gebhart/patrepeval huggingface dataset:
Development of an in-vivo active reversible butyrylcholinesterase inhibitor (2016)

Alzheimer's disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.
Abstract 1463: Pharmacological impact of epithelial-mesenchymal plasticity in the H358 lung tumor model (2010)

Abstract The phenotypic changes associated with epithelial to mesenchymal transition (EMT) give tumor cells at least two attributes that increase metastatic efficiency. First, mesenchymal cells have lost cell-cell contacts and are more invasive and can therefore escape the primary tumor, whereas epithelial cells remain anchored by cell-cell contacts in the primary tumor. Second, mesenchymal cells in vitro are less sensitive than epithelial cells to agents that inhibit the EGFR pathway. This appears to translate into the clinic, since patients with tumors that express mesenchymal markers do not respond to EGFR targeting therapeutics as well as patients with more epithelial tumors. To determine whether we can control sensitivity to EGFR inhibitors by manipulating a cell's epithelial/mesenchymal status, we examined the role of EMT and its reversibility in tumor cell sensitivity to the EGFR inhibitor erlotinib. We studied in vitro models of EMT driven by Transforming Growth Factor β (TGFβ), Hepatocyte Growth Factor + Oncostatin M (HGF+OSM), Snail or Zeb1 in the H358 non-small cell lung carcinoma model. EMT driven by TGFβ or HGF+OSM caused a significant decrease in sensitivity to erlotinib, while EMT driven by induced expression of Snail or Zeb1 was much less effective, suggesting a change in drug sensitivity requires more input than these canonical EMT transcription factors. Once mesenchymal tumor cells have localized to a metastatic site, it is thought the tumor cells must undergo a mesenchymal to epithelial transition (MET) in order to form a cohesive tumor. We examined the reversibility of EMT in our models and the corresponding erlotinib sensitivity, both by withdrawal of ligand and by pharmacological inhibition of the signaling pathways downstream of the drivers. Using these approaches, we found EMT driven by HGF+OSM was reversible as evidenced by morphology and marker changes, and this reversion correlated with an increase in erlotinib sensitivity, comparable to the parental H358 cells. EMT driven by TGFβ was partially reversed by both ligand withdrawal and pharmacological inhibition of the receptor, and the extent of reversion in erlotinib sensitivity correlated with the extent of marker reversion. These results demonstrate that the extent of reversibility of EMT is dependent on the driver. Furthermore, it may be possible to drive some erlotinib-insensitive tumors back to a more erlotinib-sensitive state with pharmacological agents, thus improving patient response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1463.
<i>miR-192</i> Regulates Dihydrofolate Reductase and Cellular Proliferation through the p53-microRNA Circuit (2008)

These results indicate that miR-192 may be another miRNA candidate that is involved in the p53 tumor suppressor network with significant effect on cell cycle control and cell proliferation.
The mixel camera — Keystone-free hyperspectral images (2013)

The mixel camera provides keystone-free high spatial resolution hyperspectral images. The camera is based on a new principle for hyperspectral imaging, where a mathematical method is combined with a hardware component in order to restore the captured hyperspectral data to its keystone-free form. Simulations performed with a Virtual Camera software, that was specifically developed for this purpose, have shown that the mixel camera could significantly outperform the current generation of hyperspectral cameras. A prototype has been built and is currently being tested.
4-Hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine:  A Novel, Potent, and Selective NR1/2B NMDA Receptor Antagonist (1999)

A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)-4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC(50) = 0.63 microM). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for alpha(1)-adrenergic receptors and inhibition of neuronal K(+) channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a approximately 25-fold increase in NR1A/2B potency (IC(50) = 0.025 microM). p-Methyl substitution on the benzyl ring (10b) produced a approximately 3-fold increase in MES activity (ED(50) = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for alpha(1) receptors and reduction in inhibition of K(+) channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperid ine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation.
Functional genomics of Plasmodium falciparum through transposon-mediated mutagenesis (2006)

Plasmodium falciparum is the causative agent for the most lethal form of human malaria, killing millions annually. Genetic analyses of P. falciparum have been relatively limited due to the lack of robust techniques to manipulate this parasite. Development of transfection technologies and whole genome analyses have helped in understanding the complex biology of this parasite. Even with this wealth of information functional genomics approaches are still very limited in P. falciparum due to the cumbersome and inefficient methods of genetic manipulation. This review focuses on a recently developed, highly efficient method for transposon-based mutagenesis and transgene expression in P. falciparum that will allow functional genomics studies to be performed proficiently on this deadly malaria parasite. By using a piggyBac-based transposition system, multiple random integrations have been obtained into the genome of the parasite. This technique could hence be employed to set up several biological screens in this lethal protozoan parasite that may lead to identification of novel drug targets and vaccine candidates.
First‐in‐human study demonstrating the safety and clinical efficacy of novel anti‐IL‐17A monoclonal antibody CJM112 in moderate to severe plaque psoriasis (2020)

