gebhart/patrepeval huggingface dataset:
Macrophage-inducible expression of a model antigen in Salmonella typhimurium enhances immunogenicity. (1995)

Attenuated Salmonella are useful oral vaccine vectors capable of carrying multiple heterologous antigen genes, but optimal expression of foreign antigens has not yet been achieved. We hypothesized that Salmonella phoP-activated genes, which are transcriptionally activated within antigen-processing macrophages, could prove useful for delivery of heterologous antigens to the immune system. We have created a suicide vector that allows the stable chromosomal insertion of heterologous antigen genes within the phoP-activated gene C (pagC) of Salmonella and permits the expression of heterologous antigens as fusion proteins between the first 84 amino acids of PagC and the chosen antigen. The Escherichia coli phoA gene encoding alkaline phosphatase was cloned into this vector; the resultant plasmid was used to construct Salmonella typhimurium strains that express PagC-alkaline phosphatase fusion proteins from a single chromosomal gene copy. Such strains were administered orally and i.p. as vaccines to BALB/c mice and compared with control strains expressing alkaline phosphatase constitutively. After 3 weeks, mouse sera were analyzed for IgG responses to S. typhimurium lipopolysaccharide and alkaline phosphatase. Remarkably, though all mice had comparable antibody responses to lipopolysaccharide, only mice immunized with strains bearing phoP-activated fusion genes had antibody responses to the heterologous antigen. We conclude that expression of a heterologous antigen from an S. typhimurium in vivo-induced promoter that is activated within macrophages markedly enhances the immunogenicity of a model antigen expressed from a single chromosomal gene copy.
Incredible RNA: Dual Functions of Coding and Noncoding (2016)

Since the RNA world hypothesis was proposed, a large number of regulatory noncoding RNAs (ncRNAs) have been identified in many species, ranging from microorganisms to mammals. During the characterization of these newly discovered RNAs, RNAs having both coding and noncoding functions were discovered, and these were considered bifunctional RNAs. The recent use of computational and high-throughput experimental approaches has revealed increasing evidence of various sources of bifunctional RNAs, such as protein-coding mRNAs with a noncoding isoform and long ncRNAs bearing a small open reading frame. Therefore, the genomic diversity of Janus-faced RNA molecules that have dual characteristics of coding and noncoding indicates that the functional roles of RNAs have to be revisited in cells on a genome-wide scale. Such studies would allow us to further understand the complex gene-regulatory network in cells. In this review, we discuss three major genomic sources of bifunctional RNAs and present a handful of examples of bifunctional RNA along with their functional roles.
Angiotensin Receptors and Their Antagonists (1996)

Angiotensins are peptide hormones derived from the protein precursor angiotensinogen by the sequential actions of proteolytic enzymes (Figure 1). The classic pathway of angiotensin synthesis includes a reaction catalyzed by angiotensin-converting enzyme (ACE), which occurs not only in plasma but also in the kidneys, brain, adrenal glands, ovaries, and possibly other tissues.1 The intrarenal renin–angiotensin system affects glomerular filtration, as discussed below, but the importance of angiotensin synthesis in other tissues is not known. Angiotensin II, the principal effector of the renin–angiotensin cascade, can also be synthesized by a pathway that does not require ACE.2 Angiotensin II stimulates a variety . . .
ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex (1998)

The t(8;21) translocation between two genes known as AML1 and ETO is seen in approximately 12-15% of all acute myeloid leukemia (AML) and is the second-most-frequently observed nonrandom genetic alteration associated with AML. AML1 up-regulates a number of target genes critical to normal hematopoiesis, whereas the AML1/ETO fusion interferes with this trans-activation. We discovered that the fusion partner ETO binds to the human homolog of the murine nuclear receptor corepressor (N-CoR). The interaction is mediated by two unusual zinc finger motifs present at the carboxyl terminus of ETO. Human N-CoR (HuN-CoR), which we cloned and sequenced in its entirety, encodes a 2,440-amino acid polypeptide and has a central domain that binds ETO. N-CoR, mammalian Sin3 (mSin3A and B), and histone deacetylase 1 (HDAC1) form a complex that alters chromatin structure and mediates transcriptional repression by nuclear receptors and by a number of oncoregulatory proteins. We found that ETO, through its interaction with the N-CoR/mSin3/HDAC1 complex, is also a potent repressor of transcription. This observation provides a mechanism for how the AML1/ETO fusion may inhibit expression of AML1-responsive target genes and disturb normal hematopoiesis.
Curve evolution models for real-time identification with application to plasma etching (1999)

