gebhart/patrepeval huggingface dataset:
DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome (2008)

Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.
ChemInform Abstract: Biosynthetic Incorporation of Advanced Precursors into Dehydrocurvularin, a Polyketide Phytotoxin from Alternaria cinerariae. (1999)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Characterization of Recombinant Skeletal Muscle (Ser-2843) and Cardiac Muscle (Ser-2809) Ryanodine Receptor Phosphorylation Mutants (2003)

Phosphorylation of the skeletal muscle (RyR1) and cardiac muscle (RyR2) ryanodine receptors has been reported to modulate channel activity. Abnormally high phosphorylation levels (hyperphosphorylation) at Ser-2843 in RyR1 and Ser-2809 in RyR2 and dissociation of FK506-binding proteins from the receptors have been implicated as one of the causes of altered calcium homeostasis observed during human heart failure. Using site-directed mutagenesis, we prepared recombinant RyR1 and RyR2 mutant receptors mimicking constitutively phosphorylated and dephosphorylated channels carrying a Ser/Asp (RyR1-S2843D and RyR2-S2809D) and Ser/Ala (RyR1-S2843A and RyR2-S2809A) substitution, respectively. Following transient expression in human embryonic kidney 293 cells, the effects of Ca2+, Mg2+, and ATP on channel function were determined using single channel and [3H]ryanodine binding measurements. In both assays, neither the skeletal nor cardiac mutants showed significant differences compared with wild type. Similarly essentially identical caffeine responses were observed in Ca2+ imaging measurements. Co-immunoprecipitation and Western blot analysis showed comparable binding of FK506-binding proteins to wild type and mutant receptors. Finally metabolic labeling experiments showed that the cardiac ryanodine receptor was phosphorylated at additional sites. Taken together, the results did not support the view that phosphorylation of a single site (RyR1-Ser-2843 and RyR2-Ser-2809) substantially changes RyR1 and RyR2 channel function.
Virus infection induced pulmonary fibrosis (2021)

Pulmonary fibrosis is the end stage of a broad range of heterogeneous interstitial lung diseases and more than 200 factors contribute to it. In recent years, the relationship between virus infection and pulmonary fibrosis is getting more and more attention, especially after the outbreak of SARS-CoV-2 in 2019, however, the mechanisms underlying the virus-induced pulmonary fibrosis are not fully understood. Here, we review the relationship between pulmonary fibrosis and several viruses such as Human T-cell leukemia virus (HTLV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV), Epstein-Barr virus (EBV), Murine γ-herpesvirus 68 (MHV-68), Influenza virus, Avian influenza virus, Middle East Respiratory Syndrome (MERS)-CoV, Severe acute respiratory syndrome (SARS)-CoV and SARS-CoV-2 as well as the mechanisms underlying the virus infection induced pulmonary fibrosis. This may shed new light on the potential targets for anti-fibrotic therapy to treat pulmonary fibrosis induced by viruses including SARS-CoV-2.
Mass Spectrometry–Based Proteomic Diagnosis of Renal Immunoglobulin Heavy Chain Amyloidosis (2010)

We conclude that LMD/MS is a sensitive and specific tool for diagnosis and accurate typing of renal amyloidosis, including Ig heavy chain amyloid.
Stability and Activity of Mesophilic Subtilisin E and Its Thermophilic Homolog:  Insights from Molecular Dynamics Simulations (1999)

