gebhart/patrepeval huggingface dataset:
5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-Based Potent and Selective CCK1 Receptor Antagonists:  Structural Modifications at the Tryptophan Domain (1999)

Analogues of the previously reported potent and highly selective CCK(1) receptor antagonist (4aS, 5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido-[1, 2-c]pyrimidine (2a) were prepared to explore the structural requirements at the Boc-tryptophan domain for CCK(1) receptor affinity. Structural modifications of 2a involved the Trp side chain, its conformational freedom, the Boc group, and the carboxamide bond. Results of the CCK binding and in vitro functional activity evaluation showed three highly strict structural requirements: the type and orientation of the Trp side chain, the H-bonding acceptor carbonyl group of the carboxamide bond, and the presence of the Trp amino protection Boc. Replacement of this acid-labile group with 3, 3-dimethylbutyryl or tert-butylaminocarbonyl conferred acid stability to analogues 14a and 15a, which retained a high potency and selectivity in binding to CCK(1) receptors, as well as an in vivo antagonist activity against the acute pancreatitis induced by caerulein in rats. Oral administration of compounds 14a and 15a also produced a lasting antagonism to the hypomotility induced by CCK-8 in mice, suggesting a good bioavailability and metabolic stability.
Cognitive performance effects following a single dose of the M1 muscarinic positive allosteric modulator VU319 (2020)

Abstract Background VU319 is an investigational positive allosteric modulator of the M 1 muscarinic acetylcholine receptor developed for cognitive enhancement in Alzheimer’s disease (AD) and other disorders. Cognitive tasks including test of attention, speed, and memory and event‐related potentials (ERPs) were used during the double‐blind, placebo controlled Single Ascending Dose (SAD) study of VU319. The main pharmacodynamic objectives of the SAD were to identify early markers of functional engagement. Following the ascending dose cohorts, a Food Effect substudy was conducted to assess whether there was any change in the cognitive performance if VU319 was dosed with food compared to in a fasted state. Method VU319 was given orally to 52 healthy volunteers aged 18‐55 years. The SAD study tested 40 participants in five dose escalating cohorts (60‐600 mg), in which 6 received VU319 and 2 received placebo. The Food Effect substudy consisted of 12 participants, in which ten received oral VU319 and two received placebo. Cognitive and electrophysiological tasks testing attention, memory and psychomotor speed were examined pre‐dosing and at 5 hours post‐dose. The tasks were selected for their sensitivity to cholinergic tone. Result Single dose treatment showed improvements in cognitive and ERP performance on the higher doses of VU319 compared to placebo. Participants responded significantly faster to targets on the continuous performance test after 600 mg compared to placebo (p = 0.03, effect size d = 1.2). On the incidental memory task, participants who received 400 and 600 mg VU319 exhibited larger P300 amplitudes compared to placebo, when present with repeated compared to novel images (d &gt; 0.8). Examination of the relationship between plasma levels of VU319 and cognitive performance showed that response time of psychomotor speed measures improved with increasing blood concentration of VU319 across doses (r&gt;0.38). Conclusion We conclude that these results demonstrate likely enhancement of the cholinergic system functioning in healthy adults following a single oral dose of VU319. These results provide an indication of the potential measures that are sensitive to cognitive activity by M 1 allosteric modulators and provide a framework to examine the cognitive impact of multiple doses of VU319 in AD patients.
Quantitative Data-Independent Acquisition Glycoproteomics of Sparkling Wine (2020)

Sparkling wine is an alcoholic beverage enjoyed around the world. The sensory properties of sparkling wine depend on a complex interplay between the chemical and biochemical components in the final product. Glycoproteins have been linked to positive and negative qualities in sparkling wine, but the glycosylation profiles of sparkling wine have not been previously investigated in detail. We analyzed the glycoproteome of sparkling wines using protein- and glycopeptide-centric approaches. We developed an automated workflow that created ion libraries to analyze sequential window acquisition of all theoretical mass spectra data-independent acquisition mass spectrometry data based on glycopeptides identified by Byonic (Protein Metrics; version 2.13.17). We applied our workflow to three pairs of experimental sparkling wines to assess the effects of aging on lees and of different yeast strains used in the liqueur de tirage for secondary fermentation. We found that aging a cuvée on lees for 24 months compared with 8 months led to a dramatic decrease in overall protein abundance and an enrichment in large glycans at specific sites in some proteins. Secondary fermentation of a Riesling wine with Saccharomyces cerevisiae yeast strain Siha4 produced more yeast proteins and glycoproteins than with S. cerevisiae yeast strain DV10. The abundance and glycosylation profiles of grape glycoproteins were also different between grape varieties. To our knowledge, this work represents the first in-depth study into protein- and peptide-specific glycosylation in sparkling wines and describes a quantitative glycoproteomic sequential window acquisition of all theoretical mass spectra/data-independent acquisition workflow that is broadly applicable to other sample types.
Heterogeneous catalysis by ultra-small bimetallic nanoparticles surpassing homogeneous catalysis for carbon–carbon bond forming reactions (2020)

