gebhart/patrepeval huggingface dataset:
Ten Years of Tau-Targeted Immunotherapy: The Path Walked and the Roads Ahead (2018)

Neurofibrillary pathology comprised of pathological tau protein is closely tied to a range of neurodegenerative disorders, the most common of which is Alzheimer's disease. While they are individually rarer, a range of other disorders, the tauopathies (including Pick's disease, progressive supranuclear palsy, corticobasal degeneration, primary progressive aphasia, and ∼50% of behavioral variant frontotemporal dementia cases) display pronounced underlying tau pathology. In all cases, the distribution and amount of tau pathology closely correlates with the severity and phenotype of cognitive impairment, and with the pattern and degree of brain atrophy. Successfully counteracting tau pathology is likely to halt or slow the progression of these debilitating disorders. This makes tau a target of prime importance, yet an elusive one. The diversity of the tau proteome and post-translational modifications, as well as pathophysiology of tau are reviewed. Beginning 2013, a range of tau-targeted immunotherapies have entered clinical development; these therapies, and their common themes and differences are reviewed. The manuscript provides an extensive discussion on epitope selection for immunotherapies against tau pathology, on immunological mechanisms involved in their action, and challenges such as immune senescence, vaccine design, or evolution of epitopes. Furthermore, we provide methodological recommendations for the characterization of active vaccines and antibodies, animal models, and the target itself - the diseased tau proteome.
A Novel Miniature Ventricular Assist Device for Hemodynamic Support (2001)

The HemoDynamics Systems enabler is a new cardiac assist pump that can expel blood from the left ventricle and provide pulsatile flow in the aorta. We evaluated the efficacy of the 18 Fr enabler. The enabler was inserted from the left ventricular apex into the ascending aorta in eight sheep. Heart failure (mild, moderate, and severe) was induced by microsphere injection into the coronary arteries to reduce cardiac output by 10-30%, 31-50%, and more than 50% from baseline, respectively. The enabler was activated, and its flow was increased to approximately 2.0 L/min. Hemodynamic variables were recorded before and after activation. In moderate heart failure, cardiac output and mean aortic pressure increased from 2.3 +/- 0.6 L/min and 59 +/- 12 mm Hg before assist to 2.8 +/- 0.6 L/min and 70 +/- 8 mm Hg at 30 minutes after activation, respectively (p < 0.01). Left atrial pressure decreased from 17 +/- 3 to 13 +/- 4 mm Hg (p < 0.05). Similar findings were observed in mild and severe heart failure. Despite its small diameter, the enabler significantly improved the hemodynamics of failing hearts and may potentially serve as a means of peripheral left ventricular support. Further study is warranted.
Enhanced Oral Absorption of Hydrophobic and Hydrophilic Drugs Using Quaternary Ammonium Palmitoyl Glycol Chitosan Nanoparticles (2011)

As 95% of all prescriptions are for orally administered drugs, the issue of oral absorption is central to the development of pharmaceuticals. Oral absorption is limited by a high molecular weight (>500 Da), a high log P value (>2.0) and low gastrointestinal permeability. We have designed a triple action nanomedicine from a chitosan amphiphile: quaternary ammonium palmitoyl glycol chitosan (GCPQ), which significantly enhances the oral absorption of hydrophobic drugs (e.g., griseofulvin and cyclosporin A) and, to a lesser extent, the absorption of hydrophilic drugs (e.g., ranitidine). The griseofulvin and cyclosporin A C(max) was increased 6- and 5-fold respectively with this new nanomedicine. Hydrophobic drug absorption is facilitated by the nanomedicine: (a) increasing the dissolution rate of hydrophobic molecules, (b) adhering to and penetrating the mucus layer and thus enabling intimate contact between the drug and the gastrointestinal epithelium absorptive cells, and (c) enhancing the transcellular transport of hydrophobic compounds. Although the C(max) of ranitidine was enhanced by 80% with the nanomedicine, there was no appreciable opening of tight junctions by the polymer particles.
TFEC, a basic helix-loop-helix protein, forms heterodimers with TFE3 and inhibits TFE3-dependent transcription activation. (1993)

