gebhart/patrepeval huggingface dataset:
Redox‐Active Catechol‐Functionalized Molecular Rods: Suitable Protection Groups and Single‐Molecule Transport Investigations (2007)

Abstract The synthesis of molecular rod 1 comprising a central redox‐active unit and two terminal acetyl‐protected sulfur groups is reported. Various protecting groups for the catechol moiety were investigated and protected precursors 14 – 18 were synthesized. In particular, ethyl orthoformate 17 can be easily and selectively deprotected in mild acidic conditions ruling out the need for a strong Lewis acid like boron tribromide. The redox activity of 1 was confirmed by cyclic voltammetric investigations. Gold–molecule–gold junctions were formed with the dimethyl‐protected rod 18 . Single‐molecule transport investigations using this molecular rod revealed a set of three single‐junction conductance values varying over two orders of magnitude.(© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2008)
PET and PET/CT in cardiovascular disease (2011)

The present review provides an overview of the role of cardiac positron emission tomography in the diagnosis and management of cardiovascular disease. It expands on the relative advantages and disadvantages over other imaging modalities as well as the available evidence supporting its value in the diagnosis and management of patients with coronary artery disease, the assessment of myocardial viability, and evaluation of the cardiac sympathetic nervous system. Furthermore, the recent developments, such as the implementation of high-end computed tomography devices to form hybrid systems, and the advances of molecular imaging probes in experimental applications are briefly discussed.
Preventing stroke in atrial fibrillation: why are so many eligible patients not receiving anticoagulant therapy? (1999)

Atrial fibrillation is responsible for more disability than any other cardiac arrhythmia because of its high incidence and the considerable potential for adverse outcomes. There is increasing evidence from epidemiologic studies that atrial fibrillation independently increases the risk of death, [[1
100-nm node lithography with KrF? (2001)

We present results looking into the feasibility of 100-nm Node imaging using KrF, 248-nm, exposure technology. This possibility is not currently envisioned by the 1999 ITRS Roadmap which lists 5 possible options for this 2005 Node, not including KrF. We show that double-exposure strong phase- shift, combined with two mask OPC, is capable of correcting the significant proximity effects present for 100-nm Node imaging at these low k<SUB>1</SUB> factors. We also introduce a new PSM Paradigm, dubbed 'GRATEFUL,' that can image aggressive 100-nm Node features without using OPC. This is achieved by utilizing an optimized 'dense-only' imaging approach. The method also allows the re-use of a single PSM for multiple levels and designs, thus addressing the mask cost and turnaround time issues of concern in PSM technology.
Vertical alignment of liquid crystal on a-SiOx thin film using the ion beam exposure (2006)

In this letter we demonstrate the vertical alignment of liquid crystal on inorganic thin film surfaces using the ion beam exposure. Nematic liquid crystal can be aligned vertically by the rotational oblique evaporation of a-SiOx thin films. However, the electro-optic switching behavior of liquid crystal along random directions results in disclination lines. By using the ion beam exposure, we can achieve highly uniform alignment without disclination lines. We found from x-ray diffraction and x-ray photoemission spectroscopy data that the vertical alignment can be achieved when x approaches 1.5 at the a-SiOx film surface. We have shown that the pretilt angle can be controlled by changing ion beam parameters, such as the ion beam energy, the angle of incidence, and the exposure time. We also have shown that a liquid crystal cell aligned vertically by the ion beam exposure exhibits the voltage-transmittance curve similar to that of a rubbed polyimide cell.
DNA Arrays in Allergy and Immunology (2001)

The DNA array technique allows the simultaneous analysis of multiple genes. This makes it an interesting tool for studies of gene expression in various diseases that are caused by or depend on multiple genes. DNA arrays are particularly applied to define certain immunological conditions such as allergic diseases. We summarize strategies on gene expression profiling of inflammatory disease and immunologically relevant cells using DNA array technology. Using DNA arrays, gene expression analysis of CD4+ T cells of allergy patients revealed interesting differences compared to healthy individuals, but also between different allergic conditions. This comparison demonstrated that T cells differed in their capacity to regulate peripheral tolerance, neuronal innervation, chemotaxis, neovascularization and epidermal growth. On the basis of these findings the DNA array technique appears to be especially interesting for the development of powerful diagnostic tools allowing fine specification and subtyping of allergic conditions, monitoring of therapy and of tailored therapy concepts.
A Novel Capsid Binding Inhibitor Displays Potent Antiviral Activity against Enterovirus D68 (2019)

