gebhart/patrepeval huggingface dataset:
Targeting Nrf2 Signaling Improves Bacterial Clearance by Alveolar Macrophages in Patients with COPD and in a Mouse Model (2011)

Patients with chronic obstructive pulmonary disease (COPD) have innate immune dysfunction in the lung largely due to defective macrophage phagocytosis. This deficiency results in periodic bacterial infections that cause acute exacerbations of COPD, a major source of morbidity and mortality. Recent studies indicate that a decrease in Nrf2 (nuclear erythroid-related factor 2) signaling in patients with COPD may hamper their ability to defend against oxidative stress, although the role of Nrf2 in COPD exacerbations has not been determined. Here, we test whether activation of Nrf2 by the phytochemical sulforaphane restores phagocytosis of clinical isolates of nontypeable Haemophilus influenza (NTHI) and Pseudomonas aeruginosa (PA) by alveolar macrophages from patients with COPD. Sulforaphane treatment restored bacteria recognition and phagocytosis in alveolar macrophages from COPD patients. Furthermore, sulforaphane treatment enhanced pulmonary bacterial clearance by alveolar macrophages and reduced inflammation in wild-type mice but not in Nrf2-deficient mice exposed to cigarette smoke for 6 months. Gene expression and promoter analysis revealed that Nrf2 increased phagocytic ability of macrophages by direct transcriptional up-regulation of the scavenger receptor MARCO. Disruption of Nrf2 or MARCO abrogated sulforaphane-mediated bacterial phagocytosis by COPD alveolar macrophages. Our findings demonstrate the importance of Nrf2 and its downstream target MARCO in improving antibacterial defenses and provide a rationale for targeting this pathway, via pharmacological agents such as sulforaphane, to prevent exacerbations of COPD caused by bacterial infection.
An Empirical Exploration of Recurrent Network Architectures (2015)

The Recurrent Neural Network (RNN) is an ex-tremely powerful sequence model that is often difficult to train. The Long Short-Term Memory (LSTM) is a specific RNN architecture whose design makes it much easier to train. While wildly successful in practice, the LSTM’s archi-tecture appears to be ad-hoc so it is not clear if it is optimal, and the significance of its individual components is unclear. In this work, we aim to determine whether the LSTM architecture is optimal or whether much better architectures exist. We conducted a thor-ough architecture search where we evaluated over ten thousand different RNN architectures, and identified an architecture that outperforms both the LSTM and the recently-introduced Gated Recurrent Unit (GRU) on some but not all tasks. We found that adding a bias of 1 to the LSTM’s forget gate closes the gap between the LSTM and the GRU. 1.
Increasing functional avidity of TCR-redirected T cells by removing defined N -glycosylation sites in the TCR constant domain (2009)

Adoptive transfer of T lymphocytes transduced with a T cell receptor (TCR) to impart tumor reactivity has been reported as a potential strategy to redirect immune responses to target cancer cells (Schumacher, T.N. 2002. Nat. Rev. Immunol. 2:512-519). However, the affinity of most TCRs specific for shared tumor antigens that can be isolated is usually low. Thus, strategies to increase the affinity of TCRs or the functional avidity of TCR-transduced T cells might be therapeutically beneficial. Because glycosylation affects the flexibility, movement, and interactions of surface molecules, we tested if selectively removing conserved N-glycoslyation sites in the constant regions of TCR alpha or beta chains could increase the functional avidity of T cells transduced with such modified TCRs. We observed enhanced functional avidity and improved recognition of tumor cells by T cells harboring TCR chains with reduced N-glycosylation (DeltaTCR) as compared with T cells with wild-type (WT) TCR chains. T cells transduced with WT or DeltaTCR chains bound tetramer equivalently at 4 degrees C, but tetramer binding was enhanced at 37 degrees C, predominantly as a result of reduced tetramer dissociation. This suggested a temperature-dependent mechanism such as TCR movement in the cell surface or structural changes of the TCR allowing improved multimerization. This strategy was effective with mouse and human TCRs specific for different antigens and, thus, should be readily translated to TCRs with any specificity.
Preventative and therapeutic vaccines for cervical cancer (2003)

