A Fluorescent Kinase Inhibitor that Exhibits Diagnostic Changes in Emission upon Binding

The development of a fluorescent LCK inhibitor that exhibits favourable solvatochromic properties upon binding the kinase is described. Fluorescent properties were realised through the inclusion of a prodan-derived fluorophore into the pharmacophore of an ATP-competitive kinase inhibitor. Fluorescence titration experiments demonstrate the solvatochromic properties of the inhibitor, in which dramatic increase in emission intensity and hypsochromic shift in emission maxima are clearly observed upon binding LCK. Microscopy experiments in cellular contexts together with flow cytometry show that the fluorescence intensity of the inhibitor correlates with the LCK concentration. Furthermore, multiphoton microscopy experiments demonstrate both the rapid cellular uptake of the inhibitor and that the two-photon cross section of the inhibitor is amenable for excitation at 700 nm

Shining New Light on the Spiropyran Photoswitch: A Photocage Decides between cis-trans or Spiro-Merocyanine Isomerization

Photochromic molecules from the spiropyran family are known to undergo light-induced interconversion between the colorless spiro- and the colored merocyanine forms. Here, we show for the first time that small structural modifications open up for an additional photoisomerization mode: reversible cis–trans isomerization of the merocyanine. Moreover, the introduction of a photocage allows for light-activated switching between the two modes

Historical changes in the phenology of British Odonata are related to climate

Responses of biota to climate change take a number of forms including distributional shifts, behavioural changes and life history changes. This study examined an extensive set of biological records to investigate changes in the timing of life history transitions (specifically emergence) in British Odonata between 1960 and 2004. The results show that there has been a significant, consistent advance in phenology in the taxon as a whole over the period of warming that is mediated by life history traits. British odonates significantly advanced the leading edge (first quartile date) of the flight period by a mean of 1.51 ±0.060 (SEM, n=17) days per decade or 3.08±1.16 (SEM, n=17) days per degree rise in temperature when phylogeny is controlled for. This study represents the first review of changes in odonate phenology in relation to climate change. The results suggest that the damped temperature oscillations experienced by aquatic organisms compared with terrestrial organisms are sufficient to evoke phenological responses similar to those of purely terrestrial taxa

Design and development of photoswitchable DFG-Out RET kinase inhibitors

REarranged during Transfection (RET) is a transmembrane receptor tyrosine kinase that is required for development of multiple human tissues, but which is also an important contributor to human cancers. RET activation through rearrangement or point mutations occurs in thyroid and lung cancers. Furthermore, activation of wild type RET is an increasingly recognized mechanism promoting tumor growth and dissemination of a much broader group of cancers. RET is therefore an attractive therapeutic target for small-molecule kinase inhibitors. Non-invasive control of RET signaling with light offers the promise of unveiling its complex spatiotemporal dynamics in vivo. In this work, photoswitchable DFG-out RET kinase inhibitors based on heterocycle-derived azobenzenes were developed, enabling photonic control of RET activity. Based on the binding mode of DFG-out kinase inhibitors and using RET kinase as the test model, we developed a photoswitchable inhibitor with a quinoline “head” constituting the azoheteroarene. This azo compound was further modified by three different strategies to increase the difference in biological activity between the E-isomer and the light enriched Z-isomer. Stilbene-based derivatives were used as model compounds to guide in the selection of substituents that could eventually be introduced to the corresponding azo compounds. The most promising quinoline-based compound showed more than a 15-fold difference in bioactivity between the two isomers in a biochemical assay. However, the same compound showed a decreased Z/E (IC50) ratio in the cellular assay, tentatively assigned to stability issues. The corresponding stilbene compound gave a Z/E (IC50) ratio well above 100, consistent with that measured in the biochemical assay. Ultimately, a 7-azaindole based photoswitchable DFG-out kinase inhibitor was shown to display more than a 10-fold difference in bioactivity between the two isomers, in both a biochemical and a cell-based assay, as well as excellent stability even under reducing conditions

A review of critical project management techniques to enhance construction SMEs project performance

Abstract: Performance is linked with implementation of project management techniques. Literature suggests that problems such as inefficiency, poor budgetary issues, improper planning, scheduling and control in projects execution are associated with inadequate implementation of the essential techniques for meeting project deliverables. These shortcomings are prevalent among Small and Medium Enterprises (SMEs) in the developing countries including South Africa. Hence, the primary objective of this paper is to review the critical project management techniques for the improvement of construction project performance especially among SMEs in South Africa. The study is based on previous literature on construction SMEs project performance as well as project management techniques implementation. The literature review centered on both international and South African context. The study revealed that critical path method, work breakdown structure, and earned value management analysis were the most occurring project management techniques from the sampled literature. Findings from this study are envisaged to be beneficial to construction stakeholders in developing relevant project management techniques to improve the performance of SMEs

Maximum-Reward Motion in a Stochastic Environment: The Nonequilibrium Statistical Mechanics Perspective

We consider the problem of computing the maximum-reward motion in a reward field in an online setting. We assume that the robot has a limited perception range, and it discovers the reward field on the fly. We analyze the performance of a simple, practical lattice-based algorithm with respect to the perception range. Our main result is that, with very little perception range, the robot can collect as much reward as if it could see the whole reward field, under certain assumptions. Along the way, we establish novel connections between this class of problems and certain fundamental problems of nonequilibrium statistical mechanics . We demonstrate our results in simulation examples

Photon echo studies of photosynthetic light harvesting

The broad linewidths in absorption spectra of photosynthetic complexes obscure information related to their structure and function. Photon echo techniques represent a powerful class of time-resolved electronic spectroscopy that allow researchers to probe the interactions normally hidden under broad linewidths with sufficient time resolution to follow the fastest energy transfer events in light harvesting. Here, we outline the technical approach and applications of two types of photon echo experiments: the photon echo peak shift and two-dimensional (2D) Fourier transform photon echo spectroscopy. We review several extensions of these techniques to photosynthetic complexes. Photon echo peak shift spectroscopy can be used to determine the strength of coupling between a pigment and its surrounding environment including neighboring pigments and to quantify timescales of energy transfer. Two-dimensional spectroscopy yields a frequency-resolved map of absorption and emission processes, allowing coupling interactions and energy transfer pathways to be viewed directly. Furthermore, 2D spectroscopy reveals structural information such as the relative orientations of coupled transitions. Both classes of experiments can be used to probe the quantum mechanical nature of photosynthetic light-harvesting: peak shift experiments allow quantification of correlated energetic fluctuations between pigments, while 2D techniques measure quantum beating directly, both of which indicate the extent of quantum coherence over multiple pigment sites in the protein complex. The mechanistic and structural information obtained by these techniques reveals valuable insights into the design principles of photosynthetic light-harvesting complexes, and a multitude of variations on the methods outlined here

Jupiter's X‐Ray and UV Dark Polar Region

We present 14 simultaneous Chandra X-ray Observatory (CXO)-Hubble Space Telescope (HST) observations of Jupiter's Northern X-ray and ultraviolet (UV) aurorae from 2016 to 2019. Despite the variety of dynamic UV and X-ray auroral structures, one region is conspicuous by its persistent absence of emission: the dark polar region (DPR). Previous HST observations have shown that very little UV emission is produced by the DPR. We find that the DPR also produces very few X-ray photons. For all 14 observations, the low level of X-ray emission from the DPR is consistent (within 2-standard deviations) with scattered solar emission and/or photons spread by Chandra's Point Spread Function from known X-ray-bright regions. We therefore conclude that for these 14 observations the DPR produced no statistically significant detectable X-ray signature