CJM112 had clinical efficacy in moderate to severe psoriasis and was generally safe and well tolerated in the doses tested. Additional neutralization of IL-17AF did not translate to increased clinical efficacy compared with secukinumab.
500 Gb/s and Beyond Photonic Integrated Circuit Module Transmitters and Receivers (2014)

Get PDF Email Share Share with Facebook Tweet This Post on reddit Share with LinkedIn Add to CiteULike Add to Mendeley Add to BibSonomy Get Citation Copy Citation Text F. Kish, M. Reffle, T. Butrie, M. Ziari, P. Evans, S. Corzine, H. Tsai, D. Pavinski, J. Zhang, J. Tang, A. Dentai, R. Muthiah, J. Pleumeekers, D. Lambert, M. Missey, V. Lal, M. Fisher, S. Murthy, R. Salvatore, S. Demars, A. James, J. Rahn, S. Kumar, M. Mitchell, J. Zhang, T. Liu, R. Nagarajan, M. Kato, and D. Welch, "500 Gb/s and Beyond Photonic Integrated Circuit Module Transmitters and Receivers," in Optical Fiber Communication Conference, OSA Technical Digest (online) (Optica Publishing Group, 2014), paper W3I.1. Export Citation BibTex Endnote (RIS) HTML Plain Text Citation alert Save article
Determination of optimal view angles for quantitative facial image analysis (2005)

In quantitative evaluation of facial skin chromophore content using color imaging, several factors such as view angle and facial curvature affect the accuracy of measured values. To determine the influence of view angle and facial curvature on the accuracy of quantitative image analysis, we acquire cross-polarized diffuse reflectance color images of a white-patched mannequin head model and human subjects while varying the angular position of the head with respect to the image acquisition system. With the mannequin head model, the coefficient of variance (CV) is determined to specify an optimal view angle resulting in a relatively uniform light distribution on the region of interest (ROI). Our results indicate that view angle and facial curvature influence the accuracy of the recorded color information and quantitative image analysis. Moreover, there exists an optimal view angle that minimizes the artifacts in color determination resulting from facial curvature. In a specific ROI, the CV is less in smaller regions than in larger regions, and in relatively flat regions. In clinical application, our results suggest that view angle affects the quantitative assessment of port wine stain (PWS) skin erythema, emphasizing the importance of using the optimal view angle to minimize artifacts caused by nonuniform light distribution on the ROI. From these results, we propose that optimal view angles can be identified using the mannequin head model to image specific regions of interest on the face of human subjects.
Enhanced cellulose degradation by targeted integration of a cohesin-fused β-glucosidase into the <i>Clostridium thermocellum</i> cellulosome (2012)

The conversion of recalcitrant plant-derived cellulosic biomass into biofuels is dependent on highly efficient cellulase systems that produce near-quantitative levels of soluble saccharides. Similar to other fungal and bacterial cellulase systems, the multienzyme cellulosome system of the anaerobic, cellulolytic bacterium Clostridium thermocellum is strongly inhibited by the major end product cellobiose. Cellobiose-induced inhibition can be relieved via its cleavage to noninhibitory glucose by the addition of exogenous noncellulosomal enzyme β-glucosidase; however, because the cellulosome is adsorbed to the insoluble substrate only a fraction of β-glucosidase would be available to the cellulosome. Towards this end, we designed a chimeric cohesin-fused β-glucosidase (BglA-CohII) that binds directly to the cellulosome through an unoccupied dockerin module of its major scaffoldin subunit. The β-glucosidase activity is thus focused at the immediate site of cellobiose production by the cellulosomal enzymes. BglA-CohII was shown to retain cellobiase activity and was readily incorporated into the native cellulosome complex. Surprisingly, it was found that the native C. thermocellum cellulosome exists as a homooligomer and the high-affinity interaction of BglA-CohII with the scaffoldin moiety appears to dissociate the oligomeric state of the cellulosome. Complexation of the cellulosome and BglA-CohII resulted in higher overall degradation of microcrystalline cellulose and pretreated switchgrass compared to the native cellulosome alone or in combination with wild-type BglA in solution. These results demonstrate the effect of enzyme targeting and its potential for enhanced degradation of cellulosic biomass.
Determinants of Glycan Receptor Specificity of H2N2 Influenza A Virus Hemagglutinin (2010)