We have identified a new basic helix-loop-helix (BHLH) DNA-binding protein, designated TFEC, which is closely related to TFE3 and TFEB. The basic domain of TFEC is identical to the basic DNA-binding domain of TFE3 and TFEB, whereas the helix-loop-helix motif of TFEC shows 88 and 85% identity with the same domains in TFE3 and TFEB, respectively. Like the other two proteins, TFEC contains a leucine zipper motif, which has a lower degree of sequence identity with homologous domains in TFE3 and TFEB than does the BHLH segment. Little sequence identity exists outside these motifs. Unlike the two other proteins, TFEC does not contain an acidic domain, which for TFE3 mediates the ability to activate transcription. Like the in vitro translation product of TFE3, the in vitro-translated TFEC binds to the mu E3 DNA sequence of the immunoglobulin heavy-chain gene enhancer. In addition, the product of cotranslation of TFEC RNA and TFE3 RNA forms a heteromeric protein-DNA complex with mu E3 DNA. In contrast to TFE3, TFEC is unable to transactivate a reporter gene linked to a promoter containing tandem copies of the immunoglobulin mu E3 enhancer motif. Cotransfection of TFEC DNA and TFE3 DNA strongly inhibits the transactivation caused by TFE3. TFEC RNA is found in many tissues of adult rats, but the relative concentrations of TFEC and TFE3 RNAs vary considerably in these different tissues. No TFEC RNA was detectable in several cell lines, including fibroblasts, myoblasts, chondrosarcoma cells, and myeloma cells, indicating that TFEC is not ubiquitously expressed.
Health Fraud: A Hardy Perennial (1997)

Quackery forms a gaudy thread in the fabric of health care through the course of American history. In the colonial years, the American market for commercial self-dosage was dominated by “patent medicines”—some of them actually patented—shipped overseas from the mother country. Packed in containers of distinctive shape, sealed in wrappers printed with boastful therapeutic claims, advertised in the slender newborn press, these British nostrums far overshadowed occasional American imitators.
Design Patterns: Elements of Reusable Object-Oriented Software (1994)

The book is an introduction to the idea of design patterns in software engineering, and a catalog of twenty-three common patterns. The nice thing is, most experienced OOP designers will find out they've known about patterns all along. It's just that they've never considered them as such, or tried to centralize the idea behind a given pattern so that it will be easily reusable.
U.S. Law and Legal Research (2007)

This presentation on the basics of U.S. law offers a general outline of the fundamental sources of U.S. law. With a foundation in the three branches of government and the laws, court decisions, and regulations that flow from them, the speaker demonstrated free and fee-based electronic resources frequently used for legal research. The focus is on Westlaw, LexisNexis, PACER the Public Access to Court Electronic Records), GPOAccess, and the official U.S. Supreme Court web site. While the web has made it possible for universities, governments, courts, and others to put user-friendly law on the web for free, the most extensive databases and the most sophisticated searching are still from companies that charge for their services.
Is Infant Immunity Actively Suppressed or Immature? (2014)

Almost 7 million children under the age 5 die each year, and most of these deaths are attributable to vaccine-preventable infections. Young infants respond poorly to infections and vaccines. In particular, dendritic cells secrete less IL-12 and IL-18, CD8<sup>pos</sup> T cells and NK cells have defective cytolysis and cytokine production, and CD4<sup>pos</sup> T cell responses tend to bias towards a Th2 phenotype and promotion of regulatory T cells (T<sub>regs</sub>). The basis for these differences is not well understood and may be in part explained by epigenetic differences, as well as immaturity of the infant's immune system. Here we present a third possibility, which involves active suppression by immune regulatory cells and place in context the immune suppressive pathways of mesenchymal stromal cells (MSC), myeloid-derived suppressor cells (MDSC), CD5<sup>pos</sup> B cells, and T<sub>regs</sub>. The immune pathways that these immune regulatory cells inhibit are similar to those that are defective in the infant. Therefore, the immune deficiencies seen in infants could be explained, in part, by active suppressive cells, indicating potential new avenues for intervention.
Staging of gastrulating mouse embryos by morphological landmarks in the dissecting microscope (1993)

We describe and illustrate a set of morphological landmarks for classifying mouse embryos by gross morphology from before gastrulation to the beginning of organogenesis. These landmarks are visible at the resolution of the dissecting microscope in embryos that are intact except for reflexion of Reichert's membrane. Adoption of these criteria should facilitate interpretation of both the expression patterns of genes and the consequences of experimental manipulation of embryos during early postimplantation development.
Method for enhancing the sensitivity of fluorescent chemosensors: energy migration in conjugated polymers (1995)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMethod for enhancing the sensitivity of fluorescent chemosensors: energy migration in conjugated polymersQin Zhou and Timothy M. SwagerCite this: J. Am. Chem. Soc. 1995, 117, 26, 7017–7018Publication Date (Print):July 1, 1995Publication History Published online1 May 2002Published inissue 1 July 1995https://pubs.acs.org/doi/10.1021/ja00131a031https://doi.org/10.1021/ja00131a031research-articleACS PublicationsRequest reuse permissionsArticle Views2755Altmetric-Citations322LEARN 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 InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts
Deep Generative Image Models using a Laplacian Pyramid of Adversarial Networks (2015)

