gebhart/patrepeval huggingface dataset:
Exogenous heat shock protein 70 binds macrophage lipid raft microdomain and stimulates phagocytosis, processing, and MHC-II presentation of antigens (2005)

The extracellular presence of endotoxin-free heat shock protein 70 (HSP70) enhances the rate and capacity of macrophage-mediated phagocytosis at 6 times the basal rate. It is protein-specific, dose- and time-dependent and involves the internalization of inert microspheres, Gram-positive and -negative bacteria and fungi. Structurally, exogenous HSP70 binds the macrophage plasma membrane, specifically on its lipid raft-microdomain. Disruption of lipid rafts, HSP70-LR interaction, or denaturing HSP70 abrogates the HSP-mediated increase in phagocytosis. Further, HSP70-mediated phagocytosis directly enhances the processing and presentation of internalized antigens via the endocytic MHC class-II pathway to CD4+ T lymphocytes. Modulating the HSP70-LR interaction presents an opportunity to intervene at the level of host-pathogen interface: a therapeutic tool for emerging infections, especially when conventional treatment with antibiotics is ineffective (antibiotic resistance) or unavailable (rapidly spreading, endemic). These results identify a new role for HSP70, a highly conserved molecule in stimulating phagocytosis: a primordial macrophage function, thereby influencing both innate and adaptive immune responses.
Internal Dynamics and Elasticity of Fractal Colloidal Gels (1998)

The dynamic structure factor of fractal colloidal gels is shown to exhibit a stretched exponential decay to a finite plateau with an exponent of about 0.7. The value of the plateau depends on both initial particle volume fraction ${\ensuremath{\varphi}}_{0}$ and scattering wave vector. We show that this behavior results from the contribution of internal elastic modes of many length scales, and present a model which accounts for the data. From the observed plateau we determine that the very small elastic modulus scales as $G\ensuremath{\sim}{\ensuremath{\varphi}}_{0}^{3.9}$, in agreement with predictions, and with direct mechanical measurements.
Synthesis of 2‐aminoquinazolinc‐4(3H)‐one derivatives as potential potassium channel openers (2000)

Abstract Starting from 2‐thioxoquinazolin‐4‐one, the synthesis of 2‐amino‐4(3 H )‐one derivatives, structurally related to potassium channels openers pinacidil and diazoxide, is described.
Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges (2013)

Recent years have witnessed much progress in both basic research and clinical trials regarding cancer immunotherapy with chimeric antigen receptor (CAR)-engineered T cells. The unique structure of CAR endows T cell tumor specific cytotoxicity and resistance to immunosuppressive microenvironment in cancers, which helps patients to better tackle the issue of immunological tolerance. Adoptive immunotherapy (AIT) using this supernatural T cell have gained momentum after decades of intense debates because of the promising results obtained from preclinical models and clinical trials. However, it is very important for us to evaluate thoroughly the challenges/obstacles before widespread clinical application, which clearly warrants more studies to improve our understanding of the mechanism underlying AIT. In this review, we focus on the critical issues related to the clinical outcomes of CAR-based adoptive immunotherapy and discuss the rationales to refine this new cancer therapeutic modality.
Dimer-Specific Potentiation of NGFI-B (Nur77) Transcriptional Activity by the Protein Kinase A Pathway and AF-1-Dependent Coactivator Recruitment (2003)

The NGFI-B (Nur77) subfamily of orphan nuclear receptors (NRs), which also includes Nurr1 and NOR1, bind the NurRE regulatory element as either homo- or heterodimers formed between subfamily members. These NRs mediate the activation of pituitary proopiomelanocortin (POMC) gene transcription by the hypothalamic hormone corticotropin-releasing hormone (CRH), an important link between neuronal and endocrine components of the hypothalamo-pituitary-adrenal axis. CRH effects on POMC transcription do not require de novo protein synthesis. We now show that CRH signals activate Nur factors through the cyclic AMP/protein kinase A (PKA) pathway. CRH and PKA rapidly increase nuclear DNA binding activity of NGFI-B dimers but not monomers. Accordingly, CRH- or PKA-activated Nur factors enhance dimer (but not monomer) target response elements. We also show that p160/SRC coactivators are recruited to Nur dimers (but not to monomers) and that coactivator recruitment to the NurRE is enhanced in response to CRH. Moreover, PKA- and coactivator-induced potentiation of NGFI-B activity are primarily exerted through the N-terminal AF-1 domain of NGFI-B. The TIF2 (SRC-2) glutamine-rich domain is required for this activity. Taken together, these results indicate that Nur factors behave as endpoint effectors of the PKA signaling pathway acting through dimers and AF-1-dependent recruitment of coactivators.
Structural requirements for the inhibition of 5-lipoxygenase by 15-hydroxyeicosa-5,8,11,13-tetraenoic acid analogs (1987)

