gebhart/patrepeval huggingface dataset:
Joint Entity Extraction and Assertion Detection for Clinical Text (2019)

Negative medical findings are prevalent in clinical reports, yet discriminating them from positive findings remains a challenging task for information extraction. Most of the existing systems treat this task as a pipeline of two separate tasks, i.e., named entity recognition (NER) and rule-based negation detection. We consider this as a multi-task problem and present a novel end-to-end neural model to jointly extract entities and negations. We extend a standard hierarchical encoder-decoder NER model and first adopt a shared encoder followed by separate decoders for the two tasks. This architecture performs considerably better than the previous rule-based and machine learning-based systems. To overcome the problem of increased parameter size especially for low-resource settings, we propose the Conditional Softmax Shared Decoder architecture which achieves state-of-art results for NER and negation detection on the 2010 i2b2/VA challenge dataset and a proprietary de-identified clinical dataset.
Mechanisms of photoswitch conjugation and light activation of an ionotropic glutamate receptor (2007)

The analysis of cell signaling requires the rapid and selective manipulation of protein function. We have synthesized photoswitches that covalently modify target proteins and reversibly present and withdraw a ligand from its binding site due to photoisomerization of an azobenzene linker. We describe here the properties of a glutamate photoswitch that controls an ion channel in cells. Affinity labeling and geometric constraints ensure that the photoswitch controls only the targeted channel, and enables spatial patterns of light to favor labeling in one location over another. Photoswitching to the activating state places a tethered glutamate at a high (millimolar) effective local concentration near the binding site. The fraction of active channels can be set in an analog manner by altering the photostationary state with different wavelengths. The bistable photoswitch can be turned on with millisecond-long pulses at one wavelength, remain on in the dark for minutes, and turned off with millisecond long pulses at the other wavelength, yielding sustained activation with minimal irradiation. The system provides rapid, reversible remote control of protein function that is selective without orthogonal chemistry.
Nell-1 Enhances Bone Regeneration in a Rat Critical-Sized Femoral Segmental Defect Model (2011)

Nell-1 in a demineralized bone matrix carrier can significantly improve bone regeneration in a critical-sized femoral segmental defect in a dose-dependent manner. The results of this study demonstrate that Nell-1 is a potent osteospecific growth factor that warrants further investigation. Results also support the potential application of Nell-1 as a bone graft substitute in multiple clinical scenarios involving repair of critical bone loss when autograft bone is limited or unavailable.
Block copolymers with low surface energy segments: siloxane- and perfluoroalkane-modified blocks (1995)

In this paper we describe the preparation and preliminary characterization of diblock copolymers with a low surface energy block. These polymers were prepared by modifying the isoprene block in styreneisoprene-based block copolymers with either short perfluoroalkyl or dimethyl siloxy ‘fingers’. Specifically, the diene block of a styrene-isoprene block copolymer containing a large proportion of pendent vinyl groups (1,2- and 3,4-isoprene) was reacted with the appropriate hydrosilane in the presence of non-acidic Pt catalyst. The degree of attachment of hydrosilane was as high as 50% of the pendent unsaturations. Pendent vinyl groups were converted more efficiently than pendent methyl vinyl groups. These block copolymers, when mixed with the styrene homopolymer, exhibited surface segregation behaviour which depended on both polymer molecular weight and processing conditions. The surface segregation properties of the resulting block copolymers were studied by a variety of techniques which include contact angle measurements, and either X-ray photoelectron spectroscopy or Rutherford backscattering spectrometry. Contact angles as high as 110° were measured for both the siloxane- and perfluoroalkane-modified materials.
TNER: A Novel Background Error Suppression Method for Mutation Detection in Circulating Tumor DNA (2017)