"High-risk" genotypes of the human papillomavirus (HPV), most commonly HPV genotype 16, are the primary etiologic agents of cervical cancer. Indeed HPV DNA is detected in 99% of cervical carcinomas. Thus, cervical cancer and other HPV-associated malignancies might be prevented or treated by the induction of the appropriate viral-antigen-specific immune responses. Transmission of papillomavirus may be prevented by the generation of antibodies to capsid proteins L1 and L2 that neutralize viral infection. HPV L1 virus-like particles (VLPs) show great promise as prophylactic HPV vaccines in ongoing clinical trials but L2-based preventative vaccines have yet to be tested in patients. Since the capsid proteins are not expressed at detectable levels by infected basal keratinocytes or in HPV-transformed cells, therapeutic vaccines generally target the nonstructural early viral antigens. Two HPV oncogenic proteins, E6 and E7, are critical to the induction and maintenance of cellular transformation and are co-expressed in the majority of HPV-containing carcinomas. Although other early viral antigens show promise for vaccination against papillomas, therapeutic vaccines targeting E6 and E7 may provide the best opportunity to control HPV-associated malignancies. Various candidate therapeutic HPV vaccines are currently being tested whereby E6 and/or E7 are administered in live vectors, as peptides or proteins, in nucleic acid form, as components of chimeric VLPs, or in cell-based vaccines. Encouraging results from experimental vaccination systems in animal models have led to several prophylactic and therapeutic vaccine clinical trials. Should this new generation of HPV preventative and therapeutic vaccines function in patients as demonstrated in animal models, oncogenic HPV infection and its associated malignancies could be controlled by vaccination. Importantly, recent advances in HPV detection and continued improvements in screening further enhance our opportunities to systematically eradicate HPV-associated malignancy.
VLSI-Compatible Carbon Nanotube Doping Technique with Low Work-Function Metal Oxides (2014)

Single-wall carbon nanotubes (SWCNTs) have great potential to become the channel material for future high-speed transistor technology. However, as-made carbon nanotube field effect transistors (CNFETs) are p-type in ambient, and a consistent and reproducible n-type carbon nanotube (CNT) doping technique has yet to be realized. In addition, for very large scale integration (VLSI) of CNT transistors, it is imperative to use a solid-state method that can be applied on the wafer scale. Herein we present a novel, VLSI-compatible doping technique to fabricate n-type CNT transistors using low work-function metal oxides as gate dielectrics. Using this technique we demonstrate wafer-scale, aligned CNT transistors with yttrium oxide (Y2Ox) gate dielectrics that exhibit n-type behavior with Ion/Ioff of 10(6) and inverse subthreshold slope of 95 mV/dec. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) analyses confirm that slow (∼1 Å/s) evaporation of yttrium on the CNTs can form a smooth surface that provides excellent wetting to CNTs. Further analysis of the yttrium oxide gate dielectric using X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD) techniques revealed that partially oxidized elemental yttrium content increases underneath the surface where it acts as a reducing agent on nanotubes by donating electrons that gives rise to n-type doping in CNTs. We further confirm the mechanism for this technique with other low work-function metals such as lanthanum (La), erbium (Er), and scandium (Sc) which also provide similar CNT NFET behavior after transistor fabrication. This study paves the way to exploiting a wide range of materials for an effective n-type carbon nanotube transistor for a complementary (p- and n-type) transistor technology.
Real-time Detection of Basal and Stimulated G Protein GTPase Activity Using Fluorescent GTP Analogues (2004)

Hydrolysis of fluorescent GTP analogues BODIPY FL guanosine 5 '-O-(thiotriphosphate) (BGTPgammaS) and BODIPY FL GTP (BGTP) by Galpha(i1) and Galpha was characterized using on-line capillary electrophoresis (o) laser-induced fluorescence assays in order that changes in sub-strate, substrate-enzyme complex, and product could be monitored separately. Apparent k values (V /[E]) (max cat) steady-state and K(m) values were determined from assays for each substrate-protein pair. When BGTP was the substrate, maximum turnover numbers for Galpha and Galpha(i1) were 8.3 +/- 1 x 10(-3) and 3.0 +/- 0.2 x 10(-2) s(-1), respectively, and K(m) values were 120 +/- 60 and 940 +/- 160 nm. Assays with BGTPgammaS yielded maximum turnover numbers of 1.6 +/- 0.1 x 10(-4) and 5.5 +/- 0.3 x 10(-4) s(-1) for Galpha and Galpha(i1); K(m) values were 14 (o)(+/-)8 and 87 +/- 22 nm. Acceleration of Galpha GTPase activity by regulators of G protein signaling (RGS) was demonstrated in both steady-state and pseudo-single-turnover assay formats with BGTP. Nanomolar RGS increased the rate of enzyme product formation (BODIPY(R) FL GDP (BGDP)) by 117-213% under steady-state conditions and accelerated the rate of G protein-BGTP complex decay by 199 -778% in pseudo-single-turnover assays. Stimulation of GTPase activity by RGS proteins was inhibited 38-81% by 40 mum YJ34, a previously reported peptide RGS inhibitor. Taken together, these results illustrate that Galpha subunits utilize BGTP as a substrate similarly to GTP, making BGTP a useful fluorescent indicator of G protein activity. The unexpected levels of BGTPgammaS hydrolysis detected suggest that caution should be used when interpreting data from fluorescence assays with this probe.
A time dependent multimedia document as an advanced communication media (1992)