The structural requirements for inhibition of RBL-1 (rat basophilic leukemia) 5-lipoxygenase by 15-hydroxyeicosa-5,8,11,13-tetraenoic acid (15-HETE, 1) were studied by systematic chemical modifications of the molecule at the hydroxyl and carboxyl groups, the double bonds, and the carboxylate and omega side chains. The most potent inhibitors were analogues that contained a 5,8-cis,cis-diene system and acted as alternate substrates for the enzyme. However, several analogues in which the 5,8-diene had been reduced were also found to inhibit the enzyme. Inhibition of 5-lipoxygenase by 15-hydroxyeicosa-11,13-dienoic acid (15-HEDE) analogues was optimal in compounds that generally contained a free carboxyl group, a carboxylate side chain of nine carbons, an omega side chain of five or six carbons, a cis,trans- or trans,cis-11,13-diene or 11,13-diyne system, and a 15-hydroxyl group. Conversion of 15-HEDE to its 16-membered lactone reduced but did not eliminate 5-lipoxygenase inhibitory activity. In contrast, a 3- to 10-fold enhancement of activity occurred when 5,15-diHETE (58) or 5-HETE (56) were cyclized to their respective delta-lactones. Molecular modeling of 15-HEDE analogues, modified in the C11-C15 region, showed that inactive analogues protrude into regions in space not occupied by active analogues. These structural studies indicate that multiple regions are important for 5-lipoxygenase inhibition by both 15-HETE and 15-HEDE analogues and that no single region plays a predominant role in inhibition.
Affective Content Analysis in Comedy and Horror Videos by Audio Emotional Event Detection (2005)

We study the problem of affective content analysis. In this paper, we think of affective contents as those video/audio segments, which may cause an audience's strong reactions or special emotional experiences, such as laughing or fear. Those emotional factors are related to the users' attention, evaluation, and memories of the content. The modeling of affective effects depends on the video genres. In this work, we focus on comedy and horror films to extract the affective content by detecting a set of so-called audio emotional events (AEE) such as laughing, horror sounds, etc. Those AEE can be modeled by various audio processing techniques, and they can directly reflect an audience's emotion. We use the AEE as a clue to locate corresponding video segments. Domain knowledge is more or less employed at this stage. Our experimental dataset consists of 40-minutes comedy video and 40-minutes horror film. An average recall and precision of above 90% is achieved. It is shown that, in addition to rich visual information, an appropriate usage of special audios is an effective way to assist affective content analysis.
Utilization of Structure-Based Design to Identify Novel, Irreversible Inhibitors of EGFR Harboring the T790M Mutation (2016)

A novel series of covalent inhibitors of EGFR (epidermal growth factor receptor) kinase was discovered through a combination of subset screening and structure-based design. These compounds preferentially inhibit mutant forms of EGFR (activating mutant and T790M mutant) over wild-type EGFR in cellular assays measuring EGFR autophosphorylation and proliferation, suggesting an improved therapeutic index in non-small cell lung cancer patients would be achievable relative to established EGFR inhibitors. We describe our design approaches, resulting in the identification of the lead compound 5, and our efforts to develop an understanding of the structure-activity relationships within this series. In addition, strategies to overcome challenges around metabolic stability and aqueous solubility are discussed. Despite limitations in its physical properties, 5 is orally bioavailable in mice and demonstrates pronounced antitumor activity in in vivo models of mutant EGFR-driven cancers.
Efficient hammerhead ribozyme-mediated cleavage of the structured heapatitis B virus encapsidation signalin vitroand in cell extracts, but not in intact cells (1995)

