gebhart/patrepeval huggingface dataset:
Diazepam binding inhibitor is a paracrine/autocrine regulator of Leydig cell proliferation and steroidogenesis: action via peripheral-type benzodiazepine receptor and independent mechanisms. (1993)

Previous studies demonstrated that the polypeptide diazepam binding inhibitor (DBI) and its receptor, the peripheral-type benzodiazepine receptor (PBR), are involved in the regulation of steroid biosynthesis and that one site of PBR action resides in mitochondria. In the present investigation, evidence is presented that a functional form of PBR is also present at the cell surface. First, PBR was immunolocalized in the rat testis using biotin-streptavidin peroxidase immunocytochemistry, and results revealed that PBR was present exclusively in the interstitial Leydig cells. Next, the distribution of PBR in MA-10 Leydig cells was further examined using confocal microscopy. MA-10 cells were either fixed and immunostained or fixed/permeabilized and immunostained for PBR, followed by generation of confocal microscope optical sections, three-dimensional reconstructions of these sections, and then generation of vertical confocal sections of the three-dimensional reconstruction. In the fixed/unpermeabilized cells, PBR immunostaining at the cell surface was clearly evident, whereas in the fixed/permeabilized cells, intracellular PBR distribution was more robust. These results suggest that the plasma membrane fraction of the receptor could mediate the action of extracellular PBR ligands on Leydig cell function. Next, we examined whether DBI, the naturally occurring PBR ligand, is secreted by testicular cells and whether it could activate the cell surface PBR. Immunolocalization of DBI demonstrated that it was present in both Leydig and Sertoli cells. Further, using an immunoblot assay, we demonstrated that DBI is present in rat testicular interstitial fluid. Metabolic labeling of cultured immature rat Sertoli cells and MA-10 mouse tumor Leydig cells, followed by immunoprecipitation of the secreted proteins with an anti-DBI antiserum, demonstrated that both Leydig and Sertoli cells secrete DBI and could serve as a cell source for the interstitial fluid DBI. Then, we partially purified the DBI present in conditioned medium and interstitial fluid by reverse phase chromatography and demonstrated it to be bioactive, based on displacement of a radiolabeled benzodiazepine (Ro5-4864)-specific ligand for PBR; pronase treatment of different preparations eliminated all bioactivity. We then examined the effects of DBI on Leydig cell function. DBI added to MA-10 cells affected DNA synthesis and cell growth in a biphasic manner; at low concentrations (1 nM), DBI was mitogenic, increasing [3H]thymidine incorporation and cell numbers by 30-40%, while at high concentrations (1 microM), DBI inhibited cell growth (30-40%). Similar effects on cell growth were obtained using the benzodiazepine Ro5-4864.
Single‐Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N‐acetylgalactosamine–Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects (2020)

Vutrisiran (ALN-TTRsc02) is a liver-directed, investigational, small interfering ribonucleic acid drug for the treatment of transthyretin (TTR)-mediated amyloidosis. This phase I, randomized, single-blind, placebo-controlled, single ascending dose study evaluated the pharmacodynamics, pharmacokinetics, and safety profile of subcutaneously administered vutrisiran (5-300 mg) in healthy subjects (n = 80). Vutrisiran treatment achieved potent and sustained TTR reduction in a dose-dependent manner, with mean maximum TTR reduction of 57-97%, maintained for ≥ 90 days post dose. Vutrisiran was rapidly absorbed (peak plasma concentration 3-5 hours post dose), had a short plasma half-life (4.2-7.5 hours), and plasma concentrations increased in a dose-proportional manner. Pharmacodynamic and pharmacokinetic results were similar in Japanese and non-Japanese subjects. Vutrisiran had an acceptable safety profile; the most common treatment-related adverse event was mild, transient injection site reactions in four (6.7%) vutrisiran-treated subjects. The favorable pharmacokinetic, pharmacodynamic, and safety results observed here support vutrisiran's continued clinical development.
Characterization of urokinase receptor expression by human placental trophoblasts (1992)

