gebhart/patrepeval huggingface dataset:
Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage (2005)

Atorvastatin is metabolized through enzymes encoded by members of the cytochrome P-450 (CYP) 3A gene family. Some patients who take atorvastatin along with concomitant medications known to inhibit CYP3A enzyme activity (e.g. itraconazole) develop rhabdomyolysis secondary to a severe drug-induced myopathy. The present study aimed to characterize the relationship between CYP3A gene polymorphisms and atorvastatin-induced muscle damage in the context of concomitant medication. The study employed a retrospective case--control (n=137) design. Study subjects were recruited from the general patient population served by Marshfield Clinic, a large horizontally integrated multispecialty group practice located in central Wisconsin, and case assignment was based upon both subjective (myalgia) and objective inclusion criteria [elevated serum creatine kinase (CK) levels]. The primary outcome was the relationship between serum CK level and CYP3A genotype. CYP3A genotype was not associated with an increased risk for the development of atorvastatin-induced muscle damage. CYP3A4*1B and CYP3A5*3 allele frequencies were similar in cases (n=68) and controls (n=69). Conversely, CYP3A genotype was associated with an increased severity of atorvastatin-induced muscle damage. An association was identified between the non-functional CYP3A5*3 allele and the magnitude of serum CK elevation in case patients experiencing myalgia. Patients who were homozygous for CYP3A5*3 demonstrated greater serum CK levels than patients who were heterozygous for CYP3A5*3, when concomitant lipid-lowering agents were sequentially removed from the analysis (P=0.025 without gemfibrozil, P=0.010 without gemfibrozil and niacin). The study demonstrates that patients who develop myalgia while taking atorvastatin are more likely to experience a greater degree of muscle damage if they express two copies of CYP3A5*3.
Planning of Fishways on Daiya River Channel Works (1995)

Daiya River flows through Nikko and Imaichi city Tochigi Pref. and joins Kinu River. In Daiya River, Sabo works (sabo dams and channel works) started at 1918, so that the hazards of disaster at downstream decreased and the inhabitable environment for fishes improved because of stability channel conditions. This paper reports the result of a study about inhabitable environmental conditions for fish and fishway hydraulic conditions, and fishway structure in planning of fishways on Daiya River channel works.
Aldosterone mediates angiotensin II‐induced interstitial cardiac fibrosis via a Nox2‐containing NADPH oxidase (2006)

Angiotensin (ANG) II (AngII) and aldosterone contribute to the development of interstitial cardiac fibrosis. We investigated the potential role of a Nox2-containing NADPH oxidase in aldosterone-induced fibrosis and the involvement of this mechanism in AngII-induced effects. Nox2-/- mice were compared with matched wild-type controls (WT). In WT mice, subcutaneous (s.c.) AngII (1.1 mg/kg/day for 2 wk) significantly increased NADPH oxidase activity, interstitial fibrosis (11.5+/-1.0% vs. 7.2+/-0.7%; P<0.05), expression of fibronectin, procollagen I, and connective tissue growth factor mRNA, MMP-2 activity, and NF-kB activation. These effects were all inhibited in Nox2-/- hearts. The mineralocorticoid receptor antagonist spironolactone inhibited AngII-induced increases in NADPH oxidase activity and the increase in interstitial fibrosis. In a model of mineralocorticoid-dependent hypertension involving chronic aldosterone infusion (0.2 mg/kg/day) and a 1% Na Cl diet ("ALDO"), WT animals exhibited increased NADPH oxidase activity, pro-fibrotic gene expression, MMP-2 activity, NF-kB activation, and significant interstitial cardiac fibrosis (12.0+/-1.7% with ALDO vs. 6.3+/-0.3% without; P<0.05). These effects were inhibited in Nox2-/- ALDO mice (e.g., fibrosis 6.8+/-0.8% with ALDO vs. 5.8+/-1.0% without ALDO; P=NS). These results suggest that aldosterone-dependent activation of a Nox2-containing NADPH oxidase contributes to the profibrotic effect of AngII in the heart as well as the fibrosis seen in mineralocorticoid-dependent hypertension.
A 65nm 8T Sub-Vt SRAM Employing Sense-Amplifier Redundancy (2007)