Abstract The use of ultra-deep, next generation sequencing of circulating tumor DNA (ctDNA) holds great promise for early detection of cancer as well as a tool for monitoring disease progression and therapeutic responses. However, the low abundance of ctDNA in the bloodstream coupled with technical errors introduced during library construction and sequencing complicates mutation detection. To achieve high accuracy of variant calling via better distinguishing low frequency ctDNA mutations from background errors, we introduce TNER (Tri-Nucleotide Error Reducer), a novel background error suppression method that provides a robust estimation of background noise to reduce sequencing errors. It significantly enhances the specificity for downstream ctDNA mutation detection without sacrificing sensitivity. Results on both simulated and real healthy subjects’ data demonstrate that the proposed algorithm consistently outperforms a current, state of the art, position-specific error polishing model, particularly when the sample size of healthy subjects is small. TNER is publicly available at https://github.com/ctDNA/TNER .
ChemInform Abstract: ON CARDIOACTIVE STEROIDS. VI. THE SYNTHESIS OF 17α‐METHYL CARDENOLIDES (1982)

Abstract Aus dem Furylsteroid (I) wird durch Oxidation, Methylierung und Reduktion ein Gemisch der epimeren Alkohole (II) erhalten, aus dem durch Oxidation mit m‐Chlorperbenzoesäur‐e (m‐CPBA) und Dehydratisierung das 17a‐Methylcardenolid (III) zugänglich ist.
Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity (2013)

Microbial exposures and sex hormones exert potent effects on autoimmune diseases, many of which are more prevalent in women. We demonstrate that early-life microbial exposures determine sex hormone levels and modify progression to autoimmunity in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). Colonization by commensal microbes elevated serum testosterone and protected NOD males from T1D. Transfer of gut microbiota from adult males to immature females altered the recipient's microbiota, resulting in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and robust T1D protection. These effects were dependent on androgen receptor activity. Thus, the commensal microbial community alters sex hormone levels and regulates autoimmune disease fate in individuals with high genetic risk.
A role for cholinesterases in tumorigenesis? (1991)

Hydrolysis of the neurotransmitter acetylcholine by acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) is the rate-limiting step in the termination of cholinergic signaling at neuromuscular junctions. A growing body of evidence suggests that these enzymes also play a role in tumorigenesis. The ACHE and BCHE genes are amplified, mutated, and/or aberrantly expressed in a variety of human tumor types. These changes could be the result of chromosome breakage, since there is an unusually high frequency of chromosomal abnormalities near the map positions of these genes (3q26-ter and 11p-ter, respectively) in such tumors, particularly hemopoietic malignancies. Both ACHE and BCHE contain the consensus peptide motif S/T-P-X-Z, which is found in many substrates of cdc2-related protein kinases. Here we consider the intriguing possibility that phosphorylation by cdc2-related kinases may be the molecular mechanism linking cholinesterases with tumor cell proliferation. We also discuss the notion that inhibition of these enzymes by commonly used organophosphorous poisons may be tumorigenic in humans.
ViewDock TDW: high-throughput visualization of virtual screening results (2010)

ViewDock TDW is an open source software; freely available on the web at http://www.tdw-prime.webs.com. Chimera UCSF is also available, free of charge, at http://www.cgl.ucsf.edu/chimera/
Newcastle Disease Virus HN Protein Alters the Conformation of the F Protein at Cell Surfaces (2002)

Conformational changes in the Newcastle disease virus (NDV) fusion (F) protein during activation of fusion and the role of HN protein in these changes were characterized with a polyclonal antibody. This antibody was raised against a peptide with the sequence of the amino-terminal half of the F protein HR1 domain. This antibody immunoprecipitated both F(0) and F(1) forms of the fusion protein from infected and transfected cell extracts solubilized with detergent, and precipitation was unaffected by expression of the HN protein. In marked contrast, this antibody detected significant conformational differences in the F protein at cell surfaces, differences that depended upon HN protein expression. The antibody minimally detected the F protein, either cleaved or uncleaved, in the absence of HN protein expression. However, when coexpressed with HN protein, an uncleaved mutant F protein bound the anti-HR1 antibody, and this binding depended upon the coexpression of specifically the NDV HN protein. When the cleaved wild-type F protein was coexpressed with HN protein, the F protein bound anti-HR1 antibody poorly although significantly more than F protein expressed alone. Anti-HR1 antibody inhibited the fusion of R18 (octadecyl rhodamine B chloride)-labeled red blood cells to syncytia expressing HN and wild-type F proteins. This inhibition showed that fusion-competent F proteins present on surfaces of syncytia were capable of binding anti-HR1. Furthermore, only antibody which was added prior to red blood cell binding could inhibit fusion. These results suggest that the conformation of uncleaved cell surface F protein is affected by HN protein expression. Furthermore, the cleaved F protein, when coexpressed with HN protein and in a prefusion conformation, can bind anti-HR1 antibody, and the anti-HR1-accessible conformation exists prior to HN protein attachment to receptors on red blood cells.
Periodate inactivation of ovotransferrin and human serum transferrin. (1980)

