gebhart/patrepeval huggingface dataset:
A GAA repeat expansion reporter model of Friedreich's ataxia recapitulates the genomic context and allows rapid screening of therapeutic compounds (2013)

Friedreich's ataxia (FRDA) is caused by large GAA expansions in intron 1 of the frataxin gene (FXN), which lead to reduced FXN expression through a mechanism not fully understood. Understanding such mechanism is essential for the identification of novel therapies for FRDA and this can be accelerated by the development of cell models which recapitulate the genomic context of the FXN locus and allow direct comparison of normal and expanded FXN loci with rapid detection of frataxin levels. Here we describe the development of the first GAA-expanded FXN genomic DNA reporter model of FRDA. We modified BAC vectors carrying the whole FXN genomic DNA locus by inserting the luciferase gene in exon 5a of the FXN gene (pBAC-FXN-Luc) and replacing the six GAA repeats present in the vector with an ∼310 GAA repeat expansion (pBAC-FXN-GAA-Luc). We generated human clonal cell lines carrying the two vectors using site-specific integration to allow direct comparison of normal and expanded FXN loci. We demonstrate that the presence of expanded GAA repeats recapitulates the epigenetic modifications and repression of gene expression seen in FRDA. We applied the GAA-expanded reporter model to the screening of a library of novel small molecules and identified one molecule which up-regulates FXN expression in FRDA patient primary cells and restores normal histone acetylation around the GAA repeats. These results suggest the potential use of genomic reporter cell models for the study of FRDA and the identification of novel therapies, combining physiologically relevant expression with the advantages of quantitative reporter gene expression.
Real-Time Visualization of an Acoustically Active Injection Catheter With Ultrasound Imaging: Algorithm and <i>In Vivo</i> Validation in a Swine Model (2019)

Unambiguous and distinct visualization of separate locations on the catheter facilitates real-time tracking of minimally invasive procedures.
Reactive Ion Beam Etching with  CF 4: Characterization of a Kaufman Ion Source and Details of SiO2 Etching (1982)

Recently, the use of reactive gases in ion milling equipment has received increasing attention. We have characterized the operation of a Kaufman‐type ion source for use with , by mass spectrometric measurements of both ionic and neutral components of the beam. Fragmentation of the parent gas to ions and neutrals is found to be extensive. Fragmentation is also strongly dependent on gas pressure and on confinement of the discharge in the source due to the axial magnetic field. Previously reported dependence of etch rate on background gas pressure is examined in more detail. It is concluded that variation of ion composition does effect etch rate, but ion‐induced reaction of adsorbed neutral species is occurring. A simple mass transport model that considers adsorption and desorption processes of reagent and product species is adequate to explain the major features of the data.
Circular RNAs: A novel type of biomarker and genetic tools in cancer (2017)

Circular RNAs (circRNAs) are a novel type of universal and diverse endogenous noncoding RNAs (ncRNAs) and they form a covalently closed continuous loop without 5' or 3' tails unlike linear RNAs. Most circRNAs are presented with characteristics of abundance, stability, conservatism, and often exhibiting tissue/developmental-stage-specific expression. CircRNAs are generated either from exons or introns by back splicing or lariat introns. CircRNAs play important roles as miRNA sponges, gene transcription and expression regulators, RNA-binding protein (RBP) sponges and protein/peptide translators. Emerging evidence revealed the function of circRNAs in cancer and may potentially serve as a required novel biomarker and therapeutic target for cancer treatment. In this review, we discuss about the origins, characteristics and functions of circRNA and how they work as miRNA sponges, gene transcription and expression regulators, RBP sponges in cancer as well as current research methods of circRNAs, providing evidence for the significance of circRNAs in cancer diagnosis and clinical treatment.
Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02) (2020)