Hepatitis B virus (HBV), the causative agent of B-type hepatitis in man, is a small enveloped DNA virus that replicates through reverse transcription of an RNA intermediate, the terminally redundant RNA pregenome. An essential highly conserved cis-element present twice on this RNA is the encapsidation signal epsilon, a stem-loop structure that is critical for pregenome packaging and reverse transcription. Epsilon is hence an attractive target for antiviral therapy. Its structure, however, is a potential obstacle to antivirals whose action depends on hybridization, e.g. ribozymes. Here we demonstrate effective in vitro cleavage inside epsilon by hammerhead ribozymes containing flanking sequences complementary to an adjacent less structured region. Upon co-transfection with a HBV expression construct corresponding ribozymes embedded in a U6 snRNA context led to a significant, though modest, reduction in the steady-state level of HBV pregenomes. Inactive ribozyme mutants revealed that antisense effects contributed substantially to this reduction, however, efficient epsilon cleavage by the intracellularly expressed ribozymes was observed in Mg(2+)-supplemented cell lysates. Artificial HBV pregenomes carrying the ribozymes in cis and model RNAs lacking all HBV sequences except epsilon exhibited essentially the same behaviour. Hence, neither the absence of co-localization of ribozyme and target nor a viral component, but rather a cellular factor(s), is responsible for the strikingly different ribozyme activities inside cells and in cellular extracts.
Use of Antimicrobial Prophylaxis for Major Surgery (2005)

Substantial opportunities exist to improve the use of prophylactic antimicrobials for patients undergoing major surgery.
Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia (2015)

Mer and Flt3 receptor tyrosine kinases have been implicated as therapeutic targets in acute myeloid leukemia (AML). In this manuscript we describe UNC1666, a novel ATP-competitive small molecule tyrosine kinase inhibitor, which potently diminishes Mer and Flt3 phosphorylation in AML. Treatment with UNC1666 mediated biochemical and functional effects in AML cell lines expressing Mer or Flt3 internal tandem duplication (ITD), including decreased phosphorylation of Mer, Flt3 and downstream effectors Stat, Akt and Erk, induction of apoptosis in up to 98% of cells, and reduction of colony formation by greater than 90%, compared to treatment with vehicle. These effects were dose-dependent, with inhibition of downstream signaling and functional effects correlating with the degree of Mer or Flt3 kinase inhibition. Treatment of primary AML patient samples expressing Mer and/or Flt3-ITD with UNC1666 also inhibited Mer and Flt3 intracellular signaling, induced apoptosis, and inhibited colony formation. In summary, UNC1666 is a novel potent small molecule tyrosine kinase inhibitor that decreases oncogenic signaling and myeloblast survival, thereby validating dual Mer/Flt3 inhibition as an attractive treatment strategy for AML.
In Vitro and in Vivo Testing of a Novel Regulatory System for Gene Therapy for Intervertebral Disc Degeneration (2011)

These data demonstrate that in vitro ligand-induced gene expression can be stimulated and effectively turned off by removal of the ligand. In addition, we demonstrated the in vivo utility of this system through showing up-regulation of GFP without nonspecific gene expression or expression in adjacent tissues. This system, therefore, has the potential to increase the safety of gene therapy in the treatment of intervertebral disc degeneration.
Metal reductions of malonates and oxalates. A covenient decarboxylation route for disubstituted malonates and synthesis of keten acetals (1971)

Alkali-metal reduction of disubstituted malonates or treatment of esters with base in the presence of trimethylchlorosilane gives high yields of the reactive disubstituted keten alkyl trimethylsilyl acetals, while diethyl oxalate, under similar conditions is reduced to 1,2-diethyl-1,2-bis(trimethylsilyloxy)ethylene.
Functional Characterization of Two Clusters of Brachypodium distachyon UDP-Glycosyltransferases Encoding Putative Deoxynivalenol Detoxification Genes (2013)