A 65nm 256kb 8T SRAM operates in sub-V, at 350mV. Peripheral assists eliminate sub-V, bitline leakage without limiting read current, and for a given area, sense-amplifier redundancy reduces read errors from offsets by a factor of five compared with device upsizing.
Synthesis of (−)-Terpestacin via Catalytic, Stereoselective Fragment Coupling:  Siccanol Is Terpestacin, Not 11-epi-Terpestacin (2003)

(-)-Terpestacin (1a, naturally occurring enantiomer) and (+)-11-epi-terpestacin (1b) were prepared using catalyst-controlled, stereoselective intermolecular reductive couplings of alkyne 4 and aldehyde 5. Related to enantioselective methods developed in our laboratory, these stereoselective fragment couplings were instrumental in confirming that "siccanol" is not 11-epi-terpestacin, but in fact is (-)-terpestacin itself.
Effect of chemical modification of sulfhydryl groups of human erythrocyte enzymes (1981)

Erythrocyte lysate proteins by five methods were chemically modified by methanethiolation with methyl methanethiolsulfonate (MMTS). This relatively newly studied agent delivers the small uncharged, non-hydrogen-bonding CH3S-group to accessible -SH groups under mild conditions. Glycolytic and nonglycolytic red cell enzymes studied could be grouped into four categories based on degree of catalytic inhibition by MMTS, which ranged from 100% to nil. NADH ((0.06 mM) protected against lactate dehydrogenase (LDH) inhibition nearly completely, and partial protection was evident at 1 microM concentrations. NAD was virtually ineffective at comparable molarities, and pyruvate failed to protect significantly. Glucose-6-phosphate dehydrogenase (G-6-PD) (but not 6-PGD) was protected by NADP (but minimally if at all by NADPH) at low molarities. Substrate G-6-P failed to protect. Mg++ alone protected enolase to a major degree against MMTS inhibition. Residual activities of several enzymes were rendered highly unstable to thermal stress, and in the case of selected enzymes, alteration of pH activity curves and catalytic activity at diminished substrate concentration was demonstrable. The highly specific modification of sulfhydryl groups of cysteinyl residues under mild conditions preserving other aspects of enzyme structure provides insights into the role of these most reactive of all amino side-chains in the enzyme proteins derived from human red cell lysates.
Distribution of Hepatitis B Virus Genotypes in Two Different Pediatric Populations from Argentina (1998)

Differences in pathogenesis and the probability of becoming a chronic carrier depend on the age at which hepatitis B virus (HBV) infection is acquired, ranging from 82% in infants less than 6 months of age to 15 to 30% in older children. HBV genotypes from 22 pediatric patients from two areas that differ in prevalence have been determined. Phylogenetic analysis shows a clear difference between the genotype distribution in Buenos Aires, a low-prevalence area, and that found in Gualeguay, Entre Ríos, a high-prevalence area. While the analysis allocated the sequences in the Buenos Aires group to genotypes A (36%), D (9%), and F (55%), the Gualeguay group presented exclusively genotype A isolates with very low nucleotide divergence, which suggests a strong founder viral population. The high prevalence of genotype F in the Buenos Aires group and its high intragroup heterogeneity agree with the American origin of this genotype.
Evidence for ATP binding and double-stranded DNA binding by Escherichia coli RecF protein (1992)

RecF protein is one of the important proteins involved in DNA recombination and repair. RecF protein has been shown to bind single-stranded DNA (ssDNA) in the absence of ATP (T. J. Griffin IV and R. D. Kolodner, J. Bacteriol. 172:6291-6299, 1990; M. V. V. S. Madiraju and A. J. Clark, Nucleic Acids Res. 19:6295-6300, 1991). In the present study, using 8-azido-ATP, a photo-affinity analog of ATP, we show that RecF protein binds ATP and that the binding is specific in the presence of DNA. 8-Azido-ATP photo-cross-linking is stimulated in the presence of DNA (both ssDNA and double-stranded DNA [dsDNA]), suggesting that DNA enhances the affinity of RecF protein for ATP. These data suggest that RecF protein possesses independent ATP- and DNA-binding sites. Further, we find that stable RecF protein-dsDNA complexes are obtained in the presence of ATP or ATP-gamma-S [adenosine-5'-O-(3-thio-triphosphate)]. No other nucleoside triphosphates served as necessary cofactors for dsDNA binding, indicating that RecF is an ATP-dependent dsDNA-binding protein. Since a mutation in a putative phosphate-binding motif of RecF protein results in a recF mutant phenotype (S. J. Sandler, B. Chackerian, J. T. Li, and A. J. Clark, Nucleic Acids Res. 20:839-845, 1992), we suggest on the basis of our data that the interactions of RecF protein with ATP, with dsDNA, or with both are physiologically important for understanding RecF protein function in vivo.
Molecular properties, functions, and potential applications of NAD kinases (2009)