This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (<i>n</i> = 1), hyperglycemia (<i>n</i> = 1), metabolic acidosis (<i>n</i> = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8<sup>+</sup> T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.<i>See related commentary by Rouanne et al., p. 1097</i>.<i>This article is highlighted in the In This Issue feature, p. 1079</i>.
Role of endothelin-1 in hypertension and vascular disease (2001)

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide and regulator of blood flow that plays an important role in blood pressure (BP) elevation in some models of experimental hypertension such as DOCA-salt rat, DOCA-salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and one-kidney, one-clip Goldblatt rats, but not in SHR, two-kidney, one-clip hypertensive rats, transgenic (mREN2)27 rats, or Nomega-nitro-L-arginine methyl ester chronically treated rats. In those models of hypertension in which ET-1 plays a vasoconstrictor role, ET-1 was shown to be overexpressed in the vessel walls, or BP has been lowered by administration of ET(A/B)- and ET(A)-selective receptor antagonists. In these experimental models, endothelin receptor antagonists also regressed vascular growth and inflammation, and improved endothelial dysfunction. Hypertensive rats treated with endothelin antagonists were protected from stroke and renal injury. In hypertensive rats without generalized vascular overproduction of ET-1, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of ET in myocardial ischemia in hypertension. Moderate-to-severe hypertensive patients presented enhanced expression of pre-proET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that this stage of hypertension may respond particularly well to endothelin antagonism. In some hypertensive patients, exaggerated vascular responses to ET-1 were found. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1. Increased plasma levels of immunoreactive ET have been described in African Americans. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor, and in ischemic heart disease and stroke. Endothelin-1 may also be involved in other forms of vascular disease, including pulmonary hypertension, after angioplasty restenosis, after allograft vasculopathy, and vasculitis. Thus, ET-1 may participate in vascular damage in cardiovascular disease and in BP elevation in experimental models and in human hypertension. Endothelin antagonists could become effective disease-modifying agents in different forms of cardiovascular disease.
Distinct functions of condensin I and II in mitotic chromosome assembly (2004)

Condensin is a protein complex associated with mitotic chromosomes that has been implicated in chromosome condensation. In vertebrates, two types of condensin complexes have recently been identified, called condensin I and II. Here, we show that in mammalian cells condensin II associates with chromatin in prophase, in contrast to condensin I which is cytoplasmic and can thus interact with chromosomes only after nuclear envelope breakdown. RNA interference experiments in conjunction with imaging of live and fixed cells revealed that condensin II is required for chromosome condensation in early prophase, whereas condensin I appears to be dispensable at this stage. By contrast, condensin I is required for the complete dissociation of cohesin from chromosome arms, for chromosome shortening and for normal timing of progression through prometaphase and metaphase, whereas normal condensin II levels are dispensable for these processes. After depletion of both condensin complexes, the onset of chromosome condensation is delayed until the end of prophase, but is then initiated rapidly before nuclear envelope breakdown. These results reveal that condensin II and I associate with chromosomes sequentially and have distinct functions in mitotic chromosome assembly.
The Role of Metallothionein in Oxidative Stress (2013)

Free radicals are chemical particles containing one or more unpaired electrons, which may be part of the molecule. They cause the molecule to become highly reactive. The free radicals are also known to play a dual role in biological systems, as they can be either beneficial or harmful for living systems. It is clear that there are numerous mechanisms participating on the protection of a cell against free radicals. In this review, our attention is paid to metallothioneins (MTs) as small, cysteine-rich and heavy metal-binding proteins, which participate in an array of protective stress responses. The mechanism of the reaction of metallothioneins with oxidants and electrophilic compounds is discussed. Numerous reports indicate that MT protects cells from exposure to oxidants and electrophiles, which react readily with sulfhydryl groups. Moreover, MT plays a key role in regulation of zinc levels and distribution in the intracellular space. The connections between zinc, MT and cancer are highlighted.
Asthma Is Inversely Associated with Helicobacter pylori Status in an Urban Population (2008)

