HTS driven by fluorescence lifetime detection of FRET identifies activators and inhibitors of cardiac myosin.

Small molecules that bind to allosteric sites on target proteins to alter protein function are highly sought in drug discovery. High-throughput screening (HTS) assays are needed to facilitate the direct discovery of allosterically active compounds. We have developed technology for high-throughput time-resolved fluorescence lifetime detection of fluorescence resonance energy transfer (FRET), which enables the detection of allosteric modulators by monitoring changes in protein structure. We tested this approach at the industrial scale by adapting an allosteric FRET sensor of cardiac myosin to high-throughput screening (HTS), based on technology provided by Photonic Pharma and the University of Minnesota, and then used the sensor to screen 1.6 million compounds in the HTS facility at Bristol Myers Squibb. The results identified allosteric activators and inhibitors of cardiac myosin that do not compete with ATP binding, demonstrating high potential for FLT-based drug discovery.

A fast radio burst source at a complex magnetized site in a barred galaxy.

Fast radio bursts (FRBs) are highly dispersed, millisecond-duration radio bursts1-3. Recent observations of a Galactic FRB4-8 suggest that at least some FRBs originate from magnetars, but the origin of cosmological FRBs is still not settled. Here we report the detection of 1,863 bursts in 82 h over 54 days from the repeating source FRB 20201124A (ref. 9). These observations show irregular short-time variation of the Faraday rotation measure (RM), which scrutinizes the density-weighted line-of-sight magnetic field strength, of individual bursts during the first 36 days, followed by a constant RM. We detected circular polarization in more than half of the burst sample, including one burst reaching a high fractional circular polarization of 75%. Oscillations in fractional linear and circular polarizations, as well as polarization angle as a function of wavelength, were detected. All of these features provide evidence for a complicated, dynamically evolving, magnetized immediate environment within about an astronomical unit (AU; Earth-Sun distance) of the source. Our optical observations of its Milky-Way-sized, metal-rich host galaxy10-12 show a barred spiral, with the FRB source residing in a low-stellar-density interarm region at an intermediate galactocentric distance. This environment is inconsistent with a young magnetar engine formed during an extreme explosion of a massive star that resulted in a long gamma-ray burst or superluminous supernova.

Evolving and evaluation of 3LP FFBP deterministic ANN model for district level long range monsoon rainfall prediction.

In order to develop a forecasting model for monsoon rainfall over the districts of Chhattisgarh, 3LP (Three Layer Perception) FFBP (Feed Forward Back Propagation) Deterministic ANN models have been proposed. In the proposed model, eleven neurons in input layer, one hidden layer with eleven neurons, a single neuron in output layer, 132 trainable weights in three layers, transfer function sigmoid 1/(1+e -deltax+eta)) with slope ä = 1, threshold ç = 0 have been used to evolve networks. Training of the network is continued till the mean square error becomes less than a pre-assigned value ranging from 0.0005 to 0.001. Data for the years 1945-2006 have been used, out of which the data of first 51 years, i.e., (-deltax + eta) 1945-1995, are used for training the network and data for the remaining period, i.e. during the period 1996-2006 are used independently for validation. In the present study, it has been observed that the mean absolute deviation (% of mean) values for the independent period (1996-2006) are less than and half of the standard deviation (% of mean) for all the districts. The performances of these 3LP FFBP Deterministic ANN models have been found to be extremely good and better evaluated over statistical trend models also. The models developed and their evaluations have been presented in this paper.

Magnitude Bias of Microlensed Sources toward the Large Magellanic Cloud.

There are lines of evidence suggesting that some of the observed microlensing events in the direction of the Large Magellanic Cloud (LMC) are caused by ordinary star lenses as opposed to dark MACHOs in the Galactic halo. Efficient lensing by ordinary stars generally requires the presence of one or more additional concentrations of stars along the line of sight to the LMC disk. If such a population behind the LMC disk exists, then the source stars (for lensing by LMC disk objects) will be drawn preferentially from the background population and will show systematic differences from LMC field stars. One such difference is that the (lensed) source stars will be farther away than the average LMC field stars, and this should be reflected in their apparent baseline magnitudes. We focus on red clump stars; these should appear in the color-magnitude diagram at a few tenths of a magnitude fainter than the field red clump. Suggestively, one of the two near-clump confirmed events, MACHO-LMC-1, is a few tenths of magnitude fainter than the clump.

What the Longest Exposures from the Hubble Space Telescope Will eveal.

Detailed simulations are presented of the longest exposures on representative fields that will be obtained with the Hubble Space Telescope, as well as predictions for the numbers and types of objects that will be recorded with exposures of different durations. The Hubble Space Telescope will reveal the shapes, sizes, and content of faint, distant galaxies and could discover a new population of Galactic stars.