The processes of implantation and placentation are both dependent on the invasion and remodeling of the uterine endometrium and vasculature by trophoblasts. Because the secretion and autocrine binding of urokinase (uPA) appears to be a common mechanism used by cells to facilitate plasmin-dependent tissue invasion, we measured the production of uPA and expression of uPA receptors by trophoblasts. Prourokinase bound specifically, reversibly, and with high affinity to cultured trophoblasts, via the uPA epidermal growth factor-like domain. Trophoblasts derived from two first-trimester placentae bound more prourokinase than cells isolated from term placentae. Furthermore, in vitro differentiation of cultured cytotrophoblasts into syncytiotrophoblasts was associated with diminished expression of urokinase receptors and a parallel decrease in the cellular content of uPA receptor mRNA. Trophoblasts also secreted prourokinase and plasminogen activator inhibitors types 1 and 2 (PAI-1 and PAI-2). Although prourokinase was secreted in amounts sufficient to endogenously saturate trophoblast uPA receptors, trophoblasts secreted greater amounts of PAI-1 and PAI-2 than uPA, and no net plasminogen activator activity was detected in trophoblast conditioned medium. In contrast, plasminogen added directly to cultured trophoblasts was readily converted to plasmin. Although the invasion and remodeling of uterine tissues by trophoblasts is a complex process dependent on several proteases of varying specificity, our findings suggest that the expression and modulation of urokinase receptors on the trophoblast cell surface may play an important role in this process.
Constellation Pharmacology: A New Paradigm for Drug Discovery (2015)

Constellation pharmacology is a cell-based high-content phenotypic-screening platform that utilizes subtype-selective pharmacological agents to elucidate the cell-specific combinations (constellations) of key signaling proteins that define specific cell types. Heterogeneous populations of native cells, in which the different individual cell types have been identified and characterized, are the foundation for this screening platform. Constellation pharmacology is useful for screening small molecules or for deconvoluting complex mixtures of biologically active natural products. This platform has been used to purify natural products and discover their molecular mechanisms. In the ongoing development of constellation pharmacology, there is a positive feedback loop between the pharmacological characterization of cell types and screening for new drug candidates. As constellation pharmacology is used to discover compounds with novel targeting-selectivity profiles, those new compounds then further help to elucidate the constellations of specific cell types, thereby increasing the content of this high-content platform.
Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models (2023)

These results pave the way for future clinical trials of Polθ inhibitors in combination with radiotherapy.
Tyrosine Phosphorylation of the β3 Cytoplasmic Domain Mediates Integrin-Cytoskeletal Interactions (1998)

Tyrosine phosphorylation of the beta3 subunit of the major platelet integrin alphaIIb beta3 has been shown to occur during thrombin-induced platelet aggregation (1). We now show that a wide variety of platelet stimuli induced beta3 tyrosine phosphorylation, but that this phosphorylation occurred only following platelet aggregation. Several lines of evidence suggest that the beta3 cytoplasmic domain tyrosine residues and/or their phosphorylation function to mediate interactions between beta3 integrins and cytoskeletal proteins. First, phospho-beta3 was retained preferentially in a Triton X-100 insoluble cytoskeletal fraction of thrombin-aggregated platelets. Second, in vitro experiments show that the cytoskeletal protein, myosin, associated in a phosphotyrosine-dependent manner with a diphosphorylated peptide corresponding to residues 740-762 of beta3. Third, mutation of both tyrosines in the beta3 cytoplasmic domain to phenylalanines markedly reduced beta3-dependent fibrin clot retraction. Thus, our data indicate that platelet aggregation is both necessary and sufficient for beta3 tyrosine phosphorylation, and this phosphorylation results in the physical linkage of alphaIIb beta3 to the cytoskeleton. We hypothesize that this linkage may involve direct binding of the phosphorylated integrin to the contractile protein myosin in order to mediate transmission of force to the fibrin clot during the process of clot retraction.
RETRACTED: Bisboronic Acids for Selective, Physiologically Relevant Direct Glucose Sensing with Surface-Enhanced Raman Spectroscopy (2016)