The H2N2 subtype of influenza A virus was responsible for the Asian pandemic of 1957-58. However, unlike other subtypes that have caused pandemics such as H1N1 and H3N2, which continue to circulate among humans, H2N2 stopped circulating in the human population in 1968. Strains of H2 subtype still continue to circulate in birds and occasionally pigs and could be reintroduced into the human population through antigenic drift or shift. Such an event is a potential global health concern because of the waning population immunity to H2 hemagglutinin (HA). The first step in such a cross-species transmission and human adaptation of influenza A virus is the ability for its surface glycoprotein HA to bind to glycan receptors expressed in the human upper respiratory epithelia. Recent structural and biochemical studies have focused on understanding the glycan receptor binding specificity of the 1957-58 pandemic H2N2 HA. However, there has been considerable HA sequence divergence in the recent avian-adapted H2 strains from the pandemic H2N2 strain. Using a combination of structural modeling, quantitative glycan binding and human respiratory tissue binding methods, we systematically identify mutations in the HA from a recent avian-adapted H2N2 strain (A/Chicken/PA/2004) that make its quantitative glycan receptor binding affinity (defined using an apparent binding constant) comparable to that of a prototypic pandemic H2N2 (A/Albany/6/58) HA.
InGaN/GaN dot-in-nanowire monolithic LEDs and lasers on (001) silicon (2017)

GaN-based nanowire arrays have been grown on (001)Si substrate by plasma-assisted molecular beam epitaxy and their structural and optical properties have been determined. In<sub>x</sub>Ga<sub>1-x</sub>N disks inserted in the nanowires behave as quantum dots with emission ranging from visible to near-infrared. We have exploited these nanowire heterostructure arrays to realize light-emitting diodes and diode lasers in which the quantum dots form the active light emitting media. The fabrication and characteristics of 630nm light-emitting diodes and 1.3μm edge-emitting diode lasers are described.
Statistical device models from worst case files and electrical test data (1999)

Two statistical metal oxide semiconductors (MOS) models are described, one based on worst case files and the other on electrical test data. The former is appropriate for predicting the variability of a process early in its life cycle, while the latter would better track a maturing process. The key statistical tool that is used to develop the models is principal component analysis (PCA), which is used in novel ways in order to derive statistical models from readily available information. The models are used to perform statistical circuit simulation in order to quantitatively predict the impact of manufacturing variations on circuit performance metrics. Due to the use of linear response surface modeling and latin hypercube sampling, the simulation cost of using the models is about the same as with worst case simulation. The modeling technique is general and is applicable to other semiconductor devices besides MOS devices which are considered in this paper.
Enhanced growth of high quality single crystal diamond by microwave plasma assisted chemical vapor deposition at high gas pressures (2009)

Single crystals of diamond up to 18 mm in thickness have been grown by microwave plasma assisted chemical vapor deposition at gas pressures of up to 350 torr. Growth rates of up to 165 μm/h at 300 torr at high power density have been achieved. The processes were evaluated by optical emission spectroscopy. The high-quality single-crystal diamond grown at optimized conditions was characterized by UV-visible absorption and photoluminescence spectroscopy. The measurements reveal a direct relationship between residual absorption and nitrogen content in the gas chemistry. Fabrication of high quality single-crystal diamond at higher growth rates should be possible with improved reactor design that allows still higher gas synthesis pressures.
Primary structure of human deoxycytidylate deaminase and overexpression of its functional protein in Escherichia coli (1993)

The cDNA encoding human dCMP deaminase was isolated from a lambda ZAPII expression library using an antibody generated against highly purified HeLa cell dCMP deaminase. The cloned cDNA consists of 1856 base pairs and encodes a protein of 178 amino acids with a calculated molecular mass of 19,985 daltons. The sequence of several cyanogen bromide-cleaved peptides derived from HeLa cell dCMP deaminase are all contained within the deduced amino acid sequence. A zinc binding region is present in the enzyme, similar to that reported for cytidine deaminase (Yang, E. C., Carlow, D., Wolfenden, R., and Short, S. A. (1992) Biochemistry 31, 4168-4174). Northern blot analysis revealed a predominant messenger RNA species of 1.9 kilobases. Expression of the active protein to about 10% of Escherichia coli's total protein was achieved by subcloning the open reading frame into a high expression system using the polymerase chain reaction. Polyacrylamide gel electrophoresis revealed a prominent protein band which comigrated with affinity purified HeLa dCMP deaminase, while Western blot analysis yielded an immunoreactive band which comigrated with the single immunoreactive affinity column purified dCMP deaminase band. The enzyme which possesses a kcat of 1.02 x 10(3) s-1 was purified to homogeneity in over 60% yield. The overexpression of dCMP deaminase should permit more exacting studies on the regulation of this important allosteric enzyme which provides substrate for DNA synthesis.
High-power and high-gain organic dye-doped polymer optical fiber amplifiers: novel techniques for preparation and spectral investigation (1997)

