gebhart/patrepeval huggingface dataset:
RVX-297, a BET Bromodomain Inhibitor, Has Therapeutic Effects in Preclinical Models of Acute Inflammation and Autoimmune Disease (2017)

Bromodomain (BD) and extra-terminal domain containing proteins (BET) are chromatin adapters that bind acetylated histone marks via two tandem BDs, BD1 and BD2, to regulate gene transcription. BET proteins are involved in transcriptional reprogramming in response to inflammatory stimuli. BET BD inhibitors (BETis) that are nonselective for BD1 or BD2 have recognized anti-inflammatory properties in vitro and counter pathology in models of inflammation or autoimmune disease. Although both BD1 and BD2 bind acetylated histone residues, they may independently regulate the expression of BET-sensitive genes. Here we characterized the ability of RVX-297, a novel orally active BETi with selectivity for BD2, to modulate inflammatory processes in vitro, in vivo, and ex vivo. RVX-297 suppressed inflammatory gene expression in multiple immune cell types in culture. Mechanistically, RVX-297 displaced BET proteins from the promoters of sensitive genes and disrupted recruitment of active RNA polymerase II, a property shared with pan-BETis that nonselectively bind BET BDs. In the lipopolysaccharide model of inflammation, RVX-297 reduced proinflammatory mediators assessed in splenic gene expression and serum proteins. RVX-297 also countered pathology in three rodent models of polyarthritis: rat and mouse collagen-induced arthritis, and mouse collagen antibody-induced arthritis. Further, RVX-297 prevented murine experimental autoimmune encephalomyelitis (a model of human multiple sclerosis) disease development when administered prophylactically and reduced hallmarks of pathology when administered therapeutically. We show for the first time that a BD2-selective BETi maintains anti-inflammatory properties and is effective in preclinical models of acute inflammation and autoimmunity.
Frailty is Associated With Incident Alzheimer’s Disease and Cognitive Decline in the Elderly (2007)

Increasing frailty is associated with incident AD and the rate of cognitive decline in older persons. These findings suggest that frailty and AD may share similar etiologies.
Tremorgenic neurotoxins from perennial ryegrass causing ryegrass staggers disorder of livestock: structure elucidation of lolitrem B (1984)

The lolitrems, tremorgenic neurotoxins from perennial ryegrass, are implicated in ryegrass staggers disorder in livestock; the assignment of structure (1) to the major neurotoxin, lolitrem B, is based on its spectroscopic properties, particularly a detailed structure of its high-field 1H and 13C n.m.r. spectra, as well as chemical evidence.
A broadband vibration energy harvester using magnetoelectric transducer (2010)

In order for vibration energy harvesters to be efficiently applicable over a range of source frequencies, recently much research has been done to broaden the frequency range of the harvesters using piezoelectric, electromagnetic and electrostatic transductions, but little has been investigated in the harvesters using magnetoelectric transducers. In this paper, a new broadband vibration energy harvester using magneto electric transducer is proposed, which takes advantage of nonlinear magnetic force and multi-cantilever beams to expand the working bandwidth in ambient low frequency vibration. A theoretical model is developed to analyze the nonlinear vibration and electrical-output performances of the harvester. A prototype is fabricated and tested. The experimental results are in agreement with the analytical results, and the harvester shows a bandwidth of 4.6Hz and power density of 0.2-0.51 mW/cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sup> over the entire frequency range under an acceleration of 0.2 g.
Phase Behavior in Thin Films of Cylinder-Forming Block Copolymers (2002)

We have experimentally determined a phase diagram for cylinder-forming polystyrene-block-polybutadien-block-polystyrene triblock copolymer in thin films. The phase behavior can be modeled in great detail by dynamic density functional theory. Deviations from the bulk structure, such as wetting layer, perforated lamella, and lamella, are identified as surface reconstructions. Their stability regions are determined by an interplay between surface fields and confinement effects.
Imaging of single uncoated DNA molecules by scanning tunneling microscopy. (1989)

