gebhart/patrepeval huggingface dataset:
Decreased Diacylglycerol Metabolism Enhances ERK Activation and Augments CD8+ T Cell Functional Responses (2010)

Modulation of T cell receptor signal transduction in CD8(+) T cells represents a novel strategy toward enhancing the immune response to tumor. Recently, levels of guanine exchange factors, RasGRP and SOS, within T cells have been shown to represent a key determinant in the regulation of the analog to the digital activation threshold of Ras. One important for regulating activation levels of RasGRP is diacylglycerol (DAG), and its levels are influenced by diacylglycerol kinase-ζ (DGKζ), which metabolizes DAG into phosphatidic acid, terminating DAG-mediated Ras signaling. We sought to determine whether DGKζ-deficient CD8(+) T cells demonstrated enhanced in vitro responses in a manner predicted by the current model of Ras activation and to evaluate whether targeting this threshold confers enhanced CD8(+) T cell responsiveness to tumor. We observed that DGKζ-deficient CD8(+) T cells conform to most predictions of the current model of how RasGRP levels influence Ras activation. But our results differ in that the EC(50) value of stimulation is not altered for any T cell receptor stimulus, a finding that suggests a further degree of complexity to how DGKζ deficiency affects signals important for Ras and ERK activation. Additionally, we found that DGKζ-deficient CD8(+) T cells demonstrate enhanced responsiveness in a subcutaneous lymphoma model, implicating the analog to a digital conversion threshold as a novel target for potential therapeutic manipulation.
Genetic Transfer Systems for Delivery of Plasmid Deoxyribonucleic Acid to Lactobacillus acidophilus ADH: Conjugation, Electroporation, and Transduction (1989)

Lactobacillus acidophilus ADH is a bacteriocin-producing human isolate that adheres to human fetal intestinal cells and human ileal cells. We have employed both electroporation and conjugation methodologies to transfer various plasraids to L. acidophilus ADH. Furthermore, we have demonstrated transduction of plasmid DNA within this strain by a temperate bacteriophage (~adh) harbored by L. acidophilus ADH. Plasmid pGK12 was introduced into strain ADH by elec-l~aOmmtiOn at frequencies as high as 3.3 x sformants/~tg of plasmid DNA. Transconjugants of strain ADH were recovered at frequencies of 10 -2 (pAMB1), 10 --4 (pVA797 ::Tn917), and 1 (pVA797) per donor cell after filter-matings with Lactococcus lactis ssp. lactis.
Micromolded arrays for separation of adherent cells (2010)

We present an efficient, yet inexpensive, approach for isolating viable single cells or colonies from a mixed population. This cell microarray platform possesses innovations in both the array manufacture and the manner of target cell release. Arrays of microwells with bases composed of detachable concave elements, termed microrafts, were fabricated by a dip-coating process using a polydimethylsiloxane mold as the template and the array substrate. This manufacturing approach enabled the use of materials other than photoresists to create the array elements. Thus microrafts possessing low autofluorescence could be fabricated for fluorescence-based identification of cells. Cells plated on the microarray settled and attached at the center of the wells due to the microrafts' concavity. Individual microrafts were readily dislodged by the action of a needle inserted through the compliant polymer substrate. The hard polymer material (polystyrene or epoxy resin) of which the microrafts were composed protected the cells from damage by the needle. For cell analysis and isolation, cells of interest were identified using a standard inverted microscope and microrafts carrying target cells were dislodged with the needle. The released cells/microrafts could be efficiently collected, cultured and clonally expanded. During the separation and collection procedures, the cells remained adherent and provided a measure of protection during manipulation, thus providing an extremely high single-cell cloning rate (>95%). Generation of a transfected cell line based on expression of a fluorescent protein demonstrated an important application for performing on-chip cell separations.
Regulation of rat growth hormone receptor gene expression (1989)

A cDNA encoding the growth hormone (GH) receptor was cloned from rat liver. Both the nucleotide and translated amino acid sequence share greater than 70% similarity with the GH receptors from rabbit and human. An RNA probe was generated from this sequence for use in a solution hybridization assay to quantitate GH receptor mRNA expression in rat tissues. Expression was detected in 9/12 tissues examined, with the highest levels observed in the liver. Expression in liver, kidney, heart and muscle was developmentally regulated, being low at birth and rising to adult levels in 5 weeks. No difference was observed between hepatic expression in males and females, although livers from pregnant rats had elevated levels. Hypophysectomy and GH treatment did not affect hepatic GH receptor mRNA levels.
Regulation of Messenger Ribonucleic Acid Encoding 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4 Isomerase in the Ovine Corpus Luteum1 (1993)