A method for formally specifying a structure of TDMD(Time Dependent Multimedia Document) is proposed. TDMD can include voice, video, test, graphics and image. Prototype system is implemented in which an interchanged document structure is parsed and each component of the document can be presented at intended time at appropriate position.
CD74: A New Candidate Target for the Immunotherapy of B-Cell Neoplasms (2007)

CD74 is an integral membrane protein that functions as a MHC class II chaperone. Moreover, it has recently been shown to have a role as an accessory-signaling molecule and has been implicated in malignant B-cell proliferation and survival. These biological functions combined with expression of CD74 on malignant B cells and limited expression on normal tissues implicate CD74 as a potential therapeutic target. The anti-CD74 monoclonal antibody LL1 has been humanized (hLL1 milatuzumab or IMMU-115) and can provide the basis for novel therapeutic approaches to B-cell malignancies, particularly because this antibody shows rapid internalization into CD74+ malignant cells. This article reviews the preclinical evaluations of LL1, its humanized form, and isotope, drug, and toxin conjugates. These studies show that unconjugated hLL1 and conjugates of hLL1 constructs with radioisotopes, doxorubicin, and frog RNase have high antitumor activity in non-Hodgkin's lymphoma and multiple myeloma in vitro and in tumor xenograft models. Single-dose studies of hLL1 in monkeys showed no adverse effects but did decrease circulating B and T lymphocytes and natural killer cells. When evaluated in combination with rituximab, either equivalent or improved efficacy, compared with either antibody alone, was observed. CD74 is a new candidate target for the immunotherapy of neoplasms expressing this antigen, which can be exploited using either a naked antibody or conjugated to isotopes, drugs, or toxins.
Isolation and characterization of endothelial progenitor cells from mouse embryos (1998)

The cardiovascular system develops early in embryogenesis from cells of mesodermal origin. To study the molecular and cellular processes underlying this transition, we have isolated mesodermal cells from murine embryos at E7.5 with characteristic properties of endothelial progenitors by using a combination of stromal cell layers and growth conditions. The isolated embryonic cells displayed unlimited stem-cell-like growth potential and a stable phenotype in culture. RNA analysis revealed that the embryonic cells express the endothelial-specific genes tie-2 and thrombomodulin (TM) as well as the early mesodermal marker fgf-3. The GSL I-B4 isolectin, a marker of early endothelial cells, specifically binds to the isolated cells. The in vitro differentiation with retinoic acid and cAMP led to a 5- to 10-fold induction of flk-1, von Willebrand Factor (vWF), TM, GATA-4 and GATA-6. Electron microscopy revealed that in vitro differentiation is associated with increased amounts of rER and Golgi, and a dramatic increase in secretory vesicles packed with vWF. When cultured in Matrigel, the embryonic cells assume the characteristic endothelial cobblestone morphology and form tubes. Injection into chicken embryos showed incorporation of the embryonic cells in the endocardium and the brain vasculature. The expression of TM, tie-2, GATA-4 and GATA-6 suggests that the isolated embryonic endothelial cell progenitors are derived from the proximal lateral mesoderm where the pre-endocardial tubes form. The properties of the endothelial cell progenitors described here provide a novel approach to analyze mediators, signaling pathways and transcriptional control in early vascular development.
Design of potent and specific integrin antagonists. Peptide antagonists with high specificity for glycoprotein IIb-IIIa. (1993)

