gebhart/patrepeval huggingface dataset:
Methotrexate revisited: effects of long-term treatment in psoriasis (1994)

In the past 22 years, 113 patients with severe psoriasis have been treated with low-dose methotrexate (MTX) in our department. The maximum weekly dosage was 15 mg (Weinstein schedule), the estimated mean cumulative dose was 4803 mg, and the estimated mean duration of therapy was 8 years and 11 months. In 81% of the patients, prolonged clearance or near clearance was achieved, indicating the potent and sustained potential of MTX in the treatment of both the pustular and erythematosquamous variants of psoriasis. Eighty-three patients (73%) had side-effects, most frequently abnormal liver function tests, nausea and gastric complaints. Apart from hair loss in seven patients, there were no mucocutaneous side-effects, probably because of the low-dose treatment schedule. In 71 patients MTX therapy was discontinued; in 33 patients because of side-effects. In 55 patients one or more liver biopsies were performed. Fibrosis was seen in seven of these patients (13%) and cirrhosis in two (4%). There was no relation between liver biopsy classification and cumulative dosage or duration of MTX therapy, nor was there any relation between liver histology and abnormal liver function tests. During this 22-year period, there were no deaths or life-threatening side-effects attributable to MTX treatment. We conclude that low-dose MTX (< or = 15 mg/week) is a relatively safe therapy for severe psoriasis, if patients are carefully selected beforehand, and regular monitoring for side-effects and drug interactions is performed during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
<title>Improving transverse actuation of piezoceramics using interdigitated surface electrodes</title> (1993)

The possibility of using interdigitated surface electrode patterns to improve the transverse actuation capability of electroceramic actuators is investigated. This pattern produces nonuniform electrical fields in the plane of the wafer which utilize the longitudinal piezoelectric effect to generate larger, more anisotropic planar actuation than conventional piezoelectric devices. Analytical models are developed for a representative electroceramic volume element of a piezoelectric wafer with interdigitated electrodes. These models incorporate full electromechanical coupling through the constitutive relations and are solved using approximate energy methods. The analytical models are compared to piezoelectric finite element solutions. The analysis predicts a range of electrode thickness and spacings which can increase the achievable transverse actuation. An experimental program was performed to validate the analytical results. The experimental results verified the analytical prediction of highly orthotropic large magnitude in plane strains.
Structure of a New Saponin from the Bark of Mimosa tenuiflora (1991)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStructure of a New Saponin from the Bark of Mimosa tenuifloraYulin Jiang, Micheline Haag-Berrurier, Robert Anton, Georges Massiot, Catherine Lavaud, Jean-Marie Teulon, and Christophe GuéchotCite this: J. Nat. Prod. 1991, 54, 5, 1247–1253Publication Date (Print):September 1, 1991Publication History Published online1 July 2004Published inissue 1 September 1991https://doi.org/10.1021/np50077a002RIGHTS & PERMISSIONSArticle Views223Altmetric-Citations18LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (348 KB) Get e-Alerts Get e-Alerts
TRPA1‐like channels enhance glycinergic transmission in medullary dorsal horn neurons (2012)