Herein we examine the origin of the high-temperature (350 K) behavior of a thermophilic mutant enzyme (labeled as 5-3H5; see Zhao and Arnold Prot. Eng. 1999, 12, 47−53) derived from subtilisin E by eight amino acid substitutions. Through the use of molecular dynamics (MD) simulations, we have provided molecular-level insights into how point mutations can affect protein structure and dynamics. From our simulations we observed a reduced rmsd in several key regions, an increased overall flexibility, an increase in the number of hydrogen bonds, and an increase in the number of stabilizing interactions in the thermophilic system. We also show that it is not a necessary requirement that thermophilic enzymes be less flexible than their mesophilic counterparts at low temperatures. However, thermophilic enzymes must retain their three-dimensional structures and flexibility at high temperatures in order to retain activity. Furthermore, we have been able to point out the effects of some of the single substitutions. Even if it is not possible yet to give general rules for rational protein design, we are able to make some predictions on how a protein should be stabilized in order to be thermophilic. In particular, we suggest that a promising strategy toward speeding up the design of thermally stable proteins would be to identify fluxional regions within a protein through the use of MD simulations (or suitable experiments). Presumably these regions allow for autocatalytic reactions to occur and are also involved in allowing water to gain access to the interior of the protein and initiate protein unfolding. These fluxional regions could also adversely affect the positioning of the catalytic machinery, thereby decreasing catalytic efficiency. Thus, once these locations have been identified, “focused” directed evolution studies could be designed that stabilize these “fluxional” regions.
Encyclopedia of Materials Characterization: Surfaces, Interfaces, Thin Films (1992)

Imaging Techniques, Elemental, Chemical, and Structural Analysis in Electron Beam Column Instruments, Structure Determination by Electron/X-Ray Diffraction/Scattering, Electron Emission Spectroscopies, X-Ray Absorption and Emission Spectroscopies, Visible/UV Emission nad Reflection, Vibrational Spectroscopies and NMR, Ion Scattering Techniques, Mass Spectroscopy and Optical Techniques, Neutron and Nuclear Techniques, Physical and Magnetic Properties
The Erythropoietic Effect of Urine and Plasma of Repeatedly Bled Rabbits (1954)

Abstract 1. The reticulocyte response of rabbits bled in a standard manner is significantly greater after the injection of anemic rabbit plasma, than after the injection of normal rabbit plasma. The effect of anemic rabbit plasma disappears after the exposure to 100 per cent oxygen, but not after exposure to air. The activity of anemic rabbit plasma is not due to the presence of high concentrations of vitamin B12 or folic acid. 2. The recovery of hemoglobin concentration after a standard hemorrhage is described by a first order exponential equation. The speed of recovery is characterized by the time constant of regeneration. The velocity of hemoglobin regeneration, after a standard hemorrhage in rabbits injected with plasma of anemic animals, is greater than that of controls injected with normal rabbit plasma. Anemic rabbit plasma loses its erythropoietic effect after boiling at pH 5.5 for 15 minutes. 3. The repeated injection of anemic rabbit plasma in normal rabbits produces a significant rise of reticulocytes, erythrocytes, and hemoglobin concentration. 4. The injection of urine of anemic animals increases the speed of hemoglobin regeneration after a standard hemorrhage in rabbits. The activity of the urine of anemic rabbits is lost by boiling at pH 9.0 for 5 minutes, but not after the same treatment at pH 5.5. Urine of anemic animals loses its erythropoietic action after 16 hours dialysis. 5. It is concluded that the plasma and urine of animal with increased erythropoiesis contains a factor or factors (erythropoietins) which are probably the humoral mediators of the primary erythropoietic stimulus.
Local concentration of folate binding protein GP38 in sections of human ovarian carcinoma by in vitro quantitative autoradiography. (1996)

Folate binding protein is overexpressed up to 80-90-fold in nonmucinous ovarian carcinomas compared with nonmalignant ovaries. Quantitation of FBP may provide a useful tool in the design of clinical studies with specific monoclonal antibodies and certain antifolate drugs that enter the cell through FBP.
Multidrug‐resistance drug‐binding peptides generated by using a phage display library (1998)

A phage display library of random decapeptides was used to generate peptide ligands that can bind multidrug-resistance (MDR) drugs mimicking, in this respect, the drug-binding activity of P-glycoprotein. Seven peptide sequences were identified that specifically bound doxorubicin. Five of these sequences expressed the core consensus motif WXXW. The displacement assay showed that the phages expressing these peptides bound MDR type drugs (vinblastine, doxorubicin, verapamil, and genistein) with the same selectivity as P-glycoprotein and did not interact with non-MDR type drugs, such as arabinosylcytosine (Ara-C) and melphalan. One of the selected peptides that showed a highest capacity for the binding (VCDWWGWGIC) was synthesized and displayed competition with the phage for doxorubicin binding. The structure modeling suggested that all the selected sequences contained a hydrophobic envelope in which MDR drugs could be docked with substantial energy minimization. Western blot analysis showed that monospecific antibody obtained against the phage expressing VCDWWGWGIC peptide could specifically recognize P-glycoprotein in the membrane fraction of MDR phenotype MCF-7ADR cells. The MDR drug-binding sequences generated during this work could provide an important tool for design and screening of new chemotherapeutic agents.
Electrokinetically Synchronized Polymerase Chain Reaction Microchip Fabricated in Polycarbonate (2004)