NAD kinase catalyzes the phosphorylation of NAD(H) to form NADP(H), using ATP as phosphoryl donor. It is the only key enzyme leading to the de novo NADP(+)/NADPH biosynthesis. Coenzymes such as NAD(H) and NADP(H) are known for their important functions. Recent studies have partially demonstrated that NAD kinase plays a crucial role in the regulation of NAD(H)/NADP(H) conversion. Here, the molecular properties, physiologic functions, and potential applications of NAD kinase are discussed.
Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease (2013)

The pace of nigrostriatal degeneration, both with regards to striatal denervation and loss of melanin and tyrosine hydroxylase-positive neurons, is poorly understood especially early in the Parkinson's disease process. This study investigated the extent of nigrostriatal degeneration in patients with Parkinson's disease at different disease durations from time of diagnosis. Brains of patients with Parkinson's disease (n=28) with post-diagnostic intervals of 1-27 years and normal elderly control subjects (n=9) were examined. Sections of the post-commissural putamen and substantia nigra pars compacta were processed for tyrosine hydroxylase and dopamine transporter immunohistochemistry. The post-commissural putamen was selected due to tissue availability and the fact that dopamine loss in this region is associated with motor disability in Parkinson's disease. Quantitative assessments of putaminal dopaminergic fibre density and stereological estimates of the number of melanin-containing and tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (both in total and in subregions) were performed by blinded investigators in cases where suitable material was available (n=17). Dopaminergic markers in the dorsal putamen showed a modest loss at 1 year after diagnosis in the single case available for study. There was variable (moderate to marked) loss, at 3 years. At 4 years post-diagnosis and thereafter, there was virtually complete loss of staining in the dorsal putamen with only an occasional abnormal dopaminergic fibre detected. In the substantia nigra pars compacta, there was a 50-90% loss of tyrosine hydroxylase-positive neurons from the earliest time points studied with only marginal additional loss thereafter. There was only a ∼10% loss of melanized neurons in the one case evaluated 1 year post-diagnosis, and variable (30 to 60%) loss during the first several years post-diagnosis with more gradual and subtle loss in the second decade. At all time points, there were more melanin-containing than tyrosine hydroxylase-positive cells. Loss of dopaminergic markers in the dorsal putamen occurs rapidly and is virtually complete by 4 years post-diagnosis. Loss of melanized nigral neurons lags behind the loss of dopamine markers. These findings have important implications for understanding the nature of Parkinson's disease neurodegeneration and for studies of putative neuroprotective/restorative therapies.
Novel KCNQ1 and HERG missense mutations in Dutch long-QT families (1999)

Congenital long QT syndrome (cLQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant (Romano Ward) or as an autosomal recessive disorder (Jervell and Lange-Nielsen syndrome). Mutations in at least five genes have been associated with the LQTS. Four genes, encoding cardiac ion channels, have been identified. The most common forms of LQTS are due to mutations in the potassium-channel genes KCNQ1 and HERG. We have screened 24 Dutch LQTS families for mutations in KCNQ1 and HERG. Fourteen missense mutations were identified. Eight of these missense mutations were novel: three in KCNQ1 and five in HERG. Novel missense mutations in KCNQ1 were Y184S, S373P, and W392R and novel missense mutations in HERG were A558P, R582C, G604S, T613M, and F640L. The KCNQ1 mutation G189R and the HERG mutation R582C were detected in two families. The pathogenicity of the mutations was based on segregation in families, absence in control individuals, the nature of the amino acid substitution, and localization in the protein. Genotype-phenotype studies indicated that auditory stimuli as trigger of cardiac events differentiate LQTS2 and LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analyses for unequivocal diagnosis of patients with LQTS. Hum Mutat 13:301–310, 1999. © 1999 Wiley-Liss, Inc.
Transduction Mechanisms in Vertebrate Olfactory Receptor Cells (1998)

