gebhart/patrepeval huggingface dataset:
Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/G and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib (2017)

Acquired epidermal growth factor receptor (EGFR) resistance mutations to osimertinib are common, including the EGFR C797S that abolishes the covalent binding of osimertinib to EGFR. Here we report the emergence of novel EGFR solvent front mutations at Gly796 (G796S/R) in addition to a hinge pocket L792F/H mutations, and C797S/G all in cis with T790M in a single patient on progression on osimertinib as detected by plasma circulating tumor DNA (ctDNA) assay in the course of clinical care. A 69-year-old Caucasian female former light-smoker presented with stage IV EGFR L858R positive adenocarcinoma who developed EGFR T790M mutation after 8 month treatment of erlotinib. The patient was initiated on osimertinib with disease shrinkage after 2 months, but tumor regrowth was observed after 5 months of osimertinib treatment. Assay of plasma ctDNA at this time revealed these different secondary resistance mutations all in trans with each other including distinct mutations at the same codon producing different amino acid changes: G796S/R (mutant allele frequency [MAF]; 14.4%), C797S/G (MAF: 2.26%), L792F/H (MAF: 0.36%), and V802F (MAF: 0.40%), in addition to the pre-existing L858R (MAF:17.9%) and T790M (MAF:18.2%) but all in cis with T790M. The G796S/R mutations are homologous with known reported solvent front mutations in ALK G1202R, ROS1 G2032R, TrkA G595R and TrkC G623R, all of which are associated with acquired resistance to type I TKIs. In silico modeling revealed mutation at G796 interferes with osimertinib binding to the EGFR kinase domain at the phenyl aromatic ring position as this residue forms a narrow "hydrophobic sandwich" with L718, while L792F/H mutation interferes with osimertinib binding at the methoxyl group on the phenyl ring. Multiple resistance mutations at differing allele frequencies including novel EGFR solvent front mutations can emerge in a single patient with progression on osimertinib potentially due to tumor hetereogeneity and definitely present a significant therapeutic and drug development challenge.
Ancestry and diversity of the HMG box superfamily (1993)

The HMG box is a novel type of DNA-binding domain found in a diverse group of proteins. The HMG box superfamily comprises a.o. the High Mobility Group proteins HMG1 and HMG2, the nucleolar transcription factor UBF, the lymphoid transcription factors TCF-1 and LEF-1, the fungal mating-type genes mat-Mc and MATA1, and the mammalian sex-determining gene SRY. The superfamily dates back to at least 1,000 million years ago, as its members appear in animals, plants and yeast. Alignment of all known HMG boxes defined an unusually loose consensus sequence. We constructed phylogenetic trees connecting the members of the HMG box superfamily in order to understand their evolution. This analysis led us to distinguish two subfamilies: one comprising proteins with a single sequence-specific HMG box, the other encompassing relatively non sequence-specific DNA-binding proteins with multiple HMG boxes. By studying the extent of diversification of the superfamily, we found that the speed of evolution was very different within the various groups of HMG-box containing factors. Comparison of the evolution of the two boxes of ABF2 and of mtTF1 implied different diversification models for these two proteins. Finally, we provide a tree for the highly complex group of SRY-like ('Sox' genes), clustering at least 40 different loci that rapidly diverged in various animal lineages.
Immersed electrokinetic finite element method (2006)

Abstract A new method is proposed for modelling the electrokinetic‐induced mechanical motion of particles in a fluid domain under an applied electric field. In this method, independent solid meshes move in a fixed background field mesh that models the fluid and the electric field. This simple strategy removes the need for expensive mesh updates. Furthermore, the reproducing kernel particle functions enable efficient coupling of various immersed deformable solids with the surrounding viscous fluid in the presence of an applied electric field. The electric force on a particle is calculated by the Maxwell stress tensor method. For the first time, three‐dimensional assembly of nano/biomaterials of various geometries and electrical properties have been comprehensively studied using the new method. Simulation of the dynamic process of electro‐manipulation of individual and multiple cells agrees well with experimental data. Preliminary results for selective deposition of viruses and stretching of a DNA molecule are also presented. Copyright © 2006 John Wiley &amp; Sons, Ltd.
The smoking behaviour of grade 10 students. (1994)

