gebhart/patrepeval huggingface dataset:
C-terminal Tail of FGF19 Determines Its Specificity toward Klotho Co-receptors (2008)

FGF19 subfamily proteins (FGF19, FGF21, and FGF23) are unique members of fibroblast growth factors (FGFs) that regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis in an endocrine fashion. Their activities require the presence of α or βKlotho, two related single-pass transmembrane proteins, as co-receptors in relevant target tissues. We previously showed that FGF19 can bind to both α and βKlotho, whereas FGF21 and FGF23 can bind only to either βKlotho or αKlotho, respectively in vitro. To determine the mechanism regulating the binding and specificity among FGF19 subfamily members to Klotho family proteins, chimeric proteins between FGF19 subfamily members or chimeric proteins between Klotho family members were constructed to probe the interaction between those two families. Our results showed that a chimera of FGF19 with the FGF21 C-terminal tail interacts only with βKlotho and a chimera with the FGF23 C-terminal tail interacts only with αKlotho. FGF signaling assays also reflected the change of specificity we observed for the chimeras. These results identified the C-terminal tail of FGF19 as a region necessary for its recognition of Klotho family proteins. In addition, chimeras between α and βKlotho were also generated to probe the regions in Klotho proteins that are important for signaling by this FGF subfamily. Both FGF23 and FGF21 require intact α or βKlotho for signaling, respectively, whereas FGF19 can signal through a Klotho chimera consisting of the N terminus of αKlotho and the C terminus of βKlotho. Our results provide the first glimpse of the regions that regulate the binding specificity between this unique family of FGFs and their co-receptors.
The sodium ion translocating oxalacetate decarboxylase of Klebsiella pneumoniae. Sequence of the biotin-containing alpha-subunit and relationship to other biotin-containing enzymes. (1988)

The gene encoding the alpha-subunit of the Na+ pump oxalacetate decarboxylase of Klebsiella pneumoniae was cloned and sequenced. The deduced primary structure of the protein was confirmed by protein sequencing of about 30% of the polypeptide chain. The gene has a GC content of 67% and codes for 596 amino acids. The N-terminal methionine is removed in the mature protein which has a calculated molecular mass of 63,600 daltons. The protein consists of two different domains that are connected by a stretch of amino acid residues susceptible to proteolytic cleavage. Limited proteolysis of the native enzyme with trypsin produced fragments of about 51 kDa and 10.2 kDa, the latter of which started with valine 491 and contained the biotin prosthetic group. Peptide sequencing indicated binding of the biotin prosthetic group to lysine 561, 35 residues from the C terminus. The decarboxylase contains an extended alanine- and proline-rich region (positions 502-532) on the N-terminal side of the 10.2-kDa biotin domain. This sequence includes a total of 16 alanine and 9 proline residues.
Treatment of HCV Infection by Targeting MicroRNA (2013)

The use of miravirsen in patients with chronic HCV genotype 1 infection showed prolonged dose-dependent reductions in HCV RNA levels without evidence of viral resistance. (Funded by Santaris Pharma; ClinicalTrials.gov number, NCT01200420.).
Proteins: structure and function (2005)

Preface. 1. An introduction to protein structure and function. 2. Amino acids: the building blocks of proteins. 3. The three-dimensional structure of proteins. 4. The structure and function of fibrous proteins. 5. The structure and function of membrane proteins. 6. The diversity of proteins. 7. Enzyme kinetics, structure, function and catalysis. 8. Protein synthesis, processing and turnover. 9. Protein expression, purification and characterization. 10. Physical methods of determining the three-dimensional structure of proteins. 11. Protein folding in vivo and in vitro. 12. Protein structure and a molecular approach to medicine. Epilogue. Glossary. Appendices. Bibliography. References. Index.
Purification and quantitation of a rat plasma selenoprotein distinct from glutathione peroxidase using monoclonal antibodies. (1987)