It is desirable, in constructing an algorithm for real-time control or identification of free surfaces, to avoid representations of the surface requiring mesh refinement at corners or special logic for topological transitions. Level set methods provide a promising framework for such algorithms. In this paper we present: 1) a mathematical representation of free surface motion that is particularly well-suited to real-time implementation; 2) a technique for estimating an isotropic and homogeneous normal velocity based on a simple measurement; and 3) an application to a semiconductor etching problem.
EXEL-7647 Inhibits Mutant Forms of ErbB2 Associated with Lapatinib Resistance and Neoplastic Transformation (2008)

Taken together, these data suggest potential target-based mechanisms of resistance to lapatinib and suggest that EXEL-7647 may be able to circumvent these effects.
Constitutive Human Telomerase Reverse Transcriptase Expression Enhances Regenerative Properties of Endothelial Progenitor Cells (2002)

These findings provide the novel evidence that telomerase activity contributes to EPC angiogenic properties; mitogenic activity, migratory activity, and cell survival. This enhanced regenerative activity of EPCs by hTERT transfer will provide novel therapeutical strategy for postnatal neovascularization in severe ischemic disease patients.
Monoclonal antibodies to the CD5 antigen can provide the necessary second signal for activation of isolated resting T cells by solid-phase-bound OKT3. (1986)

Activation of human peripheral blood T cells by the anti-CD3 antibody OKT3 has been shown to require not only cross-linking of CD3 molecules with multimeric binding of the Fc part of OKT3 to a solid support, but also a second accessory cell-provided signal. Accordingly, measurement of T cell activation in cultures of highly enriched T cells with solid-phase-bound OKT3 can be used to investigate whether other agents can replace accessory cells. In this study we examined the capacity of anti-CD5 monoclonal antibodies to provide the additional activation signal. Resting T cells were prepared by isolating E rosette-positive cells, by removing OKM1(+) and HLA-DR(+) cells by panning, and by subsequent treatment of the cells with L-leucine methyl ester to kill remaining monocytes. These T cells were unresponsive to phytohemagglutinin (PHA) or to solid-phase-bound OKT3. However, when cultured in the presence of an anti-CD5 monoclonal antibody (anti-Leu-1, OKT1, or anti-T1), a proliferative response to solid-phase-bound OKT3 (but not to soluble OKT3 or to PHA) was observed. Anti-CD5 had no functional effect by itself, but in association with solid-phase-bound OKT3 it enhanced IL 2 receptor expression and IL 2 production and it initiated T cell proliferation. T cell proliferation under these conditions could be inhibited by an IL 2 receptor blocking antibody anti-Tac, thus confirming that anti-CD5 provides the second signal for an IL 2-dependent pathway of T cell proliferation. Preincubation of T cells with anti-Leu-1 or OKT1 resulted in complete loss of CD5 antigenicity, and such CD5 modulation was sufficient to induce a proliferative response to solid-phase-bound OKT3. It is concluded that in T cell activation by solid-phase-bound OKT3 the necessary additional signal can be provided by modulation of the CD5 antigen with an anti-CD5 antibody. CD5 therefore appears to be a positive signal receptor on the T cell membrane, whose physiologic ligand still has to be determined.
Targeting the dopamine D2receptor in schizophrenia (2006)

After a 12-year search for the antipsychotic receptor, the binding site was discovered and labelled by [3H]haloperidol in 1975. Of the various neurotransmitters, dopamine was the most potent in inhibiting the binding of [3H]haloperidol, indicating that the antipsychotic receptor was a dopamine receptor, now named the dopamine D2 receptor, a major targeting site in schizophrenia. All antipsychotic drugs, including traditional and newer antipsychotics, either bind to D2 in direct relation to their clinical potencies or hinder normal dopamine neurotransmission, as in the case of partial dopamine agonists. In fact, the antipsychotic concentrations found in the plasma water of treated patients closely match the predicted therapeutic absolute concentrations, adjusted for the 60-75% D2 occupancy needed for clinical efficacy. Antipsychotics that elicit low or no Parkinsonism or prolactinaemia are loosely attached to D2 and rapidly dissociate from D2, whereas those eliciting Parkinsonism stay tightly attached to D2 for many hours. Because animal models of psychosis (amfetamine sensitisation, brain lesions) all show a marked elevation in the number of high-affinity states of D2, the antipsychotics are thought to specifically target these D2High states in psychosis in general and schizophrenia in particular.
Cloning and Molecular Analyses of a Gibberellin 20-Oxidase Gene Expressed Specifically in Developing Seeds of Watermelon (1999)