These data are consistent with the hypothesis that colonization with CagA+ H. pylori strains is inversely associated with asthma and is associated with an older age of asthma onset in an urban population. The data suggest H. pylori as a marker for protection.
Corrosion of Aluminum Nitride (AlN) in Aqueous Cleaning Solutions (2000)

The corrosion of aluminum nitride (AlN) in aqueous solutions has been evaluated in situ , using an ammonium/ammonia ion‐selective electrode. The corrosion behavior of AlN over a pH range of 5.5–12 indicates that the corrosion products that are formed act as a protective barrier layer in the pH regime where they have the lowest stability. An insoluble barrier layer is formed via the oxidation of the AlN surface in air at a temperature of 750°C for 10 min. This oxynitride layer, which is 200 Å thick, prevents the corrosion of the AlN in a pH 9.5 aqueous solution; however, the thermal conductivity is reduced by 6.6%.
beta2 knockout mice develop parenchymal iron overload: A putative role for class I genes of the major histocompatibility complex in iron metabolism. (1996)

Hemochromatosis (HC) is an inherited disorder of iron absorption, mapping within the human major histocompatibility complex (MHC). We have identified a multigene system in the murine MHC that contains excellent candidates for the murine equivalent of the human HC locus and implicate nonclassical class I genes in the control of iron absorption. This gene system is characterized by multiple copies of two head-to-head genes encoded on opposite strands and driven by one common regulatory motif. This regulatory motif has a striking homology to the promoter region of the beta-globin gene, a gene obviously involved in iron metabolism and hence termed beta-globin analogous promoter (betaGAP). Upstream of the betaGAP sequence are nonclassical class I genes. At least one of these nonclassical class I genes, Q2, is expressed in the gastrointestinal tract, the primary site of iron absorption. Also expressed in the gastrointestinal tract and downstream of the betaGAP motif is a second set of putative genes, termed Hephaestus (HEPH). Based on these observations, we hypothesized that the genes that seem to be controlled by the betaGAP regulatory motifs would be responsible for the control of Fe absorption. As a test of this hypothesis, we predicted that mice which have altered expression of class I gene products, the beta2-microglobulin knockout mice, [beta2m(-/-)], would develop Fe overload. This prediction was confirmed, and these results indicate beta2m-associated proteins are involved in the control of intestinal Fe absorption.
Determination of Fat, Protein, and Lactose in Raw Milk by Fourier Transform Infrared Spectroscopy and by Analysis with a Conventional Filter-Based Milk Analyzer (1996)

The accuracy of fat, crude protein (CP), true protein (TP), and lactose determinations of raw milk by Fourier transform infrared (FTIR) spectroscopy and by analysis with a conventional filter-based milk analyzer was assessed in 6 trials performed over a 10-month period. At each trial, 30 bulk milk samples collected from 15 European countries and 11 reconstituted milks made from raw milk components were analyzed. When calibrations were performed with reconstituted milks at each trial, accuracy standard deviations for fat, CP, TP, and lactose were, respectively, 0.050, 0.048, 0.035, and 0.076 g/100 g for the filter instrument and 0.047, 0.046, 0.042, and 0.065 g/100 g for the FTIR instrument. When a single calibration was made instead of calibrations at each trial, accuracy standard deviations increased for the filter instrument to 0.130, 0.119, 0.121, and 0.083 for fat, CP, TP, and lactose, respectively, and for the FTIR instrument to 0.082, 0.053, 0.044, and 0.084 g/100 g. Because the FTIR instrument provides more spectral information related to milk composition than does the filter instrument, single-calibration FTIR analysis of milk samples collected in different seasons is more accurate. Using reconstituted milks, prepared such that there is no correlation between fat, CP, and lactose, provides a more robust calibration than using genuine bulk milk, especially when milks with unusual composition are analyzed.
Quantifying and Reducing Posture-Dependent Distortion in Ballistocardiogram Measurements (2015)