The effect of icilin, a potent agonist of transient receptor potential ankyrin 1 (TRPA1) and TRPM8, on glycinergic transmission was examined in mechanically isolated rat medullary dorsal horn neurons by use of the conventional whole-cell patch-clamp technique. Icilin increased the frequency of glycinergic spontaneous miniature inhibitory post-synaptic currents (mIPSCs) in a dose-dependent manner. Either allyl isothiocyanate(AITC) or cinnamaldehyde, other TRPA1 agonists, also increased mIPSC frequency, but the extent of facilitation induced by AITC or cinnamaldehyde was less than that induced by icilin. However, menthol, a TRPM8 agonist, had no facilitatory effect on glycinergic mIPSCs. The icilin-induced increase in mIPSC frequency was significantly inhibited by either HC030031, a selective TRPA1 antagonist, or ruthenium red, a non-selective transient receptor potential channel blocker. Icilin failed to increase glycinergic mIPSC frequency in the absence of extracellular Ca(2+), suggesting that the icilin-induced increase in mIPSC frequency is mediated by the Ca(2+) influx from the extracellular space. In contrast, icilin still increased mIPSC frequency either in the Na(+) -free external solution or in the presence of Cd(2+), a general voltage-dependent Ca(2+) channel blocker. The present results suggest that icilin acts on pre-synaptic TRPA1-like ion channels, which are permeable to Ca(2+), to enhance glycinergic transmission onto medullary dorsal horn neurons. The TRPA1-like channel-mediated enhancement of glycinergic transmission in medullary dorsal horn neurons would contribute to the regulation of pain information from the peripheral tissues.
Down-regulation of NKG2D and NKp80 ligands by Kaposi's sarcoma-associated herpesvirus K5 protects against NK cell cytotoxicity (2008)

Natural killer (NK) cells are important early mediators of host immunity to viral infections. The NK activatory receptors NKG2D and NKp80, both C-type lectin-like homodimeric receptors, stimulate NK cell cytotoxicity toward target cells. Like other herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) down-regulates MHC class I molecules to avoid detection by cytotoxic T lymphocytes but renders cells susceptible to NK cell cytotoxicity. We now show that the KSHV immune evasion gene, K5, reduces cell surface expression of the NKG2D ligands MHC class I-related chain A (MICA), MICB, and the newly defined ligand for NKp80, activation-induced C-type lectin (AICL). Down-regulation of both MICA and AICL requires the ubiquitin E3 ligase activity of K5 to target substrate cytoplasmic tail lysine residues. The common MICA *008 allele has a frameshift mutation leading to a premature stop codon and is resistant to down-regulation because of the loss of lysine residues. K5-mediated ubiquitylation signals internalization but not degradation of MICA and causes a potent reduction in NK cell-mediated cytotoxicity. The down-regulation of ligands for both the NKG2D and NKp80 activation pathways provides KSHV with a powerful mechanism for evasion of NK cell antiviral functions.
The impact of premorbid diabetic status on the relationship between the three domains of glycemic control and mortality in critically ill patients (2012)

Premorbid diabetic status impacts the relationship of the three domains of glycemic control to risk of mortality in critically ill patients. The data presented in this review are hypothesis generating; future trials of IIT in the critically ill should stratify management and outcomes by premorbid diabetic status.
An Overview of the Structure and Function of Thrombin (2006)

The fundamental importance of thrombin in biology and medicine has made it one of the most extensively studied of all proteases. Thrombin performs essential functions in vertebrate biology as the central enzyme involved in blood coagulation and platelet aggregation, and as a mitogen and secretagogue for a variety of cell types. Thrombin is synthesized in the liver and secreted into the general circulation in an inactive zymogen form (prothrombin), a complex multidomain glycoprotein that is activated to yield thrombin at sites of vascular injury by limited proteolysis following upstream activation of the coagulation cascade. Thrombin shares its general architecture and catalytic mechanism with those of pancreatic trypsin, the prototypical digestive serine protease. However, the specificity of thrombin toward substrates and cofactors, as well as its spatiotemporal regulation by effectors and inhibitors, is directed by features of the molecule that distinguish it from relatively nonspecific serine proteases like trypsin. Structural and functional studies have demonstrated the presence of surface loops that partially occlude the active site and make specific contacts with residues adjacent to the scissile bond of substrates. Specificity toward macromolecular substrates and cofactors is additionally enhanced by anion-binding exosites that are spatially distinct from the active site. More than five decades of multidisciplinary research on thrombin have produced an abundance of functional and structural information and provided a robust framework for understanding the role of thrombin in vertebrate biology.
Allogeneic bone marrow transplantation using partially-matched related donors. (1987)

