Artificial Light Increases Local Predator Abundance, Predation Rates, and Herbivory.

Human activity is rapidly increasing the radiance and geographic extent of artificial light at night (ALAN) leading to alterations in the development, behavior, and physiological state of many organisms. A limited number of community-scale studies investigating the effects of ALAN have allowed for spatial aggregation through positive phototaxis, the commonly observed phenomenon of arthropod movement toward light. We performed an open field study (without restricted arthropod access) to determine the effects of ALAN on local arthropod community composition, plant traits, and local herbivory and predation rates. We found strong positive phototaxis in 10 orders of arthropods, with increased (159% higher) overall arthropod abundance under ALAN compared to unlit controls. The arthropod community under ALAN was more diverse and contained a higher proportion of predaceous arthropods (15% vs 8%). Predation of immobilized flies occurred 3.6 times faster under ALAN; this effect was not observed during the day. Contrary to expectations, we also observed a 6% increase in herbivory under ALAN. Our results highlight the importance of open experimental field studies in determining community-level effects of ALAN

Integration of highly probabilistic sources into optical quantum architectures: perpetual quantum computation

In this paper we introduce a design for an optical topological cluster state computer constructed exclusively from a single quantum component. Unlike previous efforts we eliminate the need for on demand, high fidelity photon sources and detectors and replace them with the same device utilised to create photon/photon entanglement. This introduces highly probabilistic elements into the optical architecture while maintaining complete specificity of the structure and operation for a large scale computer. Photons in this system are continually recycled back into the preparation network, allowing for a arbitrarily deep 3D cluster to be prepared using a comparatively small number of photonic qubits and consequently the elimination of high frequency, deterministic photon sources.Comment: 19 pages, 13 Figs (2 Appendices with additional Figs.). Comments welcom

High-performance hybrid oxide catalyst of manganese and cobalt for low-pressure methanol synthesis

Carbon dioxide capture and use as a carbon feedstock presents both environmental and industrial benefits. Here we report the discovery of a hybrid oxide catalyst comprising manganese oxide nanoparticles supported on mesoporous spinel cobalt oxide, which catalyses the conversion of carbon dioxide to methanol at high yields. In addition, carboncarbon bond formation is observed through the production of ethylene. We document the existence of an active interface between cobalt oxide surface layers and manganese oxide nanoparticles by using X-ray absorption spectroscopy and electron energy-loss spectroscopy in the scanning transmission electron microscopy mode. Through control experiments, we find that the catalyst's chemical nature and architecture are the key factors in enabling the enhanced methanol synthesis and ethylene production. To demonstrate the industrial applicability, the catalyst is also run under high conversion regimes, showing its potential as a substitute for current methanol synthesis technologies.open2

Definitions of disease burden across the spectrum of metastatic castration-sensitive prostate cancer: comparison by disease outcomes and genomics

BACKGROUND: Several definitions have attempted to stratify metastatic castrate-sensitive prostate cancer (mCSPC) into low and high-volume states. However, at this time, comparison of these definitions is limited. Here we aim to compare definitions of metastatic volume in mCSPC with respect to clinical outcomes and mutational profiles. METHODS: We performed a retrospective review of patients with biochemically recurrent or mCSPC whose tumors underwent somatic targeted sequencing. 294 patients were included with median follow-up of 58.3 months. Patients were classified into low and high-volume disease per CHAARTED, STAMPEDE, and two numeric (≤3 and ≤5) definitions. Endpoints including radiographic progression-free survival (rPFS), time to development of castration resistance (tdCRPC), and overall survival (OS) were evaluated with Kaplan-Meier survival curves and log-rank test. The incidence of driver mutations between definitions were compared. RESULTS: Median OS and tdCRPC were shorter for high-volume than low-volume disease for all four definitions. In the majority of patients (84.7%) metastatic volume classification did not change across all four definitions. High volume disease was significantly associated with worse OS for all four definitions (CHAARTED: HR 2.89; p < 0.01, STAMPEDE: HR 3.82; p < 0.01, numeric ≤3: HR 4.67; p < 0.01, numeric ≤5: HR 3.76; p < 0.01) however, were similar for high (p = 0.95) and low volume (p = 0.79) disease across all four definitions. Those with discordant classification tended to have more aggressive clinical behavior and mutational profiles. Patients with low-volume disease and TP53 mutation experienced a more aggressive course with rPFS more closely mirroring high-volume disease. CONCLUSIONS: The spectrum of mCSPC was confirmed across four different metastatic definitions for clinical endpoints and genetics. All definitions were generally similar in classification of patients, outcomes, and genetic makeup. Given these findings, the simplicity of numerical definitions might be preferred, especially when integrating metastasis directed therapy. Incorporation of tumor genetics may allow further refinement of current metastatic definitions

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Blocking AMPK β1 myristoylation enhances AMPK activity and protects mice from high-fat diet-induced obesity and hepatic steatosis

AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis and a therapeutic target for metabolic diseases. Co/post-translational N-myristoylation of glycine-2 (Gly2) of the AMPK β subunit has been suggested to regulate the distribution of the kinase between the cytosol and membranes through a “myristoyl switch” mechanism. However, the relevance of AMPK myristoylation for metabolic signaling in cells and in vivo is unclear. Here, we generated knockin mice with a Gly2-to-alanine point mutation of AMPKβ1 (β1-G2A). We demonstrate that non-myristoylated AMPKβ1 has reduced stability but is associated with increased kinase activity and phosphorylation of the Thr172 activation site in the AMPK α subunit. Using proximity ligation assays, we show that loss of β1 myristoylation impedes colocalization of the phosphatase PPM1A/B with AMPK in cells. Mice carrying the β1-G2A mutation have improved metabolic health with reduced adiposity, hepatic lipid accumulation, and insulin resistance under conditions of high-fat diet-induced obesity

Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator

The AMP-activated protein kinase (AMPK) αβγ heterotrimer is a primary cellular energy sensor and central regulator of energy homeostasis. Activating skeletal muscle AMPK with small molecule drugs improves glucose uptake and provides an opportunity for new strategies to treat type 2 diabetes and insulin resistance, with recent genetic and pharmacological studies indicating the α2β2γ1 isoform combination as the heterotrimer complex primarily responsible. With the goal of developing α2β2-specific activators, here we perform structure/function analysis of the 2-hydroxybiphenyl group of SC4, an activator with tendency for α2-selectivity that is also capable of potently activating β2 complexes. Substitution of the LHS 2-hydroxyphenyl group with polar-substituted cyclohexene-based probes resulted in two AMPK agonists, MSG010 and MSG011, which did not display α2-selectivity when screened against a panel of AMPK complexes. By radiolabel kinase assay, MSG010 and MSG011 activated α2β2γ1 AMPK with one order of magnitude greater potency than the pan AMPK activator MK-8722. A crystal structure of MSG011 complexed to AMPK α2β1γ1 revealed a similar binding mode to SC4 and the potential importance of an interaction between the SC4 2-hydroxyl group and α2-Lys31 for directing α2-selectivity. MSG011 induced robust AMPK signalling in mouse primary hepatocytes and commonly used cell lines, and in most cases this occurred in the absence of changes in phosphorylation of the kinase activation loop residue α-Thr172, a classical marker of AMP-induced AMPK activity. These findings will guide future design of α2β2-selective AMPK activators, that we hypothesise may avoid off-target complications associated with indiscriminate activation of AMPK throughout the body

DNA Dynamics Is Likely to Be a Factor in the Genomic Nucleotide Repeats Expansions Related to Diseases

Trinucleotide repeats sequences (TRS) represent a common type of genomic DNA motif whose expansion is associated with a large number of human diseases. The driving molecular mechanisms of the TRS ongoing dynamic expansion across generations and within tissues and its influence on genomic DNA functions are not well understood. Here we report results for a novel and notable collective breathing behavior of genomic DNA of tandem TRS, leading to propensity for large local DNA transient openings at physiological temperature. Our Langevin molecular dynamics (LMD) and Markov Chain Monte Carlo (MCMC) simulations demonstrate that the patterns of openings of various TRSs depend specifically on their length. The collective propensity for DNA strand separation of repeated sequences serves as a precursor for outsized intermediate bubble states independently of the G/C-content. We report that repeats have the potential to interfere with the binding of transcription factors to their consensus sequence by altered DNA breathing dynamics in proximity of the binding sites. These observations might influence ongoing attempts to use LMD and MCMC simulations for TRS–related modeling of genomic DNA functionality in elucidating the common denominators of the dynamic TRS expansion mutation with potential therapeutic applications

Transport of Charged Aerosol OT Inverse Micelles in Nonpolar Liquids

Surfactants such as Aerosol OT (AOT) are commonly used to stabilize and electrically charge nonpolar colloids in devices such as electronic ink displays. The electrical behavior of such devices is strongly influenced by the presence of charged inverse micelles, formed by excess surfactant that does not cover the particles. The presence of charged inverse micelles results in increased conductivity of the solution, affecting both the energy consumption of the device and its switching characteristics. In this work, we use transient current measurements to investigate the electrical properties of suspensions of the surfactant Aerosol OT in dodecane. No particles are added, to isolate the effect of excess surfactant. The measured currents upon application of a voltage step are found to be exponentially decaying, and can be described by an analytical model based on an equivalent electric circuit. This behavior is physically interpreted, first by the high generation rate of charged inverse micelles giving the suspension resistor like properties, and second by the buildup of layers of charged inverse micelles at both electrodes, acting as capacitors. The model explains the measurements over a large range of surfactant concentrations, applied voltages, and device thicknesses