Azari and Phillips (Azari, P., and Phillips, J. L. 1970 Arch. Biochem. Biophys. 138, 32-38) reported that periodate treatment of iron-free ovotransferrin causes a rapid loss of iron-binding activity and an oxidation of 3 to 5 tyrosines and 1 tryptophan. Rapid inactivation and loss of tyrosine in ovotransferrin has been confirmed, and the work extended to human serum transferrin and effects of denaturing concentrations of urea. Extensive (> 80%) inactivations of both ovotransferrin and human serum transferrin were observed when approximately 4 tyrosines were destroyed. Amino acid analysis and 360-MHz 1H NMR spectra confirmed that tyrosines are the only residues rapidly oxidized; the correlation of tyrosine loss with the loss of iron-binding activity suggests strongly that the tyrosines involved are those that function as ligands to metal ions bound to the protein. NMR spectra also showed that periodate oxidation causes local changes of structure in ovotransferrin (presumably at the metal-binding sites) but does not grossly alter the conformation. The addition of 5 to 8 M urea greatly retarded the inactivation and losses of tyrosine.
Protection against ventricular arrhythmias and cardiac death using adenosine and lidocaine during regional ischemia in the in vivo rat (2004)

Despite decades of research, there are few effective ways to treat ventricular fibrillation (VF), ventricular tachycardia (VT), or cardiac ischemia that show a significant survival benefit. Our aim was to investigate the combined therapeutic effect of two common antiarrhythmic compounds, adenosine and lidocaine (AL), on mortality, arrhythmia frequency and duration, and infarct size in the rat model of regional ischemia. Sprague-Dawley rats (n = 49) were anesthetized with pentobarbital sodium (60 mg.ml(-1).kg(-1) i.p.) and instrumented for regional coronary occlusion (30 min) and reperfusion (120 min). Heart rate, blood pressure, and a lead II electrocardiogram were recorded. Intravenous pretreatment began 5 min before ischemia and extended throughout ischemia, terminating at the start of reperfusion. After 120 min, hearts were removed for infarct size measurement. Mortality occurred in 58% of saline controls (n = 12), 50% of adenosine only (305 microg.kg(-1).min(-1), n = 8), 0% in lidocaine only (608 microg.kg(-1).min(-1), n = 8), and 0% in AL at any dose (152, 305, or 407 microg.kg(-1).min(-1) adenosine plus 608 microg.kg(-1).min(-1) lidocaine, n = 7, 8, and 6). VT occurred in 100% of saline controls (18 +/- 9 episodes), 50% of adenosine-only (11 +/- 7 episodes), 83% of lidocaine-only (23 +/- 11 episodes), 60% of low-dose AL (2 +/- 1 episodes, P < 0.05), 57% of mid-dose AL (2 +/- 1 episodes, P < 0.05), and 67% of high-dose AL rats (6 +/- 3 episodes). VF occurred in 75% of saline controls (4 +/- 3 episodes), 100% of adenosine-only-treated rats (3 +/- 2 episodes), and 33% lidocaine-only-treated rats (2 +/- 1 episodes) of the rats tested. There was no deaths and no VF in the low- and mid-dose AL-treated rats during ischemia, and only one high-dose AL-treated rat experienced VF (25.5 sec). Infarct size was lower in all AL-treated rats but only reached significance with the mid-dose treatment (saline controls 61 +/- 5% vs. 38 +/- 6%, P < 0.05). We conclude that a constant infusion of a solution containing AL virtually abolished severe arrhythmias and prevented cardiac death in an in vivo rat model of acute myocardial ischemia and reperfusion. AL combinational therapy may provide a primary prevention therapeutic window in ischemic and nonischemic regions of the heart.
Direct injection of a recombinant retroviral vector induces human immunodeficiency virus-specific immune responses in mice and nonhuman primates (1994)