To understand the biosynthesis and functional role of gibberellins (GAs) in developing seeds, we isolated Cv20ox, a cDNA clone from watermelon (Citrullus lanatus) that shows significant amino acid homology with GA 20-oxidases. The complementary DNA clone was expressed in Escherichia coli as a fusion protein, which oxidized GA(12) at C-20 to the C(19) compound GA(9), a precursor of bioactive GAs. RNA-blot analysis showed that the Cv20ox gene was expressed specifically in developing seeds. The gene was strongly expressed in the integument tissues, and it was also expressed weakly in inner seed tissues. In parthenocarpic fruits induced by 1-(2-chloro-4-pyridyl)-3-phenylurea treatment, the expression pattern of Cv20ox did not change, indicating that the GA 20-oxidase gene is expressed primarily in the maternal cells of developing seeds. The promoter of Cv20ox was isolated and fused to the beta-glucuronidase (GUS) gene. In a transient expression system, beta-glucuronidase staining was detectable only in the integument tissues of developing watermelon seeds.
Porcine Arterivirus Attachment to the Macrophage-Specific Receptor Sialoadhesin Is Dependent on the Sialic Acid-Binding Activity of the N-Terminal Immunoglobulin Domain of Sialoadhesin (2007)

The sialic acid-binding lectin sialoadhesin (Sn) is a macrophage-restricted receptor for porcine reproductive and respiratory syndrome virus (PRRSV). To investigate the importance of pSn sialic acid-binding activity for PRRSV infection, an R(116)-to-E mutation was introduced in the predicted sialic acid-binding domain of pSn, resulting in a mutant, pSn(RE), that could not bind sialic acids. PSn, but not pSn(RE), allowed PRRSV binding and internalization. These data show that the sialic acid-binding activity of pSn is essential for PRRSV attachment to pSn and thus identifies the variable, N-terminal domain of Sn as a PRRSV binding domain.
Five Freely Circulating miRNAs and Bone Tissue miRNAs Are Associated With Osteoporotic Fractures (2014)

Osteoporosis as a systemic skeletal disorder is characterized by increased bone fragility and the risk of fractures. According to the World Health Organization, osteoporosis is one of the 10 most common diseases and affects approximately 75 million people in Europe, the United States, and Japan. In this context, the identification of specific microRNA (miRNA) signatures is an important step for new diagnostic and therapeutic approaches. The focus of interest on miRNAs as biomarkers came with new publications identifying free circulating extracellular miRNAs associated with various types of cancer. This study aimed to identify specific miRNAs in patients with osteoporotic fractures compared with nonosteoporotic fractures. For the array analysis, miRNAs were isolated from the serum of 20 patients with hip fractures, transcribed, and the samples were pooled into 10 osteoporotic and 10 nonosteoporotic specimens. With each pool of samples, human serum and plasma miRNA PCR arrays were performed, which are able to identify 83 different miRNAs. Subsequently, a separate validation analysis of each miRNA found to be regulated in the array followed with miRNA samples isolated from the serum of 30 osteoporotic and 30 nonosteoporotic patients and miRNA samples isolated from the bone tissue of 20 osteoporotic and 20 nonosteoporotic patients. With the validation analysis of the regulated miRNAs, we identified 9 miRNAs, namely miR-21, miR-23a, miR-24, miR-93, miR-100, miR-122a, miR-124a, miR-125b, and miR-148a, that were significantly upregulated in the serum of patients with osteoporosis. In the bone tissue of osteoporotic patients, we identified that miR-21, miR-23a, miR-24, miR-25, miR-100, and miR-125b displayed a significantly higher expression. A total of 5 miRNAs display an upregulation both in serum and bone tissue. This study reveals an important role for several miRNAs in osteoporotic patients and suggested that they may be used as biomarkers for diagnostic purposes and may be a target for treating bone loss and optimizing fracture healing in osteoporotic patients.
Stereoselective Syntheses of 4-Hydroxy 4-Substituted Glutamic Acids (2005)

