Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and higher throughput platforms have emerged as potential tools to advance cardiac drug safety screening. This study evaluated ...the use of high bandwidth photometry applied to voltage-sensitive fluorescent dyes (VSDs) to assess drug-induced changes in action potential characteristics of spontaneously active hiPSC-CM. Human iPSC-CM from 2 commercial sources (Cor.4U and iCell Cardiomyocytes) were stained with the VSD di-4-ANEPPS and placed in a specialized photometry system that simultaneously monitors 2 wavebands of emitted fluorescence, allowing ratiometric measurement of membrane voltage. Signals were acquired at 10 kHz and analyzed using custom software. Action potential duration (APD) values were normally distributed in cardiomyocytes (CMC) from both sources though the mean and variance differed significantly (APD
: 229 ± 15 ms vs 427 ± 49 ms mean ± SD, P < 0.01; average spontaneous cycle length: 0.99 ± 0.02 s vs 1.47 ± 0.35 s mean ± SD, P < 0.01, Cor.4U vs iCell CMC, respectively). The 10-90% rise time of the AP (T
) was ∼6 ms and was normally distributed when expressed as 1/Formula: see text in both cell preparations. Both cell types showed a rate dependence analogous to that of adult human cardiac cells. Furthermore, nifedipine, ranolazine, and E4031 had similar effects on cardiomyocyte electrophysiology in both cell types. However, ranolazine and E4031 induced early after depolarization-like events and high intrinsic firing rates at lower concentrations in iCell CMC. These data show that VSDs provide a minimally invasive, quantitative, and accurate method to assess hiPSC-CM electrophysiology and detect subtle drug-induced effects for drug safety screening while highlighting a need to standardize experimental protocols across preparations.
ABSTRACT
We determine rotation periods for 127 stars in the ∼115-Myr-old Blanco 1 open cluster using ∼200 d of photometric monitoring with the Next Generation Transit Survey. These stars span F5–M3 ...spectral types (1.2 M⊙ ≳ M ≳ 0.3 M⊙) and increase the number of known rotation periods in Blanco 1 by a factor of four. We determine rotation periods using three methods: Gaussian process (GP) regression, generalized autocorrelation function (G-ACF), and Lomb–Scargle (LS) periodogram, and find that the GP and G-ACF methods are more applicable to evolving spot modulation patterns. Between mid-F and mid-K spectral types, single stars follow a well-defined rotation sequence from ∼2 to 10 d, whereas stars in photometric multiple systems typically rotate faster. This may suggest that the presence of a moderate-to-high mass ratio companion inhibits angular momentum loss mechanisms during the early pre-main sequence, and this signature has not been erased at ∼100 Myr. The majority of mid-F to mid-K stars display evolving modulation patterns, whereas most M stars show stable modulation signals. This morphological change coincides with the shift from a well-defined rotation sequence (mid-F to mid-K stars) to a broad rotation period distribution (late-K and M stars). Finally, we compare our rotation results for Blanco 1 to the similarly aged Pleiades: the single-star populations in both clusters possess consistent rotation period distributions, which suggests that the angular momentum evolution of stars follows a well-defined pathway that is, at least for mid-F to mid-K stars, strongly imprinted by ∼100 Myr.
We present an improved lunar digital elevation model (DEM) covering latitudes within plus or minus 60 degree , at a horizontal resolution of 512pixels per degree (60m at the equator) and a typical ...vertical accuracy 3 to 4m. This DEM is constructed from geodetically-accurate topographic heights from the Lunar Orbiter Laser Altimeter (LOLA) onboard the Lunar Reconnaissance Orbiter, to which we co-registered 43,200 stereo-derived DEMs (each ) from the SELENE Terrain Camera (TC) (1010 pixels total). After co-registration, approximately 90% of the TC DEMs show root-mean-square vertical residuals with the LOLA data of <5m compared to 50% prior to co-registration. We use the co-registered TC data to estimate and correct orbital and pointing geolocation errors from the LOLA altimetric profiles (typically amounting to <10m horizontally and <1m vertically). By combining both co-registered datasets, we obtain a near-global DEM with high geodetic accuracy, and without the need for surface interpolation. We evaluate the resulting LOLA+TC merged DEM (designated as "SLDEM2015") with particular attention to quantifying seams and crossover errors.
