gebhart/patrepeval huggingface dataset:
Synthesis of 5‐[125I]‐iodo‐zacopride, a new probe for 5‐HT3 receptor binding sites (1991)

Abstract In an attempt to develop a specific probe of serotonin 5‐HT 3 receptors, various methods have been investigated to synthesize a radioiodinated derivative of the potent 5‐HT 3 antagonist zacopride. The direct iodination of 5‐dechloro‐zacopride 2 was performed using NaI in the presence of either chloramine T or iodo‐beads. Irreproducible results or/and low yields were obtained by these methods. A third approach using a less oxidative medium allowed the synthesis of iodo‐zacopride 4 from 2 with N‐iodo‐succinimide or with NaI and N‐chlorosuccinimide. Using this third condition, high yield was obtained (49%). However, the radioiodinated compound was contaminated by some “cold” zacopride also formed during the reaction. A two step synthesis was successful to eliminate “cold” zacopride but in lower yield (2‐10%). Thus, 4‐amino‐2‐methoxy‐benzoate 5 was iodinated and then coupled with 3‐aminoquinuclidine 8 to give 5‐iodo‐zacopride 4 . Radioactive synthesis was carried out in the same condition to give 5‐[ 125 1]‐iodo‐zacopride 1 with a yield of 98%. The two enantiomers R‐and S‐5‐[ 125 1]‐iodo‐zacopride were synthesized by direct iodination.
Update on interleukin-17: a role in the pathogenesis of inflammatory arthritis and implication for clinical practice (2017)

Interleukin-17 (IL-17A) is a cytokine critical for the acute defence against extracellular bacterial and fungal infections. Excess production during chronic inflammation has been associated with many inflammatory and autoimmune disorders. The present review describes the key molecules of the IL-17 pathway, which are or could be targeted for treatment. Since targeting of IL-17A may affect defence mechanisms, the pathogenesis of such possible adverse events is analysed. Then the contributions of IL-17 to bone changes in various forms of arthritis are discussed. Finally, the results of current inhibitors of the IL-17 pathway in clinical trials are detailed. IL-17A inhibition has been first registered for the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis. Other therapeutic options are now tested in a long list of diseases.
Imaging Protein Kinase Cα Activation in Cells (1999)

Spatially resolved fluorescence resonance energy transfer (FRET) measured by fluorescence lifetime imaging microscopy (FLIM), provides a method for tracing the catalytic activity of fluorescently tagged proteins inside live cell cultures and enables determination of the functional state of proteins in fixed cells and tissues. Here, a dynamic marker of protein kinase Calpha (PKCalpha) activation is identified and exploited. Activation of PKCalpha is detected through the binding of fluorescently tagged phosphorylation site-specific antibodies; the consequent FRET is measured through the donor fluorophore on PKCalpha by FLIM. This approach enabled the imaging of PKCalpha activation in live and fixed cultured cells and was also applied to pathological samples.
Constructing Test Behavior Models Using Simulated System Answers for the Analysis of Test Behavior Anomalies. (2008)

In the standardization of test specifications, it is common that no actual systems exist against which the tests can be executed. Test specifications are developed abstractly in high level languages such as the Testing and Test Control Notation (TTCN-3), but they can only be executed when a separate adaptation layer is implemented. Static syntactical and semantical analyses as provided by the compiler and proper manual code reviews are the only means to find mistakes in such test specifications at early stages of design. In this paper, we demonstrate that it is possible to execute abstract test specifications when the system does not exist yet. We use the information provided within the test cases to simulate answers of the system by generating inverse messages to expected messages in the abstract test case. By following a specific coverage-criterion strategy, we are able to execute a sufficient amount of test paths to reverse-engineer behavioral models of test cases which can then again be used for the analyses of potential problems.
Dispersion polymerization accompanied by CO2 fixation: Synthesis of particles of polymers bearing cyclic carbonate and epoxide moieties (2010)

