gebhart/patrepeval huggingface dataset:
Structural and functional roles of the N1- and N3-protons of at tRNA's position 39 (1999)

Pseudouridine at position 39 (Psi(39)) of tRNA's anticodon stem and loop domain (ASL) is highly conserved. To determine the physicochemical contributions of Psi(39)to the ASL and to relate these properties to tRNA function in translation, we synthesized the unmodified yeast tRNA(Phe)ASL and ASLs with various derivatives of U(39)and Psi(39). Psi(39)increased the thermal stability of the ASL (Delta T (m)= 1.3 +/- 0.5 degrees C), but did not significantly affect ribosomal binding ( K (d)= 229 +/- 29 nM) compared to that of the unmodified ASL (K (d)= 197 +/- 58 nM). The ASL-Psi(39)P-site fingerprint on the 30S ribosomal subunit was similar to that of the unmodified ASL. The stability, ribosome binding and fingerprint of the ASL with m(1)Psi(39)were comparable to that of the ASL with Psi(39). Thus, the contribution of Psi(39)to ASL stability is not related to N1-H hydrogen bonding, but probably is due to the nucleoside's ability to improve base stacking compared to U. In contrast, substitutions of m(3)Psi(39), the isosteric m(3)U(39)and m(1)m(3)Psi(39)destabilized the ASL by disrupting the A(31)-U(39)base pair in the stem, as confirmed by NMR. N3-methylations of both U and Psi dramatically decreased ribosomal binding ( K (d)= 1060 +/- 189 to 1283 +/- 258 nM). Thus, canonical base pairing of Psi(39)to A(31)through N3-H is important to structure, stability and ribosome binding, whereas the increased stability and the N1-proton afforded by modification of U(39)to Psi(39)may have biological roles other than tRNA's binding to the ribosomal P-site.
Legumes : chemistry, technology, and human nutrition (1989)

Preformulation Testing, Deodatt A. Wadke, Abu T. M. Serajuddin, and Harold Jacobson Tablet Formulation and Design, Garnet E. Peck, George J. Baley, Vincent E. McCurdy, and Gilbert S. Banker Compressed Tablets by Wet Granulation, Fred J. Bandelin Compressed Tablets by Direct Compression, Ralph F. Shangraw Compressed-Coated and Layer Tablets, William C. Gunsel and Rbert G. Dusel Effervescent Tablets, Raymond Mohrle Special Tablets, James W. Conine and Michael J. Pikal Chewable Tablets, Robert W. Mendes, Aloysius O. Anaebonam, and Jahan B. Daruwala Medicated Lozenges, David Peters
CODEHOP (COnsensus-DEgenerate Hybrid Oligonucleotide Primer) PCR primer design (2003)

We have developed a new primer design strategy for PCR amplification of distantly related gene sequences based on consensus-degenerate hybrid oligonucleotide primers (CODEHOPs). An interactive program has been written to design CODEHOP PCR primers from conserved blocks of amino acids within multiply-aligned protein sequences. Each CODEHOP consists of a pool of related primers containing all possible nucleotide sequences encoding 3-4 highly conserved amino acids within a 3' degenerate core. A longer 5' non-degenerate clamp region contains the most probable nucleotide predicted for each flanking codon. CODEHOPs are used in PCR amplification to isolate distantly related sequences encoding the conserved amino acid sequence. The primer design software and the CODEHOP PCR strategy have been utilized for the identification and characterization of new gene orthologs and paralogs in different plant, animal and bacterial species. In addition, this approach has been successful in identifying new pathogen species. The CODEHOP designer (http://blocks.fhcrc.org/codehop.html) is linked to BlockMaker and the Multiple Alignment Processor within the Blocks Database World Wide Web (http://blocks.fhcrc.org).
Gating of Long-Term Potentiation by Nicotinic Acetylcholine Receptors at the Cerebellum Input Stage (2013)

The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the α7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective α7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of α7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, α7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation.
The Reduced Pyrimidines (1994)

This chapter contains sections titled: Preparation of Dihydropyrimidines Preparation of Tetrahydropyrimidines Reactions of Reduced Pyrimidines Preparation of Hexahydropyrimidines Properties of Reduced Pyrimidines
Current Collapse and High-Electric-Field Reliability of Unpassivated GaN/AlGaN/GaN HEMTs (2006)