Scanning tunneling microscope images of DNA molecules absorbed onto highly oriented pyrolytic graphite have been obtained. Three methods of deposition and sample preparation have been utilized. In the first method, a highly concentrated solution of DNA is sonicated, and a drop is deposited on freshly cleaved graphite. Under these conditions, the molecules tend to align in a parallel fashion, forming liquid-crystalline phases. In the second method, a solution of DNA is deposited directly on the graphite surface without sonication. In this case, ammonium acetate, a volatile salt, is used to decrease the amount of the residual salt crystals left after drying. In the third method, a solution containing lysed phage particles and DNA is adsorbed onto a graphite surface. The molecules are seen either isolated or in small bundles. The values of height, periodicity, and thickness observed and the handedness of the molecules are consistent with those expected for DNA. In all cases, the molecules were identified by their characteristic periodic structure and because, at higher magnification, no graphite-like structure was detectable on the surface of the molecules. Often the DNA molecules appear to adsorb in areas of the graphite that have many steps and defects. A mechanism that explains the magnitude of the tunneling currents measured in DNA is proposed. This mechanism, in turn, suggests a general method by which large insulating molecules can be rendered conductive.
Binding kinetics of Clostridium difficile toxins A and B to intestinal brush border membranes from infant and adult hamsters (1991)

This study was undertaken to determine if the relative resistance of neonates and infants to Clostridium difficile-associated intestinal disease can be related to age-dependent differences in intestinal receptors for C. difficile toxins A and B. Brush border membranes (BBMs) from the small intestines of adult and infant hamsters were examined for their ability to bind radiolabeled toxins A and B. [125I]toxin A bound to both infant and adult hamster BBMs at physiological temperature, whereas [125I]toxin B did not bind to the BBMs under any of the conditions examined. The number of [125I]toxin A molecules bound at saturation was approximately 4 x 10(10) per micrograms of membrane protein for adult BBMs and 1 x 10(11) per micrograms of membrane protein for infant BBMs. Scatchard plot analysis suggested the presence of a single class of toxin A binding sites on both infant and adult hamster BBMs. Maximal binding capacity and Kd values were 0.63 pmol/mg of protein and 66.7 nM, respectively, for the infant BBMs, and 0.24 pmol/mg of protein and 27 nM, respectively, for the adult BBMs. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analyses of extracted BBM proteins revealed differences in the proteins of infant and adult BBMs. However, there were not any detectable differences in the protein bands which bound [125I]toxin A between infant and adult hamsters. The results from these investigations indicate that differences in the binding kinetics of toxins A and/or B to infant and adult hamster BBMs do not account for the observed differences in their susceptibility to C. difficile-associated intestinal disease.
Selective Targeting and Potent Control of Tumor Growth Using an EphA2/CD3-Bispecific Single-Chain Antibody Construct (2007)

The EphA2 receptor tyrosine kinase is frequently overexpressed and functionally altered in malignant cells and thus provides opportunities for selective targeting of tumor cells. We describe here the development of a novel, bispecific single-chain antibody (bscAb) referred to as bscEphA2xCD3. This molecule simultaneously targets EphA2 on tumor cells and the T-cell receptor/CD3 complex on T cells and possesses structural and functional characteristics of the recently developed BiTE technology. An EphA2-specific single-chain antibody was selected for recognition of an epitope that is preferentially exposed on malignant cells based on the concept of epitope exclusion; this was fused to a CD3-specific single-chain antibody to generate bscEphA2xCD3. The resultant bscAb redirected unstimulated human T cells to lyse EphA2-expressing tumor cells both in vitro and in vivo. In separate experiments, efficient tumor cell lysis was achieved in vitro at drug concentrations <or=1 microg/mL, at a low T-cell effector-to-tumor target cell ratio (1:1), and with tumor cells that possess few available binding sites (2,400 per cell) for bscEphA2xCD3. Time-lapsed microscopy revealed potent cytotoxic activity of bscEphA2xCD3-activated T cells against monolayers of malignant cells but not against monolayers of nontransformed EphA2-positive cells except at the edges of the monolayer where the target epitope was exposed. BscEphA2xCD3 was also efficacious in human xenograft mouse models modified to show human T-cell killing of tumors. Together, our results reveal opportunities for redirecting the potent activity of cytotoxic T cells towards tumor cells that express selectively accessible epitopes and establish EphA2-specific bscAb molecules as novel and potent therapeutics with selectivity for tumor cells.
A Methodology for Assessing the Remaining Life of Electronic Products (2006)