The 4-hydroxy 4-substituted glutamic acid moiety is a common substructure of biologically important natural products such as monatin [(2S,4S)-2], lycoperdic acid (3), and dysiherbaine (4). To develop methodology for syntheses of these natural products, cycloadditions of nitrone 5 with 2-substituted 2-propen-1-ols 6 and 2-substituted acrylates 8 were investigated. Reactions of nitrone 5 with alcohols 6 in the presence of MgBr2OEt2 gave cycloadducts 7 in a highly stereoselective manner, whereas noncatalyzed reactions of 5 with acrylates 8 afforded adducts 9. Using the former reaction, syntheses of monatin [(2S,4S)-2], monatin derivative 18, and lycoperdic acid (3) were accomplished. The C4-epimer of monatin [(2S,4R)-2)] was also synthesized by employing the latter cycloaddition.
Improved pharmacokinetic properties of a polyethylene glycol-modified form of interferon-beta-1a with preserved in vitro bioactivity. (2001)

Interferon therapies suffer from a relatively short half-life of the products in circulation. To address this issue we investigated the effects of polyethylene glycol modification (PEGylation) on the pharmacokinetic properties of human interferon (IFN)-beta-1a. PEGylation with a linear 20-kDa PEG targeted at a single site on the N-terminal amine had no deleterious effect on its specific activity in an in vitro antiviral assay. In monkeys, PEG IFN-beta-1a treatment induced neopterin and beta2-microglobulin expression (pharmacodynamic markers of activity). Systemic clearance values in monkeys, rats, and mice decreased, respectively, from 232, 261, and 247 ml/h/kg for the unmodified IFN-beta-1a to 30.5, 19.2, and 18.7 ml/h/kg for the PEGylated form, while volume of distribution values decreased from 427, 280, and 328 ml/kg to 284, 173, and 150 ml/kg. The decreased clearance and volume of distribution resulted in higher serum antiviral activity in the PEG IFN-beta-1a-treated animals. In the rat, a more extensive set of dosing routes was investigated, including intraperitoneal, intratracheal, and oral administration. Bioavailability for the PEG IFN-beta-1a was similar to the unmodified protein for each of the extravascular routes examined. For the intraperitoneal route, bioavailability was almost 100%, whereas for the oral and intratracheal routes absorption was low (<5%). In rats, subcutaneous bioavailability was moderate (28%), whereas in monkeys it was approximately 100%. In all instances an improved pharmacokinetic profile for the PEGylated IFN-beta-1a was observed. These findings demonstrate that PEGylation greatly alters the pharmacokinetic properties of IFN-beta-1a, resulting in an increase in systemic exposure following diverse routes of administration.
Blood‐spinal cord barrier after spinal cord injury: Relation to revascularization and wound healing (2003)

Spinal cord injury produces prominent disruption of the blood-spinal cord barrier. We have defined the blood-spinal cord barrier breakdown to the protein luciferase (61 kDa) in the acutely injured murine spinal cord and during revascularization. We show that newly formed and regenerating blood vessels that have abnormal permeability exhibit differential expression of the glucose-1 transporter (Glut-1), and that its expression is dependent on astrocytes. There was overt extravasation of luciferase within the first hour after injury, a period that coincided with marked tissue disruption within the epicenter of the lesion. Although there was a significant reduction in the number of blood vessels relative to controls by 24 hr after injury, abnormal barrier permeability remained significantly elevated. A second peak of abnormal barrier permeability at 3-7 days postinjury coincided with prominent revascularization of the epicenter. The barrier to luciferase was restored by 21 days postinjury and vascularity was similar to that of controls. During wound-healing process, the cord was reorganized into distinct domains. Between 14 and 21 days postinjury, each domain consisted primarily of nonneuronal cells, including macrophages. Astrocytes were limited characteristically to the perimeter of each domain. Only blood vessels affiliated closely with astrocytes in the perimeter expressed Glut-1, whereas blood vessels within each domain of the repairing cord did not express it. Together, these data demonstrate that both injured and regenerating vessels exhibit abnormal permeability and suggest that Glut-1 expression during revascularization is dependent on the presence of astrocytes.
Organophosphorus Hydrolase-Based Assay for Organophosphate Pesticides (1999)