The cytotoxic T-lymphocyte (CTL) response plays an important role in controlling the severity and duration of viral infections. Immunization by direct in vivo administration of retroviral vector particles represents an efficient means of introducing and expressing genes and, subsequently, the proteins they encode in vivo in mammalian cells. In this manner foreign proteins can be provided to the endogenous, class I major histocompatibility complex antigen presentation pathway leading to CTL activation. A nonreplicating recombinant retroviral vector, encoding the human immunodeficiency virus type 1 (HIV-1) IIIB envelope and rev proteins, has been developed and examined for stimulation of immune responses in mouse, rhesus macaque, and baboon models. Animals were immunized by direct intramuscular injection of the retroviral vector particles. Vector-immunized mice, macaques, and baboons generated long-lived CD8+, major histocompatibility complex-restricted CTL responses that were HIV-1 protein specific. The CTL responses were found to be dependent on the ability of the retroviral vector to transduce cells. The vector also elicited HIV-1 envelope-specific antibody responses in mice and baboons. These studies demonstrate the ability of a retroviral vector encoding HIV-1 proteins to stimulate cellular and humoral immune responses and suggest that retrovector immunization may provide an effective means of inducing or augmenting CTL responses in HIV-1-infected individuals.
Engineering microenvironments to control stem cell fate and function (2008)

The two definitive characteristics of stem cells, the capacity for proliferation without loss of potency and the ability to differentiate into specialized cell type(s), endow these cells with great promise for the development of cell replacement therapies for degenerative disease and injury. Furthermore, stem cells are increasingly being recognized as versatile systems for developmental biologists to study lineage specification and tissue organization.
A dielectric hybrid mode antenna feed: A simple alternative to the corrugated horn (1986)

A hybrid-mode horn antenna has been analyzed theoretically and experimentally. It consists of a conical metal horn with a dielectric core inside, separated from the metal wall by another dielectric layer with lower permittivity than for the core material. It is characterized by a very simple design and excellent electrical performance. The horn can support the balanced hybrid HE <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">11</inf> -mode, and exhibits low cross polarization and low sidelobes over a wide frequency range. Compared to corrugated horns, the new horn has a simpler design, is easier to analyze, and has the potential of similar cross-polar bandwidth as for corrugated horns with ring-loaded corrugations. Drawbacks are the effects of dielectric losses. Thus the new horn represents an attractive alternative to the corrugated horn antenna.
Targeted replacement of normal and mutant CFTR sequences in human airway epithelial cells using DNA fragments (1998)

Recent studies have reported that mutant genomic cystic fibrosis (CF) transmembrane conductance regulator ( CFTR ) sequences can be corrected in transformed CF airway epithelial cell lines by targeted replacement with small fragments of DNA with wild-type sequence. To determine if the observed genotype modification following small fragment homologous replacement (SFHR) was limited to transformed CF cell lines, further studies were carried out in both transformed and non-transformed primary normal airway epithelial cells. The endogenous genotype of these normal cell lines was modified following liposome or dendrimer transfection using DNA fragments with DeltaF508 CFTR sequence (488 nt, complementary single strands) designed to also contain a unique restriction enzyme cleavage site (Xho I). Replacement at the appropriate genomic locus by exogenous DeltaF508 CFTR DNA and its expression as mRNA was demonstrated by PCR amplification of genomic DNA and mRNA-derived cDNA as well as Xho I digestion of the PCR products. These studies show that SFHR occurs in both transformed and non-transformed primary human airway epithelial cells and indicate that single base substitution (the silent mutation giving rise to the Xho I site) and deletion or insertion of at least three consecutive bases can be achieved in both normal and CF epithelial cells. Furthermore, these studies reiterate the potential of SFHR as a strategy for a number of gene targeting applications, such as site-specific mutagenesis, development of transgenic animals, development of isogenic cell lines and for gene therapy.
Cytolysis induced by human lymphotoxin. (1972)