Enterovirus D68 (EV-D68) is a respiratory viral pathogen that primarily infects children under the age of 8. Although EV-D68 infection typically leads to moderate to severe respiratory illnesses, recent years have seen increasing cases of EV-D68 triggered neurological complications such as acute flaccid myelitis (AFM). There is currently no vaccine or antiviral available for EV-D68; we therefore aimed to develop potent and specific small molecule antivirals against EV-D68. In this study, we report our discovery of a viral capsid inhibitor <b>R856932</b> that inhibits multiple contemporary EV-D68 strains with single-digit to submicromolar efficacy. Mechanistic studies have shown that the tetrazole compound <b>R856932</b> binds to the hydrophobic pocket of viral capsid protein VP1, thereby preventing viral uncoating and release of viral genome in the infected cells. The mechanism of action of <b>R856932</b> was confirmed by time-of-addition, Western blot, RT-qPCR, viral heat inactivation, serial viral passage, and reverse genetics experiments. A single mutation located at VP1, A129V, confers resistance against <b>R856932</b>. However, a recombination virus encoding VP1-A129V appeared to have compromised fitness of replication compared to the wild-type EV-D68 virus as shown by the competition growth assay. Overall, the hit compound identified in this study, <b>R856932</b>, represents a promising starting point with a confirmed mechanism of action that can be further developed into EV-D68 antivirals.
Abstract 5641: Effects of G1T48, a novel orally bioavailable selective estrogen receptor degrader (SERD), and the CDK4/6 inhibitor, G1T38, on tumor growth in animal models of endocrine resistant breast cancer (2017)

Abstract Background: The combination of targeting the CDK4/6 and ER signaling pathways with palbociclib and fulvestrant is a proven therapeutic strategy for the treatment of ER positive breast cancer. However, the poor physicochemical properties of fulvestrant require monthly intramuscular injections to patients, which limit the pharmacokinetic and pharmacodynamic activity of the compound. Therefore, an orally available compound that more rapidly reaches steady state may lead to a better clinical response in patients. Here we report the preclinical characterization of G1T48, a novel, orally bioavailable, non-steroidal small molecule inhibitor of ERα, which is a potent, selective antagonist that down regulates ERα in vitro and in vivo in ER-positive models of breast cancer. Methods: Breast cancer cells expressing clinically relevant ESR1 mutations (ER-Y537S, ER-D538G) were threated with G1T38, G1T48, and mechanistically distinct SERMs/SERDs and cellular proliferation was assessed by measuring DNA content (Hoechst dye). Ovariectomized nu/nu mice bearing xenograft tumors of clinically relevant tamoxifen (TamR) and aromatase (long term estrogen deprived) resistant ER+ breast cancer were treated with G1T38 and G1T48, alone or in combination, with clinically relevant comparators. Time to progression and tumor volume were assessed over a 4 week dosing period. Results: G1T38 and G1T48 significantly inhibited cellular proliferation of MCF7 breast cancer cells bearing endocrine resistant ER mutations, ER-Y537S and ER-D538G. G1T48 treatment led to dramatic reductions in ER protein levels. Importantly, tumor growth inhibition was observed in mouse models of sensitive and resistant human breast cancer when G1T48 was dosed as a single agent or in combination with G1T38, a potent, selective CDK4/6 inhibitor. Conclusions: G1T38, a novel CDK4/6 inhibitor, and G1T48, a novel SERD, either alone or in combination, demonstrated highly potent inhibition of tumor growth in animal models of tamoxifen and aromatase resistance. G1T48 also demonstrated activity in models of endocrine resistance mediated by ER mutation. G1T48 is currently completing IND enabling studies. Citation Format: Suzanne E. Wardell, Alexander P. Yllanes, Jennifer G. Baker, Robert M. Baldi, Taylor K. Krebs, Jessica Sorrentino, John Bisi, Jay Strum, John D. Norris. Effects of G1T48, a novel orally bioavailable selective estrogen receptor degrader (SERD), and the CDK4/6 inhibitor, G1T38, on tumor growth in animal models of endocrine resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5641. doi:10.1158/1538-7445.AM2017-5641
A high-throughput Raman notch filter set (1990)