Abstract Radical dispersion polymerization of glycidyl methacrylate accompanied by CO 2 fixation yielded particles of polymers bearing cyclic carbonate and epoxide moieties in the presence of polymeric dispersion stabilizers. Cellulose acetate successfully stabilized the dispersion, whereas poly( N ‐vinylpyrrolidone) did not. Spherical particles with diameters of 1–10 μm could be prepared under the optimized conditions. The epoxide moieties in the particle were hydrolyzed selectively keeping the shapes of the particles. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010
Directed evolution of ligand dependence: Small-molecule-activated protein splicing (2004)

Artificial molecular switches that modulate protein activities in response to synthetic small molecules would serve as tools for exerting temporal and dose-dependent control over protein function. Self-splicing protein elements (inteins) are attractive starting points for the creation of such switches, because their insertion into a protein blocks the target protein's function until splicing occurs. Natural inteins, however, are not known to be regulated by small molecules. We evolved an intein-based molecular switch that transduces binding of a small molecule into the activation of an arbitrary protein of interest. Simple insertion of a natural ligand-binding domain into a minimal intein destroys splicing activity. To restore activity in a ligand-dependent manner, we linked protein splicing to cell survival or fluorescence in Saccharomyces cerevisiae. Iterated cycles of mutagenesis and selection yielded inteins with strong splicing activities that highly depend on 4-hydroxytamoxifen. Insertion of an evolved intein into four unrelated proteins in living cells revealed that ligand-dependent activation of protein function is general, fairly rapid, dose-dependent, and posttranslational. Our directed-evolution approach therefore evolved small-molecule dependence in a protein and also created a general tool for modulating the function of arbitrary proteins in living cells with a single cell-permeable, synthetic small molecule.
Site-directed irreversible inhibitors of the erbB family of receptor tyrosine kinases as novel chemotherapeutic agents for cancer. (2000)

The erbB family of tyrosine kinases represents a versatile set of four plasma membrane receptors that possesses enormous diversity in signaling capability. The rationale to target this receptor system as an approach to cancer chemotherapy has continued to become more compelling with time. Both preclinical and clinical data strongly support the involvement of these receptors in the formation and progression of human cancers as well as establish a high correlation in cancer patients between receptor/ligand expression and poor prognosis. During the past 4 years significant progress has been made in the area of epidermal growth factor receptor tyrosine kinase inhibitors and new structural classes have emerged that exhibit enormous improvements with regard to potency, specificity, and in vitro and in vivo efficacy. More recent advancements in this field have resulted in the discovery of very specific, irreversible inhibitors of the erbB family that provide unique pharmacological properties and exceptional efficacy. The in vivo performance of these modern kinase inhibitors has improved to the point where several compounds are either in clinical trials or very near to that point in their development. This article will provide a brief biological review of the erbB family and the justification for targeting this receptor family in cancer therapeutics, and then highlight some of the more promising kinase antagonists with emphasis on irreversible inhibitors.
Differential Regulation of Vascular Endothelial Growth Factor Receptors (VEGFR) Revealed by RNA Interference:  Interactions of VEGFR-1 and VEGFR-2 in Endothelial Cell Signaling (2005)

Vascular endothelial growth factor (VEGF) plays a central role in vascular homeostasis. VEGF receptors (VEGFRs) include several subtypes that may have a differential role in endothelial signal transduction, but interactions among these receptors are incompletely understood. In these studies, we designed small interfering RNA (siRNA) duplexes that targeted specific VEGFR subtypes in bovine aortic endothelial cells (BAEC). siRNA-mediated downregulation of VEGFR-2 by its cognate siRNA resulted in a significant attenuation of VEGF-mediated signaling. Compared to control siRNA-treated cells, VEGFR-2 siRNA markedly inhibited VEGF-mediated activation of PI3K/Akt/GSK3-beta as well as MAP kinase and PKC pathways. VEGFR-2 siRNA also blocked VEGF-stimulated phosphorylation and dephosphorylation of endothelial nitric oxide synthase (eNOS) at Ser(1179) and Ser(116), respectively. VEGFR-2-specific siRNA had no effect on the abundance of VEGFR-1 protein. By contrast, VEGFR-1-specific siRNA markedly not only downregulated the abundance of VEGFR-1 but also significantly reduced VEGFR-2 protein and mRNA abundance. VEGFR-1 siRNA had no effect on the stability of VEGFR-2 protein or mRNA. However, VEGFR-1 siRNA significantly inhibited VEGFR-2 promoter activity, as determined in luciferase assays using VEGFR-2 promoter fusion constructs in transfected BAEC. Deletion of either the 5' E box or the 3' E box and the GATA element in the VEGFR-2 promoter completely abolished the inhibition of VEGFR-2 promoter activity elicited by VEGFR-1 siRNA. Taken together, our data suggest that VEGFR-1 receptor is a critical determinant of VEGFR-2 abundance, while VEGFR-2 is the key receptor directly responsible for endothelial cell signaling stimulated by VEGF.
Understanding dialectical behavior therapy. (2000)