Palladium catalyzed cross-coupling reactions represent a significant advancement in contemporary organic synthesis as these reactions are of strategic importance in the area of pharmaceutical drug discovery and development. Supported palladium-based catalysts are highly sought-after in carbon-carbon bond forming catalytic processes to ensure catalyst recovery and reuse while preventing product contamination. This paper reports the development of heterogeneous Pd-based bimetallic catalysts supported on fumed silica that have high activity and selectivity matching those of homogeneous catalysts, eliminating the catalyst's leaching and sintering and allowing efficient recycling of the catalysts. Palladium and base metal (Cu, Ni or Co) contents of less than 1.0 wt% loading are deposited on a mesoporous fumed silica support (surface area SABET = 350 m2 g-1) using strong electrostatic adsorption (SEA) yielding homogeneously alloyed nanoparticles with an average size of 1.3 nm. All bimetallic catalysts were found to be highly active toward Suzuki cross-coupling (SCC) reactions with superior activity and stability for the CuPd/SiO2 catalyst. A low CuPd/SiO2 loading (Pd: 0.3 mol%) completes the conversion of bromobenzene and phenylboronic acid to biphenyl in 30 minutes under ambient conditions in water/ethanol solvent. In contrast, monometallic Pd/SiO2 (Pd: 0.3 mol%) completes the same reaction in three hours under the same conditions. The combination of Pd with the base metals helps in retaining the Pd0 status by charge donation from the base metals to Pd, thus lowering the activation energy of the aryl halide oxidative addition step. Along with its exceptional activity, CuPd/SiO2 exhibits excellent recycling performance with a turnover frequency (TOF) of 280 000 h-1 under microwave reaction conditions at 60 °C. Our study demonstrates that SEA is an excellent synthetic strategy for depositing ultra-small Pd-based bimetallic nanoparticles on porous silica for SCC. This avenue not only provides highly active and sintering-resistant catalysts but also significantly lowers Pd contents in the catalysts without compromising catalytic activity, making the catalysts very practical for large-scale applications.
Solder parameter sensitivity for CSP life-time prediction using simulation-based optimization method (2002)

Finite element modelling is widely used for estimating the solder joint reliability of electronic packages. However, the solder properties are strong process and geometry dependent. Even for the same type of solder, measurements conducted by different people at different locations show different results, due to differences in application conditions, benching etc. Those differences may lead to difference in constitutive equations and/or the parameter values. Therefore the effect of the solder parameter variation and parameter sensitivity should be taken into account before a reliable solder fatigue prediction can be made. In this research, simulation-based optimisation method is used to investigate the sensitivity of the chosen solder parameters for the solder fatigue prediction using inelastic strain criterion.
OP22SIMULTANEOUS INTRA-CAVITY DELIVERY OF MULTIPLE CHEMOTHERAPEUTICS FROM A MOULDABLE NEUROSURGICALLY-APPLIED POLYMER PASTE (2015)