This paper demonstrates the direct sensing of glucose at physiologically relevant concentrations with surface-enhanced Raman spectroscopy (SERS) on gold film-over-nanosphere (AuFON) substrates functionalized with bisboronic acid receptors. The combination of selectivity in the bisboronic acid receptor and spectral resolution in the SERS data allow the sensors to resolve glucose in high backgrounds of fructose and, in combination with multivariate statistical analysis, detect glucose accurately in the 1-10 mM range. Computational modeling supports assignments of the normal modes and vibrational frequencies for the monoboronic acid base of our bisboronic acids, glucose and fructose. These results are promising for the use of bisboronic acids as receptors in SERS-based in vivo glucose monitoring sensors.
Isolation and characterization of reactive intermediates and active catalysts in homogeneous catalysis (1985)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIsolation and characterization of reactive intermediates and active catalysts in homogeneous catalysisPaul G. Gassman, David W. Macomber, and Stephen M. WillgingCite this: J. Am. Chem. Soc. 1985, 107, 8, 2380–2388Publication Date (Print):April 1, 1985Publication History Published online1 May 2002Published inissue 1 April 1985https://doi.org/10.1021/ja00294a031RIGHTS & PERMISSIONSArticle Views1705Altmetric-Citations53LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (1 MB) Get e-Alerts Get e-Alerts
Coherent detection in a receive diversity PLC system under Nakagami-m noise environment (2016)

This paper proposes to use N-branch diversity reception for a power line communication (PLC) system with binary phase-shift keying to improve the reliability of data transmission. The PLC channel is subject to Rayleigh fading and additive Nakagami-m background noise with m <; 1, which is caused by multiple noise sources. The optimal detector for this system is derived by approximating the noise distribution by Hoyt distribution. A closed form expression and a series expression for the symbol error probability for even and odd N, respectively, are obtained. The advantage of using multiple receive branches in terms of achieving better error performance and its power efficiency are shown through numerical results. The effect of the shape parameter m of the background noise on the performance of the optimal receiver is also demonstrated.
Ensemble Approaches for Uncertainty in Spoken Language Assessment (2020)

Deep learning has dramatically improved the performance of automated systems on a range of tasks including spoken language assessment. One of the issues with these deep learning approaches is that they tend to be overconfident in the decisions that they make, with potentially serious implications for deployment of systems for high-stakes examinations. This paper examines the use of ensemble approaches to improve both the reliability of the scores that are generated, and the ability to detect where the system has made predictions beyond acceptable errors. In this work assessment is treated as a regression problem. Deep density networks, and ensembles of these models, are used as the predictive models. Given an ensemble of models measures of uncertainty, for example the variance of the predicted distributions, can be obtained and used for detecting outlier predictions. However, these ensemble approaches increase the computational and memory requirements of the system. To address this problem the ensemble is distilled into a single mixture density network. The performance of the systems is evaluated on a free speaking prompt-response style spoken language assessment test. Experiments show that the ensembles and the distilled model yield performance gains over a single model, and have the ability to detect outliers.
A novel DAG-dependent mechanism links PKCa and Cyclin B1 regulating cell cycle progression (2014)

Through the years, different studies showed the involvement of Protein Kinase C (PKC) in cell cycle control, in particular during G1/S transition. Little is known about their role at G2/M checkpoint. In this study, using K562 human erythroleukemia cell line, we found a novel and specific mechanism through which the conventional isoform PKCα positively affects Cyclin B1 modulating G2/M progression of cell cycle. Since the kinase activity of this PKC isoform was not necessary in this process, we demonstrated that PKCα, physically interacting with Cyclin B1, avoided its degradation and stimulated its nuclear import at mitosis. Moreover, the process resulted to be strictly connected with the increase in nuclear diacylglycerol levels (DAG) at G2/M checkpoint, due to the activity of nuclear Phospholipase C β1 (PLCβ1), the only PLC isoform mainly localized in the nucleus of K562 cells. Taken together, our findings indicated a novel DAG dependent mechanism able to regulate the G2/M progression of the cell cycle.
High-power stable field-plated AlGaN-GaN MOSHFETs (2005)

