarding particularly the limitations of network connections, limited computing power and the characteristics of mobile users. This paper proposes an architecture and a software framework - the hydrogen context framework -which support context-awareness for considering these constraints. It is extensible to consider all kind of context information and comprises a layered architecture. To prove the feasibility the framework has been implemented to run on mobile devices. A context-aware postbox is realized to demonstrate the capabilities of the framework.
Relationship between Retinal Nerve Fiber Layer and Visual Field Sensitivity as Measured by Optical Coherence Tomography in Chiasmal Compression (2006)

This is the first study to compare the structure-function correlation of RNFL measured by OCT with SAP in patients with chiasmal compression. RNFL is topographically related globally and sectorally to decreased SAP, with the temporal sectors showing the strongest correlations. The correlation between RNFL and VFS strengthens as the time from surgical intervention increases.
Design Principles, Biomechanical Data and Clinical Experience with a Polycentric Knee Offering Controlled Stance Phase Knee Flexion: A Preliminary Report (1997)

The OTTO BOCK 3R60 prosthetic knee joint allows controlled flexion of the prosthetic knee under weightbearing in early stance phase, more closely simulating this aspect of gait than was previously possible. As the amputee transfers weight onto the prosthesis in early stance phase, this knee gradually flexes up to 15 degrees, thereby cushioning the impact of weight acceptance. In contrast to all previous polycentric knees, stability of this new design is biomechanically increased by stance flexion, rendering a locking feature unnecessary. Clinically, the amputee perceives this prosthesis as stable and comfortable. The biomechanical features of this design concept, initial clinical observations and preliminary conclusions from laboratory gait analysis are summarized.
Biosynthesis of the immunosuppressants FK506, FK520, and rapamycin involves a previously undescribed family of enzymes acting on chorismate (2011)

The macrocyclic polyketides FK506, FK520, and rapamycin are potent immunosuppressants that prevent T-cell proliferation through initial binding to the immunophilin FKBP12. Analogs of these molecules are of considerable interest as therapeutics in both metastatic and inflammatory disease. For these polyketides the starter unit for chain assembly is (4R,5R)-4,5-dihydroxycyclohex-1-enecarboxylic acid derived from the shikimate pathway. We show here that the first committed step in its formation is hydrolysis of chorismate to form (4R,5R)-4,5-dihydroxycyclohexa-1,5-dienecarboxylic acid. This chorismatase activity is encoded by fkbO in the FK506 and FK520 biosynthetic gene clusters, and by rapK in the rapamycin gene cluster of Streptomyces hygroscopicus. Purified recombinant FkbO (from FK520) efficiently catalyzed the chorismatase reaction in vitro, as judged by HPLC-MS and NMR analysis. Complementation using fkbO from either the FK506 or the FK520 gene cluster of a strain of S. hygroscopicus specifically deleted in rapK (BIOT-4010) restored rapamycin production, as did supplementation with (4R,5R)-4,5-dihydroxycyclohexa-1,5-dienecarboxylic acid. Although BIOT-4010 produced no rapamycin, it did produce low levels of BC325, a rapamycin analog containing a 3-hydroxybenzoate starter unit. This led us to identify the rapK homolog hyg5 as encoding a chorismatase/3-hydroxybenzoate synthase. Similar enzymes in other bacteria include the product of the bra8 gene from the pathway to the terpenoid natural product brasilicardin. Expression of either hyg5 or bra8 in BIOT-4010 led to increased levels of BC325. Also, purified Hyg5 catalyzed the predicted conversion of chorismate into 3-hydroxybenzoate. FkbO, RapK, Hyg5, and Bra8 are thus founder members of a previously unrecognized family of enzymes acting on chorismate.