INTRODUCTION: A thermo-setting biomaterial containing a depot of clinically relevant chemotherapeutics applied to the post-surgical resection cavity offers an opportunity for localised control of residual malignant glioma. Here we evaluate mouldable polymer matrices of poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) microparticles for tailored combination drug release. METHOD: Clinically-approved or experimental chemotherapeutics, alone and in combination, were loaded onto PLGA/PEG microparticle matrices, or encapsulated inside PLGA microspheres. Mono- and dual-therapy release rates were measured by liquid chromatography and stability verified by mass spectrometry. Cytotoxicity of released drugs was assessed using patient-derived invasive margin cells and flank mouse xenografts. RESULTS: Temozolomide (TMZ), etoposide (ETO) and methotrexate were released from PLGA/PEG alone or in dual combinations over 2 weeks in vitro, whilst irinotecan, cilengitide and imatinib released over a similar period as monotherapies. Cytotoxicity was not impaired by polymer interaction. Drug encapsulation in PLGA microspheres dampens the rapid burst release. PLGA/PEG overcomes TMZ instability, resulting in a 10-day release where the AIC active component was measured. In vivo ETO release markedly reduced glioma bioluminescence with longer-term survivors relative to resection-only controls. CONCLUSION: We have developed a PLGA-based platform technology to deliver multiple clinically relevant chemotherapy agents, including TMZ, from a single matrix. Prolonged release kinetics can be achieved by drug encapsulating drugs, potentially filling the 3 week therapy gap that currently exists between surgery and radiotherapy commencement.
Correction of LAMP3-associated salivary gland hypofunction by aquaporin gene therapy (2022)

Sjögren's disease (SjD) is a chronic autoimmune sialadenitis resulting in salivary gland hypofunction with dry mouth symptom. Previous studies showed that lysosome-associated membrane protein 3 (LAMP3) overexpression is involved in the development of salivary gland hypofunction associated with SjD. However, the molecular mechanisms are still unclear, and no effective treatment exists to reverse gland function in SjD. Analysis on salivary gland samples from SjD patients showed that salivary gland hypofunction was associated with decreased expression of sodium-potassium-chloride cotransporter-1 (NKCC1) and aquaporin 5 (AQP5), which are membrane proteins involved in salivation. Further studies revealed that LAMP3 overexpression decreased their expression levels by promoting endolysosomal degradation. Additionally, we found that LAMP3 overexpression enhanced gene transfer by increasing internalization of adeno-associated virus serotype 2 (AAV2) via the promoted endolysosomal pathway. Retrograde cannulation of AAV2 vectors encoding AQP1 gene (AAV2-AQP1) into salivary glands induced glandular AQP1 expression sufficient to restore salivary flow in LAMP3-overexpressing mice. LAMP3 could play a critical role in the development of salivary gland hypofunction in SjD by promoting endolysosomal degradation of NKCC1 and AQP5. But it also could enhance AAV2-mediated gene transfer to restore fluid movement through induction of AQP1 expression. These findings suggested that AAV2-AQP1 gene therapy is useful in reversing salivary gland function in SjD patients.
(Invited) Sustainability, Safety, Scalability, Rechargeability, and Manufacturability Courtesy of Architected Zinc Anodes (2022)

Towards the goal of decarbonizing electrification, concerns remain over the sustainability of the requisite Li and Co, as well as the stringent transportation limits on the amount and operational state of Li allowed in airfreight. Rechargeable zinc-based batteries using aqueous electrolyte offer a compelling alternative to lithium-based batteries with the added benefit of a two-electron anode that augments the energy density, helping to compensate for lower cell voltage inherent to aqueous electrolytes. To solve the standing caveat with rechargeable zinc-based batteries — that they form separator-piercing dendrites — we built on our understanding of the importance of 3D co-continuous wiring of electrons, ion, and molecules in energy-storing nanoarchitectures. Sponge form factors fabricated by fusing ~50 µm zinc particles into a monolithic pore–solid architecture physically prevents formation of dendrites even at high charging current density [1,2]. Throughout the story of the NRL Zn sponge anode, each successive generation of the electrode has been fabricated with manufacturability as a foremost consideration, such that the current sponge formulation (Gen 5) is processed quickly, at scale, to sizes necessary for decarbonizing electrification. I will present the performance of these “big and strong” zinc sponges versus a variety of cathodes and the potential paths forward for the development and transition of this safer energy-storage technology. [1] J.F. Parker, C.N. Chervin, E.S. Nelson, D.R. Rolison, J.W. Long, “Wiring zinc in three dimensions re-writes battery performance―Dendrite-free cycling.” Energy Environ. Sci. , 7 , 1117–1124 (2014). [2] J.F. Parker, C.N. Chervin, I.R. Pala, M. Machler, M.F. Burz, J.W. Long, and D.R. Rolison, “Rechargeable nickel–3D zinc batteries: An energy-dense, safer alternative to lithium-ion.” Science , 356 , 415–418 (2017).
Synthetic peptides representing sequences within gp41 of HIV as immunogens for murine T- and B-cell responses (1995)