Scheel (this issue) shows that the effectiveness and mechanism of action of dialectical behavior therapy (DBT) for borderline personality disordered (BPD) patients are not as conclusive or well understood as many have come to believe. Scheel's conclusions are well balanced, and she does point out the strengths of the DBT approach. Most important, Scheel provides clear guidance about the types of studies that need to be conducted to fully establish DBT as the treatment of choice for BPD. Future studies are going to have to forgo the TAU control and use well-established alternative treatments. Controls for dosage of the treatments, therapists, supervision, and therapeutic allegiance will have to be implemented. In addition, a broader, more representative outcome battery will need to be used. An important virtue of Scheel's review is that it exemplifies the virtues of the clinical science approach to evaluating psychosocial treatment through falsification of hypotheses.
Prognostic significance of soluble urokinase plasminogen activator receptor in serum and cytosol of tumor tissue from patients with primary breast cancer. (2002)

This study shows that high preoperative aa-s-suPAR levels are significantly associated with poor outcome for breast cancer patients independent of lymph node status, tumor size, and estrogen receptor status.
Energy band engineered unified-RAM (URAM) for multi-functioning 1T-DRAM and NVM (2008)

A novel fusion memory is proposed as a new paradigm of silicon based memory technology. An O/N/O gate dielectric and a floating body are combined with a FinFET, and the non-volatile memory (NVM) and high speed capacitorless 1T-DRAM are performed in a single transistor. A nitride trap layer is used as an electron storage node for NVM, and hetero-epitaxially grown Si/Si <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1-x</sub> Ge <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">x</sub> energy band engineered bulk substrates allow excess hole storage for 1T-DRAM. Highly reliable 1T-DRAM and NVM are demonstrated.
Novel Triaryl Sulfonamide Derivatives as Selective Cannabinoid Receptor 2 Inverse Agonists and Osteoclast Inhibitors: Discovery, Optimization, and Biological Evaluation (2013)

Cannabinoid receptors have gained increasing attention as drug targets for developing potential therapeutic ligands. Here, we report the discovery and optimization of triaryl sulfonamides as a novel series possessing significant CB2 receptor affinity and selectivity. Four sets of triaryl ligands were designed and synthesized for further structural modifications and led to the identification of eight compounds as potent and selective CB2 inverse agonists with high binding affinity (CB2K(i) < 10 nM). Especially, compound 57 exhibited the strongest binding affinity on the CB2 receptor (CB2K(i) of 0.5 nM) and the best selectivity over the CB1 receptor (selectivity index of 2594). Importantly, 57 also showed potent inhibitory activity on osteoclast formation, and it was confirmed by a cell viability assay that the inhibition effects were not derived from the cytotoxicity. Finally, 3D QSAR studies confirmed our SAR findings that three bulky groups play an important role for CB2 receptor binding affinity.
PDL-1 Blockade Impedes T Cell Expansion and Protective Immunity Primed by Attenuated Listeria monocytogenes (2008)