By phase-contrast cinemicroscopy, highly purified human lymphotoxin induced two forms of cytolysis-one characterized by slow (1 to 2 hours) swelling (ballooning-type) and the other by sudden (3 to 5 minutes) shrinkage of the cell body and violent agitation of residual debris (popcorn-type). Specifically sensitized lymphocytes likewise caused both forms of lysis, morphologically indistinguishable from lymphotoxin-induced cytolysis. Lymphotoxin also inhibited cell division; mitoses diminished and virtually ceased before the onset of cytolysis. Many of the ultrastructural features preceding early lysis were similar to those associated with failure of osmoregulatory mechanisms-ie, condensation of mitochondria, dilation of rough-surfaced endoplasmic reticulum, separation of polysomes into individual units and expansion of the cell sap. After exposure to lymphotoxin for 12 hours or more, most remaining cells exhibited these same ultrastructural changes but lacked striking mitochondrial lesions.
Coughing frequency in patients with persistent cough: assessment using a 24 hour ambulatory recorder (1994)

Cough is an important symptom of many respiratory disorders. We determined the frequency and diurnal variation of cough in normal subjects and in patients with asthma or with persistent cough of unknown cause. We used a portable, solid-state, multiple-channel recorder to record cough sounds over a 24 h period. The audio-signal was recorded from a unidirectional microphone strapped over the chest wall, and electromyographic (EMG) signals from the lower respiratory muscles were simultaneously registered with surface electrodes. The recorded digital data were examined on an IBM-compatible computer, and the typical signals induced by cough (as assessed by voluntary or experimentally-induced cough) were counted. In 12 normal subjects, only 0-16 coughs were recorded over 24 h. In 21 stable asthmatics with a history of chronic cough ("asthma") the median number was 282 (ranges: 45-1,577), and in 14 patients with the predominant symptom of daily dry coughs ("chronic coughers") the median number was 794 (64-3,639). In both groups of patients, there was a diurnal variation of coughs, such that the least numbers occurred between 2 and 5 a.m. (< 3% of total). In the asthma group, there was no significant correlation between forced expiratory volume in one second (FEV1) (% predicted) or diurnal variation of peak expiratory flow and cough frequency. In the chronic coughers, there was a significant correlation between daytime cough numbers and daytime cough symptoms scores but not for the night-time values. Our data show that cough frequency is not determined by the severity of asthma in relatively stable asthmatics on inhaled steroids, and is reduced during sleep in both asthmatics and chronic cough patients. This portable cough recorder may be useful in the assessment of drug therapy for chronic cough.
Endogenous Fluorescence Spectroscopy of Cell Suspensions for Chemopreventive Drug Monitoring (2004)

Cancer chemopreventive agents such as N-4-(hydroxyphenyl)retinamide (4HPR) are thought to prevent cancers by suppressing growth or inducing apoptosis in precancerous cells. Mechanisms by which these drugs affect cells are often not known, and the means to monitor their effects is not available. In this study endogenous fluorescence spectroscopy was used to measure metabolic changes in response to treatment with 4HPR in ovarian and bladder cancer cell lines. Fluorescence signals consistent with nicotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FAD) and tryptophan were measured to monitor cellular activity through redox status and protein content. Cells were treated with varying concentrations of 4HPR and measured in a stable environment with a sensitive fluorescence spectrometer. Results suggest that redox signal of all cells changed in a similar dose-dependant manner but started at different baseline levels. Redox signal changes depended primarily on changes consistent with NADH fluorescence, whereas the FAD fluorescence remained relatively constant. Similarly, tryptophan fluorescence decreased with increased drug treatment, suggesting a decrease in protein production. Given that each cell line has been shown to have a different apoptotic response to 4HPR, fluorescence redox values along with changes in tryptophan fluorescence may be a response as well as an endpoint marker for chemopreventive drugs.