gebhart/patrepeval huggingface dataset:
Persistent Sodium Currents in Mesencephalic V Neurons Participate in Burst Generation and Control of Membrane Excitability (2005)

The functional and biophysical properties of a persistent sodium current (I(NaP)) previously proposed to participate in the generation of subthreshold oscillations and burst discharge in mesencephalic trigeminal sensory neurons (Mes V) were investigated in brain stem slices (rats, p7-p12) using whole cell patch-clamp methods. I(NaP) activated around -76 mV and peaked at -48 mV, with V1/2 of -58.7 mV. Ramp voltage-clamp protocols showed that I(NaP) undergoes time- as well as voltage-dependent inactivation and recovery from inactivation in the range of several seconds (tau(onset) = 2.04 s, tau(recov) = 2.21 s). Riluzole (< or =5 microM) substantially reduced I(NaP), membrane resonance, postinhibitory rebound (PIR), and subthreshold oscillations, and completely blocked bursting, but produced modest effects on the fast transient Na+ current (I(NaT)). Before complete cessation, burst cycle duration was increased substantially, while modest and inconsistent changes in burst duration were observed. The properties of the I(NaT) were obtained and revealed that the amplitude and voltage dependence of the resulting "window current" were not consistent with those of the observed I(NaP) recorded in the same neurons. This suggests an additional mechanism for the origin of I(NaP). A neuronal model was constructed using Hodgkin-Huxley parameters obtained experimentally for Na+ and K+ currents that simulated the experimentally observed membrane resonance, subthreshold oscillations, bursting, and PIR. Alterations in the model g(NaP) parameters indicate that I(NaP) is critical for control of subthreshold and suprathreshold Mes V neuron membrane excitability and burst generation.
Supplementary Figure 2 from DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with <i>In Silico</i> Analysis to Identify Novel Therapeutic Targets (2023)

&lt;p&gt;Hits of the DiSCoVER analysis&lt;/p&gt;
Fast surface temperature measurement of Teflon propellant-in-pulsed ablative discharges using HgCdTe photovoltaic cells (2006)

High-speed mercury cadmium telluride photovoltaic detectors, sensitive to infrared emission, are investigated as a means of measuring surface temperature on a microsecond time frame during pulsed ablative discharges with Teflon™ as the ablated material. Analysis is used to derive a governing equation for detector output voltage for materials with wavelength dependent emissivity. The detector output voltage is experimentally calibrated against thermocouples embedded in heated Teflon. Experimental calibration is performed with Teflon that has been exposed to ∼200 pulsed discharges and non-plasma-exposed Teflon and is compared to theoretical predictions to analyze emissivity differences. The diagnostic capability is evaluated with measurements of surface temperature from the Teflon propellant of electric micropulsed plasma thrusters. During the pulsed current discharge, there is insufficient information to claim that the surface temperature is accurately measured. However, immediately following the discharge, the postpulse cooling curve is measured. The statistical spread of postpulse surface temperature from shot to shot, most likely due to arc constriction and localization, is investigated to determine an operational envelope for postpulse temperature and mass ablation. This information is useful for determining postpulse ablation contributions to mass loss as well as evaluation of theoretical discharge models currently under development.
Acute Effects of Vitamin C on Platelet Responsiveness to Nitric Oxide Donors and Endothelial Function in Patients with Chronic Heart Failure (2001)

Chronic heart failure (CHF) is characterized by a prothrombotic state, which may relate to increased platelet aggregability, endothelial dysfunction, and increased oxidative stress. We investigated the effect of vitamin C in CHF on ex vivo platelet aggregation and platelet responsiveness to the anti-aggregatory effects of the nitric oxide (NO) donors glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). We also examined parameters of oxidative stress and endothelial function in patients. In this double-blind, randomized, crossover study vitamin C (2 g) or placebo was given intravenously to 10 patients with CHF. We measured adenosine 5-diphosphate (ADP)-induced platelet aggregation, flow-mediated dilatation (FMD) in the brachial artery using ultrasonic wall-tracking, and plasma levels of lipid-derived free radicals using electron paramagnetic resonance spectroscopy. Vitamin C did not affect ex vivo platelet aggregability but enhanced the inhibition of platelet aggregation by SNP (62.7+/-10.2 to 82.7+/-4.8%, p = 0.03) and tended to increase responses to GTN (40.5+/-9.0 to 53.4+/-7.3, p = 0.06). The effect of vitamin C on platelet responsiveness to the antiaggregatory effects of SNP was inversely related to basal response to SNP (r = -0.9, p < 0.01); a similar trend was observed with GTN (r = -0.6, p = 0.1). Vitamin C also increased FMD (1.9+/-0.6 to 5.8+/-1.5%, p = 0.02) and reduced plasma lipid-derived free radicals by 49+/-19% (p < 0.05). In patients with CHF acute intravenous administration of vitamin C enhances platelet responsiveness to the anti-aggregatory effects of NO donors and improves endothelial function, suggesting a potential role for vitamin C as a therapeutic agent in CHF.
Workflow to Image Unconformities with Deep Electromagnetic LWD Measurements Enables Well Placement in Complex Scenarios (2013)