Remaining life assessment is an estimate of the reliability of a product in its life cycle application environment based on health monitoring and prognostics analyses. This paper reviews remaining life assessment methodologies that are currently employed for engineering products, and discusses their potential applicability to electronic systems. Based on this review, a generic 'Health Status Assessment' methodology for assessing the remaining life of electronic products is derived. The methodology is applied to an electronic circuit board used in a space application.
The biosynthesis of cyclopropane and cyclopropene fatty acids in higher plants (Malvaceae) (1972)

Abstract The biosynthesis of cyclopropane and cyclopropene fatty acids has been investigated in immature seeds, leaves and callus tissue cultures of several species of Malvaceae. Chemical characterization of labeled cyclopropane and cyclopropene fatty acids obtained from incubations with l ‐[ 14 CH 3 ] methionine confirmed that the ring methylene group was derived from the methyl group of methionine. The variation with time in the distribution of radioactivity in the products of incubations with [ 14 CH 3 ] methionine and [2‐ 14 C] acetate suggested that the pathway involved initial formation of dihydrosterculic acid from oleic acid with subsequent desaturation to sterculic acid and α‐oxidation to malvalic and dihydromalvalic acids. Direct evidence in favor of this pathway was provided by the conversion of [1‐ 14 C] oleic acid to dihydrosterculic and sterculic acids and by the desaturation of [1‐ 14 C] dihydrosterculic acid to sterculic acid, the first time that these processes have been demonstrated in higher plants. No conversion of [1‐ 14 C] stearolic acid to sterculic acid could be obtained under the same conditions. The presence of an active fatty acid α‐oxidation system was demonstrated in the callus cultures.
Microenvironmental regulation of E-cadherin-mediated adherens junctions (2008)

The interaction between tumor cells and the microenvironment has substantial effects on tumor cell behavior by influencing cell-cell as well as cell-matrix contacts. The underlying molecular mechanisms are only partially unraveled. In this review we focus on the influence of the stromal microenvironment, especially collagen type I and type III on cellular adhesion and epithelial to mesenchymal transition (EMT). Extensive studies have emphasized that components of the microenvironment such as fibrillar collagen or growth factors like transforming growth factor beta are involved in induction of dedifferentiation of epithelial cells accompanied by disruption of the E-cadherin adhesion complex and reduced E-cadherin concentrations. On the molecular level many different proteins have been identified which are involved in the regulation of EMT, such as activation of integrins, intracellular kinases such as Src, focal adhesion kinase (FAK) or phosphatidylinositol-3 kinase (PI3-kinase) and alteration of catenin phosphorylation. The reduced cellular adhesion influences the tissue integrity and allows tumor cells to disseminate from the primary tumor representing an early step in cancer metastasis.
Dry eye: an inflammatory ocular disease. (2014)

Keratoconjunctivitis sicca, or dry eye, is a common ocular disease prompting millions of individuals to seek ophthalmological care. Regardless of the underlying etiology, dry eye has been shown to be associated with abnormalities in the pre-corneal tear film and subsequent inflammatory changes in the entire ocular surface including the adnexa, conjunctiva and cornea. Since the recognition of the role of inflammation in dry eye, a number of novel treatments have been investigated designed to inhibit various inflammatory pathways. Current medications that are used, including cyclosporine A, corticosteroids, tacrolimus, tetracycline derivatives and autologous serum, have been effective for management of dry eye and lead to measurable clinical improvement.
Smoothing Noisy Data Using Dynamic Programming and Generalized Cross-Validation (1988)

Smoothing and differentiation of noisy data using spline functions requires the selection of an unknown smoothing parameter. The method of generalized cross-validation provides an excellent estimate of the smoothing parameter from the data itself even when the amount of noise associated with the data is unknown. In the present model only a single smoothing parameter must be obtained, but in a more general context the number may be larger. In an earlier work, smoothing of the data was accomplished by solving a minimization problem using the technique of dynamic programming. This paper shows how the computations required by generalized cross-validation can be performed as a simple extension of the dynamic programming formulas. The results of numerical experiments are also included.
Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity (2008)