We report a rapid and versatile organophosphorus hydrolase (OPH)-based method for measurement of organophosphates. This assay is based on a substrate-dependent change in pH at the local vicinity of the enzyme. The pH change is monitored using fluorescein isothiocyanate (FITC), which is covalently immobilized to the enzyme. This method employs the use of poly(methyl methacrylate) beads to which the FITC-labeled enzyme is adsorbed. Analytes were then measured using a microbead fluorescence analyzer. The dynamic concentration range for the assay extends from 25 to 400 &mgr;M for paraoxon with a detection limit of 8 &mgr;M. Organophosphorus insecticides measured using this technique included ethylparathion, methylparathion, dursban, fensulfothion, crotoxyphos, diazinon, mevinphos, dichlorvos, and coumaphos. This technique was used to measure coumaphos in biodegradation samples of cattle dip wastes and showed a high correlation (r2 = 0.998) to an HPLC method.
Modulating the tumor immune microenvironment as an ovarian cancer treatment strategy (2012)

After more than 30 years of iterations of surgical debulking plus chemotherapy, the need for complementary ovarian cancer treatments has become clear. In the ovarian cancer microenvironment, myeloid immunosuppressive leukocytes, lymphocytes, fibroblasts and endothelial cells, as well as their secreted products, surface molecules and paracrine survival factors, all provide opportunities for novel interventions. The potential of targeting microenvironmental elements in ovarian cancer patients is underscored by recently successful anti-angiogenic therapies. The compartmentalized nature of ovarian cancer, its immunogenicity and its accessibility make it an ideal disease for targeting non-tumor host cells. This review discusses the 'state-of-the-art' of the field, with an emphasis on the potential of modulating the activity of abundant microenvironmental immune cells, which govern both angiogenesis and immunosuppression.
Selective lysis of breast carcinomas by simultaneous stimulation of sodium channels and blockade of sodium pumps (2018)

Sodium influx through voltage-gated sodium channels (VGSCs) coupled with balanced removal of sodium ions via Na<sup>+</sup>, K<sup>+</sup>-ATPase is a major determinant of cellular homeostasis and intracellular ionic concentration. Interestingly, many metastatic carcinomas express high levels of these channels. We hypothesized that if excess VGSCs are activated and Na<sup>+</sup>, K<sup>+</sup>-ATPase is simultaneously blocked, the intracellular Na<sup>+</sup> concentration should increase, resulting in water movement into the cell, causing swelling and lytic cell death. MDA-MB-231 breast cancer cells over-express VGSCs by 7-fold. To test our hypothesis, we treated these cells <i>in vitro</i> with the Na<sup>+</sup>, K<sup>+</sup>-ATPase blocker, ouabain, and then stimulated with a sublethal electric current. For <i>in vivo</i> histologic and survival studies, MDA-MB-231 xenografts were established in Nu/J mice. Mice injected with saline or ouabain were electrically stimulated with trains of 10 msec 10V DC pulses. Within seconds to minutes, the cells swelled and lysed. MCF-10a cells, which express normal VGSCs levels, were unaffected by this treatment. Cells from the weakly-malignant cell line, MCF-7, which express 3-fold greater VGSCs than MCF-10a cells, displayed an intermediate time-to-lysis. The rate of lysis correlated directly with the degree of sodium channel expression and malignancy. We also demonstrated efficacy in cell lines from prostate, colon and lung carcinomas. Treated MDA-MB-231 xenografts showed 60-80% cell death. In survival studies, TOL-treated mice showed significantly slower tumor growth vs. controls. These results are evidence that this "targeted osmotic lysis" represents a novel method for selectively killing cancer cells and warrants further investigation as a potential treatment for advanced and end-stage breast cancer.
Chromosome motors on the move. From motion to spindle checkpoint activity. (2001)

Spindle assembly and chromosome segregation require the concerted activities of a variety of microtubule-dependent motors. This review focuses on our current knowledge of the roles played by the chromosome-associated motors during mitosis. While some appear to function conventionally in moving chromosomes along microtubules others seem to act in different ways. For example, by docking microtubules to chromosome arms, chromatin-associated motors prevent chromosome loss and participate in spindle formation and stability. Kinetochore motors participate in the formation of stable kinetochore fibers or in the control of microtubule dynamics and are involved in spindle checkpoint activity. Chromosome-associated motors thus appear to be key molecules that function in complementary ways to ensure the accuracy of chromosome segregation.