Studies with 75Se have shown the existence of a rat plasma selenoprotein in addition to glutathione peroxidase. Because the function of the protein is not known, it has been referred to as selenoprotein P. A partially purified preparation was used to produce a monoclonal antibody to selenoprotein P. The antibody did not bind glutathione peroxidase as evidenced by its failure to remove glutathione peroxidase activity from rat plasma by immunoprecipitation. An immunoaffinity column was prepared with the monoclonal antibody, and selenoprotein P was purified 1270-fold from rat plasma in a two-step procedure. The purified selenoprotein P migrated in a single band with an Mr of 57,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Autoradiography demonstrated that this band contained 75Se when the protein was purified from rats which had received 75SeO2-(3). A competitive radioimmunoassay for selenoprotein P was developed. The selenoprotein P concentration in plasma of selenium-replete rats was determined with this assay to be 51 +/- 3.7 micrograms/ml. It was less than 5 micrograms/ml in plasma from selenium-deficient rats. Injection of 50 micrograms of selenium into selenium-deficient rats caused an increase in selenoprotein P from less than 10% of control to 52% of control in 6 h. Plasma glutathione peroxidase activity increased only from 2.2 to 3.1% of control. These experiments demonstrate that rat plasma contains a selenoprotein distinct from glutathione peroxidase. The concentration of this selenoprotein is depressed in selenium deficiency, as is glutathione peroxidase activity, but selenoprotein P increases more rapidly when selenium is supplied than does glutathione peroxidase activity.
Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment. (1995)

Ultra-low picomolar concentrations of the opioid antagonists naloxone (NLX) and naltrexone (NTX) have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse dorsal root ganglion (DRG) neurons, whereas higher nanomolar concentrations antagonize excitatory and inhibitory opioid functions. Pretreatment of naive nociceptive types of DRG neurons with picomolar concentrations of either antagonist blocks excitatory prolongation of the Ca(2+)-dependent component of the action potential duration (APD) elicited by picomolar-nanomolar morphine and unmasks inhibitory APD shortening. The present study provides a cellular mechanism to account for previous reports that low doses of NLX and NTX paradoxically enhance, instead of attenuate, the analgesic effects of morphine and other opioid agonists. Furthermore, chronic cotreatment of DRG neurons with micromolar morphine plus picomolar NLX or NTX prevents the development of (i) tolerance to the inhibitory APD-shortening effects of high concentrations of morphine and (ii) supersensitivity to the excitatory APD-prolonging effects of nanomolar NLX as well as of ultra-low (femtomolar-picomolar) concentrations of morphine and other opioid agonists. These in vitro studies suggested that ultra-low doses of NLX or NTX that selectively block the excitatory effects of morphine may not only enhance the analgesic potency of morphine and other bimodally acting opioid agonists but also markedly attenuate their dependence liability. Subsequent correlative studies have now demonstrated that cotreatment of mice with morphine plus ultra-low-dose NTX does, in fact, enhance the antinociceptive potency of morphine in tail-flick assays and attenuate development of withdrawal symptoms in chronic, as well as acute, physical dependence assays.
The Calgary Biofilm Device: New Technology for Rapid Determination of Antibiotic Susceptibilities of Bacterial Biofilms (1999)

Determination of the MIC, based on the activities of antibiotics against planktonic bacteria, is the standard assay for antibiotic susceptibility testing. Adherent bacterial populations (biofilms) present with an innate lack of antibiotic susceptibility not seen in the same bacteria grown as planktonic populations. The Calgary Biofilm Device (CBD) is described as a new technology for the rapid and reproducible assay of biofilm susceptibilities to antibiotics. The CBD produces 96 equivalent biofilms for the assay of antibiotic susceptibilities by the standard 96-well technology. Biofilm formation was followed by quantitative microbiology and scanning electron microscopy. Susceptibility to a standard group of antibiotics was determined for National Committee for Clinical Laboratory Standards (NCCLS) reference strains: Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Staphylococcus aureus ATCC 29213. Growth curves demonstrated that biofilms of a predetermined size could be formed on the CBD at specific time points and, furthermore, that no significant difference (P > 0.1) was seen between biofilms formed on each of the 96 pegs. The antibiotic susceptibilities for planktonic populations obtained by the NCCLS method or from the CBD were similar. Minimal biofilm eradication concentrations, derived by using the CBD, demonstrated that for biofilms of the same organisms, 100 to 1,000 times the concentration of a certain antibiotic were often required for the antibiotic to be effective, while other antibiotics were found to be effective at the MICs. The CBD offers a new technology for the rational selection of antibiotics effective against microbial biofilms and for the screening of new effective antibiotic compounds.
Sympathetic Overactivity in Patients with Chronic Renal Failure (1992)