Long-term ON-state and OFF-state high-electric-field stress results are presented for unpassivated GaN/AlGaN/GaN high-electron-mobility transistors on SiC substrates. Because of the thin GaN cap layer, devices show minimal current-collapse effects prior to high-electric-field stress, despite the fact that they are not passivated. This comes at the price of a relatively high gate-leakage current. Under the assumption that donor-like electron traps are present within the GaN cap, two-dimensional numerical device simulations provide an explanation for the influence of the GaN cap layer on current collapse and for the correlation between the latter and the gate-leakage current. Both ON-state and OFF-state stresses produce simultaneous current-collapse increase and gate-leakage-current decrease, which can be interpreted to be the result of gate-drain surface degradation and reduced gate electron injection. This study shows that although the thin GaN cap layer is effective in suppressing surface-related dispersion effects in virgin devices, it does not, per se, protect the device from high-electric-field degradation, and it should, to this aim, be adopted in conjunction with other technological solutions like surface passivation, prepassivation surface treatments, and/or field-plate gate
High density interconnection using photosensitive polyimide and electroplated copper conductor lines (2003)

Multilayer, high-density, thin-film interconnect structures with a wiring density of up to 1000 lines per inch per signal layer, fabricated using a photosensitive polyimide as the dielectric and electroplated copper conductor lines, are discussed. Lithographic considerations associated with the patterning of high-aspect-ratio (>1.0) polyimide precursor features and their distortions during high-temperature annealing were investigated. An anisotropic shrinkage causing inward skewing of the feature profiles was observed. The shrinkage strongly depended on the ultraviolet exposure conditions and appears to be related to nonuniformity in the precursor crosslink density. The viability of electroplating techniques for fabrication of small-geometry copper features was examined. In contrast to the conventional approach, electroplating of copper features in patterned polyimide trenches provides excellent planarization in interconnect structures containing high-aspect-ratio features. Transmission characteristics of high-frequency signals in these lossy interconnect lines were measured. Minimal degradation of the pulse shape and attenuation of the pulse amplitude was observed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Programming Windows (1990)

This is the best-known, most widely praised, and most widely used how-to programming book on the planet. It is the one book that no aspiring or experienced developer can afford to be without. Updated for Windows 95, this bestseller is now a 32-bit book with 32-bit programs neatly tucked into a CD. Charles Petzold covers the new Windows 95 concerns such as multithreading, GDI and OLE enhancements, and preemptive multitasking. A guaranteed bestseller. (Operating Systems)
Interferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases. (1996)

The success of solid tumor growth and metastasis is dependent upon angiogenesis. Neovascularization within the tumor is regulated, in part, by a dual and opposing system of angiogenic and angiostatic factors. We now report that IP-10, a recently described angiostatic factor, as a potent angiostatic factor that regulates non-small cell lung cancer (NSCLC)-derived angiogenesis, tumor growth, and spontaneous metastasis. We initially found significantly elevated levels of IP-10 in freshly isolated human NSCLC samples of squamous cell carcinoma (SCCA). In contrast, levels of IP-10 were equivalent in either normal lung tissue or adenocarcinoma specimens. The neoplastic cells in specimens of SCCA were the predominant cells that appeared to express IP-10 by immunolocalization. Neutralization of IP-10 in SCCA tumor specimens resulted in enhanced tumor-derived angiogenic activity. Using a model of human NSCLC tumorigenesis in SCID mice, we found that NSCLC tumor growth was inversely correlated with levels of plasma or tumor-associated IP-10. IP-10 in vitro functioned as neither an autocrine growth factor nor as an inhibitor of proliferation of the NSCLC cell lines. Reconstitution of intratumor IP-10 for a period of 8 wk resulted in a significant inhibition of tumor growth, tumor-associated angiogenic activity and neovascularization, and spontaneous lung metastases, whereas, neutralization of IP-10 for 10 wk augmented tumor growth. These findings support the notion that tumor-derived IP-10 is an important endogenous angiostatic factor in NSCLC.
Akt/Protein Kinase B Signaling Inhibitor-2, a Selective Small Molecule Inhibitor of Akt Signaling with Antitumor Activity in Cancer Cells Overexpressing Akt (2004)