Ballistocardiography is a noninvasive measurement of the mechanical movement of the body caused by cardiac ejection of blood. Recent studies have demonstrated that ballistocardiogram (BCG) signals can be measured using a modified home weighing scale and used to track changes in myocardial contractility and cardiac output. With this approach, the BCG can potentially be used both for preventive screening and for chronic disease management applications. However, for achieving high signal quality, subjects are required to stand still on the scale in an upright position for the measurement; the effects of intentional (for user comfort) or unintentional (due to user error) modifications in the position or posture of the subject during the measurement have not been investigated in the existing literature. In this study, we quantified the effects of different standing and seated postures on the measured BCG signals, and on the most salient BCG-derived features compared to reference standard measurements (e.g., impedance cardiography). We determined that the standing upright posture led to the least distorted signals as hypothesized, and that the correlation between BCG-derived timing interval features (R-J interval) and the preejection period, PEP (measured using ICG), decreased significantly with impaired posture or sitting position. We further implemented two novel approaches to improve the PEP estimates from other standing and sitting postures, using system identification and improved J-wave detection methods. These approaches can improve the usability of standing BCG measurements in unsupervised settings (i.e., the home), by improving the robustness to nonideal posture, as well as enabling high-quality seated BCG measurements.
Sleep-related penile tumescence as a function of age (1975)

The authors conducted a study of nocturnal penile tumescence (NPT) in 125 healthy males aged 3 to 79 by means of EEG recordings to provide normative data on how general the phenomenon is, its range of charateristics, and how it is related to man's sexual function. The results indicate that NPT occurs consistently in a healthy male population, that its expression is significantly affected by age, that it is related to stage of psychosexual development, and that it is worthy of further investigation. Clinical experience indicates that it is a useful, objective method of discriminating among various types of biogenic and psychogenic impotence.
Immunological Studies of the Glycoprotein Allergen Ag-54 (Cla h II) in <i>Cladosporium herbarum</i> with Special Attention to the Carbohydrate and Protein Moieties (1989)

The glycoprotein allergen Ag-54 (Cla h II) isolated from Cladosporium herbarum was split into its carbohydrate and protein moieties by using alkaline-borohydride treatment and deglycosylation, respectively. The native Ag-54, the deglycosylated protein and the protein-free carbohydrate moieties were tested for IgE-binding activity by radioallergosorbent test inhibition using selected sera from individuals with C. herbarum allergy. The deglycosylated material had a stronger allergenic activity than the native Ag-54 with all the sera tested. The Ag-54 carbohydrate moieties were not found to possess any IgE-binding activity. The galactoglucomannan part of the carbohydrate moiety was isolated and it was demonstrated to precipitate IgG rabbit antibody. Removal of the galactofuranose units by mild acid hydrolysis did not alter the IgG-binding capacity of the polysaccharide, indicating that galactofuranose was not immunodominant.
Alkali metal intercalates of molybdenum disulfide (1973)

Natural molybdenite and single crystals of MoS2 grown by chemical vapor transport were intercalated with the alkali group of metals (Li, Na, K, Rb, and Cs) by means of the liquid ammonia technique. Stoichiometries and x-ray data of all intercalates were determined and a complete indexing of the x-ray patterns of K0.4MoS2 and Rb0.3MoS2 was achieved. The x-ray results show insignificant changes in the ao axis and considerable expansion of co axis after intercalation (Δco : 6.745, 2.704, 4.286, 4.899, and 7.312 Å for Li0.4MoS2, Na0.3Mos2, K0.4MoS2, Rb0.3MoS2, and Cs0.3MoS2, respectively). All intercalated crystals were superconducting (Tonset: 3.7, 4.1, 6.1, 6.25, and 6.30 for Li0.4MoS2, Na0.3MoS2, K0.4MoS2, Rb0.3Mos2, and Cs0.3MoS2, respectively). The superconductivity is believed to be due to an electron transfer from the alkali metal to an empty band of MoS2, resulting in an increase in electron density as well as in the density of states at the Fermi surface.
Synchronous generator model identification and parameter estimation from operating data (2003)