A chevron-type Raman notch filter (RNF) set is described. lt combines a high signal throughput (up to 90% around 1600 cm−1 and ≳80% between and 700 and 2700 cm−1) with a laser line suppression of 108–109. The filter set can be used to replace the first two dispersion stages in triple-stage Raman monochromators commonly employed in multichannel detection systems. This yields a gain in intensity of the detected Raman signal of a factor of 4. It is shown that in Raman spectrometers with a backscatter geometry, the filter set can also be used to optically couple the microscope and the spectrometer. This leads to a further increase in signal intensity of a factor of 3–4 as compared to the situation where a beam splitter is used. Additional advantages of the RNF set are the fact that signal throughput is almost polarization independent over a large spectral interval and that it offers the possibility to simultaneously record Stokes and anti-Stokes spectra.
BREAKDOWN OF THE BLOOD-BRAIN BARRIER PRECEDES SYMPTOMS AND OTHER MRI SIGNS OF NEW LESIONS IN MULTIPLE SCLEROSIS (1990)

From an extensive serial magnetic resonance imaging (MRI) study in multiple sclerosis (MS) we have identified 4 cases in which disruption of the blood-brain barrier, as detected by gadolinium-DTPA enhancement, preceded other MRI abnormalities and in 1 case clinical evidence of the new lesion. This supports the view that a defect in the blood-brain barrier, and therefore inflammation, is an early and possibly crucial event in the pathogenesis of the new lesion in MS. These cases showed a marked discrepancy between MRI abnormality and symptoms. The mechanisms contributing to this disparity are discussed, and it is concluded that far from being surprising it is to be expected.
Cardiac sympathovagal balance during sleep apnea episodes (1996)

The main acute cardiovascular effects of obstructive sleep apnea syndrome (OSAS) are elevation of blood pressure and reflectory bradycardia, which are followed by an abrupt tachycardia on resumption of breathing. This haemodynamic instability is related to hypoxemia and arousal, and may lead to increased risk from cardiac arrhythmias and sudden cardiac death, as well as to the development of chronic arterial hypertension, in these patients. The aim of this study was to apply frequency domain analysis of heart rate variability (HRV) measured from continuous electrocardiogram (ECG) recordings to evaluate how cardiac autonomic function, and especially cardiac sympathovagal tone, changes during sleep apnea episodes. We identified 41 apneas leading to more than 4%-unit arterial oxygen desaturation in 12 patients (11 men, 1 woman (correction for women), age range 27-67 years). Frequency domain analysis of HRV was performed from ECG recordings using 4 min epochs starting 20 min before apnea began and lasting 20 min after the beginning of apnea. The mean (+/-SEM) fall in oxygen saturation during the apnea was 6.8 +/- 0.6%-units. While high frequency band (HF, reflects cardiac vagal activity) remained unchanged, low frequency band (LF, mainly sympathetic activity) showed a constant increase, leading to significant change in the sympathovagal balance (LF/HF ratio). In conclusion, concordantly with previous peripheral sympathetic-nerve recordings, frequency domain analysis of HRV is able to detect sympathetic activation during sleep apnea episodes, leading to marked change in the sympathovagal balance.
Physical and immunochemical studies of the globular domain of type IV collagen. Cryptic properties of the Goodpasture antigen. (1985)

The globular domain of type IV collagen from bovine glomerular basement membrane was isolated under nondenaturing conditions. It was shown to exist in a hexameric form comprising monomeric and dimeric subunits, with the Goodpasture antigen residing in monomer M2 and dimer D2 as previously described (Butkowski, R. J., Wieslander, J., Wisdom, B. J., Barr, J. F., Noelken, M. E., and Hudson, B. G. (1985) J. Biol. Chem. 260, 3739-3747). The epitope, however, is sequestered inside the hexamer, but becomes exposed and binds with the Goodpasture antibody upon dissociation of the hexamer into its subunits after treatment with concentrated guanidine HC1 or dilute acetic acid (pH less than 3.0). The process is completely reversible even from the denatured state. Circular dichroism studies show that the conformation of each subunit is unusually resistant to change in 6 M guanidine HC1 at 25 degrees C. This suggests that exposure of the epitope by dissociation requires minimal or no unfolding of subunits. The results provide additional evidence for localization of the Goodpasture antigen to the globular domain of type IV collagen. Moreover, these studies extend the conclusion (Weber, H., Engel, J., Wiedemann, H., Glanville, R., and Timpl, R. (1984) Eur. J. Biochem. 139, 401-410) about a tumor basement membrane, to an authentic physiological membrane, that the globular domain is a major cross-linking site in the type IV collagen matrix.
Overexpression of protein kinase C β1 in the SW480 colon cancer cell line growth suppression (1995)