Members of the snake venon-derived, "disintegrin" peptide family containing the Arg-Gly-Asp (RGD) amino acid sequence are among the most potent inhibitors of the binding of adhesive proteins to platelet glycoprotein (GP) IIb-IIIa. However, GPIIb-IIIa antagonists containing the RGD sequence are not integrin specific and inhibit the adhesive functions of many other RGD-dependent integrins. The single disintegrin peptide, barbourin, containing a conservative amino acid substitution of Lys (K) for Arg (R) in the RGD sequence, is however, highly specific for GPIIb-IIIa. Using this information we have tested the hypothesis that both structural and conformational elements of barbourin are important for its high affinity and selectivity for platelet GPIIb-IIIa by synthesizing a series of conformationally constrained, disulfide-bridged peptides containing the KGD amino acid sequence. Incorporation of the KGD sequence into a cyclic peptide template, followed by systematic optimization of the cyclic ring size, optimization of secondary hydrophobic binding site interactions, and the derivatization of the lysyl side chain functionality of the KGD sequence has resulted in peptide analogs which display inhibitory potency and GPIIb-IIIa selectivity comparable to that of barbourin. This study demonstrates that the specificity and potency of the disintegrin family of antagonists, in particular barbourin, can be mimicked by small, conformationally restrained peptides.
Regulated expression of platelet factor 4 in human monocytes—role of PARs as a quantitatively important monocyte activation pathway (2005)

Human mononuclear phagocytes have recently been shown to express constitutively and even more so, upon stimulation with bacteria, fungi, lipopolysaccharide (LPS), zymosan, or thrombin platelet basic protein (PBP). This CXC chemokine as well as platelet factor 4 (PF4), which is located genomically at a short distance from the PBP, were previously considered to be specific markers for the megakaryocyte cell lineage. Both chemokines have signaling and antimicrobial activity. In the present studies, transcriptional and expressional regulation of PF4 and related chemokines was studied in human monocytes. As shown by quantitative mRNA analysis, Western blots, radioimmunoprecipitation of cell extracts, and immunofluorescence and quantitatively with enzyme-linked immunosorbent assay, human monocytes express PF4 in the same order of magnitude as the known, regulated CXC chemokine interleukin (IL)-8. Expression of PF4 is up-regulated at the mRNA and protein level by thrombin and mediated by proteinase-activated receptors (PARs), resulting in a 32- to 128-fold higher mRNA level and leading to an up-to-sixfold increase of the peptide concentration in monocyte culture supernatants. Thrombin and the synthetic ligand of PAR-1 and PAR-2, SFLLRN, also induced comparable increases in the levels of mRNA for PBP, IL-8, regulated on activation, normal T expressed and secreted (RANTES), monocyte chemoattractant protein-1, and macrophage-inflammatory protein-1alpha and increased synthesis of these chemokines as shown by immunofluorescence or a quantitative immunobead-based method. The induction of increased mRNA levels for all chemokines by SFLLRN was unsurpassed by LPS, zymosan, interferon-gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and IL-1. Activation of monocytes through PARs represents an alternate activation mechanism, independent from IFN-gamma, TNF-alpha, or other signaling pathways.
Biological Identification of Peptides that Specifically Bind to Poly(phenylene vinylene) Surfaces: Recognition of the Branched or Linear Structure of the Conjugated Polymer (2010)

Peptides that bind to poly(phenylene vinylene) (PPV) were identified by the phage display method. Aromatic amino acids were enriched in these peptide sequences, suggesting that a π-π interaction is the key interaction between the peptides and PPV. The surface plasmon resonance (SPR) experiments using chemically synthesized peptides demonstrated that the Hyp01 peptide, with the sequence His-Thr-Asp-Trp-Arg-Leu-Gly-Thr-Trp-His-His-Ser, showed an affinity constant (7.7 × 10(5) M(-1)) for the target, hyperbranched PPV (hypPPV) film. This value is 15-fold greater than its affinity for linear PPV (linPPV). In contrast, the peptide screened for linPPV (Lin01) showed the reverse specificity for linPPV. These results suggested that the Hyp01 and Lin01 peptides selectively recognized the linear or branched structure of PPVs. The Ala-scanning experiment, circular dichroism (CD) spectrometry, and molecular modeling of the Hyp01 peptide indicated that adequate location of two Trp residues by forming the polyproline type II (P(II)) helical conformation allowed the peptide to specifically interact with hypPPV.
Organic light-emitting diodes using 3- or 5-hydroxyflavone–metal complexes (1997)