In this paper we introduce a generative parametric model capable of producing high quality samples of natural images. Our approach uses a cascade of convolutional networks within a Laplacian pyramid framework to generate images in a coarse-to-fine fashion. At each level of the pyramid, a separate generative convnet model is trained using the Generative Adversarial Nets (GAN) approach (Goodfellow et al.). Samples drawn from our model are of significantly higher quality than alternate approaches. In a quantitative assessment by human evaluators, our CIFAR10 samples were mistaken for real images around 40% of the time, compared to 10% for samples drawn from a GAN baseline model. We also show samples from models trained on the higher resolution images of the LSUN scene dataset.
Two Antigenically Distinct Subtypes of Human Immunodeficiency Virus Type 1: Viral Genotype Predicts Neutralization Serotype (1994)

At least five distinct genetic subtypes (genotypes) of human immunodeficiency virus type 1 (HIV-1) have been identified by DNA sequencing. Current vaccine candidates are based on virus strains from North America and Europe that represent only one subtype. The extent to which distinct genotypes of HIV-1 correspond to antigenically distinguishable serotypes is largely unknown and may be critically important to vaccine design. Cross-neuralization studies were done with viruses and plasma from two different genotypes. Based on neutralization susceptibility, 10 primary HIV-1 isolates from Thailand and the United States were classified into one of two antigenic subtypes that correlated with viral genotype. The existence of serotypes of HIV-1 suggests that a broadly effective vaccine may have to include strains from multiple subtypes. Neutralization of these primary HIV-1 isolates differed substantially from results with laboratory strains. Future neutralization studies using primary isolates and multiple genotypes may be important for assessment of HIV-1 antigenic diversity.
Text Detection Using Edge Gradient and Graph Spectrum (2010)

In this paper, we propose a new unsupervised text detection approach which is based on Histogram of Oriented Gradient and Graph Spectrum. By investigating the properties of text edges, the proposed approach first extracts text edges from an image and localize candidate character blocks using Histogram of Oriented Gradients, then Graph Spectrum is utilized to capture global relationship among candidate blocks and cluster candidate blocks into groups to generate bounding boxes of text objects in the image. The proposed method is robust to the color and size of text. ICDAR 2003 text locating dataset and video frames were used to evaluate the performance of the proposed approach. Experimental results demonstrated the validity of our approach.
Molecular characterization of enterohemorrhagic Escherichia coli O157:H7 isolates dispersed across Japan by pulsed-field gel electrophoresis and multiple-locus variable-number tandem repeat analysis. (2008)

We identified seven distinct subtypes of enterohemorrhagic Escherichia coli (EHEC) O157:H7 isolates that were derived from sporadic cases and outbreaks from multiple prefectures in Japan in 2005. A surveillance system utilizing pulsed-field gel electrophoresis (PFGE), PulseNet Japan, was used. Some strains showed indistinguishable PFGE patterns using another restriction enzyme (BlnI or SpeI) in each subtype of EHEC O157:H7 isolates that were routinely subtyped by the XbaI PFGE pattern. In order to examine the genotypic relatedness of these strains, we carried out a multiple-locus variable-number tandem repeat (VNTR) analysis (MLVA). By using the MLVA system, we found that three of seven subtypes of EHEC O157:H7 strains that were isolated from sporadic cases dispersed across multiple prefectures within a few months showed indistinguishable PFGE patterns and identical MLVA types. Strains belonging to the other four subtypes of EHEC O157:H7 in the PFGE analysis were further classified into different clusters of EHEC O157:H7. Therefore, compared to PFGE, MLVA showed greater discriminatory power with respect to analysis of the isolates in this study.
Identifying biological pathways that underlie primordial short stature using network analysis (2014)

Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure.
miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor (2010)

Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and have a negative impact on PR function. In this study, we uncovered a previously undescribed regulatory pathway whereby micro-RNAs (miRNAs) serve as hormonally modulated and conserved mediators of contraction-associated genes in the pregnant uterus in the mouse and human. Using miRNA and gene expression microarray analyses of uterine tissues, we identified a conserved family of miRNAs, the miR-200 family, that is highly induced at term in both mice and humans as well as two coordinately down-regulated targets, zinc finger E-box binding homeobox proteins ZEB1 and ZEB2, which act as transcriptional repressors. We also observed up-regulation of the miR-200 family and down-regulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. We further demonstrated that ZEB1 is directly up-regulated by the action of progesterone (P(4))/PR at the ZEB1 promoter. Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contraction-associated genes, oxytocin receptor and connexin-43, and block oxytocin-induced contractility in human myometrial cells. Together, these findings implicate the miR-200 family and their targets, ZEB1 and ZEB2, as unique P(4)/PR-mediated regulators of uterine quiescence and contractility during pregnancy and labor and shed light on the molecular mechanisms involved in preterm birth.
Induction of NFAT-mediated Transcription by Gq-coupled Receptors in Lymphoid and Non-lymphoid Cells (1996)