Schild, Detlev, and Diego Restrepo. Transduction Mechanisms in Vertebrate Olfactory Receptor Cells. Physiol. Rev. 78: 429–466, 1998. — Considerable progress has been made in the understanding of transduction mechanisms in olfactory receptor neurons (ORNs) over the last decade. Odorants pass through a mucus interface before binding to odorant receptors (ORs). The molecular structure of many ORs is now known. They belong to the large class of G protein-coupled receptors with seven transmembrane domains. Binding of an odorant to an OR triggers the activation of second messenger cascades. One second messenger pathway in particular has been extensively studied; the receptor activates, via the G protein G olf , an adenylyl cyclase, resulting in an increase in adenosine 3′,5′-cyclic monophosphate (cAMP), which elicits opening of cation channels directly gated by cAMP. Under physiological conditions, Ca 2+ has the highest permeability through this channel, and the increase in intracellular Ca 2+ concentration activates a Cl − current which, owing to an elevated reversal potential for Cl − , depolarizes the olfactory neuron. The receptor potential finally leads to the generation of action potentials conveying the chemosensory information to the olfactory bulb. Although much less studied, other transduction pathways appear to exist, some of which seem to involve the odorant-induced formation of inositol polyphosphates as well as Ca 2+ and/or inositol polyphosphate-activated cation channels. In addition, there is evidence for odorant-modulated K + and Cl − conductances. Finally, in some species, ORNs can be inhibited by certain odorants. This paper presents a comprehensive review of the biophysical and electrophysiological evidence regarding the transduction processes as well as subsequent signal processing and spike generation in ORNs.
Cloning of a Complementary DNA for Auxin-Induced 1-Aminocyclopropane-1-carboxylate Synthase and Differential Expression of the Gene by Auxin and Wounding (1991)

1-Aminocyclopropane-l-carboxylate (ACC) synthase induced by auxin was purified from slices of immature cucumber fruits, and partial amino acid sequences were determined. By using oligonucleotides synthesized based on the determined amino acid sequence, a complementary DNA for auxin-induced ACC synthase from winter squash (Cucurbita maxima Duch. cv Ebisu) was cloned and its sequence was determined. The sequence of the cDNA for the auxin-induced enzyme was markedly different from that for the wound-induced enzyme from the same plant [Nakajima et al. (1990) Plant Cell Physiol. 31: 1021], and the two cDNAs did not cross-hybridize. The results show that a gene for the auxin-induced enzyme (accA) is different from that for the wound-induced enzyme (accW). When hypocotyl sections of etiolated seedlings of winter squash were treated with IAA, the expression of accA was observed after 20 min and the level of mRNA increased maximally after 1 h, while only a small amount of the transcript of accW appeared. In wounded slices of mesocarp in which a large amount of mRNA for cccW was present, the transcript of accA was not detected. We conclude that ACC synthase is encoded in two different genes which are expressed differentially by auxin and wounding. Possible biological significance of the presence of two genes for the enzyme is discussed.
Ectopic Expression of Guanylyl Cyclase C in CD34+ Progenitor Cells in Peripheral Blood (2001)

These data suggest that GC-C may be useful for detecting circulating colorectal cancer cells. They also demonstrate that CD34+ cells are a source of ectopically expressed epithelial cell-specific markers and that CD34+ cells may contribute to the high false-positive rate generally observed when those markers are used to detect rare circulating metastatic cancer cells by RT-PCR.
Chimeric pigs following blastocyst injection of transgenic porcine primordial germ cells (1999)

