Preferential utilization of NADPH as the endogenous electron donor for NAD(P)H:quinone oxidoreductase 1 (NQO1) in intact pulmonary arterial endothelial cells

The goal was to determine whether endogenous cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1) preferentially uses NADPH or NADH in intact pulmonary arterial endothelial cells in culture. The approach was to manipulate the redox status of the NADH/NAD+ and NADPH/NADP+ redox pairs in the cytosolic compartment using treatment conditions targeting glycolysis and the pentose phosphate pathway alone or with lactate, and to evaluate the impact on the intact cell NQO1 activity. Cells were treated with 2-deoxyglucose, iodoacetate, or epiandrosterone in the absence or presence of lactate, NQO1 activity was measured in intact cells using duroquinone as the electron acceptor, and pyridine nucleotide redox status was measured in total cell KOH extracts by high-performance liquid chromatography. 2-Deoxyglucose decreased NADH/NAD+ and NADPH/NADP+ ratios by 59 and 50%, respectively, and intact cell NQO1 activity by 74%; lactate restored NADH/NAD+, but not NADPH/NADP+ or NQO1 activity. Iodoacetate decreased NADH/NAD+ but had no detectable effect on NADPH/NADP+ or NQO1 activity. Epiandrosterone decreased NQO1 activity by 67%, and although epiandrosterone alone did not alter the NADPH/NADP+ or NADH/NAD+ ratio, when the NQO1 electron acceptor duroquinone was also present, NADPH/NADP+ decreased by 84% with no impact on NADH/NAD+. Duroquinone alone also decreased NADPH/NADP+ but not NADH/NAD+. The results suggest that NQO1 activity is more tightly coupled to the redox status of the NADPH/NADP+ than NADH/NAD+ redox pair, and that NADPH is the endogenous NQO1 electron donor. Parallel studies of pulmonary endothelial transplasma membrane electron transport (TPMET), another redox process that draws reducing equivalents from the cytosol, confirmed previous observations of a correlation with the NADH/NAD+ ratio

Data-driven PDE discovery with evolutionary approach

The data-driven models allow one to define the model structure in cases when a priori information is not sufficient to build other types of models. The possible way to obtain physical interpretation is the data-driven differential equation discovery techniques. The existing methods of PDE (partial derivative equations) discovery are bound with the sparse regression. However, sparse regression is restricting the resulting model form, since the terms for PDE are defined before regression. The evolutionary approach described in the article has a symbolic regression as the background instead and thus has fewer restrictions on the PDE form. The evolutionary method of PDE discovery (EPDE) is described and tested on several canonical PDEs. The question of robustness is examined on a noised data example

Characterization of theThreshold for NAD(P)H:quinone Oxidoreductase Activity in Intact Sulforaphane-treated Pulmonary Arterial Endothelial Cells

Treatment of bovine pulmonary arterial endothelial cells in culture with the phase II enzyme inducer sulforaphane (5 μM, 24 h; sulf-treated) increased cell-lysate NAD(P)H:quinone oxidoreductase (NQO1) activity by 5.7 ± 0.6 (mean ± SEM)-fold, but intact-cell NQO1 activity by only 2.8 ± 0.1-fold compared to control cells. To evaluate the hypothesis that the threshold for sulforaphane-induced intact-cell NQO1 activity reflects a limitation in the capacity to supply NADPH at a sufficient rate to drive all the induced NQO1 to its maximum activity, total KOH-extractable pyridine nucleotides were measured in cells treated with duroquinone to stimulate maximal NQO1 activity. NQO1 activation increased NADP+ in control and sulf-treated cells, with the effect more pronounced in the sulf-treated cells, in which the NADPH was also decreased. Glucose-6-phosphate dehydrogenase (G-6-PDH) inhibition partially blocked NQO1 activity in control and sulf-treated cells, but G-6-PDH overexpression via transient transfection with the human cDNA alleviated neither the restriction on intact sulf-treated cell NQO1 activity nor the impact on the NADPH/NADP+ ratios. Intracellular ATP levels were not affected by NQO1 activation in control or sulf-treated cells. An increased dependence on extracellular glucose and a rightward shift in the Km for extracellular glucose were observed in NQO1-stimulated sulf-treated vs control cells. The data suggest that glucose transport in the sulf-treated cells may be insufficient to support the increased metabolic demand for pentose phosphate pathway-generated NADPH as an explanation for the NQO1 threshold

Multi-layered Spectral Formation in SNe Ia Around Maximum Light

We use the radiative transfer code PHOENIX to study the line formation of the wavelength region 5000-7000 Angstroms. This is the region where the SNe Ia defining Si II feature occurs. This region is important since the ratio of the two nearby silicon lines has been shown to correlate with the absolute blue magnitude. We use a grid of LTE synthetic spectral models to investigate the formation of line features in the spectra of SNe Ia. By isolating the main contributors to the spectral formation we show that the ions that drive the spectral ratio are Fe III, Fe II, Si II, and S II. While the first two strongly dominate the flux transfer, the latter two form in the same physical region inside of the supernova. We also show that the naive blackbody that one would derive from a fit to the observed spectrum is far different than the true underlying continuum.Comment: 35 pages, 15 figures, ApJ (2008) 684 in pres