Infection with attenuated Listeria monocytogenes (Lm) is a robust in vivo model for examining how Ag-specific T cells are primed, and subsequent challenge with virulent Lm allows for the protective effects of T cell priming to be quantified. Herein, we investigated the role of programmed death ligand 1 (PDL-1) in T cell priming and immunity conferred after primary infection with Lm DeltaactA followed by virulent Lm challenge. In striking contrast to the inhibitory role of PDL-1 on T cell immunity in other infection models, marked reductions in the magnitude of T cell expansion and the kinetics of T cell proliferation were observed with PDL-1 blockade after primary Lm DeltaactA infection. More importantly, PDL-1 blockade beginning before primary infection and maintained throughout the experiment resulted in delayed bacterial clearance and T cell expansion after secondary challenge with virulent Lm. These results indicate that for immunity to intracellular bacterial infection, PDL-1 plays an important stimulatory role for priming and expansion of protective T cells.
Pavement cracking measurements using 3D laser-scan images (2013)

Pavement condition surveying is vital for pavement maintenance programs that ensure ride quality and traffic safety. This paper first introduces an automated pavement inspection system which uses a three-dimensional (3D) camera and a structured laser light to acquire dense transverse profiles of a pavement lane surface when it carries a moving vehicle. After the calibration, the 3D system can yield a depth resolution of 0.5 mm and a transverse resolution of 1.56 mm pixel−1 at 1.4 m camera height from the ground. The scanning rate of the camera can be set to its maximum at 5000 lines s−1, allowing the density of scanned profiles to vary with the vehicle's speed. The paper then illustrates the algorithms that utilize 3D information to detect pavement distress, such as transverse, longitudinal and alligator cracking, and presents the field tests on the system's repeatability when scanning a sample pavement in multiple runs at the same vehicle speed, at different vehicle speeds and under different weather conditions. The results show that this dedicated 3D system can capture accurate pavement images that detail surface distress, and obtain consistent crack measurements in repeated tests and under different driving and lighting conditions.
Chemical Force Microscopy of Mixed Self-Assembled Monolayers of Alkanethiols on Gold:  Evidence for Phase Separation (2004)

Mixed self-assembled monolayers formed by the coadsorption of hydroxyl- and methyl-terminated alkanethiols with similar chain lengths have been characterized by friction force microscopy. Friction coefficients have been determined by assuming a fit to Amonton's law. The friction coefficients vary linearly with the fraction of polar-terminated adsorbates in the self-assembled monolayer (SAM). With carboxylic acid-terminated tips, the coefficient of friction increases with the fraction of hydroxyl-terminated thiols, while with methyl-terminated tips it decreases. Similar trends are observed for pull-off forces, which increase and decrease as a function of the fraction of polar-terminated adsorbates for carboxylic acid- and methyl-terminated adsorbates, respectively. Analysis of histograms of adhesion forces has yielded insights into the phase structure of mixed SAMs. Single-component monolayers yield histograms that may be fitted to symmetric Gaussian distributions, irrespective of the nature of the terminal group on either the tip or the SAM. However, mixed monolayers yield broad, asymmetric distributions that could not be fitted with a Gaussian distribution. The best explanation for these data is that mixed SAMs of hydroxyl- and methyl-terminated alkanethiols of similar chain length form phase-separated structures.
Preclinical and clinical development of the oral multikinaseinhibitor sorafenib in cancer treatment (2005)