Accumulated studies have shown that activation of the Akt pathway plays a pivotal role in malignant transformation and chemoresistance by inducing cell survival, growth, migration, and angiogenesis. Therefore, Akt is believed to be a critical target for cancer intervention. Here, we report the discovery of a small molecule Akt pathway inhibitor, Akt/protein kinase B signaling inhibitor-2 (API-2), by screening the National Cancer Institute Diversity Set. API-2 suppressed the kinase activity and phosphorylation level of Akt. The inhibition of Akt kinase resulted in suppression of cell growth and induction of apoptosis in human cancer cells that harbor constitutively activated Akt due to overexpression of Akt or other genetic alterations such as PTEN mutation. API-2 is highly selective for Akt and does not inhibit the activation of phosphatidylinositol 3'-kinase, phosphoinositide-dependent kinase-1, protein kinase C, serum- and glucocorticoid-inducible kinase, protein kinase A, signal transducer and activators of transcription 3, extracellular signal-regulated kinase-1/2, or c-Jun NH(2)-terminal kinase. Furthermore, API-2 potently inhibited tumor growth in nude mice of human cancer cells in which Akt is aberrantly expressed/activated but not of those cancer cells in which it is not. These findings provide strong evidence for pharmacologically targeting Akt for anticancer drug discovery.
Cotranslational folding and calnexin binding during glycoprotein synthesis. (1995)

To analyze cotranslational folding of influenza hemagglutinin in the endoplasmic reticulum of live cells, we used short pulses of radiolabeling followed by immunoprecipitation and analysis with a two-dimensional SDS/polyacrylamide gel system which was nonreducing in the first dimension and reducing in the second. It separated nascent glycopolypeptides of different length and oxidation state. Evidence was obtained for cotranslational disulfide formation, generation of conformational epitopes, N-linked glycosylation, and oligosaccharide-dependent binding of calnexin, a membrane-bound chaperone that binds to incompletely folded glycoproteins via partially glucose-trimmed oligosaccharides. When glycosylation or oligosaccharide trimming was inhibited, the folding pathway was perturbed, suggesting a role for N-linked oligosaccharides and calnexin during translation of hemagglutinin.
Novel Structurally Designed Vaccine for S. aureus α-Hemolysin: Protection against Bacteremia and Pneumonia (2012)

Staphylococcus aureus (S. aureus) is a human pathogen associated with skin and soft tissue infections (SSTI) and life threatening sepsis and pneumonia. Efforts to develop effective vaccines against S. aureus have been largely unsuccessful, in part due to the variety of virulence factors produced by this organism. S. aureus alpha-hemolysin (Hla) is a pore-forming toxin expressed by most S. aureus strains and reported to play a key role in the pathogenesis of SSTI and pneumonia. Here we report a novel recombinant subunit vaccine candidate for Hla, rationally designed based on the heptameric crystal structure. This vaccine candidate, denoted AT-62aa, was tested in pneumonia and bacteremia infection models using S. aureus strain Newman and the pandemic strain USA300 (LAC). Significant protection from lethal bacteremia/sepsis and pneumonia was observed upon vaccination with AT-62aa along with a Glucopyranosyl Lipid Adjuvant-Stable Emulsion (GLA-SE) that is currently in clinical trials. Passive transfer of rabbit immunoglobulin against AT-62aa (AT62-IgG) protected mice against intraperitoneal and intranasal challenge with USA300 and produced significant reduction in bacterial burden in blood, spleen, kidney, and lungs. Our Hla-based vaccine is the first to be reported to reduce bacterial dissemination and to provide protection in a sepsis model of S. aureus infection. AT62-IgG and sera from vaccinated mice effectively neutralized the toxin in vitro and AT62-IgG inhibited the formation of Hla heptamers, suggesting antibody-mediated neutralization as the primary mechanism of action. This remarkable efficacy makes this Hla-based vaccine a prime candidate for inclusion in future multivalent S. aureus vaccine. Furthermore, identification of protective epitopes within AT-62aa could lead to novel immunotherapy for S. aureus infection.
The GSK3 hypothesis of Alzheimer’s disease (2007)