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human tumor cells, providing unique opportunities for anticancer therapeutic intervention. NVP-BEZ235 is an imidazo[4,5-c]quinoline derivative that inhibits PI3K and mTOR kinase activity by binding to the ATP-binding cleft of these enzymes. In cellular settings using human tumor cell lines, this molecule is able to effectively and specifically block the dysfunctional activation of the PI3K pathway, inducing G(1) arrest. The cellular activity of NVP-BEZ235 translates well in in vivo models of human cancer. Thus, the compound was well tolerated, displayed disease stasis when administered orally, and enhanced the efficacy of other anticancer agents when used in in vivo combination studies. Ex vivo pharmacokinetic/pharmacodynamic analyses of tumor tissues showed a time-dependent correlation between compound concentration and PI3K/Akt pathway inhibition. Collectively, the preclinical data show that NVP-BEZ235 is a potent dual PI3K/mTOR modulator with favorable pharmaceutical properties. NVP-BEZ235 is currently in phase I clinical trials.
Cellular and molecular alterations in human epithelial cells transformed by recombinant human papillomavirus DNA. (1993)

Human papillomaviruses (HPVs) contribute to the development of benign and malignant cervical cancer; however, the exact role of papillomaviruses in the multistage carcinogenesis process is unclear. The development of HPV-immortalized cervical and foreskin cell lines represents a useful model for studying the role of HPVs in cervical cancer. Studies with these cells show that HPV genes regulate epithelial cell growth and differentiation. Transfection of HPV types associated with invasive cervical cancer results in immortalization of human epithelial cells, whereas HPVs not associated with cancer are ineffective. The combination of E6 and E7 genes, which are normally retained and expressed in cervical carcinomas, is sufficient for immortalization; however, the E7 gene alone induces immortality less efficiently. Although the immortalized cells actively express HPV oncoproteins observed in cervical cancer, after injection of immortal cells into nude mice, tumors are rare, having been reported only for HPV-18. Immortalized cells are resistant to terminal differentiation; in fact, HPVs may contribute to the carcinogenic process by uncoupling the processes of cell growth and differentiation. Host regulation of viral genes also is important in the malignant process. Endogenous cytokines modify HPV gene expression and influence the pathogenesis of HPV infection in the cervix. HPV gene expression is regulated by cellular transcriptional activators and repressors. This normal regulation is altered by viral integration. HPVs become integrated preferentially at chromosomal regions near fragile sites and protooncogenes. In fact, immortality is associated with induction of structural rearrangements frequently affecting HPV integration sites. Structural and numerical alterations nonrandomly involve chromosomes 1, 11, 19, and 20, with chromosome 1 alteration being the most predominant. Wild-type functions of Rb and p53 are necessary to control normal cell growth, and mutation or loss of these suppressor genes often contributes to cancer development. In HPV-containing carcinomas, pRb and p53 were wild type. However, in carcinomas lacking HPV, both suppressor genes were mutated. Functional inactivation of these tumor suppressor genes by HPV oncoproteins E6 and E7 may explain this difference. Treatment of HPV-immortalized cells with ras or a subfragment of herpes simplex virus (HSV) of HPV-immortalized cells resulted in locally invasive carcinomas when the cells were implanted subcutaneously in nude mice. These experiments indicate that HPV integration and expression are insufficient for malignancy but that HPVs do participate in the multistep development of cancer.
Replication of latent Epstein-Barr virus genomes in Raji cells (1987)

The replication of the 50 to 60 latent, predominantly extrachromosomal, Epstein-Barr virus genomes maintained by the Burkitt-lymphoma-derived Raji cell line was investigated by using a Meselson-Stahl density transfer approach. Samples of DNA isolated from cells cultivated for different periods in bromodeoxyuridine-supplemented medium were fractionated according to density, and the distribution of viral and cellular DNAs among the heavy-, hybrid-, and light-density species was quantitated. The results indicate that the majority of latent Epstein-Barr virus DNA plasmids each replicate once during the cell cycle.
Constituents of Asclepiadaceae Plants. XVII. Components of Cynanchum wilfordi HEMSLEY (1966)