Three experiments were conducted to determine how steady-state levels of mRNA encoding 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) in the ovine corpus luteum vary 1) between the two steroidogenic luteal cell types, 2) during the estrous cycle, and 3) during prostaglandin F2 alpha (PGF2 alpha)-induced luteolysis. In the first experiment, RNA (10 micrograms) was isolated from purified preparations (n = 4) of large or small steroidogenic luteal cells. Large luteal cells contained 42% more (p < 0.05) message for 3 beta-HSD per microgram RNA than did small luteal cells, while the amount of mRNA for tubulin did not differ between the two types of luteal cells. To determine whether luteal levels of mRNA for 3 beta-HSD differ during the estrous cycle, corpora lutea were collected from cycling ewes (n = 3/day) on Days 3, 6, 9, 12, and 15 postestrus. Levels of mRNA for 3 beta-HSD were similar on Days 3, 6, 9, and 12 but were lower (p < 0.05) on Day 15 postestrus, while levels of mRNA for tubulin were unchanged. In the final experiment, ewes were treated on Day 10 postestrus with two injections of PGF2 alpha (5 mg each) or saline (control) at a 4-h interval. Corpora lutea were collected from ewes (n = 4/treatment) 1 h or 8 h after the second injection of PGF2 alpha or 8 h after the second saline injection.(ABSTRACT TRUNCATED AT 250 WORDS)
Granulocyte–macrophage colony-stimulating factor inactivation in CAR T-cells prevents monocyte-dependent release of key cytokine release syndrome mediators (2019)

Chimeric antigen receptor T-cell (CAR T-cell) therapy has been shown to be clinically effective for managing a variety of hematological cancers. However, CAR T-cell therapy is associated with multiple adverse effects, including neurotoxicity and cytokine release syndrome (CRS). CRS arises from massive cytokine secretion and can be life-threatening, but it is typically managed with an anti-IL-6Ra mAb or glucocorticoid administration. However, these treatments add to a patient's medication burden and address only the CRS symptoms. Therefore, alternative strategies that can prevent CRS and neurotoxicity associated with CAR T-cell treatment are urgently needed. Here, we explored a therapeutic route aimed at preventing CRS rather than limiting its consequences. Using a cytokine-profiling assay, we show that granulocyte-macrophage colony-stimulating factor (GMCSF) is a key CRS-promoting protein. Through a combination of <i>in vitro</i> experiments and gene-editing technology, we further demonstrate that antibody-mediated neutralization or TALEN-mediated genetic inactivation of GMCSF in CAR T-cells drastically decreases available GMCSF and abolishes macrophage-dependent secretion of CRS biomarkers, including monocyte chemoattractant protein 1 (MCP-1), interleukin (IL) 6, and IL-8. Of note, we also found that the genetic inactivation of GMCSF does not impair the antitumor function or proliferative capacity of CAR T-cells <i>in vitro</i> We conclude that it is possible to prevent CRS by using "all-in-one" GMCSF-knockout CAR T-cells. This approach may eliminate the need for anti-CRS treatment and may improve the overall safety of CAR T-cell therapies for cancer patients.
Fabrication of High‐Purity, Double‐Walled Carbon Nanotube Buckypaper (2006)

Recently, much attention has been paid to double‐walled carbon nanotubes (DWNTs). This article highlights a recent advance in the fabrication of high‐purity DWNT buckypaper through a combination of a catalytic chemical vapor deposition and an optimized two‐step purification process. The DWNTs have small diameters (below 2 nm) and are packed in a hexagonal array. Their highly enhanced thermal stability (up to 2300 °C) is believed to derive from their coaxial structure. DWNT buckypaper exhibits superior mechanical and electrical properties, accessible surface area, and structural integrity, and may eventually replacing single‐walled carbon nanotubes in numerous applications.
Clinical characteristics of responders to interferon therapy for relapsing MS (2003)