Rhodamine B (RB), Rhodamine 6G (R6G), Oxazine 4 perchlorate (O4PC), and 4-Dicyanomethylene-2-methyl-6-(p-dimethylaminostyryl-4H-pyran)-doped graded-index (GI) polymer optical fiber amplifiers (POFA's) were successfully prepared by novel techniques to prevent degradation of organic dyes and to enhance solubility of the dyes in methyl methacrylate and in poly(methyl methacrylate) (PMMA). High-power (620 W) and high-gain (33-dB, 2070 times) amplification was achieved for RB-doped GI POFA's based on the spectral investigation of dyes in PMMA bulk. It should be noted that amplification in the low-loss region of polymer optical fibers was achieved in the R6G- and O4PC-doped GI POFA.
A Recombinant Newcastle Disease Virus with Low-Level V Protein Expression Is Immunogenic and Lacks Pathogenicity for Chicken Embryos (2001)

Newcastle disease virus (NDV) edits its P-gene mRNA by inserting a nontemplated G residue(s) at a conserved editing site (3'-UUUUUCCC-template strand). In the wild-type virus, three amino-coterminal P-gene-derived proteins, P, V, and W, are produced at frequencies of approximately 68, 29, and 2%, respectively. By applying the reverse genetics technique, editing-defective mutants were generated in cell culture. Compared to the wild-type virus, mutants lacking either six nucleotides of the conserved editing site or the unique C-terminal part of the V protein produced as much as 5, 000-fold fewer infectious progeny in vitro or 200,000-fold fewer in 6-day-old embryonated chicken eggs. In addition, both mutants were unable to propagate in 9- to 11-day-old embryonated specific-pathogen-free (SPF) chicken eggs. In contrast, a mutant (NDV-P1) with one nucleotide substitution (UUCUUCCC) grew in eggs, albeit with a 100-fold-lower infectious titer than the parent virus. The modification in the first two mutants described above led to complete abolition of V expression, whereas in NDV-P1 the editing frequency was reduced to less than 2%, and as a result, V was expressed at a 20-fold-lower level. NDV-P1 showed markedly attenuated pathogenicity for SPF chicken embryos, unlike currently available ND vaccine strains. These findings indicate that the V protein of NDV has a dual function, playing a direct role in virus replication as well as serving as a virulence factor. Administration of NDV-P1 to 18-day-old embryonated chicken eggs hardly affected hatchability. Hatched chickens developed high levels of NDV-specific antibodies and were fully protected against lethal challenge, demonstrating the potential use of editing-defective recombinant NDV as a safe embryo vaccine.
Solving concisely expressed combinatorial auction problems (2002)

Combinatorial auctions provide a valuable mechanism for the allocation of goods in settings where buyer valuations exhibit complex structure with respect to substitutability and complementarity. Most algorithms are designed to work with explicit bids for concrete bundles of goods. However, logical bidding languages allow the expression of complex utility functions in a natural and concise way, and have recently attracted considerable attention. Despite the power of logical languages, no current winner determination algorithms exploit the specific structure of logically specified bids to solve problems more effectively. In this paper, we describe techniques to do just this. Specifically, we propose a direct integer program (IP) formulation of the winner determination problem for bids in the LGB logical language. This formulation is linear in the size of the problem and can be solved effectively using standard optimization packages. We compare this formulation and its solution time to those of the corresponding set of flat bids, demonstrating the immense utility of exploiting the structure of logically expressed bids. We also consider an extension of LGB and show that these can also be solved using linear constraints.
Molecular Design of Luminescent Gold(III) Emitters as Thermally Evaporable and Solution-Processable Organic Light-Emitting Device (OLED) Materials (2021)

The advancement of high-efficiency luminescent and thermally stable organometallic complexes has offered opportunities for the commercialization of metal phosphors for fabricating organic light-emitting devices (OLEDs). Since the first report on the potential use of iridium(III) and platinum(II) complexes for applications in OLEDs in the late 1990s, extensive efforts have been made by researchers on the development of various heavy metal-containing compounds with rich photophysical and luminescence properties and the engineering of device architectures to improve device efficiencies. Apart from the more well-studied iridium(III) and platinum(II) complexes, complexes of gold(III) recently have demonstrated their capabilities to serve as phosphorescent or thermally stimulated delayed phosphorescent or thermally activated delayed fluorescent emitters, and their promising performances in OLEDs have attracted growing interest in the past decade. Nowadays, complexes of gold(III) with emission energies ranging from sky-blue to near-infrared with high electroluminescence performances have been obtained. In addition, high-efficiency vacuum-deposited and solution-processed OLEDs with benchmark efficiencies comparable to those of the iridium(III) and platinum(II) complexes have been realized. This Focus Review summarizes the development of various series of luminescent gold(III) complexes to date and highlights important milestones in the development and advancement of gold(III)-based OLEDs. Focus will be made on the molecular design strategies for gold(III) emitters for application as dopants in OLEDs, including those fabricated by vacuum-deposition and solution-processing techniques.