Within the gp41 glycoprotein of the human immunodeficiency virus type 1 (HIV-1) there is a relatively conserved region which appears accessible to the immune system during the course of HIV infection and is recognised by antibody from virtually all patients with AIDS. This region has also been shown to function as a target for human T cells. We have examined synthetic peptides spanning this sequence, between residues 572 and 604, with a view to evaluating their potential as immunogens. Peptides 572GIKQLQARILAVERYLKDQQ591 and 579RILAVERYLKDQQLLGGIWGCSGK601 were good immunogens in two different strains of mice while peptide 576LQARILAVERYLKDQQ591 was an inferior immunogen, and peptide 593LGIWGCSGKLIC604 was non-immunogenic unless coupled to a carrier protein. For both antibody and T cell responses it was apparent that sequences that could function as determinants within one peptide could not do so in the context of a different peptide immunogen. It follows that by judicious choice of immunogen sequence it may be possible to direct the immune response towards a desired fine specificity. Unwanted responses by CD4+ T cells isolated from certain peptide-primed animals were also observed. These T cells showed an unusual reactivity in that they were incapable of recognising their determinant AVERYLKDQQ if it was extended at the C-terminal end with the native sequence and as such would not be expected to recognise the native molecule unless processing created the identical C-terminus.
1129: The Expression and Role of Foxatranscription Factor Proteins in Prostate Cancer Progression (2007)

You have accessJournal of UrologyModerated Poster 33, Monday, May 21, 2007, 3:30 - 5:30 pm1 Apr 20071129: The Expression and Role of Foxatranscription Factor Proteins in Prostate Cancer Progression Janni Mirosevich, Nan Gao, Aparna Gupta, Przemyslaw W. Twardowski, Timothy G. Wilson, Scott B. Shappell, Richard Jove, and Robert J. Matusik Janni MirosevichJanni Mirosevich More articles by this author , Nan GaoNan Gao More articles by this author , Aparna GuptaAparna Gupta More articles by this author , Przemyslaw W. TwardowskiPrzemyslaw W. Twardowski More articles by this author , Timothy G. WilsonTimothy G. Wilson More articles by this author , Scott B. ShappellScott B. Shappell More articles by this author , Richard JoveRichard Jove More articles by this author , and Robert J. MatusikRobert J. Matusik More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)31343-0AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "1129: The Expression and Role of Foxatranscription Factor Proteins in Prostate Cancer Progression." The Journal of Urology, 177(4S), pp. 372–373 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 177Issue 4SApril 2007Page: 372-373 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Janni Mirosevich More articles by this author Nan Gao More articles by this author Aparna Gupta More articles by this author Przemyslaw W. Twardowski More articles by this author Timothy G. Wilson More articles by this author Scott B. Shappell More articles by this author Richard Jove More articles by this author Robert J. Matusik More articles by this author Expand All Advertisement PDF downloadLoading ...
Continuously tunable RF-MEMS varactor for high power applications (2008)

A high power continuously tunable RF-MEMS capacitor (varactor) for frequencies from DC−4.0 GHz is presented. The device is specified for 0.8–1.6 pF analog tuning range and provides a Q factor of ≫100 for frequencies below 2.0 GHz. Using silicon bulk technology and wafer bonding techniques, RF and electrostatic actuation electrodes are arranged vertically. It enables controlled counteracting the attractive electrostatic forces generated by high RF signal amplitudes (self actuation). Using a time domain reflectometer based measurement setup and a resonating test circuit, stability against CW signals of up to 55 V rms has been shown. Due to the highly damped mechanical response, the capacitance setup is intrinsically insensitive to RF bursts (tp=20 μs) of more than 120 V rms.
Carotenoid Isomerase Is Key Determinant of Petal Color of Calendula officinalis (2011)