Clinical profiles of patients with relapsing MS who respond to IFNB may differ from those who do not with a more inflammatory and less neurodegenerative disease at the time IFNB is initiated.
Cytoplasmic and Nuclear Retained DMPK mRNAs Are Targets for RNA Interference in Myotonic Dystrophy Cells (2005)

Small interfering RNA (siRNA) duplexes induce the specific cleavage of target RNAs in mammalian cells. Their involvement in down-regulation of gene expression is termed RNA interference (RNAi). It is widely believed that RNAi predominates in the cytoplasm. We report here the co-existence of cytoplasmic and nuclear RNAi phenomena in primary human myotonic dystrophy type 1 (DM1) cells by targeting myotonic dystrophy protein kinase (DMPK) mRNAs. Heterozygote DM1 myoblasts from a human DM1 fetus produce a nuclear retained mutant DMPK transcript with large CUG repeats ( approximately 3,200) from one allele of the DMPK gene and a wild type transcript with 18 CUG repeats, thus providing for both a nuclear and cytoplasmic expression profile to be evaluated. We demonstrate here for the first time down-regulation of the endogenous nuclear retained mutant DMPK mRNAs targeted with lentivirus-delivered short hairpin RNAs (shRNAs). This nuclear RNAi(-like) phenomenon was not observed when synthetic siRNAs were delivered by cationic lipids, suggesting either a link between processing of the shRNA and nuclear import or a separate pathway for processing shRNAs in the nuclei. Our observation of simultaneous RNAi on both cytoplasmic and nuclear retained DMPK has important implications for post-transcriptional gene regulation in both compartments of mammalian cells.
The role of CTLA‐4 in the regulation of T cell immune responses (1999)

Over the past few years a great deal of research has examined how T cell-dependent immune responses are initiated and subsequently regulated. Ligation of the TCR with an antigenic peptide bound to an MHC protein on a professional APC provides the crucial antigen-specific stimulus required for T cell activation. Interaction of CD28 with CD80 or CD86 molecules on APC initiates a costimulatory or second signal within the T cell which augments and sustains T cell activation initiated through the TCR. However, recently it has become clear that T cell immune responses are a result of a balance between stimulatory and inhibitory signals. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a cell surface molecule that is expressed nearly exclusively on CD4+ and CD8+ T cells. Investigation into the role of CTLA-4 in the regulation of T cell immune responses has revealed that CTLA-4 is a very important molecule involved in the maintenance of T cell homeostasis. In the present review, evidence for the proposed inhibitory role of CTLA-4 is examined and a model suggesting a role for CTLA-4 in both early and late stages of T cell activation is presented.
Human antibody to OFA-I, a tumor antigen, produced in vitro by Epstein-Barr virus-transformed human B-lymphoid cell lines. (1982)

We established two long-term human B-lymphoblastoid cell lines (L55 and L72) transformed by Epstein-Barr virus that produced IgM kappa antibodies to the human tumor antigen, OFA-I. Periphral blood lymphocytes obtained from melanoma patients were used as the source of the B lymphocytes. Antibody specificity was determined by the immune adherence assay using various human cancer and noncancer tissues as targets. L55 antibody (designated anti-OFA-I-1) reacted with a variety of human tumor types whereas L72 antibody (designated anti-OFA-I-2) reacted only with tumor cells of neuroectodermal origin (melanoma, glioma, and neuroblastoma). The levels of IgM detected in the spent medium of 1 X 10(6) L55 and L72 cells were 4 and 9 micrograms/ml, respectively, by radioimmunoassay.
Small-Molecule Inhibition of TNF-α (2005)

We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-alpha activity in biochemical and cell-based assays with median inhibitory concentrations of 22 and 4.6 micromolar, respectively. Formation of an intermediate complex between the compound and the intact trimer results in a 600-fold accelerated subunit dissociation rate that leads to trimer dissociation. A structure solved by x-ray crystallography reveals that a single compound molecule displaces a subunit of the trimer to form a complex with a dimer of TNF-alpha subunits.
Optimization of three-dimensional micropost microcavities for cavity quantum electrodynamics (2002)