The roots of Cynanchum wilfordi HEMSLEY were found to contain a glycoside mixture. The glycosides showed a positive Keller-Kiliani reaction, suggesting the presence of a 2-deoxysugar. The sugar portion of the glycoside was found to be D-cymarose. The aglycone was shown to be an ester. Alkaline hydrolysis of the ester aglycone afforded three kind of pregnane compounds, sarcostin (I), deacylcynanchogenin (II), and deacylmetaplexigenin (III). Cinnamic acid was found in the acidic fractions.
Evaluation of primers and PCR conditions for the analysis of 16S rRNA genes from a natural environment (2003)

We investigated biases occurring in the polymerase chain reaction (PCR) amplification of 16S rRNA genes from an environmental sample, by comparing the clone libraries that we had previously prepared from the gut homogenate of the termite Reticulitermes speratus. We detected a significant increase in the expected number of phylotypes by lowering the annealing temperature, and a significant decrease in the proportion of clones belonging to the predominant group by raising the number of PCR cycles. We also found that the Bacteria-universal primer, 63F, introduced a seriously biased amplification caused by primer mismatches, in contrast to a previous report. These results, together with suggestions from previous studies using simplified model samples, will help us to recognize the limitations of PCR-based analysis.
Gefitinib resistance caused by a secondary mutation of the epidermal growth factor receptor (2005)

2637 Mutations of the epidermal growth factor receptor gene conferring sensitivity to anilinoquinazoline EGFR inhibitors have recently been identified. Despite the typical dramatic tumor responses to such inhibitors, patients will eventually relapse with time and the mechanism of relapse has not been identified. A patient with advanced lung adenocarcinoma with a del747-752 EGFR mutation treated with gefitinib had a durable remission, but relapsed after 24 months of treatment. The DNA sequencing of exons 18-21 of his original specimen as well as his biopsy on relapse demonstrated persistence of the 747-752 deletion. The DNA sequence of his tumor biopsy from his relapse revealed a new, secondary C-to-T base pair change leading to a Thr-Met amino acid substitution at position 790. This amino acid change corresponds to one of the common bcr-abl kinase mutations conferring STI-571 resistance. Structural modeling suggested that this change would lead to the introduction of a bulkier amino acid side chain into a hydrophobic pocket of the ATP-binding site of the EGFR molecule. Further modeling also suggested that this substitution would lead to likely steric hindrance of either erlotinib or gefitinib binding due to the juxtaposition of the methionine side chain and the acetylene or chloride side chain of the anilino group of the respective inhibitor. Plasmid constructs were generated introducing this amino acid change into wild-type, L858R mutant, del747-753insS as well as del747-752 constructs. In transient transfection experiments, equal expression as well as phosphoprotein generation upon EGF stimulation between all the corresponding construct pairs (primary versus resistance mutant) was seen. While gefitinib completely inhibited EGF-stimulated phospho-EGFR generation of the non-resistance mutant constructs at concentrations of 2-20 nM, all four constructs carrying the Thr-Met substitution showed high level resistance to gefitinib with sustained EGFR phosphorylation at concentrations as high as 2 μM. A screen of commercially available EGFR inhibitors demonstrated that one of the screened inhibitors, CL-387,785, inhibited both the del747-752 as well as the del747-752 plus resistance mutant constructs with nearly the same potency with full inhibition observed at a concentration as low as 30nM. CL-387,785 is an irreversible, anilinoquinazoline inhibitor of EGFR. In summary, we have identified a novel, in vivo occurring mutation of the EGFR conferring gefitinib resistance and thereby describe the first resistance mutation in an oncogenic tyrosine kinase in a common epithelial cancer. We also demonstrate an alternative compound which can inhibit this mutant receptor, suggesting that drugs of this class might be useful in patients who relapse while on treatment with gefitinib.