Tumor survival, growth and metastasis depend on efficient tumor cell proliferation and tumor angiogenesis, and targeting both of these processes simultaneously could prove to be therapeutically relevant. The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation, and angiogenesis and is often aberrantly activated in human tumors due to the presence of activated Ras or mutant B-Raf, or elevation of growth factor receptors. Sorafenib, which belongs chemically to a class that can be described as bis-aryl ureas, was selected for further pharmacologic characterization based on potent inhibition of Raf-1 and its favorable kinase selectivity profile. Further characterization showed that sorafenib suppresses both wild-type and V599E mutant B-Raf activity in vitro. In addition, sorafenib demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular-endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived growth factor (PDGFR)-beta Flt-3, and c-KIT. Preclinically, sorafenib showed broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models. A total of four phase I studies using oral sorafenib as a single agent have been completed, and the compound showed a favorable safety profile with mild to moderate diarrhea being the most common treatment-related adverse event. The maximum tolerated dose was 400 mg b.i.d. continuous. Single-agent phase II trials reported so far demonstrated antitumor activity of sorafenib in patients with hepatocellular carcinoma, sarcoma and renal cell cancer (RCC). Based on phase II results in RCC patients, a placebo-controlled phase III study was performed, which randomized a total of 905 patients, most of whom were treated previously. The partial response rate was 2% for sorafenib and 0% for placebo. Stable disease was observed in 78% and 55% of patients on sorafenib and placebo, respectively. Sorafenib significantly prolonged median progression-free survival (24 weeks) compared with placebo (12 weeks) in all subsets of patients evaluated. Approval of sorafenib by the U.S. Food and Drug Administration for this indication is pending. A first-line phase III study in RCC as well as phase III studies in hepatocellular carcinoma and metastatic melanoma have been initiated.
Time-resolved visualization of the heat flow in VO2∕Al2O3 films (2007)

The authors performed resistance switching of a VO2 film grown on the Al2O3 substrate by applying electric pulses. As a consequence, Joule heat of about 1W has been induced in a 15×50μm2 area between the two electrodes. Using synchrotron-based infrared microspectroscopy, the authors mapped the propagation of Joule heat around the electrodes with a micrometric spatial resolution and in a submicrosecond time scale. They found that the experimental observations are well described by the Fourier law of heat conduction demonstrating the possibility of local temperature control in a micrometric length scale.
Experimental assessment by high frequency ultrasound of articular cartilage thickness and osteoarthritic changes. (1995)

High frequency ultrasonic images obtained in vitro provide highly accurate and reproducible measurements of the thickness and subsurface characteristics of normal and OA articular cartilage.
Existence of Two γ Subunits of the G Proteins in Brain (1989)

Although amino acid sequences have been determined for the alpha and beta subunits of Gs, Gi, and Go, sequences have not been reported for the gamma subunits of these G proteins. In the present paper, we determined the sequences of peptides prepared by partial proteolysis of two different forms of the gamma subunit of Gs, Gi, and Go from bovine brain. Using oligonucleotide probes based on the sequences of two of these peptides, a cDNA clone was isolated from a bovine adrenal cDNA library. This clone contained a 0.9-kilobase cDNA insert that included an open reading frame of 213 bases encoding a 71-amino acid polypeptide with an estimated Mr of 7850. The amino acid sequence predicted for the adrenal cDNA clone was identical to that determined for one form of the gamma subunit from brain. In addition, an antibody to a peptide based on the predicted amino acid sequence of this cDNA clone reacted specifically with one of the brain gamma subunits, indicating the adrenal cDNA clone encodes a gamma subunit present in both adrenal gland and brain. Also, evidence is presented, demonstrating the existence of a second, structurally distinct, form of the gamma subunit of Gs, Gi, and Go in brain.
Article does not explain the origin of free-solution protein interaction signals (2016)

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans the biological, physical, and social sciences.
Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. (1994)

The pharmacological inhibition of excitatory amino acid neurotransmission has evolved to be a major topic in neuropharmacology since enhanced synaptic action of glutamate and possibly other related neurotransmitters has been suggested to play a role both in acute neurological conditions such as ischemia and epilepsy and in chronic degenerative neurological diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. While antagonists at N-methyl-D-aspartate (NMDA) type glutamate receptors include psychotomimetic and neurotoxic agents such as phencyclidine and MK-801, the aminoadamantanes represent a class of drugs which may be largely free of such actions and which have already been used clinically as antiviral and antiparkinsonian agents. Multiple in vitro studies have recently delineated the neuroprotective properties of amantadine, and of its more potent congener, memantine, which appear to mediate neuroprotection via inhibition of NMDA receptor-dependent glutamate activity. Thus, neuroprotection targeting glutamate receptors does apparently not have to be associated with prominent psychotogenicity, and the development and evaluation of new neuroprotective drugs will have to performed in consideration both of the relative safety and of the good clinical effect of the already known and established aminoadamantanes.