This paper presents a detailed analysis, based on the first-principles finite-difference time-domain method, of the resonant frequency, quality factor $(Q),$ mode volume $(V),$ and radiation pattern of the fundamental ${(HE}_{11})$ mode in a three-dimensional distributed-Bragg-reflector (DBR) micropost microcavity. By treating this structure as a one-dimensional cylindrical photonic crystal containing a single defect, we are able to push the limits of $Q/V$ beyond those achievable by standard micropost designs, based on the simple rules established for planar DBR microcavities. We show that some of the rules that work well for designing large-diameter microposts (e.g., high-refractive-index contrast) fail to provide high-quality cavities with small diameters. By tuning the thicknesses of mirror layers and the spacer, the number of mirror pairs, the refractive indices of high- and low-refractive index regions, and the cavity diameter, we are able to achieve Q as high as ${10}^{4},$ together with a mode volume of $1.6$ cubic wavelengths of light in the high-refractive-index material. The combination of high Q and small V makes these structures promising candidates for the observation of such cavity-quantum-electrodynamics phenomena as strong coupling between a quantum dot and the cavity field, and single-quantum-dot lasing.
Eternal—a component‐based framework for transparent fault‐tolerant CORBA (2002)

Abstract Enterprises are increasingly involved in worldwide round‐the‐clock e‐commerce and e‐business, which requires them to be operational 24 hours per day, 7 days per week. With outages leading to loss of revenue, reputation and customers, fault tolerance becomes increasingly important. By mixing the fault tolerance logic into the application logic, existing fault tolerance practices render applications more complex, more prone to errors, and more difficult to maintain and build. The Eternal system is a component‐based middleware framework that provides transparent fault tolerance for enterprise applications, and that ensures continuous $24\times7$ operation without requiring special skills of the application programmers. The Eternal system implements the new Fault‐Tolerant CORBA standard. Copyright © 2002 John Wiley &amp; Sons, Ltd.
Initial Combination of Empagliflozin and Linagliptin in Subjects With Type 2 Diabetes (2015)

Reductions from baseline in HbA1c with empagliflozin/linagliptin were significantly different versus linagliptin and empagliflozin 10 mg but not versus empagliflozin 25 mg. Empagliflozin/linagliptin was well tolerated.
Adsorption of chain molecules with a polar head a scaling description (1977)

The adsorption of chain molecules at an interface is investigated assuming that the molecule has both a polar head type of attraction localized on the chain and a uniform interaction of the chain monomers with the surface. A scaling description of the chain configurations and interactions is used. It is shown that the presence of a uniform surface attraction changes the phase diagram drastically. Both a low density two-dimensional regime and a high density phase with the chains confined in narrow cylinders can occur. The transition between the two phases is first order. Power laws for the surface density, layer thickness and surface pressure are derived. The qualitative similarity with the behaviour observed for short chain lipids and surfactants is also noted and it is suggested that a uniform surface interaction may also play an important role there.
An Ocular Melanoma-Associated Antigen (1992)

Monoclonal antibody (MAb) 8-1H defines a highly conserved ocular melanoma-associated antigen. Based on a potential binding site of MAb8-1, we identified, molecularly cloned, and sequenced the gene, encoding this melanoma-associated antigen from a uveal melanoma copy DNA library. Nucleotide sequence analysis of the melanoma-associated antigen revealed characteristics of a membrane-bound protein of 238 amino acids (approximately 25 kd) with four transmembrane domains. The sequence of the ocular melanoma-associated antigen is identical to the sequence of a recently reported cutaneous melanoma-associated antigen, substantiating our previous studies regarding common antigens between ocular and cutaneous melanoma. In addition, the melanoma-associated antigen shares sequence homology with a number of transmembrane proteins that appear to be involved in growth regulation. The implication of the biological function of this ocular melanoma-associated antigen, its relevance to the malignant phenotype, and clinical applications of the molecular characterization of this melanoma-associated antigen are described.
Targeted mutagenesis of DNA using triple helix-forming oligonucleotides linked to psoralen. (1993)

Oligonucleotides can bind as third strands of DNA in a sequence-specific manner in the major groove in homopurine/homopyrimidine stretches in duplex DNA. Here we use a 10-base triplex-forming oligonucleotide linked to a psoralen derivative at its 5' end to achieve site-specific, targeted mutagenesis in an intact, double-stranded lambda phage genome. Site-specific triplex formation delivers the psoralen to the targeted site in the lambda DNA, and photoactivation of the psoralen produces adducts and thereby mutations at that site. Mutations in the targeted gene were at least 100-fold more frequent than those in a nontargeted gene, and sequence analysis of mutations in the targeted gene showed that 96% were in the targeted region and 56% were found to be the same T.A to A.T transversion precisely at the targeted base pair. The ability to reproducibly and predictably target mutations to sites in intact duplex DNA by using modified oligonucleotides may prove useful as a technique for gene therapy, as an approach to antiviral therapeutics, and as a tool for genetic engineering.
Robust adaptive beamforming (1987)