Orange petals of calendula (Calendula officinalis) accumulate red carotenoids with the cis-configuration at the C-5 or C-5' position (5-cis-carotenoids). We speculated that the orange-flowered calendula is a carotenoid isomerase (crtiso) loss-of-function mutant that impairs the cis-to-trans conversion of 5-cis-carotenoids. We compared the sequences and enzyme activities of CRTISO from orange- and yellow-flowered calendulas. Four types of CRTISO were expressed in calendula petals. The deduced amino acid sequence of one of these genes (CoCRTISO1) was different between orange- and yellow-flowered calendulas, whereas the sequences of the other three CRTISOs were identical between these plants. Analysis of the enzymatic activities of the CoCRTISO homologs showed that CoCRTISO1-Y, which was expressed in yellow petals, converted carotenoids from the cis-to-trans-configuration, whereas both CoCRTISO1-ORa and 1-ORb, which were expressed in orange petals, showed no activity with any of the cis-carotenoids we tested. Moreover, the CoCRTISO1 genotypes of the F2 progeny obtained by crossing orange and yellow lines linked closely to petal color. These data indicate that CoCRTISO1 is a key regulator of the accumulation of 5-cis-carotenoids in calendula petals. Site-directed mutagenesis showed that the deletion of Cys-His-His at positions 462-464 in CoCRTISO1-ORa and a Gly-to-Glu amino acid substitution at position 450 in CoCRTISO1-ORb abolished enzyme activity completely, indicating that these amino acid residues are important for the enzymatic activity of CRTISO.
Biosynthesis of heterogeneous forms of multidrug resistance-associated glycoproteins. (1987)

Multidrug-resistant J774.2 mouse macrophage-like cells, selected for resistance to colchicine, vinblastine, or taxol, overexpress antigenically related glycoproteins with distinct electrophoretic mobilities. These plasma membrane glycoproteins are likely to play a pivotal role in the expression of the multidrug resistance phenotype. To determine how these multidrug resistance-associated glycoproteins differ, the biosynthesis and N-linked carbohydrate composition of these proteins were examined and compared. Vinblastineor colchicine-selected cells made a 125-kDa precursor that was rapidly processed (t1/2 approximately equal to 20 min) to mature forms of 135 and 140 kDa, respectively. Heterogeneity between the 135- and 140-kDa forms of the molecule can be attributed to N-linked carbohydrate. In contrast, taxol-selected cells made two precursors, 125 and 120 kDa, which appeared within 5 and 15 min after the onset of pulse labeling, respectively. They were processed to mature forms of 140 and 130 kDa. Since a single deglycosylated precursor or mature form was not observed after enzymatic removal of N-linked oligosaccharides, other differences, besides N-linked glycosylation, which occur in early processing compartments, are likely to account for the two multidrug resistance-associated glycoproteins in taxol-selected cells. These results demonstrate that a family of multidrug resistance-associated glycoproteins can be differentially expressed.
Multifunctional ORMOSIL and PAA nanoparticles (2009)

Various problems arising during molecular imaging of different fluoroprobes and metabolites used in PDT can be circumvented by focusing on multifunctional therapy agents. Thus an effective photo sensitizer coupled with other useful roles to play in PDT treatment make nanoparticles as a good vehicle for different delivery assuming multifunctional roles not only in PDT but also as therapeutic agents for targeted delivery. A new approach is the involving use of 100 nm NPs as photo sensitizers and/or imaging agents. In our Lab., we employ two such NPs and are ORMOSIL (organically Modified Silica) and PAA (Polyacrylamide) which are found to be biologically very safe without disturbing the therapeutic value. The size of the nanoparticles determined by TEM and Dynamic Light Scattering are ~30 nm. These NPs are taken up in conjunction with cyanine dye at near infra red as it has been reported in literature that encapsulated NPs shows very low singlet oxygen production compared with the post-loaded NPs though the reasons are not yet clear. Therefore, we investigated the idea of post-loading or adsorbing vis-a-vis encapsulation.
Trustworthy pervasive computing: the hard security problems (2004)

We examine five security problems that are barriers to mainstream pervasive computing. These are: device authentication, privacy, trust management, device assurance, recourse, and availability. We argue that the trust, security, and privacy issues inherent in pervasive computing environments present unique challenges that require a fundamental reexamination of how to build large-scale, trustworthy, distributed systems.
Performance Impact of Signal Reflections in a Single–Fiber Bidirectional System (2021)

Single–fiber bidirectional transmission systems using the same wavelength for both directions suffer from reflection induced interference. Experimental results demonstrate the dependence of system performance and of the threshold of the forward error correction (FEC) on signal waveform variations induced by fiber effects. Larger signal distortions lead to slightly larger impact of the interference, but reduce the shift of the FEC threshold to smaller bit error ratios.