This paper presents a novel method for DNA thermal amplification using the polymerase chain reaction (PCR) in an electrokinetically driven synchronized continuous flow PCR (EDS-CF-PCR) configuration carried out in a microfabricated polycarbonate (PC) chip. The synchronized format allowed patterning a shorter length microchannel for the PCR compared to nonsynchronized continuous flow formats, permitting the use of smaller applied voltages when the flow is driven electrically and also allowed flexibility in selecting the cycle number without having to change the microchip architecture. A home-built temperature control system was developed to precisely configure three isothermal zones on the chip for denaturing (95 degrees C), annealing (55 degrees C), and extension (72 degrees C) within a single-loop channel. DNA templates were introduced into the PCR reactor, which was filled with the PCR cocktail, by electrokinetic injection. The PCR cocktail consisted of low salt concentrations (KCl) to reduce the current in the EDS-CF-PCR device during cycling. To control the EOF in the PC microchannel to minimize dilution effects as the DNA "plug" was shuttled through the temperature zones, Polybrene was used as a dynamic coating, which resulted in reversal of the EOF. The products generated from 15, 27, 35, and 40 EDS-CF-PCR amplification cycles were collected and analyzed using microchip electrophoresis with LIF detection for fragment sizing. The results showed that the EDS-CF-PCR format produced results similar to that of a conventional block thermal cycler with leveling effects observed for amplicon generation after approximately 25 cycles. To the best of our knowledge, this is the first report of electrokinetically driven synchronized PCR performed on chip.
A decreased expression of angiopoietin-like 3 is protective against atherosclerosis in apoE-deficient mice (2003)

KK/Snk mice (previously KK/San) possessing a recessive mutation (hypl) of the angiopoietin-like 3 (Angptl3) gene homozygously exhibit a marked reduction of VLDL due to the decreased Angptl3 expression. Recently, we proposed that Angptl3 is a new class of lipid metabolism modulator regulating VLDL triglyceride (TG) levels through the inhibition of lipoprotein lipase (LPL) activity. In this study, to elucidate the role of Angptl3 in atherogenesis, we investigated the effects of hypl mutation against hyperlipidemia and atherosclerosis in apolipoprotein E knockout (apoEKO) mice. ApoEKO mice with hypl mutation (apoEKO-hypl) exhibited a significant reduction of VLDL TG, VLDL cholesterol, and plasma apoB levels compared with apoEKO mice. Hepatic VLDL TG secretion was comparable between both apoE-deficient mice. Turnover studies revealed that the clearance of both [3H]TG-labeled and 125I-labeled VLDL was significantly enhanced in apoEKO-hypl mice. Postprandial plasma TG levels also decreased in apoEKO-hypl mice. Both LPL and hepatic lipase activities in the postheparin plasma increased significantly in apoEKO-hypl mice, explaining the enhanced lipid metabolism. Furthermore, apoEKO-hypl mice developed 3-fold smaller atherogenic lesions in the aortic sinus compared with apoEKO mice. Taken together, the reduction of Angptl3 expression is protective against hyperlipidemia and atherosclerosis, even in the absence of apoE, owing to the enhanced catabolism and clearance of TG-rich lipoproteins.
Transcriptional activation of hedgehog target genes in Drosophila is mediated directly by the cubitus interruptus protein, a member of the GLI family of zinc finger DNA-binding proteins. (1996)