Adaptive beamforming algorithms can be extremely sensitive to slight errors in array characteristics. Errors which are uncorrelated from sensor to sensor pass through the beamformer like uncorrelated or spatially white noise. Hence, gain against white noise is a measure of robustness. A new algorithm is presented which includes a quadratic inequality constraint on the array gain against uncorrelated noise, while minimizing output power subject to multiple linear equality constraints. It is shown that a simple scaling of the projection of tentative weights, in the subspace orthogonal to the linear constraints, can be used to satisfy the quadratic inequality constraint. Moreover, this scaling is equivalent to a projection onto the quadratic constraint boundary so that the usual favorable properties of projection algorithms apply. This leads to a simple, effective, robust adaptive beamforming algorithm in which all constraints are satisfied exactly at each step and roundoff errors do not accumulate. The algorithm is then extended to the case of a more general quadratic constraint.
Epidemiology of Group B Streptococcal Disease in the United States: Shifting Paradigms (1998)

Since its emergence 25 years ago, group B streptococcus has become recognized as a cause of serious illness in newborns, pregnant women, and adults with chronic medical conditions. Heavy colonization of the genital tract with group B streptococcus also increases the risk that a woman will deliver a preterm low-birthweight infant. Early-onset infections (occurring at < 7 days of age) are associated with much lower fatality than when they were first described, and their incidence is finally decreasing as the use of preventive antibiotics during childbirth increases among women at risk. New serotypes of group B streptococcus have emerged as important pathogens in adults and newborns. Clinical and laboratory practices--in obstetrics, pediatrics, and clinical microbiology--have an impact on disease and/or its prevention, and protocols established at the institutional level appear to be critical tools for the reduction of perinatal disease due to group B streptococcus. Since intrapartum antibiotics will prevent at best only a portion of the full burden of group B streptococcal disease, critical developments in vaccine evaluation, including study of polysaccharide-protein conjugate vaccines, offer the potential for enhanced prevention in the relatively near future.
Selectivity of Digitalis Glycosides for Isoforms of Human Na,K-ATPase (2010)

There are four isoforms of the alpha subunit (alpha1-4) and three isoforms of the beta subunit (beta1-3) of Na,K-ATPase, with distinct tissue-specific distribution and physiological functions. alpha2 is thought to play a key role in cardiac and smooth muscle contraction and be an important target of cardiac glycosides. An alpha2-selective cardiac glycoside could provide important insights into physiological and pharmacological properties of alpha2. The isoform selectivity of a large number of cardiac glycosides has been assessed utilizing alpha1beta1, alpha2beta1, and alpha3beta1 isoforms of human Na,K-ATPase expressed in Pichia pastoris and the purified detergent-soluble isoform proteins. Binding affinities of the digitalis glycosides, digoxin, beta-methyl digoxin, and digitoxin show moderate but highly significant selectivity (up to 4-fold) for alpha2/alpha3 over alpha1 (K(D) alpha1 > alpha2 = alpha3). By contrast, ouabain shows moderate selectivity ( approximately 2.5-fold) for alpha1 over alpha2 (K(D) alpha1 <or= alpha3 < alpha2). Binding affinities for the three isoforms of digoxigenin, digitoxigenin, and all other aglycones tested are indistinguishable (K(D) alpha1 = alpha3 = alpha2), showing that the sugar determines isoform selectivity. Selectivity patterns for inhibition of Na,K-ATPase activity of the purified isoform proteins are consistent with binding selectivities, modified somewhat by different affinities of K(+) ions for antagonizing cardiac glycoside binding on the three isoforms. The mechanistic insight on the role of the sugars is strongly supported by a recent structure of Na,K-ATPase with bound ouabain, which implies that aglycones of cardiac glycosides cannot discriminate between isoforms. In conclusion, several digitalis glycosides, but not ouabain, are moderately alpha2-selective. This supports a major role of alpha2 in cardiac contraction and cardiotonic effects of digitalis glycosides.