The purpose of this study was to describe smoking behaviour among Grade 10 adolescents and to explore their knowledge of tobacco-related health risks. Seventy-eight males and 71 females, with a mean age of 15.2 years, completed self-administered questionnaires. Twenty-nine percent of the males and 21% of the females claimed to currently smoke, for an overall smoking rate of 26%. Student smoking was not related to gender or to parental smoking. However, students were more likely to smoke if they had a sibling who smoked (p = .0009). As well, students with more friends who smoked were more likely to smoke than students with fewer friends who smoked (p = .0000). The adolescents who smoked had a high level of knowledge regarding health risks of smoking, as did the nonsmoking adolescents. Because experimentation with and initiation of smoking begins in childhood and early teenage years, preventive measures should be started in early childhood.
Intrinsic structural disorder and sequence features of the cell cycle inhibitor p57Kip2 (2001)

The cell cycle inhibitor p57Kip2 induces cell cycle arrest by inhibiting the activity of cyclin-dependent kinases. p57, although active as a cyclin A-CDK2 inhibitor, is largely unfolded or intrinsically disordered as shown by circular dichroism and fluorescence spectra characteristic of an unfolded protein and a hydrodynamic radius consistent with an unfolded structure. In addition, the N-terminal domain of p57 is both functionally independent as a cyclin A-CDK2 inhibitor and unstructured, as demonstrated by circular dichroism and fluorescence spectra indicative of unfolded proteins, a lack of 1H chemical shift dispersion and a hydrodynamic radius consistent with a highly unfolded structure. The amino acid compositions of full-length p57 and the excised QT domain of p57 exhibit significant deviations from the average composition of globular proteins that are consistent with the observed intrinsic disorder. However, the amino acid composition of the CDK inhibition domain of p57 does not exhibit such a striking deviation from the average values observed for proteins, implying that a general low level of hydrophobicity, rather than depletion or enrichment in specific amino acids, contributes to the intrinsic disorder of the excised p57 CDK inhibition domain.
Purification and Characterization of Guanosine Diphospho-D-mannose Dehydrogenase (1989)

Alginate-producing Pseudomonas aeruginosa are usually associated with the cystic fibrosis lung environment and contribute to the high mortality rates observed among these patients. The present paper describes the purification and enzymatic properties of guanosine diphospho-D-mannose dehydrogenase (EC 1.1.1.132), a key enzyme in alginate biosynthesis by mucoid P. aeruginosa. The enzyme was overproduced using a plasmid vector containing algD (the gene encoding this enzyme) under control of the tac promoter. It was purified from cell-free lysates by lowering the pH to 5.0, heating the extract to 57.5 degrees C for 10 min, and discarding the protein pellet. The enzyme was selectively precipitated from the supernatant fraction with 45% acetone, resuspended in a 100 mM triethanolamine acetate buffer, pH 7.6, and ultimately purified by Bio-Sil TSK-400 gel filtration chromatography. The subunit molecular weight (Mr 48,000) as well as the N-terminal amino acid sequence corresponded to those predicted from the DNA sequence of algD. The native protein migrated as a hexamer of 290,000 molecular weight upon Bio-Gel A-1.5m gel filtration chromatography. Kinetic analysis demonstrated an apparent Km of 14.9 microM for the substrate GDP-D-mannose and 185 microM for the cofactor NAD+. GDP-D-mannuronic acid was identified as the enzyme reaction product. Several compounds (including GMP, ATP, GDP-D-glucose, and maltose) were found to inhibit enzymatic activity. GMP, the most potent of these inhibitors, exhibited competitive inhibition with an apparent Ki of 22.7 microM. Enzyme activity was also sensitive to the sulfhydryl group modifying agents iodoacetamide and p-hydroxymercuribenzoate. The addition of excess dithiothreitol restored enzyme activity, suggesting a possible involvement of cysteine residues in enzymatic activity.
Location of antigenic sites defined by neutralizing monoclonal antibodies on the S1 avian infectious bronchitis virus glycopolypeptide (1992)