We describe novel AlGaN-GaN metal-oxide-semiconductor heterostructure field-effect transistors (MOSHFETs) with record high power-voltage efficiencies (PVE = RF power/Drain bias), up to 0.43W/V-mm at 2 GHz. The RF powers of 15 W/mm at 35 V (PVE=0.43 W/V-mm) and 20 W/mm at 55 V (PVE= 0.36W/V-mm) were measured, which are approximately 50% higher than the previously reported values of PVE=0.25 W/V-mm (30 W/mm at 120 V). The MOSHFET devices exhibit an extremely stable operation for times in excess of 120 hours at power levels close to 20 W/mm. This is also the first demonstration of stability for a III-N microwave FET device at such a high power level. The key features of our new device design are (i) current collapse-free operation using trapped charge removing field-plates over leaky dielectric layers; (ii) selective area doping to achieve record low access resistances and (iii) an insulated gate design suppressing forward gate currents responsible for device degradation. In the paper we will present detailed experimental evidence to support our explanations for achieving the record RF-performance for the III-N FETs for the first time
Automated Fault Location and Isolation in Distribution Grids With Distributed Control and Unreliable Communication (2014)

This paper presents the analysis and simulation of the performance of fault location and isolation (FLI) in an automated power distribution feeder. This system is composed of two coupled networks: a power system consisting of a distribution feeder with multiple load buses, and an unreliable communication network of the distributed intelligent agents in the system, namely, the substation automation and fault protection units separating segments of the feeder. We provide a complete specification of a distributed algorithm for FLI and an exact characterization of the time from the occurrence of a fault to its location and isolation. Both apply to a distribution feeder with an arbitrary number of buses. These models are then refined into a hybrid simulation that combines three models executing in parallel: a power system model based on dc power flow, a distributed automation system model for the intelligent agents constructed using the IEC 61499 distributed automation standard, and an abstract communication network model that unreliably links the physically distributed agents. The results demonstrate the effect of communication network reliability at two levels of design abstraction, the correspondence of results at the two levels, and the use of a modern cosimulation framework to verify the performance of distributed smart grid automation algorithms.
An experimental and numerical study on cavitating shear flows. (2000)

The dynamics of incipient and developed vortex cavitation was examined. The present work is divided into two parts: the first part deals with cavitation inception, that was studied numerically, and the second part deals with developed cavitation, that was studied experimentally. Incipient cavitation was studied by using a Direct Numerical Simulations (DNS) method for multi-phase flows developed by Unverdi and Tryggvason (1992). The interaction between non-cavitating and cavitating bubbles and the vortex flow was simulated. Incipient cavitation is difficult to observe experimentally because the minimum length scales of the cavitating flow are very small (the size of cavitation nuclei are often on the order of 10 mum) and because the nuclei capture process is stochastic and occurs at different locations in a turbulent flow. The numerical study analyzed the capture time of the bubbles, the bubble trajectory as it gets entrained by the vortex, the effect of the bubble and vortex core diameter ratio, the effect of the cavitation number, and bubble Weber number. The DNS results were compared with a simple one-way coupled particle-tracking (PT) model, using the equation of Johnson and Hsieh (1966) and the Raleigh-Plesset equation (Plesset, 1948). In the PT model different drag and lift coefficients were used in order to determine which model agrees well with the DNS results. It was determined that the drag coefficient given by Haberman and Morton (1953) gave a trajectory that was closer to the trajectory computed with DNS than the drag coefficient by Clift et al. (1978). A lift coefficient that is between the values given by Saffman (1965) and Dandy and Dwyer (1990) would give better comparison with the DNS results. Developed cavitation in a shear layer was studied experimentally in order to determine the effect that the growth and collapse of cavitation have on the dynamics of shear flows. Planar Particle Imaging Velocimetry (PIV) was used to measure the velocity field, the vorticity, strain rates and Reynolds stresses of the flow downstream of the cavitating and non-cavitating shear layer, and the flow pressures and void fraction were also measured. Cavitating shear flows with different cavitation numbers were compared to the non-cavitating shear flow. It was determined that the cavitating flows have higher levels of vorticity, strain rate, and Reynolds stresses in the core of the shear layer, but the differences were not significant. The average flow field was not significantly altered both in terms of average velocities and mean pressure drop across the test section. Downstream of the shear layer, the development of cavitation reduced somewhat the growth of the shear layer (by a factor of about 5%). The reduction of the shear layer thickness is consistent with the observations of Brown and Roshko (1974), Hermanson and Dimotakis (1989), and Belahadji et al. (1995).
Communication Orale : "Polymères plasma pour la modification ou synthèse de polymères - Membranes pour piles à combustible" (2008)