The nuclear factor of activated T cells (NFAT) was discovered as an inducible transcription factor activated by antigen stimulation of the T cell receptor in lymphocytes. Stimulation of NFAT-mediated transcription is now reported in both lymphoid and non-lymphoid cells following activation of a neurotransmitter receptor. Carbachol induces robust luciferase responses in Jurkat and pheochromocytoma PC12 cells expressing an NFAT-luciferase reporter construct and a Gq-coupled m3 muscarinic receptor. Cyclosporin blocks this response in PC12 cells, as in Jurkat cells. In PC12 cells expressing a Gi-coupled m2 muscarinic receptor, carbachol induces NFAT-mediated luciferase activity that is strictly dependent upon co-expression of a chimeric G alpha q/alpha i subunit, which confers Gq-effector coupling on Gi-linked receptors. These findings suggest that neurotransmitters, autacoids, or hormones acting on Gq-protein-coupled receptors may serve as physiological stimulators of NFAT in lymphoid and non-lymphoid cells.
Synthesis, Characterization, and 1H NMR Self-Diffusion Studies of Dendritic Aliphatic Polyesters Based on 2,2-Bis(hydroxymethyl)propionic Acid and 1,1,1-Tris(hydroxyphenyl)ethane (1996)

Dendritic aliphatic polyesters of one, two, three, and four generations (Mw: 906, 1856, 3754, and 7549 g/mol) were synthesized in the convergent fashion, using 2,2-bis(hydroxymethyl)propionic acid as building block and 1,1,1-tris(hydroxyphenyl)ethane as core molecule. Dendrons of one to four generations were synthesized from the building block and in a final step coupled to the core molecule. The focal point of the dendrons was protected by a benzyl ester group and deprotected by catalytic hydrogenolysis. The esterifications were performed by conversion of the acid into the corresponding acid chloride and followed by reaction of the acid chloride with the hydroxyl groups in the presence of triethylamine and dimethylaminopyridine. The simplicity of the 1H-NMR and 13C-NMR spectras and elemental analyses suggest that pure and monodisperse dendrimers were obtained. Molecular self-diffusion studies of first, second, third, and fourth generation dendrimers were performed, in chloroform, using pulsed-field spin echo 1H NMR spectroscopy. The self-diffusion coefficients were calculated with the standard form of the Stejskal−Tanner equation. The effective radii of the dendrimers were estimated from the diffusion coefficients by assuming a spherical geometry for all dendrimers. The radii obtained were 7.8, 10.3, 12.6, and 17.1 Å for the first, second, third, and fourth generation dendrimer, respectively.
Unravelling the activation mechanisms of protein kinase B/Akt (2003)

Over the past decade, protein kinase B (PKB, also termed Akt) has emerged as an important signaling mediator between extracellular cues and modulation of gene expression, metabolism, and cell survival. The enzyme is tightly controlled and consequences of its deregulation include loss of growth control and oncogenesis. Recent work has better characterized the mechanism of PKB activation, including upstream regulators and secondary binding partners. This minireview refreshes some old concepts with new twists and highlights current outstanding questions.
Rapamycin relieves lentiviral vector transduction resistance in human and mouse hematopoietic stem cells (2014)

Transplantation of genetically modified hematopoietic stem cells (HSCs) is a promising therapeutic strategy for genetic diseases, HIV, and cancer. However, a barrier for clinical HSC gene therapy is the limited efficiency of gene delivery via lentiviral vectors (LVs) into HSCs. We show here that rapamycin, an allosteric inhibitor of the mammalian target of rapamycin complexes, facilitates highly efficient lentiviral transduction of mouse and human HSCs and dramatically enhances marking frequency in long-term engrafting cells in mice. Mechanistically, rapamycin enhanced postbinding endocytic events, leading to increased levels of LV cytoplasmic entry, reverse transcription, and genomic integration. Despite increasing LV copy number, rapamycin did not significantly alter LV integration site profile or chromosomal distribution in mouse HSCs. Rapamycin also enhanced in situ transduction of mouse HSCs via direct intraosseous infusion. Collectively, rapamycin strongly augments LV transduction of HSCs in vitro and in vivo and may prove useful for therapeutic gene delivery.