Porcine primordial germ cell (PGC) derived cell lines of WAPhGH-transgenic pigs have been established that were able to contribute to chimeras. PGCs were isolated from day 25 to 28 genital ridges of more than 30 individual transgenic fetuses in order to have an easy to follow marker gene. To support undifferentiated growth, cell lines were derived and stable maintained on STO no. 8 feeder cells, a murine embryonic fibroblast cell line expressing recombinant, membrane-bound porcine stem cell factor (SCF). Fifteen lines proliferated in an undifferentiated state up to passage 13; two lines were maintained for more than 23 passages. Cell staining experiments for differentiation markers in several cell lines, indicated the presence of pluripotent cells in prolonged cultures. Further characterization using karyotyping revealed a normal, euploid set of chromosomes in cells of passages 15 and higher. Pluripotency of freshly isolated, short-term (up to 24 hr before injection) and long-term cultured, frozen/thawed cells was tested by injection into day 6 recipient blastocysts to give rise to chimeric piglets. The injected embryos (n = 209) were endoscopically transferred into the uterine horns of 11 recipient gilts. Tissue analysis from 49 fetuses and eighteen liveborn piglets for PGC contribution in chimeras was carried out using PCR analysis for the presence of the marker transgene. Thirty-two fetuses showed detectable chimerism in up to five out of 12 tissues analyzed. Skin samples from eight piglets were positive for the transgene, four of them displayed coat colour chimerism. Mol. Reprod. Dev. 54:244–254, 1999. © 1999 Wiley-Liss, Inc.
Percutaneous Radiofrequency Lumbar Facet Rhizotomy in Mechanical Low Back Pain Syndrome (1997)

During the period from March 1992 to June 1996, we performed percutaneous radiofrequency (RF) facet rhizotomy in 324 patients with low back pain. Employing the lesion generator, we coagulated branches of the zygapophyseal nerve to treat low back pain. The follow-up period was 6-51 months (average: 22.5 months). There were no complications during the procedure and the follow-up period and no poor results were observed. Two-hundred and thirty-one patients (103 females and 128 males) had mechanical low back pain syndrome and showed marked improvement of pain after the procedure, including 29 cases with previous spinal surgery. We concluded that percutaneous RF facet rhizotomy is a safe and effective procedure for low back pain patients, especially for those with mechanical low back pain syndrome.
Isolation and biochemical characterization of plasma monoclonal free light chains in amyloidosis and multiple myeloma: a pilot study of intact and truncated forms of light chains and their charge properties (2008)

The developed procedure may be applied to reveal distinguishing chemical features of FLC in serum, which could be important in predicting the pathologic form of disease, and in yielding information to better understand the mechanism(s) involved in the deposition of light chains in tissues.
Effect of JAK2 V617F on thrombotic risk in patients with essential thrombocythemia: measuring the uncertain (2008)

Current data about thrombotic risk in ET patients harboring the JAK2 V617F mutation remain partially inconclusive.[1][1], [2][2] A systematic literature review of MEDLINE up to February 2008 to identify studies of ET in the JAK2 era was conducted using the following search algorithm: JAK2 AND (
Structure-Based Mutagenesis Study of Hepatitis C Virus NS3 Helicase (1999)

The NS3 protein of hepatitis C virus (HCV) is a bifunctional protein containing a serine protease in the N-terminal one-third, which is stimulated upon binding of the NS4A cofactor, and an RNA helicase in the C-terminal two-thirds. In this study, a C-terminal hexahistidine-tagged helicase domain of the HCV NS3 protein was expressed in Escherichia coli and purified to homogeneity by conventional chromatography. The purified HCV helicase domain has a basal ATPase activity, a polynucleotide-stimulated ATPase activity, and a nucleic acid unwinding activity and binds efficiently to single-stranded polynucleotide. Detailed characterization of the purified HCV helicase domain with regard to all four activities is presented. Recently, we published an X-ray crystallographic structure of a binary complex of the HCV helicase with a (dU)(8) oligonucleotide, in which several conserved residues of the HCV helicase were shown to be involved in interactions between the HCV helicase and oligonucleotide. Here, site-directed mutagenesis was used to elucidate the roles of these residues in helicase function. Four individual mutations, Thr to Ala at position 269, Thr to Ala at position 411, Trp to Leu at position 501, and Trp to Ala at position 501, produced a severe reduction of RNA binding and completely abolished unwinding activity and stimulation of ATPase activity by poly(U), although the basal ATPase activity (activity in the absence of polynucleotide) of these mutants remained intact. Alanine substitution at Ser-231 or Ser-370 resulted in enzymes that were indistinguishable from wild-type HCV helicase with regard to all four activities. A mutant bearing Phe at Trp-501 showed wild-type levels of basal ATPase, unwinding activity, and single-stranded RNA binding activity. Interestingly, ATPase activity of this mutant became less responsive to stimulation by poly(U) but not to stimulation by other polynucleotides, such as poly(C). Given the conservation of some of these residues in other DNA and RNA helicases, their role in the mechanism of unwinding of double-stranded nucleic acid is discussed.