2ème Journée des Polyméristes Languedociens, 5 Décembre 2008, Montpellier (France)
Nonlinear laser synchrotron source experiment for tunable, monochromatic X-rays (2004)

Summary form only given. The laser synchrotron source (LSS) experiment at the Naval Research Laboratory generates X-rays using Thomson scattering of laser photons from a relativistic electron beam. Previous experiments utilized a thermionic RF electron gun operating at 2.856 GHz to produce electron beams with an energy of 4.1 MeV and average currents of 300 mA over the 300-nsec macropulse. A Nd:Glass laser (5 J, 10 nsec, 1.053 m wavelength) was used in a 180-degree scattering geometry. Experimental results included the generation of 372 eV photons with 2% bandwidth and 2/spl times/10/sup 7/ photons per pulse. A new experiment is underway to investigate nonlinear Thomson scattering using a new photocathode RF gun (BNL IV design) and the T/sup 3/ laser (/spl sim/1 J, 0.3 psec). When this laser is focused to a spot size of 10 /spl mu/m the peak intensity reaches 6/spl times/10/sup 18/ W/cm/sup 2/ with a corresponding laser strength parameter a/sub 0/=2.2. The quiver motion of an electron in such an intense field is relativistic, and the scattered radiation occurs at higher harmonics of the linear Doppler-upshifted frequency. The new experiment has two laser pulse compressors: one for the uv pulse which illuminates the photocathode and one for the main (scattering) laser pulse. This allows the electron beam and scattering beam pulse lengths to be varied independently. The nominal RF gun operating parameters are 4.5 MeV, 100 A peak current, <1 nC charge, pulse lengths of a few psec, and a normalized rms emittance of 3 /spl pi/-mm-mrad. Results will be presented on the conditioning and initial operation of the RF gun.
Synaptotagmin-7 is a key factor for bipolar-like behavioral abnormalities in mice (2020)

The pathogenesis of bipolar disorder (BD) has remained enigmatic, largely because genetic animal models based on identified susceptible genes have often failed to show core symptoms of spontaneous mood cycling. However, pedigree and induced pluripotent stem cell (iPSC)-based analyses have implicated that dysfunction in some key signaling cascades might be crucial for the disease pathogenesis in a subpopulation of BD patients. We hypothesized that the behavioral abnormalities of patients and the comorbid metabolic abnormalities might share some identical molecular mechanism. Hence, we investigated the expression of insulin/synapse dually functioning genes in neurons derived from the iPSCs of BD patients and the behavioral phenotype of mice with these genes silenced in the hippocampus. By these means, we identified synaptotagmin-7 (Syt7) as a candidate risk factor for behavioral abnormalities. We then investigated Syt7 knockout (KO) mice and observed nocturnal manic-like and diurnal depressive-like behavioral fluctuations in a majority of these animals, analogous to the mood cycling symptoms of BD. We treated the Syt7 KO mice with clinical BD drugs including olanzapine and lithium, and found that the drug treatments could efficiently regulate the behavioral abnormalities of the Syt7 KO mice. To further verify whether Syt7 deficits existed in BD patients, we investigated the plasma samples of 20 BD patients and found that the Syt7 mRNA level was significantly attenuated in the patient plasma compared to the healthy controls. We therefore concluded that Syt7 is likely a key factor for the bipolar-like behavioral abnormalities.