Neutralizing monoclonal antibodies directed against five antigenic sites on the spike (S) S1 glycopolypeptide of avian infectious bronchitis virus (IBV) were used to select neutralization-resistant variants of the virus. By comparing the nucleotide sequence of such variants with the sequence of the IBV parent strain, we located five antigenic sites on the amino acid sequence of the S1 glycopolypeptide. The variants had mutations within three regions corresponding to amino acid residues 24 to 61, 132 to 149 and 291 to 398 of the S1 glycopolypeptide. The location of three overlapping antigenic sites on the IBV spike protein was similar to the location of antigenic sites on the spike protein of other coronaviruses.
Ulceration and Perforation of the Intestine Due to Necrotizing Arteriolitis (1963)

Although disseminated arteritis frequently causes gastrointestinal symptoms, it seldom presents an acute abdominal emergency.1 It is uncommon for involvement of the gastrointestinal tract to be severe enough to dominate the clinical picture and to be the principal cause of death.2 During the past three years 3 patients have been seen at the Pennsylvania Hospital with disseminated arteritis of varied etiology, which led to discrete intestinal ulceration, perforation, peritonitis and death.Case ReportsCase 1 (P.H. A53226). A 17-year-old girl was in good health until May, 1960, when a school examination detected hypertension (blood pressure of 160/110). In November she complained . . .
Cloning and nucleotide sequencing of transthyretin (prealbumin) cDNA from rat choroid plexus and liver (1989)

Journal Article Cloning and nucleotide sequencing of transthyretin (prealbumin) cDNA from rat choroid plexus and liver Get access Wei Duan, Wei Duan The Russell Grimwade School of Biochemistry, University of MelbourneParkville, Victoria 3052, Australia Search for other works by this author on: Oxford Academic PubMed Google Scholar Timothy Cole, Timothy Cole The Russell Grimwade School of Biochemistry, University of MelbourneParkville, Victoria 3052, Australia Search for other works by this author on: Oxford Academic PubMed Google Scholar Gerhard Schreiber Gerhard Schreiber The Russell Grimwade School of Biochemistry, University of MelbourneParkville, Victoria 3052, Australia Search for other works by this author on: Oxford Academic PubMed Google Scholar Nucleic Acids Research, Volume 17, Issue 10, 25 May 1989, Page 3979, https://doi.org/10.1093/nar/17.10.3979 Published: 25 May 1989 Article history Received: 18 April 1989 Published: 25 May 1989
Antisense RNA: Function and Fate of Duplex RNA in Cells of Higher Eukaryotes (1998)

There is ample evidence that cells of higher eukaryotes express double-stranded RNA molecules (dsRNAs) either naturally or as the result of viral infection or aberrant, bidirectional transcriptional readthrough. These duplex molecules can exist in either the cytoplasmic or nuclear compartments. Cells have evolved distinct ways of responding to dsRNAs, depending on the nature and location of the duplexes. Since dsRNA molecules are not thought to exist naturally within the cytoplasm, dsRNA in this compartment is most often associated with viral infections. Cells have evolved defensive strategies against such molecules, primarily involving the interferon response pathway. Nuclear dsRNA, however, does not induce interferons and may play an important posttranscriptional regulatory role. Nuclear dsRNA appears to be the substrate for enzymes which deaminate adenosine residues to inosine residues within the polynucleotide structure, resulting in partial or full unwinding. Extensively modified RNAs are either rapidly degraded or retained within the nucleus, whereas transcripts with few modifications may be transported to the cytoplasm, where they serve to produce altered proteins. This review summarizes our current knowledge about the function and fate of dsRNA in cells of higher eukaryotes and its potential manipulation as a research and therapeutic tool.
Mesenchymal stem cells: Will they have a role in the clinic? (2002)

In addition to hematopoietic stem cells (HSC), human post natal bone marrow contains another stem cell capable of giving rise to multiple mesenchymal cell lineages. Termed mesenchymal stem cells (MSCs) based on their capacity for multi-lineage differentiation, these cells can easily be obtained following a simple bone marrow aspiration procedure and subsequently expanded in culture through as many as 50 population doublings. This extensive capacity for expansion in vitro at clinical scale has recently facilitated the development of clinical trials designed to assess the safety, feasibility, and efficacy of transplanting MSC for a variety of pathological conditions. This review focuses on the background and rationale for performing clinical studies of MSC transplantation and will discuss the potential role that MSC may play in the correction or modification of human diseases.
Known and novel post-transcriptional regulatory sequences are conserved across plant families (2012)