Chronic renal failure may be accompanied by reversible sympathetic activation, which appears to be mediated by an afferent signal arising in the failing kidneys.
Knowledge sources for Natural Language Processing. (1996)

This paper aims at reviewing the problem of feeding Natural Language Processing (NLP) tools with convenient linguistic knowledge in the medical domain. A syntactic approach lacks the potential to solve a number of typical situations with ambiguities and is clearly insufficient for quality treatment of natural language. On the other hand, a conceptual approach relies on some modelling of the domain, of which the elaboration is d long-term process and where the ultimate solutions are far from being recognised and universally accepted. In-between is the beauty of the compromise. How can we significantly improve the coverage of linguistic knowledge in the years to come?
Limiting thickness h_{epi} for epitaxial growth and room-temperature Si growth on Si(100) (1990)

Si molecular-beam epitaxy (MBE) on smooth Si(100) surfaces is shown to occur at room temperature. We demonstrate for the first time that Si deposition becomes amorphous after growth of a limiting epitaxial thickness (${\mathit{h}}_{\mathrm{epi}}$). ${\mathit{h}}_{\mathrm{epi}}$ is \ensuremath{\approxeq}10--30 \AA{} at room temperature and increases rapidly at higher temperatures with a rate-dependent activation energy in the range 0.4--1.5 eV. The effect is tentatively linked to surface roughening during growth at low temperatures, and is probably general in MBE, also occurring for Si/Si(111), Ge/Si(100, and GaAs/GaAs(100).
Synthesis and Structure–Activity Relationship Studies of 4-((2-Hydroxy-3-methoxybenzyl)amino)benzenesulfonamide Derivatives as Potent and Selective Inhibitors of 12-Lipoxygenase (2014)

Human lipoxygenases (LOXs) are a family of iron-containing enzymes which catalyze the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Our group has taken a particular interest in platelet-type 12-(S)-LOX (12-LOX) because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Herein, we report the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. Top compounds, exemplified by 35 and 36, display nM potency against 12-LOX, excellent selectivity over related lipoxygenases and cyclooxygenases, and possess favorable ADME properties. In addition, both compounds inhibit PAR-4 induced aggregation and calcium mobilization in human platelets and reduce 12-HETE in β-cells.
Distribution, diversity and evolution of the bacterial mercury resistance (mer) operon (1997)

Mercury and its compounds are distributed widely across the earth. Many of the chemical forms of mercury are toxic to all living organisms. However, bacteria have evolved mechanisms of resistance to several of these different chemical forms, and play a major role in the global cycling of mercury in the natural environment. Five mechanisms of resistance to mercury compounds have been identified, of which resistance to inorganic mercury (HgR) is the best understood, both in terms of the mechanisms of resistance to mercury and of resistance to heavy metals in general. Resistance to inorganic mercury is encoded by the genes of the mer operon, and can be located on transposons, plasmids and the bacterial chromosome. Such systems have a worldwide geographical distribution, and furthermore, are found across a wide range of both Gram-negative and Gram-positive bacteria from both natural and clinical environments. The presence of mer genes in bacteria from sediment cores suggest that mer is an ancient system. Analysis of DNA sequences from mer operons and genes has revealed genetic variation both in operon structure and between individual genes from different mer operons, whilst analysis of bacteria which are sensitive to inorganic mercury has identified a number of vestigial non-functional operons. It is hypothesised that mer, due to its ubiquity with respect to geographical location, environment and species range, is an ancient system, and that ancient bacteria carried genes conferring resistance to mercury in response to increased levels of mercury in natural environments, perhaps resulting from volcanic activity. Models for the evolution of both a basic mer operon and for the Tn21-related family of mer operons and transposons are suggested. The study of evolution in bacteria has recently become dominated by the generation of phylogenies based on 16S rRNA genes. However, it is important not to underestimate the roles of horizontal gene transfer and recombinational events in evolution. In this respect mer is a suitable system for evaluating phylogenetic methods which incorporate the effects of horizontal gene transfer. In addition, the mer operon provides a model system in the study of environmental microbiology which is useful both as an example of a genotype which is responsive to environmental pressures and as a generic tool for the development of new methodology for the analysis of bacterial communities in natural environments.
Crystal Structure of the PH−BEACH Domains of Human LRBA/BGL (2004)