Plant small-molecule UDP-glycosyltransferases (UGT) glycosylate a vast number of endogenous substances but also act in detoxification of metabolites produced by plant-pathogenic microorganisms. The ability to inactivate the Fusarium graminearum mycotoxin deoxynivalenol (DON) into DON-3-O-glucoside is crucial for resistance of cereals. We analyzed the UGT gene family of the monocot model species Brachypodium distachyon and functionally characterized two gene clusters containing putative orthologs of previously identified DON-detoxification genes from Arabidopsis thaliana and barley. Analysis of transcription showed that UGT encoded in both clusters are highly inducible by DON and expressed at much higher levels upon infection with a wild-type DON-producing F. graminearum strain compared with infection with a mutant deficient in DON production. Expression of these genes in a toxin-sensitive strain of Saccharomyces cerevisiae revealed that only two B. distachyon UGT encoded by members of a cluster of six genes homologous to the DON-inactivating barley HvUGT13248 were able to convert DON into DON-3-O-glucoside. Also, a single copy gene from Sorghum bicolor orthologous to this cluster and one of three putative orthologs of rice exhibit this ability. Seemingly, the UGT genes undergo rapid evolution and changes in copy number, making it difficult to identify orthologs with conserved substrate specificity.
Genetics and immunology: reinvigorated (2015)

Immune checkpoint blockade therapy is changing oncology by improving the outcome of patients with advanced malignancies. Our research has revealed the genetic features of tumors present in patients who initiate a successful antitumor immune response and derive clinical benefit from immune checkpoint blockade therapy versus non-responders.
4-Aminopyridine and spinal cord injury: a review (1994)

Demyelination of axons within the spinal cord represents a significant component of the pathology of contusive and compressive spinal cord injury (SCI) and the associated conduction deficits most probably contribute to the paralysis and sensory loss experienced by SCI patients. 4-Aminopyridine (4-AP) is a potassium (K+) channel blocking agent that has been shown capable of restoring conduction across demyelinated internodes in neurons of the spinal cord. Recent clinical trials of 4-AP provide evidence that limited and transient neurological gain may be derived by some SCI patients with longstanding injury. The present review traces the historical development of 4-AP, describes the mechanism of action and rationale for use in SCI, and provides an overview of the clinical trials conducted to date. The early trials give rise to optimism that pharmaceutical management of conduction deficits may have a role to play in restoring neurological function in some patients with SCI.
Assessment of coronary flow reserve by transthoracic Doppler echocardiography in left apical ballooning syndrome (2007)

We present the time course of transthoracic coronary flow reserve in the left anterior descending artery in a patient who suffered a transient left apical ballooning syndrome.
Sequence similarity of mammalian epoxide hydrolases to the bacterial haloalkane dehalogenase and other related proteins (1994)

Direct comparison of the amino acid sequences of microsomal and soluble epoxide hydrolase superficially indicates that these enzymes are unrelated. Both proteins, however, share significant sequence similarity to a bacterial haloalkane dehalogenase that has earlier been shown to belong to the alpha/beta hydrolase fold family of enzymes. The catalytic mechanism for the dehalogenase has been elucidated in detail [Verschueren et al. (1993) Nature 363, 693-698] and proceeds via an ester intermediate where the substrate is covalently bound to the enzyme. From these observations we conclude (i) that microsomal and soluble epoxide hydrolase are distantly related enzymes that have evolved from a common ancestral protein together with the haloalkane dehalogenase and a variety of other proteins specified in the present paper, (ii) that these enzymes most likely belong to the alpha/beta hydrolase fold family of enzymes and (iii) that the enzymatic epoxide hydrolysis proceeds via a hydroxy ester intermediate, in contrast to the presently favoured base-catalyzed direct attack of the epoxide by an activated water.
Drug Resistance in Epilepsy: Putative Neurobiologic and Clinical Mechanisms (2005)

Drug-resistant epilepsy with uncontrolled severe seizures despite state-of-the-art medical treatment continues to be a major clinical problem for up to one in three patients with epilepsy. Although drug resistance may emerge or remit in the course of epilepsy or its treatment, in most patients, drug resistance seems to be continuous and to occur de novo. Unfortunately, current antiepileptic drugs (AEDs) do not seem to prevent or to reverse drug resistance in most patients, but add-on therapy with novel AEDs is able to exert a modest seizure reduction in as many as 50% of patients in short-term clinical trials, and a few become seizure free during the trial. It is not known why and how epilepsy becomes drug resistant, while other patients with seemingly identical seizure types can achieve seizure control with medication. Several putative mechanisms underlying drug resistance in epilepsy have been identified in recent years. Based on experimental and clinical studies, two major neurobiologic theories have been put forward: (a) removal of AEDs from the epileptogenic tissue through excessive expression of multidrug transporters, and (b) reduced drug-target sensitivity in epileptogenic brain tissue. On the clinical side, genetic and clinical features and structural brain lesions have been associated with drug resistance in epilepsy. In this article, we review the laboratory and clinical evidence to date supporting the drug-transport and the drug-target hypotheses and provide directions for future research, to define more clearly the role of these hypotheses in the clinical spectrum of drug-resistant epilepsy.
Muerte inesperada del lactante: Diagnóstico de situación en la ciudad de Montevideo (2003)