A novel technique to estimate and model parameters of a 460-MVA large steam turbine generator from operating data is presented. First, data from small excitation disturbances are used to estimate linear model armature circuit and field winding parameters of the machine. Subsequently, for each set of steady state operating data, saturable inductances L/sub ds/ and L/sub qs/ are identified and modeled using nonlinear mapping functions-based estimators. Using the estimates of the armature circuit parameters, for each set of disturbance data collected at different operating conditions, the rotor body parameters of the generator are estimated using an output error method (OEM). The developed nonlinear models are validated with measurements not used in the estimation procedure.
Recent Design, Placement, and Evaluation Techniques Lead to Improved Gravel Pack Performance (1985)

ABSTRACT Gravel packing has been the method of choice for sand control for the last 40–50 years. Historically gravel packs have impaired the productivity of sand controlled well completions. Only recently through the use of Well Flow, Nodal or Systems Analysis1,2 has the technology from perforating, formation damage prevention, and gravel pack design been assembled in order to effectively understand these damage mechanisms. On-site supervision and execution of better designs is crucial to sand control success. Better gravel placement, downhole tools, and planning have enhanced our ability to execute, these designs.
ARIA can be released from extracellular matrix through cleavage of a heparin-binding domain. (1995)

ARIA, or acetylcholine receptor-inducing activity, is a polypeptide that stimulates the synthesis of acetylcholine receptors in skeletal muscle. Here we demonstrate that the ability of ARIA to induce phosphorylation of its receptor in muscle is blocked by highly charged glycosaminoglycans. ARIA constructs lacking the NH2-terminal portion, containing an immunoglobulin-like domain, are fully active and are not inhibited by glycosaminoglycans. Limited proteolysis of ARIA with subtilisin blocks the glycosaminoglycan interaction by degrading this NH2-terminal portion, but preserves the active, EGF-like domain. We also show that ARIA can be released from freshly dissociated cells from embryonic chick spinal cord and cerebellum by either heparin, high salt or limited proteolysis with subtilisin, suggesting that ARIA is bound to the extracellular matrix through charged interactions. We present a model of how ARIA may be stored in extracellular matrix at developing synapses and how its release may be mediated by local proteolysis.
Activation of host antiviral RNA-sensing factors necessary for herpes simplex virus type 1-activated transcription of host cell fucosyltransferase genes FUT3, FUT5, and FUT6 and subsequent expression of sLex in virus-infected cells (2009)

Herpes simplex virus type 1 (HSV-1) induces expression of a selectin receptor, the carbohydrate epitope sialyl Lewis X (sLe(x)), at the surface of infected cells. The molecular background to this phenomenon is that a viral immediate early RNA interacts with as yet unidentified host factors, eventually resulting in transcription of three dormant host fucosyltransferase genes (FUT3, FUT5, and FUT6), whose gene products are rate-limiting for synthesis of sLe(x). The aim of the present study was to define the immediate targets for the viral RNA in this process. We found that the Protein Kinase R (PKR) inhibitors 2-aminopurine (2-AP) and C16 inhibited FUT3, FUT5, and FUT6 expression as well as HSV-1-induced expression of sLe(x), indicating a primary role of PKR as a viral RNA target. The PKR-dependent activation of the FUT genes seemed neither to involve PKR effects on translation nor to involve NF-kappaB- or JNK-dependent activation. IMD-0354, known as an inhibitor of the NF-kappaB-activating factor IKK-2, induced FUT transcription via a novel IKK-2-independent mechanism, irrespective of whether the cells were virus-infected or not. Altogether, the results suggested that PKR is the primary target for HSV-1 early RNA during induction of FUT3, FUT5, and FUT6, and that the subsequent steps in the transcriptional activation of these host genes involve a hitherto unknown IMD-0354, yet IKK-2-independent, pathway.