On-chip polarimetry for high-throughput screening of nanoliter and smaller sample volumes

A polarimetry technique for measuring optical activity that is particularly suited for high throughput screening employs a chip or substrate (22) having one or more microfluidic channels (26) formed therein. A polarized laser beam (14) is directed onto optically active samples that are disposed in the channels. The incident laser beam interacts with the optically active molecules in the sample, which slightly alter the polarization of the laser beam as it passes multiple times through the sample. Interference fringe patterns (28) are generated by the interaction of the laser beam with the sample and the channel walls. A photodetector (34) is positioned to receive the interference fringe patterns and generate an output signal that is input to a computer or other analyzer (38) for analyzing the signal and determining the rotation of plane polarized light by optically active material in the channel from polarization rotation calculations

Synthesis and multiplexed activity profiling of synthetic acylphloroglucinol scaffolds

Reported here are novel formic-acid-mediated rearrangements of dearomatized acylphloroglucinols to access a structurally diverse group of synthetic acylphloroglucinol scaffolds (SASs). Density-functional theory (DFT) optimized orbital and stereochemical analyses shed light on the mechanism of these rearrangements. Products were evaluated by multiplexed activity profiling (MAP), an unbiased platform which assays multiple biological readouts simultaneously at single-cell resolution for markers of cell signaling, and can aid in distinguishing genuine activity from assay interference. MAP identified a number of SASs that suppressed pS6 (Ser235/236), a marker for activation of the mTOR and ERK signaling pathways. These results illustrate how biomimetic synthesis and multiplexed activity profiling can reveal the pharmacological potential of novel chemotypes by diversity-oriented synthesis.R35 GM118173 - NIGMS NIH HHS; R01 CA226833 - NCI NIH HHS; U01 TR002625 - NCATS NIH HHS; R24 GM111625 - NIGMS NIH HHS; R01 GM092218 - NIGMS NIH HHS; P30 DK058404 - NIDDK NIH HHS; P41 GM076263 - NIGMS NIH HHS; T32 GM007347 - NIGMS NIH HHS; F30 CA236131 - NCI NIH HHS; P30 CA068485 - NCI NIH HHS; T32 GM065086 - NIGMS NIH HHSAccepted manuscrip

Progression of diabetes retinal status within community screening programmes and potential implications for screening intervals

Objective This study aimed to follow the natural progression of retinal changes in patients with diabetes. Such information should inform decisions with regard to the screening intervals for such patients Research Design and Methods An observational study was undertaken linking the data from seven diabetes retinal screening programmes across the UK for retinal grading results between 2005 and 2012. Patients with absent or background retinopathy were followed up for progression to the endpoints referable retinopathy, and treatable retinopathy (proliferative retinopathy). Results In total 354,549 patients were observed for up to four years during which 16,196 progressed to referable retinopathy. Of patients with no retinopathy in either eye for two successive screening episodes at least 12 months apart between 0.3 (95% confidence interval 0.3-0.8)% and 1.3 (1.0-1.6)% progressed to referable retinopathy and rates of treatable eye disease were less than 0.3% at two years. The corresponding progression rates for patients with bilateral background retinopathy in successive screening episodes was 13-29% and up to 4% respectively in the different programmes. Conclusions It may be possible to risk stratify patients according to baseline retinal criteria into low and high risk of progressing to proliferative retinopathy. Screening intervals for such diverse groups of patients could safely be modified according to their risk

The Gravity Collective: A Search for the Electromagnetic Counterpart to the Neutron Star-Black Hole Merger GW190814

We present optical follow-up imaging obtained with the Katzman Automatic Imaging Telescope, Las Cumbres Observatory Global Telescope Network, Nickel Telescope, Swope Telescope, and Thacher Telescope of the LIGO/Virgo gravitational wave (GW) signal from the neutron star-black hole (NSBH) merger GW190814. We searched the GW190814 localization region (19 deg$^{2}$ for the 90th percentile best localization), covering a total of 51 deg$^{2}$ and 94.6% of the two-dimensional localization region. Analyzing the properties of 189 transients that we consider as candidate counterparts to the NSBH merger, including their localizations, discovery times from merger, optical spectra, likely host-galaxy redshifts, and photometric evolution, we conclude that none of these objects are likely to be associated with GW190814. Based on this finding, we consider the likely optical properties of an electromagnetic counterpart to GW190814, including possible kilonovae and short gamma-ray burst afterglows. Using the joint limits from our follow-up imaging, we conclude that a counterpart with an $r$-band decline rate of 0.68 mag day$^{-1}$, similar to the kilonova AT 2017gfo, could peak at an absolute magnitude of at most $-17.8$ mag (50% confidence). Our data are not constraining for ''red'' kilonovae and rule out ''blue'' kilonovae with $M>0.5 M_{\odot}$ (30% confidence). We strongly rule out all known types of short gamma-ray burst afterglows with viewing angles $<$17$^{\circ}$ assuming an initial jet opening angle of $\sim$$5.2^{\circ}$ and explosion energies and circumburst densities similar to afterglows explored in the literature. Finally, we explore the possibility that GW190814 merged in the disk of an active galactic nucleus, of which we find four in the localization region, but we do not find any candidate counterparts among these sources.Comment: 86 pages, 9 figure

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Nitrososynthase-Triggered Oxidative Carbon–Carbon Bond Cleavage in Baumycin Biosynthesis

Baumycins are coproduced with the clinically important anticancer secondary metabolites daunorubicin and doxorubicin, which are glycosylated anthracyclines isolated from Streptomyces peucetius. The distinguishing feature of baumycins is the presence of an unusual acetal moiety appended to daunosamine, which is hydrolyzed during acidic extraction of daunorubicin from fermentation broth. The structure of the baumycin acetal suggests that it is likely derived from an unknown C3″-methyl deoxysugar cleaved between the C3″ and C4″ positions. This is supported by analysis of the baumycin/daunorubicin biosynthetic gene cluster (<i>dox</i>), which also encodes putative proteins consistent with production of an anthracycline dissacharide containing a branched sugar. Notably, the <i>dnmZ</i> gene in the <i>dox</i> gene cluster possesses high translated sequence similarity to nitrososynthases, which are flavin-dependent amine monooxygenases involved in the four-electron oxidation of amino sugars to nitroso sugars. Herein we demonstrate that DnmZ is an amino sugar nitrososynthase that initiates the conversion of thymidine-5′-diphosphate-l-<i>epi</i>-vancosamine to a ring-opened product via a previously uncharacterized retro oxime-aldol reaction