Objetivo: 1) Aplicar un protocolo de estudio uniforme a todos los lactantes fallecidos en forma inesperada en la ciudad de Montevideo. 2) Obtener el diagnostico de situacion en relacion a las verdaderas causas de mortalidad infantil inesperada en la ciudad de Montevideo. 3) Realizar el diagnostico de situacion y posicionamiento real del sindrome de muerte subita del lactante dentro de las muertes inesperadasMaterial y metodo: a los lactantes fallecidos inesperadamente en Montevideo, en el periodo comprendido entre octubre de 1998 y marzo de 2000 se les aplico sistematicamente: 1) Autopsia completa protocolizada, con fotografia, radiologia, toma de muestras para enfermedades metabolicas, microbiologia, toxicologia y estudio bioquimico (ionograma del humor vitreo). 2) Se realizo histologia completa de todos los organos. 3.) Se investigaron las circunstancias que rodearon a la muerte y se reviso la historia clinica. 4) Se discutio cada caso en grupo multidisciplinario. Resultados: Se estudiaron 115 casos de los cuales 109 (95%) correspondieron a menores de un ano y 6 a menores entre los 12 y 18 meses. En 65% de los casos se confirmo una causa de muerte. Correspondieron al grupo de Muerte Explicable. Dentro de este grupo la infeccion respiratoria baja, las causas cardiacas, la diarrea con deshidratacion y la sepsis constituyeron las causas mas importantes. El sindrome de muerte subita del lactante represento el 20% de la muestra y la zona gris el 15%. Conclusiones: La realizacion sistematica de la autopsia protocolizada por patologo pediatra y forense ha permitido conocer la verdadera causa de muerte en los lactantes de Montevideo que han fallecido inesperadamente. El desarrollo del programa Muerte Inesperada del Lactante ha permitido tomar un tema que en el Uruguay estaba limitado a los archivos judiciales y ponerlo en la mesa de discusion pediatrica para su aplicacion en la docencia, investigacion y planificacion de politicas de salud, siguiendo los criterios actualmente sugeridos por la literatura internacional
Validation of image defect models for optical character recognition (1996)

Considers the problem of evaluating character image generators that model distortions encountered in optical character recognition (OCR). While a number of such defect models have been proposed, the contention that they produce the desired result is typically argued in an ad hoc and informal way. The authors introduce a rigorous and more pragmatic definition of when a model is accurate: they say a defect model is validated if the OCR errors induced by the model are indistinguishable from the errors encountered when using real scanned documents. The authors describe four measures to quantify this similarity, and compare and contrast them using over ten million scanned and synthesized characters in three fonts. The measures differentiate effectively between different fonts and different scans of the same font regardless of the underlying text.
Physiologically aged red blood cells undergo erythrophagocytosis in vivo but not in vitro (2012)

The large senescent erythrocyte population found in hypertransfused mice mimics physiologically aged erythrocytes. For effective erythrophagocytosis of these senescent erythrocytes, macrophages depend on some features of the intact phagocytosing tissue for support.
<title>Two-photon photochromism of a photorefractive organic material for holographic recording</title> (2000)

We report the two-photon induced photoisomerization of 3-[1-(1,2- dimethyl-1H-indol-3-yl)-ethylidene]-4-isopropylidene-dihydro-furan- 2,5-dione (1), a photochromic compound with (lambda) <SUB>max</SUB>equals385nm, using 775 fs pulses. The resulting photoisomer has a (lambda) <SUB>max</SUB>equals582 nm. The kinectic rate contant for the isomerization reaction w as measured at two different intensities (two different powers), showing a quadratic dependence with respect to the pump intensity. Results of pump-probe solution phase experiments and guest/host polymer thin film interferometric imaging studies are shown. A two-photon absorption molecular cross-section (sigma) 2equals10.3 x 10<SUP>- 45</SUP> cm<SUP>4</SUP> s/photon was measured using Z-scan, supporting a two photon induced isomerization process.