Using a retroviral vector system we have established derivatives of the E8 subclone of the human colon cancer cell line SW480 that stably overproduce a full-length rat cDNA encoding the beta 1 isoform of protein kinase C (PKC beta 1). In contrast to vectrol control cells, when treated with the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA), the overexpressing cell lines displayed a striking increase in doubling time, and a decrease in saturation density. Western blot analysis indicated that treatment with TPA was also associated with translocation and partial downregulation of the exogenous PKC beta 1 in the over-expressor cell lines. These results extend previous evidence that PKC beta 1 can inhibit the growth of the HT29 human colon cancer cell line. The HT29 cells have a normal c-k-ras oncogene but the SW480 cells used in the present study have an activating mutation in this oncogene. Thus PKC beta 1 can function as a suppressor in both types of colon cancer cells.
Effects of protein conformation in docking: improved pose prediction through protein pocket adaptation (2009)

Computational methods for docking ligands have been shown to be remarkably dependent on precise protein conformation, where acceptable results in pose prediction have been generally possible only in the artificial case of re-docking a ligand into a protein binding site whose conformation was determined in the presence of the same ligand (the "cognate" docking problem). In such cases, on well curated protein/ligand complexes, accurate dockings can be returned as top-scoring over 75% of the time using tools such as Surflex-Dock. A critical application of docking in modeling for lead optimization requires accurate pose prediction for novel ligands, ranging from simple synthetic analogs to very different molecular scaffolds. Typical results for widely used programs in the "cross-docking case" (making use of a single fixed protein conformation) have rates closer to 20% success. By making use of protein conformations from multiple complexes, Surflex-Dock yields an average success rate of 61% across eight pharmaceutically relevant targets. Following docking, protein pocket adaptation and rescoring identifies single pose families that are correct an average of 67% of the time. Consideration of the best of two pose families (from alternate scoring regimes) yields a 75% mean success rate.
Development of New Vaccines against Dengue Fever and Japanese Encephalitis (2001)

Mosquito-borne dengue (DEN) and Japanese encephalitis (JE) viruses are the leading causes of arthropod-transmitted viral disease in humans. A licensed tetravalent vaccine that provides effective, long-term immunity against all four serotypes of DEN virus is needed, but is currently unavailable. Improvements to currently available JE vaccines are also needed. Past and recent strategies for the development of new DEN and JE vaccines include inactivated and live attenuated viruses, engineered viruses and chimeric viruses derived from infectious cDNA clones of DEN or JE virus, recombinant poxviruses, recombinant baculoviruses, protein expression in Escherichia coli, and naked DNA vaccines. This report summarizes some of the recent developments in DEN and JE vaccinology, particularly vaccine strategies that involve live attenuated viruses, engineered viruses derived from infectious cDNA clones, and naked DNA vaccines.
Yeast artificial chromosome libraries containing large inserts from mouse and human DNA. (1991)

Yeast artificial chromosome (YAC) libraries have been difficult to construct with average insert sizes greater than 400 kilobase pairs when DNA is size-fractionated in low-melting-point agarose. By using yeast chromosome in mock cloning experiments, we found that polyamines should be present whenever agarose containing high molecular weight DNA is melted to protect DNA from degradation. By incorporating polyamines during the cloning procedure, we constructed YAC libraries from mouse and human DNA with average insert sizes of 700 and 620 kilobase pairs, respectively. Several genome equivalents of these YAC libraries were replicated onto the surface of many duplicate agar plates using a 40,000 multipin transfer device. High-density filter replicas were screened by hybridization, and 70 mouse YAC clones from 31 loci and 132 human YAC clones from 49 loci were isolated.
Synthesis, resolution and radioiodination of S(−)trans‐5‐hydroxy‐2‐[N‐n‐propyl‐N‐(3′‐iodo‐2′‐propenyl)amino]tetralin‐S(−)trans‐5‐OH‐PIPAT: A new dopamine D2‐like receptor ligand (1995)