Abstract The advent of deep-reading directional electromagnetic logging-while-drilling measurements brings opportunities in imaging complex formations around the wellbore. In this context, basing the inversions on an assumption of a layered medium is not always sufficient to decouple geometrical effects in complex formation scenarios. Rather than attempting to invert all variables of a generic 2D formation model simultaneously, we describe in this paper how the use of 2D inversions can be enabled through a robust workflow specifically designed for a class of formation models, in this case the angular unconformity. We demonstrate how the successive application of 1D inversion to subsets of tool data gradually builds a formation model for use as input to a 2D inversion, which accounts for complex couplings present in the data in such environments. The validity and the performance of the method are established through synthetic and field datasets.
SOME TRAFFIC ISSUES IN THE DESIGN OF VIRTUAL PRIVATE NETWORKS OVER ATM (1996)

The emergence of broadband technologies such as ATM gives rise to new developments in the domain of virtual private networks (VPNs). In this paper, a target broadband VPN (B-VPN) service is proposed, which combines the cost savings of classic VPN services and the powerful features of private corporate networks (service integration, statistical multiplexing, etc.) enlarged by the use of ATM. To reach this B-VPN service, some architectural issues related to the network supporting the B-VPN service are discussed. The traffic implications of the possible architectural choices are then examined, and from this discussion some basic principles for a VPN architecture are drawn. Finally, target VPN architectures are proposed.
Quality Adjustable Query Processing Framework for Wireless Sensor Networks (2011)

Existing in-network query processing techniques are categorized as approximation and aggregation based approaches. The former achieves lower query response delay at the expense of accuracy, while the latter reduces query response inaccuracy by executing queries at the actual sensor nodes resulting in longer delay. In this paper, we propose a query processing framework which is delay as well as accuracy aware and capable of dynamic adjustment to meet user/application requirements. When query response is required within specific delay, it provides approximated sensor data meeting the delay requirement. On the other hand, when query response accuracy is vital, it tolerates longer delay in acquiring response with the desired accuracy. To achieve this, we propose a novel method of constructing a delay aware spanning tree (DAST) based on query load and organizing sensor data with varied accuracy. Experimental results illustrate superiority of the proposed framework against competing approaches.
WE-D-304A-02: Exploring Non-Linear Feature Space Dimension Reduction and Data Representation in Breast CADx (2009)

Purpose: Preliminary study to explore potential of recently developed non-linear dimension reduction and data representation techniques as applied to breast lesion CADx generated feature spaces. Method and Materials: Two new methods were explored: Laplacian eignenmaps of (Belkin and Niyogi) and t-distributed stochastic neighbor embedding (t-SNE) (van der Maaten and Hinton). The properties of these methods were evaluated in the context of malignancy classification performance as well as visual inspection of the sparseness for two and three dimensional mapping representations. The robustness of the proposed techniques were tested against four separate imaging modality feature databases, including 2956 ultrasound (US), 735 full-field digital mammography (FFDM), 850 screen-film mammography (SFM), and 356 DCE-MRI biopsy proven breast mass lesions. Using the reduced dimension mapped feature output as input, as opposed to feature selection, two classifiers, linear and non-linear, were tested: Markov Chain Monte Carlo based Bayesian artificial neural network (MCMC-BANN) and linear discriminate analysis (LDA). To evaluate performance, the AUC was estimated for each classifier using ROC analysis and 0.632+ bootstrap validation on over 500 samples. In addition, performance was compared to a non-linear Automatic Relevance Determination (ARD), linear step-wise feature selection method, as well as a linear reduction Principle Component Analysis based method. Results: The new methods were found to match or exceed performance of current state-of-the-art breast lesion CADx algorithms for feature selection and classification across all modalities. Additionally, the new techniques possess the added benefit of naturally delivering sparse lower dimensional representations for visual interpretation, thus, revealing intricate data structure of the feature space. Conclusion: These methods maintain predictive power while also preserving both local and global structural information present in the original high dimensional feature space for breast lesion feature data used in CADx. Conflict of Interest: M. Giger is a stockholder and receives royalties from Hologic.
Bone Embedding Technique with Inhibited Pmma Monomer (1982)