Members of the Hedgehog (Hh) family of secreted proteins have been identified recently as key signaling molecules that regulate a variety of inductive interactions central to the development of both Drosophila and vertebrates. Despite their widespread importance, the way in which Hh signals are transduced inside the cell remains poorly understood. The best candidate for a transcription factor that mediates Hh signaling in Drosophila is the product of the cubitus interruptus (ci) gene, a zinc finger protein that exhibits significant homology to protein products of the vertebrate GLI gene family. Here, we show that elevated levels of Ci are sufficient to activate patched (ptc) and other hh target genes, even in the absence of hh activity. We also show that Ci can function as a transcriptional activator in yeast and demonstrate that the zinc finger domain of the protein is sufficient for its target specificity. Finally, we identify sequences in the promoter region of the ptc gene, a primary target of Hh signaling, that are identical to the consensus-binding sequence of the GLI protein and are required for reporter gene expression in response to Hh activity. Taken together, our results strongly support the role for Ci as the transcriptional activator that mediates hh signaling.
Interception of reactive, DNA adduct‐forming metabolites present in rodent serum following carcinogen exposure: Implications for use of body fluids in biomonitoring (1993)

The detection of adduct-forming metabolites in the serum of carcinogen treated animals by 32P-postlabeling was evaluated as a novel approach to overcome the stringent requirement of obtaining DNA from tissues in human biomonitoring assessments. Benzo[a]pyrene (BP) was given i.p. to B6C3F1, C57B1/6, ICR, and DBA/2 mouse strains as well as Sprague-Dawley rats. Three adducts related to BP were detected in the liver and/or lung of Sprague-Dawley rats or B6C3F1, C57B1/6, and ICR mice; a single adduct was detected in the liver and lung of the DBA/2 mouse strain. Adducts chromatographically similar to those found in these tissues were also detected when salmon sperm DNA was incubated with the serum of BP-treated animals. Benzidine treatment induced the formation of one adduct in the liver of B6C3F1 mice, which was chromatographically similar to dG-C8-N'-acetylbenzidine. An identical adduct was detected in the salmon sperm DNA incubated with the serum of these mice. Cyclopenta[cd]pyrene treatment produced four major and three minor adducts in the liver or lung of B6C3F1 mice, all but two of which were detected in DNA incubated with serum of cyclopenta[cd]pyrene-treated animals. Large interstrain differences in the serum level of BP adduct-forming metabolites as well as tissue DNA adducts were found which correlated with previously observed strain-specific trends in sensitivity to PAH-mediated carcinogenesis. Thus, levels of BP adduct-forming metabolites were found in the following descending order: B6C3F1, C57B1/6, ICR, and DBA/2. BP-derived adduct-forming metabolites were detectable as late as 2 d and 5 d post-treatment in the serum of C57B1/6 mice or Sprague-Dawley rats, respectively, which seems to coincide well with the reported species-specific turnover of serum albumin; a protein know to be involved in the transport of reactive metabolites throughout the systemic circulation. The results obtained clearly indicate the presence of adduct-forming carcinogen metabolites in the serum of treated animals, which seemingly irrespective of their chemical nature, can be intercepted with exogenous DNA and detected by 32P-postlabeling. Successful application of a serum-based approach coupled with the use of the generally applicable, ultrasensitive 32P-postlabeling assay could evade the need for obtaining DNA from tissues, currently the major impediment in human biomonitoring studies.
A Novel Synthesis of the 2-Aminoimidazol-4-carbaldehyde Derivatives, Versatile Synthetic Intermediates for 2-Aminoimidazole Alkaloids (2006)

The title synthesis was achieved by the reaction of t-but­oxycarbonylguanidine with 3-bromo-1,1-dimethoxypropan-2-one as a key step. Starting with 1-tert-butoxycarbonyl-2-tert-butoxycarbonylaminoimidazol-4-carbaldehyde thus obtained expeditious synthesis of oroidin, hymenidin, dispacamide and monobromodispacamide, the representative 2-aminoimidazole alkaloids, was accomplished.
66. A Protective Vaccine for the Rapid Response to Pandemic AVian Influenza (2005)