The beige and Chediak-Higashi syndrome (BEACH) domain defines a large family of eukaryotic proteins that have diverse cellular functions in vesicle trafficking, membrane dynamics, and receptor signaling. The domain is the only module that is highly conserved among all of these proteins, but the exact functions of this domain and the molecular basis for its actions are currently unknown. Our previous studies showed that the BEACH domain is preceded by a novel, weakly conserved pleckstrin homology (PH) domain. We report here the crystal structure at 2.4 A resolution of the PH-BEACH domain of human LRBA/BGL. The PH domain has the same backbone fold as canonical PH domains, despite sharing no sequence homology with them. However, our binding assays demonstrate that the PH domain in the BEACH proteins cannot bind phospholipids. The BEACH domain contains a core of several partially extended peptide segments that is flanked by helices on both sides. The structure suggests intimate association between the PH and the BEACH domains, and surface plasmon resonance studies confirm that the two domains of the protein FAN have high affinity for each other, with a K(d) of 120 nM.
Viral Dynamics of Hepatitis C Early After Orthotopic Liver Transplantation: Evidence for Rapid Turnover of Serum Virions (1996)

The pathogenesis of hepatitis C virus (HCV) infection is likely to be associated with viral replication in vivo, but little is known concerning the dynamics of HCV turnover. We performed serial measurements of serum HCV-RNA levels following orthotopic liver transplantation (OLT) in nine patients with HCV-positive cirrhosis. Serum HCV-RNA levels were determined by quantitative polymerase chain reaction before, immediately after, and for up to 1 month after OLT. There was a rapid decline in HCV-RNA levels from 3.1 +/- 1.3 x 10(5) copies/ mL (mean +/- SEM) preoperatively to 0.15 +/- 0.6 x 10(5) copies/mL on the first and 0.16 +/- 0.6 x 10(5) copies/mL on the second postoperative day (mean viral half-life, 4.0 +/- 0.5 h). Thereafter, HCV-RNA levels increased in all but one patient, and by postoperative day 8 reached 3.6 +/- 1.3 x 10(5) copies/mL, exceeding the preoperative levels irrespective of the use or not of rescue immunosuppressive therapy including steroid bolus administration. In most patients, serum virions continued to increase averaging 11.6 +/- 2.8 x 10(5) copies/mL on the 30th postoperative day. These findings indicate that the half-life of HCV is quite short, and that extrahepatic viral replication contributes little to the total virus pool in serum. Furthermore, the marked HCV replication beginning as early as the third postoperative day strongly suggests that the liver graft is rapidly reinfected by HCV after OLT.
Multiple Si layer ICs (2000)

Continuous scaling of VLSI circuits is reducing gate delays but rapidly increasing interconnect delays. Semiconductor Industry Association (SIA) roadmap predicts that, beyond the 130 nm technology node, performance improvement of advanced VLSI is likely to begin to saturate unless a paradigm shift from present IC architecture is introduced. This paper presents a comprehensive analytical treatment of ICs with multiple Si layers (3-D ICs). It is shown that significant improvement in performance (more than 145%) and reduction in wire-limited chip area can be achieved with 3-D ICs with vertical inter-layer interconnects (VILICs). This analysis is based on dividing a chip into separate blocks, each occupying a separate physical level. A scheme to optimize interconnect distribution among different interconnect tiers is presented and the effect of transferring the repeaters to upper Si layers has been quantified in this analysis. Furthermore, thermal analysis of ICs with two Si layers is presented. It is demonstrated that using a thermally responsible design and/or a high-performance heat sinking technology, die temperatures for ICs with two Si layers can be reduced well below present die temperatures. Finally, implications of 3-D architecture on several circuit designs are also discussed.
Plasmid-mediated mineralization of naphthalene, phenanthrene, and anthracene (1993)