Unwashed inhibited thin and thick methyl methacrylate monomer was used for successful embedding of bone by increasing the quantity of benzoyl peroxide catalyst until the activity of the hydroquihone inhibitor was overwhelmed. Seven bones were embedded using 1, 2, 4, 6, 8, 10 or 12 grams of benzoyl peroxide per 100 milliliters of thick monomer. Two grams per 100 ml was found to be optimal. Higher concentrations resulted in uncontrolled polymerization while at 1 g/100 ml the solution remained liquid.
Binding Free-Energy Calculation Is a Powerful Tool for Drug Optimization: Calculation and Measurement of Binding Free Energy for 7-Azaindole Derivatives to Glycogen Synthase Kinase-3β (2014)

Present computational lead (drug)-optimization is lacking in thermodynamic tactics. To examine whether calculation of binding free-energy change (ΔG) is effective for the lead-optimization process, binding ΔGs of 7-azaindole derivatives to the ATP binding site of glycogen synthase kinase-3β (GSK-3β) were calculated. The result was a significant correlation coefficient of r = 0.895 between calculated and observed ΔGs. This indicates that calculated ΔG reflects the inhibitory activities of 7-azaindole derivatives. In addition to quantitative estimation of activity, ΔG calculation characterizes the thermodynamic behavior of 7-azaindole derivatives, providing also useful information for inhibitor optimization on affinity to water molecules.
Cytokines Delivered by Biodegradable Microspheres Promote Effective Suppression of Human Tumors by Human Peripheral Blood Lymphocytes in the SCID–Winn Model (2000)

A new technology for the local and sustained delivery of immunostimulatory molecules to the tumor environment for cancer immunotherapy was evaluated. The ability of cytokines delivered by biodegradable microspheres to promote the antitumor activity of human peripheral blood lymphocytes (PBL) was tested in a human PBL, human tumor, and SCID mouse (SCID-Winn) model. Co-engraftment of human recombinant IL-12-loaded microspheres with human PBL and tumors in SCID mice promoted complete tumor suppression in as many as 100% of the mice, whereas microspheres loaded with polyethyleneglycol-interleukin-2 suppressed but did not eliminate the growth of tumor xenografts. Control microspheres (loaded with bovine serum albumin) in the presence of human PBL or cytokine-loaded microspheres in the absence of human PBL had no tumor-suppressive effect. Coincident with the enhancement of the human PBL-mediated antitumor activity in mice treated with IL-12-loaded microspheres was the production and release of human IFN-gamma indicating that IL-12 released from the microspheres results in the activation of the engrafted human PBL. The results establish that biodegradable microspheres represent an effective tool for the local and sustained delivery of cytokines to the tumor environment for cancer immunotherapy.
High-coherence hybrid-integrated 780 nm source by self-injection-locked second-harmonic generation in a high-Q silicon-nitride resonator (2023)

By self-injection-locking a 1560 nm distributed feedback semiconductor laser to a high-$Q$ silicon nitride resonator, a high-coherence 780 nm second harmonic signal is generated via the photogalvanic-induced second-order nonlinearity. A record-low frequency noise floor of 4 Hz$^2$/Hz is achieved for the 780 nm emission. The approach can be generalized for signal generation over a wide range of visible and near-visible bands.
New targets for increasing endogenous testosterone production: clinical implications and review of the literature (2014)

Over the past several decades, our understanding of the regulatory mechanisms of testosterone production has increased significantly. Concurrently, the medical treatment of hypogonadism, particularly in the ageing male has increased. This review article consolidates some of our insights into the regulatory mechanisms of endogenous testosterone production and examines promising new targets that may allow endogenous production of testosterone to be re-established in males with primary hypogonadism. We examined the published scientific literature regarding regulatory mechanisms of testosterone biosynthesis with a focus on Leydig cell physiology and small-molecule regulation that resulted in increased testosterone production. We identified several pathways that have been manipulated pharmacologically to increase Leydig cell testosterone production, including phosphodiesterases, the cholesterol translocator protein, the electron transport chain of mitochondria, cyclooxygenases and osteocalcin. Manipulation of these pathways with small molecules has helped further our understanding of the regulatory pathways of testosterone biosynthesis. Herein, we identified five future targets that might promote increased endogenous testosterone production through the Leydig cell instead of relying on exogenous testosterone administration.
ChemInform Abstract: In silico Drug Discovery Based on the Integration of Bioinformatics and Chemoinformatics (2009)

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Data from Simultaneous Targeting of Two Distinct Epitopes on MET Effectively Inhibits MET- and HGF-Driven Tumor Growth by Multiple Mechanisms (2023)