Abstract A new dopamine D2‐like receptor ligand, ( R,S ) trans ‐5‐hydroxy‐2‐[N‐n‐propyl‐N‐(3′‐iodo‐2′‐propenyl)amino]tetralin (( R,S)trans ‐5‐OH‐PIPAT, 3 ), based on high affinity dopamine receptor agonist 5‐hydroxy‐2‐[N,N‐(di‐n‐propyl)‐2‐amino]tetralin (5‐OH‐DPAT, 1 ). was prepared. The synthesis was achieved by a reductive amination of 5‐methoxy‐2‐tetralone with n‐propylamine, followed by N‐alkylation, to afford 5‐methoxy‐N‐propyl‐N‐2′‐propynyl‐2‐aminotetralin, 7 . Reduction of 7 with tributyltin hydride gave the tri‐n‐butyl tin derivative, 8 , which was converted to 9 by an iododemetalation reaction. Demethylation of 9 gave the desired compound, ( R,S ) trans ‐5‐OH‐PIPAT, 3 . The resolved ( R ) and ( S ) trans ‐5‐OH‐PIPAT, 3 were also quantitatively prepared. In vitro binding studies showed the stereoselectivity of this new compound for binding to dopamine D2‐like receptors. S (‐)‐ 3 displayed high binding affinity, with inhibition constants (K i ) of 0.38, 0.09 and 0.67 nM for dopamine D2H (expressed in HEK293 cells), D3 (expressed in Sf9 cells) and D4H receptors (expressed in CHO cells), respectively. Using the same binding assays, the less active R (+) isomer displayed K i values of 7.29, 4.87 and 16.44 nM for D2H, D3 and D4H receptors, respectively. In addition, radiolabeling was successfully performed, either with the racemic tin derivative, ( R,S )‐ 11 , or using the optically resolved tin derivatives R (+)‐or S (‐)‐1 11 , to give the final radiolabeled product, [125I] R (+) or S (‐)‐ 3 .
Protein biochip systems for the clinical laboratory (2005)

Classical methods of protein analysis such as electrophoresis, ELISA and liquid chromatography are generally time-consuming, labor-intensive and lack high-throughput capacity. In addition, all existing methods used to measure proteins necessitate multiple division of the original sample and individual tests carried out for each substance, with an associated cost for each test. The chip system allows several tests to be performed simultaneously without dividing the original patient sample. This system facilitates the development of multiplexed assays that simultaneously measure many different analytes in a small sample volume. These emerging technologies fall into two categories: 1) spotted array-based tools, and 2) microfluidic-based tools. Miniaturized and multiplexed immunoassays allow a great deal of information to be obtained from a single sample. These analytical systems are referred to as "lab-on-a-chip" devices. This article presents current trends and advances in miniaturized multiplexed immunoassay technologies, reviewing different systems from research to point-of-care assays. We focus on a subset of chip-based assays that may be used in a clinical laboratory and are directly applicable for biomedical diagnosis. Recent advances in biochip assays combine the power of miniaturization, microfluidics, micro- to nanoparticles, and quantification. A number of applications are just beginning to be explored. The power of biochip assays offers great promise for point-of-care clinical testing and monitoring of many important analytes.
The Genetic Stability of a Conditional Live HIV-1 Variant Can Be Improved by Mutations in the Tet-On Regulatory System That Restrain Evolution (2006)

Live attenuated human immunodeficiency virus type 1 (HIV-1) vaccines are considered unsafe because more quickly replicating pathogenic virus variants may evolve after vaccination. As an alternative vaccine approach, we have previously presented a doxycycline (dox)-dependent HIV-1 variant that was constructed by incorporating the tetracycline-inducible gene expression system (Tet-On system) into the viral genome. Replication of this HIV-rtTA variant is driven by the dox-inducible transcriptional activator rtTA and can be switched on and off at will. A large scale evolution study was performed to test the genetic stability of this conditional live vaccine candidate. In several long term cultures, we selected for HIV-rtTA variants that no longer required dox for replication. These evolved variants acquired a typical amino acid substitution either at position 19 or 37 in the rtTA protein. Both mutations caused rtTA activity and viral replication in the absence of dox. We designed a novel rtTA variant with a higher genetic barrier toward these undesired evolutionary routes. The corresponding HIV-rtTA variant did not lose dox control in long term cultures, demonstrating its improved genetic stability.
Investigation of the Reactions of some New Fluorine containing 3-Aroylmethylene-indol-2-ones with Urea and Thiourea Derivatives (1995)

Department of Chemistry, University of Rajasthan, Jaipur-302 004<br> <em>Manuscript received 26 July 1993, revised 17 February 1994. accepted 25 April 1994</em> Investigation of the Reactions of some New Fluorine containing 3-Aroylmethylene-indol-2-ones with Urea and Thiourea Derivatives