Six patients with advanced leukemia and one with severe combined immunodeficiency syndrome received allogeneic bone marrow transplantation (BMT) from HLA haploidentical donors who were compatible for one or two loci on the non-shared chromosome. Methotrexate was used for prophylaxis against acute graft-versus-host disease (GVHD). All patients engrafted but developed moderate to severe acute GVHD, and three patients died. Two leukemic patients relapsed but two others survived and were free of disease 403 and 936 days post-transplant. BMT using related partially matched donors may result in durable engraftment and long-term survivors. The implications of using such donors in expanding the application of BMT are discussed.
Replacement of Massive Blood Loss (1998)

Treatment of massive blood loss has experienced major changes during the recent decade. The transition towards pure component therapy has been the most significant issue, which has compelled the clinician to revise some of their basic strategies in treatment of massively bleeding patients. The importance of adequate volume resuscitation with crystalloids and colloids is still unrefutable, but the therapy of hemorrhagic derangements has changed. Plasma-poor red cells (RC) are now commonly used instead of whole blood (WB) or packed red blood cells (PRBC) to correct oxygen carrying capacity during massive blood loss. As the plasma content of RC is minimal, deficit of plasma and coagulation factors develops earlier than during transfusion of WB and PRBC. Hypofibrinogenemia develops first followed by other coagulation factor deficits and later by thrombocytopenia. Therefore the use of fresh frozen plasma (FFP) is the primary intervention to treat abnormal bleeding encountered in the replacement of massive blood loss with RC. As the development of thrombocytopenia is a highly individual phenomenon, the transfusion of platelets should be guided by repeatedly determined platelet counts.
In Vivo Evaluation of a

Pyridoxalated-Hemoglobin-Polyoxyethylene Conjugate (1988)

A pyridoxylated-hemoglobin-polyoxyethylene conjugate (PHP) was developed from outdated human red cell hemoglobin through chemical modifications. The PHP has a mean molecular weight of approximately 90,000 daltons, with an acceptable P50 of 22 +/- 0.7 mmHg. This report describes exchange transfusion studies (ET) to a final hematocrit of 5 +/- 2% (n = 5) with PHP in mongrel dogs. Hespan (a plasma expander) was used as a control (n = 6). All the animals with PHP tolerated the procedure well and have survived more than 8 months to date. Five out of the six dogs receiving Hespan died within a week (p = 0.004). Reduction of hematological and coagulation parameters occurred following the ET and returned to the normal range by 4 weeks post ET. Serum electrolytes and renal function parameters (urea, creatinine) remained in the normal range. A transient slight increase in the hepatic enzyme SGOT was observed. At 2 weeks post ET open biopsies of major organs showed vacuolized cells in the liver and kidneys. Normal histology was noted at 3 months. The oxygen transporting properties examined showed effective oxygen delivery to the tissues for 6 hours post ET. PHP continued to transport oxygen for up to 48 hours studied post ET. Half-life of PHP in the circulation was 36.3 +/- 3.5 hours. Urinary loss of hemoglobin measured up to 48 hours after ET was 9.4 +/- 1.6% of the injected net hemoglobin. The PHP effectively supported life at lethal levels of anemia and is a physiologically acceptable solution. It has a relatively long intravascular residence time and transports oxygen to the tissue effectively for at least 6 hours.
Real-Time Observation of Transcription Initiation and Elongation on an Endogenous Yeast Gene (2011)

Cellular messenger RNA levels are achieved by the combinatorial complexity of factors controlling transcription, yet the small number of molecules involved in these pathways fluctuates stochastically. It has not yet been experimentally possible to observe the activity of single polymerases on an endogenous gene to elucidate how these events occur in vivo. Here, we describe a method of fluctuation analysis of fluorescently labeled RNA to measure dynamics of nascent RNA--including initiation, elongation, and termination--at an active yeast locus. We find no transcriptional memory between initiation events, and elongation speed can vary by threefold throughout the cell cycle. By measuring the abundance and intranuclear mobility of an upstream transcription factor, we observe that the gene firing rate is directly determined by trans-activating factor search times.
Reinforcement Learning and Episodic Memory in Humans and Animals: An Integrative Framework (2016)