Three key metrics for readout systems in quantum processors are measurement speed, fidelity, and footprint. Fast high-fidelity readout enables midcircuit measurements, a necessary feature for many ...dynamic algorithms and quantum error correction, while a small footprint facilitates the design of scalable, highly connected architectures with the associated increase in computing performance. Here, we present two complementary demonstrations of fast high-fidelity single-shot readout of spins in silicon quantum dots using a compact, dispersive charge sensor: a radio-frequency single-electron box. The sensor, despite requiring fewer electrodes than conventional detectors, performs at the state of the art achieving spin readout fidelity of 99.2% in less than6μsfitted from a physical model. We demonstrate that low-loss high-impedance resonators, highly coupled to the sensing dot, in conjunction with Josephson parametric amplification are instrumental in achieving optimal performance. We quantify the benefit of Pauli spin blockade over spin-dependent tunneling to a reservoir, as the spin-to-charge conversion mechanism in these readout schemes. Our results place dispersive charge sensing at the forefront of readout methodologies for scalable semiconductor spin-based quantum processors.
Rapid and reversible methods for perturbing the function of specific proteins are desirable tools for probing complex biological systems. We have developed a general technique to regulate the ...stability of specific proteins in mammalian cells using cell-permeable, synthetic molecules. We engineered mutants of the human FKBP12 protein that are rapidly and constitutively degraded when expressed in mammalian cells, and this instability is conferred to other proteins fused to these destabilizing domains. Addition of a synthetic ligand that binds to the destabilizing domains shields them from degradation, allowing fused proteins to perform their cellular functions. Genetic fusion of the destabilizing domain to a gene of interest ensures specificity, and the attendant small-molecule control confers speed, reversibility, and dose-dependence to this method. This general strategy for regulating protein stability should enable conditional perturbation of specific proteins with unprecedented control in a variety of experimental settings.
45 years of rotation of the Crab pulsar Lyne, A. G; Jordan, C. A; Graham-Smith, F ...
Monthly notices of the Royal Astronomical Society,
01/2015, Letnik:
446, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The 30-Hz rotation rate of the Crab pulsar has been monitored at Jodrell Bank Observatory since 1984 and by other observatories before then. Since 1968, the rotation rate has decreased by about ...0.5 Hz, interrupted only by sporadic and small spin-up events (glitches). 24 of these events have been observed, including a significant concentration of 15 occurring over an interval of 11 yr following MJD 50000. The monotonic decrease of the slowdown rate is partially reversed at glitches. This reversal comprises a step and an asymptotic exponential with a 320-d time constant, as determined in the three best-isolated glitches. The cumulative effect of all glitches is to reduce the decrease in slowdown rate by about 6 per cent. Overall, a low mean braking index of 2.342(1) is measured for the whole period, compared with values close to 2.5 in intervals between glitches. Removing the effects of individual glitches reveals an underlying power-law slowdown with the same braking index of 2.5. We interpret this value in terms of a braking torque due to a dipolar magnetic field in which the inclination angle between the dipole and rotation axes is increasing. There may also be further effects due to a monopolar particle wind or infalling supernova debris.
To evaluate the performance of individual biomarkers and a multi-biomarker disease activity (MBDA) score in the early rheumatoid arthritis (RA) patient population from the computer assisted ...management in early rheumatoid arthritis (CAMERA) study.