The well-characterized plasmid-encoded naphthalene degradation pathway in Pseudomonas putida PpG7(NAH7) was used to investigate the role of the NAH plasmid-encoded pathway in mineralizing phenanthrene and anthracene. Three Pseudomonas strains, designated 5R, DFC49, and DFC50, were recovered from a polynuclear aromatic hydrocarbon-degrading inoculum developed from a manufactured gas plant soil slurry reactor. Plasmids pKA1, pKA2, and pKA3, approximately 100 kb in size, were isolated from these strains and characterized. These plasmids have homologous regions of upper and lower NAH7 plasmid catabolic genes. By conjugation experiments, these plasmids, including NAH7, have been shown to encode the genotype for mineralization of [9-14C]phenanthrene and [U-14C]anthracene, as well as [1-14C]naphthalene. One strain, Pseudomonas fluorescens 5RL, which has the complete lower pathway inactivated by transposon insertion in nahG, accumulated a metabolite from phenanthrene and anthracene degradation. This is the first direct evidence to indicate that the NAH plasmid-encoded catabolic genes are involved in degradation of polynuclear aromatic hydrocarbons other than naphthalene.
Attributable Mortality of Nosocomial Candidemia, Revisited (2003)

We reexamined the attributable mortality of nosocomial candidemia 15 years after a retrospective cohort study performed at our hospital demonstrated an attributable mortality of 38%. For all episodes of nosocomial candidemia between 1 July 1997 and 30 June 2001, we matched control patients with case patients by age, sex, date of hospital admission, underlying disease(s), length of time at risk, and surgical procedure(s). We analyzed 108 matched pairs. There were no statistically significant differences in age, sex, underlying disease(s), time at risk, surgical procedure, or vital signs at admission between cases and controls. The crude mortality among case patients was 61% (66 of 108 patients), compared with 12% (13 of 108) among control patients, for an attributable mortality of 49% (95% CI, 38%-60%). Nosocomial candidemia is still associated with an extremely high crude and attributable mortality--much higher than that expected from underlying disease alone.
Grading quality of evidence and strength of recommendations in clinical practice guidelines: Part 2 of 3. The GRADE approach to grading quality of evidence about diagnostic tests and strategies (2009)

The GRADE approach to grading the quality of evidence and strength of recommendations provides a comprehensive and transparent approach for developing clinical recommendations about using diagnostic tests or diagnostic strategies. Although grading the quality of evidence and strength of recommendations about using tests shares the logic of grading recommendations for treatment, it presents unique challenges. Guideline panels and clinicians should be alert to these special challenges when using the evidence about the accuracy of tests as the basis for clinical decisions. In the GRADE system, valid diagnostic accuracy studies can provide high quality evidence of test accuracy. However, such studies often provide only low quality evidence for the development of recommendations about diagnostic testing, as test accuracy is a surrogate for patient-important outcomes at best. Inferring from data on accuracy that using a test improves outcomes that are important to patients requires availability of an effective treatment, improved patients' wellbeing through prognostic information, or - by excluding an ominous diagnosis - reduction of anxiety and the opportunity for earlier search for an alternative diagnosis for which beneficial treatment can be available. Assessing the directness of evidence supporting the use of a diagnostic test requires judgments about the relationship between test results and patient-important consequences. Well-designed and conducted studies of allergy tests in parallel with efforts to evaluate allergy treatments critically will encourage improved guideline development for allergic diseases.
Block liposome and nanotube formation is a general phenomenon of two-component membranes containing multivalent lipids (2011)

We report a study on the formation of block liposomes (BLs) and nanotubes from membranes comprised of mixtures of membrane curvature-stabilizing multivalent cationic lipids MVL3(3+) and MVL5(5+) with neutral 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). In conjunction with prior work on MVLBG2(16+), our experiments suggest that BL and nanotube formation is a general phenomenon in membranes containing multivalent lipids, thus enhancing the relevance of BLs for applications such as gene/drug storage and delivery or templating.