Glycogen synthase kinase 3 (GSK3) is a constitutively active, proline-directed serine/threonine kinase that plays a part in a number of physiological processes ranging from glycogen metabolism to gene transcription. GSK3 also plays a pivotal and central role in the pathogenesis of both sporadic and familial forms of Alzheimer's disease (AD), an observation that has led us to coin the 'GSK3 hypothesis of AD'. According to this hypothesis, over-activity of GSK3 accounts for memory impairment, tau hyper-phosphorylation, increased beta-amyloid production and local plaque-associated microglial-mediated inflammatory responses; all of which are hallmark characteristics of AD. If our 'GSK3 hypothesis of AD' is substantiated and GSK3 is indeed a causal mediator of AD then inhibitors of GSK3 would provide a novel avenue for therapeutic intervention in this devastating disorder.
Initiation of actinorhodin export in Streptomyces coelicolor (2006)

Many microorganisms produce molecules having antibiotic activity and expel them into the environment, presumably enhancing their ability to compete with their neighbours. Given that these molecules are often toxic to the producer, mechanisms must exist to ensure that the assembly of the export apparatus accompanies or precedes biosynthesis. Streptomyces coelicolor produces the polyketide antibiotic actinorhodin in a multistep pathway involving enzymes encoded by genes that are clustered together. Embedded within the cluster are genes for actinorhodin export, two of which, actR and actA resemble the classic tetR and tetA repressor/efflux pump-encoding gene pairs that confer resistance to tetracycline. Like TetR, which represses tetA, ActR is a repressor of actA. We have identified several molecules that can relieve repression by ActR. Importantly (S)-DNPA (an intermediate in the actinorhodin biosynthetic pathway) and kalafungin (a molecule related to the intermediate dihydrokalafungin), are especially potent ActR ligands. This suggests that along with the mature antibiotic(s), intermediates in the biosynthetic pathway might activate expression of the export genes thereby coupling export to biosynthesis. We suggest that this could be a common feature in the production of many bioactive natural products.
Effectiveness of Photodynamic Therapy with Topical 5-Aminolevulinic Acid and Intense Pulsed Light versus Intense Pulsed Light Alone in the Treatment of Acne Vulgaris: Comparative Study (2006)

Background Photodynamic therapy (PDT) involves the activation of a photosensitizing agent by light to produce oxygen intermediates that destroy target tissues. Topical 5-aminolevulinic acid (ALA) is converted to protoporphyrin IX, a very potent photosensitizer, which accumulates in human skin, particularly in the epidermis and its appendages. Objective To study the effect of PDT in acne vulgaris using topical ALA and intense pulsed light (IPL). Methods Thirteen individuals with varying degrees of acne were treated after a 3-week washout period. Twenty percent ALA hydrochloride (DUSA Pharmaceuticals, Wilmington, MA, USA) was applied to half of the face, and after 3 hours, the whole face was exposed to intense pulsed light (Quantum SR, Lumenis, Santa Clara, CA, USA) using a 560 nm cutoff filter starting at a fluence of 26 J/cm. The procedure was done twice at 2-week intervals, and the patients were clinically evaluated on the second, fourth, and eighth weeks. Results All patients had no apparent improvement on the second week on both facial halves. In fact, some of the patients developed acute acneiform eruptions on the side treated with ALA. By the fourth week, however, most of the patients had visible improvement of facial acne that was more significant on the ALA-treated side of the face. This persisted until the eighth week post-treatment. On the other hand, the facial half treated with intense pulsed light only showed a return to baseline of their facial acne. Conclusion ALA-IPL are beneficial in the management of acne vulgaris and may be used in combination with other forms of acne treatment or may be an alternative treatment for patients who do not want to take systemic retinoids.
RNA Quantitative Analysis from Fixed and Paraffin-Embedded Tissues: Membrane Hybridization and Capillary Electrophoresis (1998)