Twenty biomarkers were measured in the CAMERA cohort, in which patients were treated with either intensive or conventional methotrexate-based treatment strategies. The MBDA score was calculated using the concentrations of 12 biomarkers (SAA, IL-6, TNF-RI, VEGF-A, MMP-1, YKL-40, MMP-3, EGF, VCAM-1, leptin, resistin and CRP) according to a previously trained algorithm. The performance of the scores was evaluated relative to clinical disease activity assessments. Change in MBDA score over time was assessed by paired Wilcoxon rank sum test. Logistic regression was used to evaluate the ability of disease activity measures to predict radiographic progression.
The MBDA score had a significant correlation with the disease activity score based on 28 joints-C reactive protein (DAS28-CRP) (r=0.72; p<0.001) and an area under the receiver operating characteristic curve for distinguishing remission/low from moderate/high disease activity of 0.86 (p<0.001) using a DAS28-CRP cut-off of 2.7. In multivariate analysis the MBDA score, but not CRP, was an independent predictor of disease activity measures. Additionally, mean (SD) MBDA score decreased from 53 (18) at baseline to 39 (16) at 6 months in response to study therapy (p<0.0001). Neither MBDA score nor clinical variables were predictive of radiographic progression.
This multi-biomarker test performed well in the assessment of disease activity in RA patients in the CAMERA study. Upon further validation, this test could be used to complement currently available disease activity measures and improve patient care and outcomes.
Gaia Early Data Release 3 Hodgkin, S. T.; Harrison, D. L.; Breedt, E. ...
Astronomy and astrophysics (Berlin),
08/2021, Letnik:
652
Journal Article
Recenzirano
Odprti dostop
Context.
Since July 2014, the
Gaia
mission has been engaged in a high-spatial-resolution, time-resolved, precise, accurate astrometric, and photometric survey of the entire sky.
Aims.
We present the
...Gaia
Science Alerts project, which has been in operation since 1 June 2016. We describe the system which has been developed to enable the discovery and publication of transient photometric events as seen by
Gaia
.
Methods.
We outline the data handling, timings, and performances, and we describe the transient detection algorithms and filtering procedures needed to manage the high false alarm rate. We identify two classes of events: (1) sources which are new to
Gaia
and (2)
Gaia
sources which have undergone a significant brightening or fading. Validation of the
Gaia
transit astrometry and photometry was performed, followed by testing of the source environment to minimise contamination from Solar System objects, bright stars, and fainter near-neighbours.
Results.
We show that the
Gaia
Science Alerts project suffers from very low contamination, that is there are very few false-positives. We find that the external completeness for supernovae,
C
E
= 0.46, is dominated by the
Gaia
scanning law and the requirement of detections from both fields-of-view. Where we have two or more scans the internal completeness is
C
I
= 0.79 at 3 arcsec or larger from the centres of galaxies, but it drops closer in, especially within 1 arcsec.
Conclusions.
The per-transit photometry for
Gaia
transients is precise to 1% at
G
= 13, and 3% at
G
= 19. The per-transit astrometry is accurate to 55 mas when compared to
Gaia
DR2. The
Gaia
Science Alerts project is one of the most homogeneous and productive transient surveys in operation, and it is the only survey which covers the whole sky at high spatial resolution (subarcsecond), including the Galactic plane and bulge.
Psi4NumPy demonstrates the use of efficient computational kernels from the open-source Psi4 program through the popular NumPy library for linear algebra in Python to facilitate the rapid development ...of clear, understandable Python computer code for new quantum chemical methods, while maintaining a relatively low execution time. Using these tools, reference implementations have been created for a number of methods, including self-consistent field (SCF), SCF response, many-body perturbation theory, coupled-cluster theory, configuration interaction, and symmetry-adapted perturbation theory. Furthermore, several reference codes have been integrated into Jupyter notebooks, allowing background, underlying theory, and formula information to be associated with the implementation. Psi4NumPy tools and associated reference implementations can lower the barrier for future development of quantum chemistry methods. These implementations also demonstrate the power of the hybrid C++/Python programming approach employed by the Psi4 program.
PDF