3- or 5-hydroxyflavone-metal complexes were synthesized and applied to organic light-emitting diodes (OLEDs) as an emitting material and an electron transport material. When bis(5-hydroxyflavonato)beryllium [Be(5Fla)2] was used as an emitting material, the OLED showed a luminance of 1900 cd/m2 with yellow. On the other hand, when used as an electron transport material in an organic three-layer cell, a high luminance of more than 10 000 cd/m2 was obtained. Furthermore, the turn-on voltage of the OLED could be lowered to 2.4 V and its lifetime was more than 1300 h. Be(5Fla)2 was found to have a good electron transporting capability and good stability.
Activation of SAPK/JNK by TNF Receptor 1 Through a Noncytotoxic TRAF2-Dependent Pathway (1997)

Interaction of the p55 tumor necrosis factor receptor 1 (TNF-R1)-associated signal transducer TRADD with FADD signals apoptosis, whereas the TNF receptor-associated factor 2 protein (TRAF2) is required for activation of the nuclear transcription factor nuclear factor kappa B. TNF-induced activation of the stress-activated protein kinase (SAPK) was shown to occur through a noncytotoxic TRAF2-dependent pathway. TRAF2 was both sufficient and necessary for activation of SAPK by TNF-R1; conversely, expression of a dominant-negative FADD mutant, which blocks apoptosis, did not interfere with SAPK activation. Therefore, SAPK activation occurs through a pathway that is not required for TNF-R1-induced apoptosis.
A Safeguard System for Induced Pluripotent Stem Cell-Derived Rejuvenated T Cell Therapy (2015)

The discovery of induced pluripotent stem cells (iPSCs) has created promising new avenues for therapies in regenerative medicine. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern for clinical translation. To address this issue, we demonstrated the efficacy of suicide gene therapy by introducing inducible caspase-9 (iC9) into iPSCs. Activation of iC9 with a specific chemical inducer of dimerization (CID) initiates a caspase cascade that eliminates iPSCs and tumors originated from iPSCs. We introduced this iC9/CID safeguard system into a previously reported iPSC-derived, rejuvenated cytotoxic T lymphocyte (rejCTL) therapy model and confirmed that we can generate rejCTLs from iPSCs expressing high levels of iC9 without disturbing antigen-specific killing activity. iC9-expressing rejCTLs exert antitumor effects in vivo. The system efficiently and safely induces apoptosis in these rejCTLs. These results unite to suggest that the iC9/CID safeguard system is a promising tool for future iPSC-mediated approaches to clinical therapy.
Optimal Airline Seat Allocation with Fare Classes Nested by Origins and Destinations (1990)

Previous research in the optimal allocation of airline seats has followed one of two themes: marginal seat revenue or mathematical programming. Both approaches capture important elements of the revenue management problem. The marginal seat revenue approach accounts for the “nesting” of fare classes in computer reservation systems, but can only control seat inventory by bookings on legs. The mathematical programming approach will handle realistically large problems and will account for multiple origin–destination itineraries and side constraints, but it does not account for fare class nesting in the reservation systems. This paper combines both approaches by developing equations to find the optimal allocation of seats when fare classes are nested on an origin–destination itinerary and the inventory is not shared among origin–destinations. These results are applicable to seat allocation in certain reservations systems, point-of-sale control, and acceptance of groups over their entire itinerary. A special case of the analysis produces the optimal booking limits for leg-based seat allocation with nested fare classes.
Cloning of a 67-kD Neutrophil Oxidase Factor with Similarity to a Noncatalytic Region of p60 c-src (1990)

Chronic granulomatous diseases (CGDs) are characterized by recurrent infections resulting from impaired superoxide production by a phagocytic cell, nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) oxidase. Complementary DNAs were cloned that encode the 67-kilodalton (kD) cytosolic oxidase factor (p67), which is deficient in 5% of CGD patients. Recombinant p67 (r-p67) partially restored NADPH oxidase activity to p67-deficient neutrophil cytosol from these patients. The p67 cDNA encodes a 526-amino acid protein with acidic middle and carboxyl-terminal domains that are similar to a sequence motif found in the noncatalytic domain of src-related tyrosine kinases. This motif was recently noted in phospholipase C-gamma, nonerythroid alpha-spectrin (fodrin), p21ras-guanosine triphophatase-activating protein (GAP), myosin-1 isoforms, yeast proteins cdc-25 and fus-1, and the 47-kD phagocyte oxidase factor (p47), which suggests the possibility of common regulatory features.