Fixed and paraffin-embedded tissues from pathology department archives are available for RNA expression analysis. We describe a general method for quantitation of specific RNA sequence extracted from single 6-8-micron human histological tissue sections cut from paraffin blocks. For each specific mRNA, the range of linear relationship between the log of the initial total RNA concentration and the log of the specific product after reverse transcription (RT)-PCR must be established. We usually perform RT with avian myeloblastosis virus (AMV)-RT, using specific antisense primers and a variable number of cycles of PCR amplification. The number of cycles must be adjusted within the range in which a linear relationship exists between the log of the amount of amplification product and the number of cycles. The quantity of specific product is standardized relative to beta-actin mRNA to normalize for the degree of RNA degradation, which can be quite different among samples. The amplification products were quantified by dot blot and 32P-labeled hybridization probe or by capillary electrophoresis with a laser-induced fluorescence detector. The intratest variation range was for the dot blot mean +/- 10% standard deviation (SD) and for the capillary electrophoresis mean +/- 3% SD.
Intracellular metabolism of a 2'-O-methyl-stabilized ribozyme after uptake by DOTAP transfection or asfree ribozyme. A study by capillary electrophoresis (1998)

The uptake and cellular metabolism of a fluorescein-labelled synthetic ribozyme stabilized by 2'- O -methyl modification and a 3' inverted thymidine have been studied, employing capillary gel electrophoresis as a novel and efficient analytical method. After internalization by DOTAP transfection, electrophoretic peaks of intact ribozyme and different degradation products were easily resolved and the amount of intracellular intact ribozyme was quantified to >10(7) molecules/cell at the peak value after 4 h transfection. On further incubation the amount of intracellular intact ribozyme decreased due to both degradation and efflux from the cell. However, even after 48 h incubation there were still >10(6) intact ribozyme molecules/cell. Clear differences both in uptake and in metabolism were seen when comparing DOTAP transfection with the uptake of free ribozyme. Fluorescence microscopy studies indicated that the ribozyme was mainly localized in intracellular granules, probably not accessible to target mRNA. This implies that agents able to release the intact ribozyme from intracellular vesicles into the cytosol should have a considerable potential for increasing the biological effects of synthetic ribozymes.
PHASE 1 SAFETY AND IMMUNOGENICITY TRIAL OF MALARIA VACCINE RTS,S/AS02A IN ADULTS IN A HYPERENDEMIC REGION OF WESTERN KENYA (2006)

We conducted a phase 1 trial of candidate malaria vaccine RTS,S/AS02A in western Kenya to determine its safety and immunogenicity in healthy adults in an area hyperendemic for malaria. Twenty adults were enrolled and received RTS,S/AS02A (50 microg of RTS,S in 0.5 mL of AS02A) by intramuscular injection on a 0-, 28-, and 178-day schedule. All 60 scheduled immunizations were given, and 18 of 20 volunteers completed the last study visit on day 210. The vaccine was safe and well-tolerated. There were no vaccine-related severe adverse events. The most common solicited adverse events associated with immunization were injection site pain and headache. The geometric mean concentration of antibodies to circumsporozoite protein was 1.9 microg/mL at baseline and it increased 2-4 weeks after each dose to 16, 17.8, and 36.6 microg/mL, respectively. These safety and immunogenicity data from adults in hyperendemic Kenya are comparable to data reported earlier from two trials in west African adults in hypo-endemic and meso-endemic areas of The Gambia. We conclude that in this small study, RTS,S/AS02A is safe and similarly immunogenic in malaria-exposed African adults of different ethnicity in different transmission settings.
Alternative splicing within the TGF‐β type I receptor gene (ALK‐5) generates two major functional isoforms in vascular smooth muscle cells (2000)

We have identified in rat vascular smooth muscle cells (SMCs) the simultaneous expression of two TGF-beta type I receptor (ALK-5) cDNAs, occurring as a consequence of alternate usage of AG splice acceptor motifs separated by 12 nucleotides located at an intron-exon junction. When translated the resultant full length proteins differ from each other only by the in-frame presence or absence of Gly-Pro-Phe-Ser residues adjacent to their transmembrane domain. Stable expression of these alternate ALK-5 isoforms in ALK-5-deficient cells demonstrated that both were competent in signaling TGF-beta-induced growth inhibition and gene transcription, but with an apparently distinct potency. Our data suggest that alternate splicing within the ALK-5 gene is an important mechanism whereby SMCs may regulate their response to TGF-beta.