The sequence elements that mediate post-transcriptional gene regulation often reside in the 5' and 3' untranslated regions (UTRs) of mRNAs. Using six different families of dicotyledonous plants, we developed a comparative transcriptomics pipeline for the identification and annotation of deeply conserved regulatory sequences in the 5' and 3' UTRs. Our approach was robust to confounding effects of poor UTR alignability and rampant paralogy in plants. In the 3' UTR, motifs resembling PUMILIO-binding sites form a prominent group of conserved motifs. Additionally, Expansins, one of the few plant mRNA families known to be localized to specific subcellular sites, possess a core conserved RCCCGC motif. In the 5' UTR, one major subset of motifs consists of purine-rich repeats. A distinct and substantial fraction possesses upstream AUG start codons. Half of the AUG containing motifs reveal hidden protein-coding potential in the 5' UTR, while the other half point to a peptide-independent function related to translation. Among the former, we added four novel peptides to the small catalog of conserved-peptide uORFs. Among the latter, our case studies document patterns of uORF evolution that include gain and loss of uORFs, switches in uORF reading frame, and switches in uORF length and position. In summary, nearly three hundred post-transcriptional elements show evidence of purifying selection across the eudicot branch of flowering plants, indicating a regulatory function spanning at least 70 million years. Some of these sequences have experimental precedent, but many are novel and encourage further exploration.
Hybrid iFR-FFR decision-making strategy: implications for enhancing universal adoption of physiology-guided coronary revascularisation (2013)

A hybrid iFR-FFR decision-making strategy for revascularisation could increase adoption of physiology-guided PCI, by more than halving the need for vasodilator administration, whilst maintaining high classification agreement with an FFR-only strategy.
Chaperone‐mediated autophagy in health and disease (2009)

Chaperone-mediated autophagy (CMA) is a lysosomal pathway that participates in the degradation of cytosolic proteins. CMA is activated by starvation and in response to stressors that result in protein damage. The selectivity intrinsic to CMA allows for removal of damaged proteins without disturbing nearby functional ones. CMA works in a coordinated manner with other autophagic pathways, which can compensate for each other. Interest in CMA has recently grown because of the connections established between this autophagic pathway and human pathologies. Here we review the unique properties of CMA compared to other autophagic pathways and its relevance in health and disease.
A game theoretic approach to flow control in an integrated environment with two classes of users (2003)

With the power as the performance criterion, a game-theoretical approach is proposed and analyzed. A network or system optimization solution leads to a Pareto optimal point. In a user or individual optimization setting the Nash and the Stackelberg equilibria are found. A decentralized and easily implementable algorithm is proved to converge to the Nash equilibrium. The choice of the strategy to be used depends on the particular application and the desirable overall performance.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Pyrolysis of cellulose catalysed by nanopowder metal oxides: production and characterisation of a chiral hydroxylactone and its role as building block (2007)

As a bulk component of plant biomass, cellulose plays a key role in the route leading to viable chemicals from renewable resources. Pyrolysis is a thermal treatment that converts cellulose into a liquid material (bio-oil) containing dehydrated monomers, among which the anhydrosugars levoglucosan (LGA) and levoglucosenone (LGO) have been widely investigated as chiral multifunctional synthons. A chiral cyclic hydroxylactone (LAC, 1) is also produced, but its potential as chemical intermediate has never been scrutinised, probably because it is generated only in minute amounts. In this study, experiments with a fixed bed reactor showed that the yields of LAC could be significantly increased by pyrolysing cellulose for few minutes at 350 °C in the presence of nanopowder (NP) titanium dioxide, aluminium oxide, and aluminium titanate (AlTi). When pyrolysis was conducted with NP AlTi at 500 °C, LAC became the principal anhydromonosaccharide and could be isolated from the resulting bio-oil with simple operations (6% overall yield). Its structure could be definitively assigned to the (1R,5S)-1-hydroxy-3,6-dioxabicyclo[3.2.1]octan-2-one by extensive NMR analysis and high resolution EI-MS experiments, providing a firm evidence of its previous attribution. The significance of LAC as building block for follow-up bioproducts was evaluated in some examples, including the synthesis of a suitable amide by the effective and eco-friendly microwave assisted methodology.
The Potential of Pulsed Underwater Streamer Discharges as a Disinfection Technique (2008)