We review the psychology and neuroscience of reinforcement learning (RL), which has experienced significant progress in the past two decades, enabled by the comprehensive experimental study of simple learning and decision-making tasks. However, one challenge in the study of RL is computational: The simplicity of these tasks ignores important aspects of reinforcement learning in the real world: (a) State spaces are high-dimensional, continuous, and partially observable; this implies that (b) data are relatively sparse and, indeed, precisely the same situation may never be encountered twice; furthermore, (c) rewards depend on the long-term consequences of actions in ways that violate the classical assumptions that make RL tractable. A seemingly distinct challenge is that, cognitively, theories of RL have largely involved procedural and semantic memory, the way in which knowledge about action values or world models extracted gradually from many experiences can drive choice. This focus on semantic memory leaves out many aspects of memory, such as episodic memory, related to the traces of individual events. We suggest that these two challenges are related. The computational challenge can be dealt with, in part, by endowing RL systems with episodic memory, allowing them to (a) efficiently approximate value functions over complex state spaces, (b) learn with very little data, and (c) bridge long-term dependencies between actions and rewards. We review the computational theory underlying this proposal and the empirical evidence to support it. Our proposal suggests that the ubiquitous and diverse roles of memory in RL may function as part of an integrated learning system.
Single-Point Active Alignment Method (SPAAM) for Optical See-Through HMD Calibration for Augmented Reality (2002)

Augmented reality (AR) is a technology in which a user's view of the real world is enhanced or augmented with additional information generated from a computer model. To have a working AR system, the see-through display system must be calibrated so that the graphics are properly rendered. The optical see-through systems present an additional challenge because, unlike the video see-through systems, we do not have direct access to the image data to be used in various calibration procedures. This paper reports on a calibration method we developed for optical see-through headmounted displays. We first introduce a method for calibrating monocular optical seethrough displays (that is, a display for one eye only) and then extend it to stereo optical see-through displays in which the displays for both eyes are calibrated in a single procedure. The method integrates the measurements for the camera and a six-degrees-offreedom tracker that is attached to the camera to do the calibration. We have used both an off-the-shelf magnetic tracker as well as a vision-based infrared tracker we have built. In the monocular case, the calibration is based on the alignment of image points with a single 3D point in the world coordinate system from various viewpoints. In this method, the user interaction to perform the calibration is extremely easy compared to prior methods, and there is no requirement for keeping the head immobile while performing the calibration. In the stereo calibration case, the user aligns a stereoscopically fused 2D marker, which is perceived in depth, with a single target point in the world whose coordinates are known. As in the monocular case, there is no requirement that the user keep his or her head fixed.
Synthesis of (aryloxy)alkylamines. 2. Novel imidazo-fused heterocycles with calcium channel blocking and local anesthetic activity (1988)

A series of imidazo-fused heterocycles substituted with an aryloxy)alkylamine side chain were prepared as modifications to butoprozine (I) and found to possess calcium channel blocking activity similar in potency to that of bepridil in trachea smooth muscle and similar to that of verapamil in nitrendipine binding affinity in rabbit cardiac muscle. Of the various imidazo-fused heterocycles prepared, the imidazo[1,2-a]pyridines were also found to be potent local anesthetic agents. While most compounds in this series were equipotent to lidocaine in our initial screen, compounds 2 and 35 showed local anesthetic activity approximately 100 times more potent than lidocaine in our preliminary assays. These compounds represent a novel structural class of local anesthetic agents, and compound 2 is under further investigation.
Directed Evolution of Adenine Base Editors with Increased Activity and Therapeutic Application (2020)