State-Dependent Computation Using Coupled Recurrent Networks

Although conditional branching between possible behavioral states is a hallmark of intelligent behavior, very little is known about the neuronal mechanisms that support this processing. In a step toward solving this problem, we demonstrate by theoretical analysis and simulation how networks of richly interconnected neurons, such as those observed in the superficial layers of the neocortex, can embed reliable, robust finite state machines. We show how a multistable neuronal network containing a number of states can be created very simply by coupling two recurrent networks whose synaptic weights have been configured for soft winner-take-all (sWTA) performance. These two sWTAs have simple, homogeneous, locally recurrent connectivity except for a small fraction of recurrent cross-connections between them, which are used to embed the required states. This coupling between the maps allows the network to continue to express the current state even after the input that elicited that state iswithdrawn. In addition, a small number of transition neurons implement the necessary input-driven transitions between the embedded states. We provide simple rules to systematically design and construct neuronal state machines of this kind. The significance of our finding is that it offers a method whereby the cortex could construct networks supporting a broad range of sophisticated processing by applying only small specializations to the same generic neuronal circuit

Quantifying Spectral Features of Type Ia Supernovae

We introduce a new technique to quantify highly structured spectra for which the definition of continua or spectral features in the observed flux spectra is difficult. The method employs wavelet transformation which allows the decomposition of the observed spectra into different scales. A procedure is formulated to define the strength of spectral features so that the measured spectral indices are independent of the flux levels and are insensitive to the definition of continuum and also to reddening. This technique is applied to Type Ia supernovae spectra, where correlations are revealed between the luminosity and spectral features. The current technique may allow for luminosity corrections based on spectral features in the use of Type Ia supernovae as cosmological probe.Comment: 35 pages, 15 figure

Serendipitous Discovery of Light-Induced \u3cem\u3e(In Situ)\u3c/em\u3e Formation of An Azo-Bridged Dimeric Sulfonated Naphthol as a Potent PTP1B Inhibito

Background Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results. Results Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC50 of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC50 of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5. Conclusion We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds

Universal Mechanical Polycomputation in Granular Matter

Unconventional computing devices are increasingly of interest as they can operate in environments hostile to silicon-based electronics, or compute in ways that traditional electronics cannot. Mechanical computers, wherein information processing is a material property emerging from the interaction of components with the environment, are one such class of devices. This information processing can be manifested in various physical substrates, one of which is granular matter. In a granular assembly, vibration can be treated as the information-bearing mode. This can be exploited to realize "polycomputing": materials can be evolved such that a single grain within them can report the result of multiple logical operations simultaneously at different frequencies, without recourse to quantum effects. Here, we demonstrate the evolution of a material in which one grain acts simultaneously as two different NAND gates at two different frequencies. NAND gates are of interest as any logical operations can be built from them. Moreover, they are nonlinear thus demonstrating a step toward general-purpose, computationally dense mechanical computers. Polycomputation was found to be distributed across each evolved material, suggesting the material's robustness. With recent advances in material sciences, hardware realization of these materials may eventually provide devices that challenge the computational density of traditional computers.Comment: Accepted to the Genetic and Evolutionary Computation Conference 2023 (GECCO '23

Spectral Modeling of SNe Ia Near Maximum Light: Probing the Characteristics of Hydro Models

We have performed detailed NLTE spectral synthesis modeling of 2 types of 1-D hydro models: the very highly parameterized deflagration model W7, and two delayed detonation models. We find that overall both models do about equally well at fitting well observed SNe Ia near to maximum light. However, the Si II 6150 feature of W7 is systematically too fast, whereas for the delayed detonation models it is also somewhat too fast, but significantly better than that of W7. We find that a parameterized mixed model does the best job of reproducing the Si II 6150 line near maximum light and we study the differences in the models that lead to better fits to normal SNe Ia. We discuss what is required of a hydro model to fit the spectra of observed SNe Ia near maximum light.Comment: 29 pages, 14 figures, ApJ, in pres

The DICE calibration project: design, characterization, and first results

We describe the design, operation, and first results of a photometric calibration project, called DICE (Direct Illumination Calibration Experiment), aiming at achieving precise instrumental calibration of optical telescopes. The heart of DICE is an illumination device composed of 24 narrow-spectrum, high-intensity, light-emitting diodes (LED) chosen to cover the ultraviolet-to-near-infrared spectral range. It implements a point-like source placed at a finite distance from the telescope entrance pupil, yielding a flat field illumination that covers the entire field of view of the imager. The purpose of this system is to perform a lightweight routine monitoring of the imager passbands with a precision better than 5 per-mil on the relative passband normalisations and about 3{\AA} on the filter cutoff positions. The light source is calibrated on a spectrophotometric bench. As our fundamental metrology standard, we use a photodiode calibrated at NIST. The radiant intensity of each beam is mapped, and spectra are measured for each LED. All measurements are conducted at temperatures ranging from 0{\deg}C to 25{\deg}C in order to study the temperature dependence of the system. The photometric and spectroscopic measurements are combined into a model that predicts the spectral intensity of the source as a function of temperature. We find that the calibration beams are stable at the $10^{-4}$ level -- after taking the slight temperature dependence of the LED emission properties into account. We show that the spectral intensity of the source can be characterised with a precision of 3{\AA} in wavelength. In flux, we reach an accuracy of about 0.2-0.5% depending on how we understand the off-diagonal terms of the error budget affecting the calibration of the NIST photodiode. With a routine 60-mn calibration program, the apparatus is able to constrain the passbands at the targeted precision levels.Comment: 25 pages, 27 figures, accepted for publication in A&