<para xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> In this paper, we investigate the effectiveness of pulsed underwater streamer discharges for water disinfection and its scalability to large throughputs. For this paper, we have built a coaxial streamer reactor containing a central cylindrical anode covered by a thin porous layer of almandine. The reactor was supplied by electric pulses with amplitudes of up to 100 kV and pulse durations between 200 and 400 ns at a repetition rate of up to 20 Hz. Different chemical probes have been used as the main diagnostic to determine the production rates and the accumulation of oxidants in the bulk water. It has been found that the number and the length of streamers scaled linearly with the applied voltage amplitude, whereas the pulse duration only affected the streamer length. All oxidant production rates scaled linearly with the number-length product of streamers. OH-radical concentrations of up to 100 mM appear at the streamer-water-boundary. However, because of the limited volume of streamers and the limited range of OH radicals, the most important oxidant with respect to decontamination is <formula formulatype="inline"><tex>$\hbox{H}_{2}\hbox{O}_{2}$</tex></formula> which accumulates in the water and, by interacting with the intense UV radiation and the shock waves from the streamers, produces OH radicals in the bulk water. Placing water-filled cuvettes from different materials in the reactor, we found that the contribution of shock waves to the production of oxidants in the bulk water seems more important than the contribution of UV radiation. The production of oxidants can be enhanced by percolating suitable gases through the active zone of the reactor. Most effective is the use of oxygen. About 20 <formula formulatype="inline"><tex>$\hbox{J/cm}^{3}$</tex> </formula> of electrical energy was required to reduce the concentration of <emphasis emphasistype="italic"> Pseudomonas putida</emphasis> bacteria by six orders of magnitude. However, up to 180 <formula formulatype="inline"> <tex>$\hbox{J/cm}^{3}$</tex></formula> of specific energy input was necessary to reduce the bacterial freight in waste water from a municipal sewage plant by just two orders of magnitude. This has been explained by the high conductivity of waste water which drastically reduces the length of streamers for the same electrical parameters. Therefore, it seems unlikely that underwater streamer discharges alone can become competitive with other advanced oxidation processes like ozonation, UV irradiation, or irradiation with megaelectronvolt electron beams. However, it seems conceivable that a combination of underwater streamer discharges with ozonation or other processes can lead to a more effective and economic decontamination technique. </para>
Characterization of Immune Response of Young Pigs to Porcine Circovirus Type 2 Infection (2000)

A longitudinal study was conducted to characterize the immune response of young swine to infection with porcine circovirus type 2 (PCV-2). Five 8-week-old cesarean-derived, colostrum-deprived pigs were inoculated intranasally and intramuscularly with a field isolate of PCV-2 at a concentration of 10(4) TCID50/mL. Along with monitoring for clinical signs and viremia, serum samples were collected from all pigs at day 0 and thereafter every 7 days postinoculation (PI) until the termination of the study on day 35 PI. No clinical signs were observed in any of the animals during the study period. In all pigs, PCV-2 was detected by polymerase chain reaction (PCR) in serum samples collected on days 7, 14, and 21 PI. Viral DNA and antigens were detected by in situ hybridization and immunohistochemistry in tonsil, spleen, medial iliac lymph nodes, and ileum collected from each pig at the end of the study. Collectively, naïve young swine were shown to be susceptible to PCV-2. Virus-specific antibody was detected by an indirect fluorescent antibody (IFA) assay on day 14 PI, but virus-neutralizing antibody was not detected until day 28 PI. As neutralizing antibodies developed, cross-reactivity with PCV type 1 (PCV-1) also developed on the IFA test. Western immunoblot analysis revealed three PCV-2 proteins with molecular masses of 28 kd, 28.5 kd, and 35 kd. The 35-kd protein was also demonstrated in PCV-1, suggesting that this protein induced the cross-reactivity between PCV types 1 and 2. Antibody to the 28-kd protein was detected on day 14 PI and later, indicating that this protein was the most immunogenic. Because of its immunogenicity and specificity to PCV-2, and 28-kd protein might provide the antigenic basis for the development of diagnostic tests for detection of PCV-2 antibody.