The recent emergence of highly pathogenic avian influenza strains in poultry and their subsequent transmission to human populations in Vietnam and Thailand has raised concerns about the potential pandemic spread of lethal disease. Current strategies of influenza vaccination are limited by the length of time required to generate vaccines and the inability of such vaccines to induce cross-reactive immunity. Here we describe the development in 5 weeks of a prototype adenoviral-based influenza A vaccine specific to the A/Vietnam/1203/2004 (H5N1) (VN/1203/04) strain isolated during the 2003–2004 lethal human outbreak in Vietnam. Vaccinated mice were fully protected from intranasal challenge with VN/1203/04. Protection was associated with limited neutralizing antibodies response and induction of broad cellular immunity able to provide heterosubtypic immunity, supporting the concurrent role for T cells and humoral immunity in protection against influenza infection. These data demonstrate that adenoviral-based vaccines can be generated as a rapid response to an outbreak and may be effective at preventing the pandemic spread of highly pathogenic avian influenza viruses.
Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans (2009)

Upstream ORFs (uORFs) are mRNA elements defined by a start codon in the 5' UTR that is out-of-frame with the main coding sequence. Although uORFs are present in approximately half of human and mouse transcripts, no study has investigated their global impact on protein expression. Here, we report that uORFs correlate with significantly reduced protein expression of the downstream ORF, based on analysis of 11,649 matched mRNA and protein measurements from 4 published mammalian studies. Using reporter constructs to test 25 selected uORFs, we estimate that uORFs typically reduce protein expression by 30-80%, with a modest impact on mRNA levels. We additionally identify polymorphisms that alter uORF presence in 509 human genes. Finally, we report that 5 uORF-altering mutations, detected within genes previously linked to human diseases, dramatically silence expression of the downstream protein. Together, our results suggest that uORFs influence the protein expression of thousands of mammalian genes and that variation in these elements can influence human phenotype and disease.
Statistical significance of quantitative PCR (2007)

Overall, qPCR data analysis methods differ significantly in their performance, and this analysis identifies methods that provide DNA quantification estimates of high precision, robustness and reliability. These methods allow reliable estimations of relative expression ratio of two-fold or higher, and our analysis provides an estimation of the number of biological samples that have to be analyzed to achieve a given precision.
Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation (2002)

Acute graft-versus-host disease (aGVHD) is still a major obstacle in clinical allogeneic bone marrow (BM) transplantation. CD4(+)CD25(+) regulatory T (T(reg)) cells have recently been shown to suppress proliferative responses of CD4(+)CD25(-) T cells to alloantigenic stimulation in vitro and are required for ex vivo tolerization of donor T cells, which results in their reduced potential to induce aGVHD. Here we show that CD4(+)CD25(+) T cells isolated from the spleen or BM of donor C57BL/6 (H-2(b)) mice that have not been tolerized are still potent inhibitors of the alloresponse in vitro and of lethal aGVHD induced by C57BL/6 CD4(+)CD25(-) T cells in irradiated BALB/c (H-2(d)) hosts in vivo. The addition of the CD4(+)CD25(+) T(reg) cells at a 1:1 ratio with responder/inducer CD4(+)CD25(-) T cells resulted in a >90% inhibition of the mixed leukocyte reaction and marked protection from lethal GVHD. This protective effect depended in part on the ability of the transferred CD4(+)CD25(+) T cells to secrete interleukin 10 and occurred if the T(reg) cells were of donor, but not host, origin. Our results demonstrate that the balance of donor-type CD4(+)CD25(+) T(reg) and conventional CD4(+)CD25(-) T cells can determine the outcome of aGVHD.
Long Short-Term Memory-Networks for Machine Reading (2016)

In this paper we address the question of how to render sequence-level networks better at handling structured input. We propose a machine reading simulator which processes text incrementally from left to right and performs shallow reasoning with memory and attention. The reader extends the Long Short-Term Memory architecture with a memory network in place of a single memory cell. This enables adaptive memory usage during recurrence with neural attention, offering a way to weakly induce relations among tokens. The system is initially designed to process a single sequence but we also demonstrate how to integrate it with an encoder-decoder architecture. Experiments on language modeling, sentiment analysis, and natural language inference show that our model matches or outperforms the state of the art.