The foundational adenine base editors ( e.g. ABE7.10) enable programmable C•G to T•A point mutations but editing efficiencies can be low at challenging loci in primary human cells. Here we further evolve ABE7.10 using a library of adenosine deaminase variants to create ABE8s. At NGG PAM sites, ABE8s result in ∼1.5x higher editing at protospacer positions A5-A7 and ∼3.2x higher editing at positions A3-A4 and A8-A10 compared with ABE7.10. Non-NGG PAM variants have a ∼4.2-fold overall higher on-target editing efficiency than ABE7.10. In human CD34+ cells, ABE8 can recreate a natural allele at the promoter of the γ-globin genes HBG1 and HBG2, with up to 60% efficiency, causing persistence of fetal hemoglobin. In primary human T cells, ABE8s achieve 98-99% target modification which is maintained when multiplexed across three loci. Delivered as mRNA, ABE8s induce no significant levels of sgRNA-independent off-target adenine deamination in genomic DNA and very low levels of adenine deamination in cellular mRNA.
Treatment of refractory rheumatoid arthritis--the thalidomide experience. (1989)

In an open study, 17 patients (16 women, 1 man) with refractory or severe rheumatoid arthritis were treated with thalidomide. Two withdrew from the study in the first weeks. Thirteen patients received 531 +/- 63 mg/day of thalidomide for 18.8 +/- 8.8 weeks; in 2 the dose was 300 mg/day during 62 and 65 weeks. Seven patients attained complete remission, 5 partial remission, and the last 3 no improvement at all. Remissions lasted 6 years in 1 patient, 2 years in 3, 1 year in one, and varied between 8 months and 8 weeks in 7. After relapse, 5 patients received a 2nd course of treatment and attained remission again. This lasted 24, 10, and 9 months in 3; two are taking 100 mg/day of thalidomide as a maintenance dose and remain asymptomatic after 36 and 30 months. The side effects were drowsiness, constipation, hard swelling of the lower limbs, erythema of the face and limbs with local pruritus or burning sensation, hair loss, cough, nasal obstruction, fever, and skin and mucosal dryness. In 8 patients there was mild eosinophilia (less than 10%) and in 2 leukopenia. A 33-year-old woman showed amenorrhea up to 2 months after stopping treatment. After a 2nd course of treatment, 2 patients developed peripheral sensory neuropathy, which resolved spontaneously in 6 months. We believe these findings justify controlled trials with this agent.
Nanoimprint Mold for 2.5 Tbit/in.2 Directed Self-Assembly Bit Patterned Media with Phase Servo Pattern (2012)

We demonstrate the mold fabrication and replication process for the production of 0.8 and 2.5 Tbit/in. 2 directed self-assembly bit patterned media (DSA-BPM). These devices are fabricated with 33 and 17 nm dot pitch patterns using the microphase segregation structure of polystyrene–poly(dimethylsiloxane) as an etching mask template. The self-assembled dot arrays are simultaneously ordered on both the circular tracks for the data area and the arbitrary marks for the servo area by DSA using groove guides. We fabricated the Si mold with dot pillars of 19.3 nm height for the 2.5 Tbit/in. 2 DSA-BPM from the poly(dimethylsiloxane) dot mask. We also demonstrated the nickel mold replication of the 0.8 Tbit/in. 2 DSA-BPM by electroforming from the Si mold.
Advanced beamforming concepts: source localization using the bispectrum, Gabor transform, Wigner-Ville distribution, and nonstationary signal representations (2002)

It is noted that power spectral estimation provides one approach to direction-finding. This approach readily generalizes to produce a collection of newer direction-finding algorithms. Estimation of the bispectrum yields a bispectral direction finder. Estimates of time-frequency distributions produce Wigner-Ville and Gabor direction-finders. Some types of nonstationary time series admit spectral estimators which can be used to localize a source. Chaotic signals can also be localized using recently developed parameter estimators. It is concluded that D.L. Johnson's (1982) approach to bearing estimation as a form of spectral estimation readily generalizes whenever a statistically consistent estimator of a signal attribute can be found.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>