&lt;div&gt;Abstract&lt;p&gt;Increased MET activity is linked with poor prognosis and outcome in several human cancers currently lacking targeted therapies. Here, we report on the characterization of Sym015, an antibody mixture composed of two humanized IgG&lt;sub&gt;1&lt;/sub&gt; antibodies against nonoverlapping epitopes of MET. Sym015 was selected by high-throughput screening searching for antibody mixtures with superior growth-inhibitory activity against MET-dependent cell lines. Synergistic inhibitory activity of the antibodies comprising Sym015 was observed in several cancer cell lines harboring amplified &lt;i&gt;MET&lt;/i&gt; locus and was confirmed &lt;i&gt;in vivo&lt;/i&gt;. Sym015 was found to exert its activity via multiple mechanisms. It disrupted interaction of MET with the HGF ligand and prompted activity-independent internalization and degradation of the receptor. In addition, Sym015 induced high levels of CDC and ADCC &lt;i&gt;in vitro&lt;/i&gt;. The importance of these effector functions was confirmed &lt;i&gt;in vivo&lt;/i&gt; using an Fc-effector function–attenuated version of Sym015. The enhanced effect of the two antibodies in Sym015 on both MET degradation and CDC and ADCC is predicted to render Sym015 superior to single antibodies targeting MET. Our results demonstrate strong potential for use of Sym015 as a therapeutic antibody mixture for treatment of MET-driven tumors. Sym015 is currently being tested in a phase I dose escalation clinical trial (NCT02648724). &lt;i&gt;Mol Cancer Ther; 16(12); 2780–91. ©2017 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;
A multi-coordinating polymer ligand optimized for the functionalization of metallic nanocrystals and nanorods (2016)

We report the design and use of a multi-coordinating polymer ligand that is ideally suited for functionalizing gold nanoparticles and nanorods, and promoting their steric stabilization in buffer media. The ligand is prepared via a one-step nucleophilic addition reaction between poly(isobutylene-alt-maleic anhydride) and amine-modified anchoring groups and hydrophilic moieties. Surface functionalization of gold nanoparticles and nanorods with this polymer yields nanocrystals that exhibit excellent long-term colloidal stability over a broad range of conditions, including pH changes and in growth media, as verified using dynamic light scattering measurements combined with agarose gel electrophoresis. This polymer coating can also prevent the formation of protein corona. These features bode well for use in biological applications where small size, reduced nonspecific interactions and colloidal stability are highly desired. Furthermore, this design can be easily expanded to functionalize a variety of other inorganic nanocrystals.
Scaling information pathways in optical fibers by topological confinement (2023)

Spatial mode-count scalability in optical fibers is of paramount importance for addressing the upcoming information-capacity crunch, reducing energy consumption per bit, and for enabling advanced quantum computing networks, but this scalability is severely limited by perturbative mode mixing. We show an alternative means of light guidance, in which light's orbital angular momentum creates a centrifugal barrier for itself, thereby enabling low-loss transmission of light in a conventionally forbidden regime wherein the mode mixing can be naturally curtailed. This enables kilometer-length-scale transmission of a record ~50 low-loss modes with cross-talk as low as -45 decibels/kilometer and mode areas of ~800 square micrometers over a 130-nanometer telecommunications spectral window. This distinctive light-guidance regime promises to substantially increase the information content per photon for quantum or classical networks.
Unique receptor dissociation kinetics of the novel endothelin receptor antagonist macitentan (2012)

Association and dissociation rates of G protein-coupled receptor antagonists can influence their in vivo pharmacological activity, such as duration of action, activity in situations of increased agonist concentrations and ultimately clinical efficacy.

Using signaling assays in human pulmonary arterial smooth muscle cells (PASMC), we investigated the endothelin (ET) receptor inhibition kinetics of macitentan, a novel ET receptor antagonist currently in phase 3 clinical trials in pulmonary arterial hypertension, and compared them with the kinetics of bosentan and ambrisentan.

Calcium flux assays showed that macitentan, but not ambrisentan or bosentan, increased in potency (10-fold) upon prolongation of antagonist pre-incubation time from 10 min to 120 min, indicating slow apparent association of macitentan with ET receptors. Macitentan furthermore displayed a slow receptor dissociation rate, as inhibition of ET-1-induced calcium flux persisted for more than 60 min after macitentan wash-out. Conversely, bosentan and ambrisentan did not maintain receptor blockade after washout and displayed a ∼15-fold shorter receptor occupancy half life than macitentan. The slow dissociation kinetics rendered macitentan an efficient antagonist of ET-1-induced IP3 synthesis and ET-1-induced sustained calcium flux across the whole range of ET-1 concentrations tested. In contrast, bosentan and ambrisentan did not display antagonism against high ET-1 concentrations in these assays.

In pulmonary arterial smooth muscle cells, macitentan is a slow-offset competitive antagonist and, unlike ambrisentan and bosentan, capable of efficient receptor blockade in functional assays irrespective of the ET-1 concentration.