In vivo E2F reporting reveals efficacious schedules of MEK1/2–CDK4/6 targeting and mTOR–s6 resistance mechanisms

Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho-S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho-S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor AZD2014. Mechanistically, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance. SIGnIFICAnCE: Mutant BRAF and NRAS melanomas acquire resistance to combined MEK and CDK4/6 inhibition via upregulation of mTOR pathway signaling. This resistance mechanism provides the preclinical basis to utilize mTORC1/2 inhibitors to improve MEKi plus CDK4/6i drug regimens

Location Dependent Dirichlet Processes

Dirichlet processes (DP) are widely applied in Bayesian nonparametric modeling. However, in their basic form they do not directly integrate dependency information among data arising from space and time. In this paper, we propose location dependent Dirichlet processes (LDDP) which incorporate nonparametric Gaussian processes in the DP modeling framework to model such dependencies. We develop the LDDP in the context of mixture modeling, and develop a mean field variational inference algorithm for this mixture model. The effectiveness of the proposed modeling framework is shown on an image segmentation task

Improving detection of surface discontinuities in visual-force control systms

In this paper, a new approach to detect surface discontinuities in a visual–force control task is described. A task which consists in tracking a surface using visual–force information is shown. In this task, in order to reposition the robot tool with respect to the surface it is necessary to determine the surface discontinuities. This paper describes a new method to detect surface discontinuities employing sensorial information obtained from a force sensor, a camera and structured light. This method has proved to be more robust than previous systems even in situations where high frictions occur

Termites mitigate the effects of drought in tropical rainforest

Acknowledgments: This work was supported by the South East Asia Rainforest Research Partnership (SEARRP) with permission from the Maliau Basin Management Committee. We thank G. Reynolds, U. Jami, and L. Kruitbos for coordinating fieldwork; S. Both and U. Kritzler for help in establishing the experimental plots; R. Walsh for providing rainfall data; and A. Zanne and A. Cheesman for discussions on experimental design. We thank J. Nash from Bayer Southeast Asia Pte-Ltd, Singapore, for donating Premise 200SC and Agenda 10SC. We thank J. Rees, A. Tagliabue, M. Begon, R. Williams, W. Cheng, C. Dahlsjö, R. Kitching, and J. Barlow for comments on the manuscript. Finally, we thank all our field assistants: R. Binti Manber, A. Jupri, F. John, Y. Binti Suffian, E. Bin Esing, D. Bin Paul, Z. Bin Angau, A. Allbanah Bin Anchun, N. Angau, D. Ku Shamirah Binti Pg Bakar, E. Binti Nahun, R. Rusili, A. Bin Rantau, R. Bin Sahamin, A. Mastor, M. Adzim Bin Rahili, M. Azuan, H. Nasir, and N. Fazzli. Funding: This publication is a contribution from the UK NERC-funded Biodiversity And Land-use Impacts on Tropical Ecosystem Function (BALI) consortium (NERC grant NE/L000016/1). Author contributions: C.L.P., H.M.G., L.A.A., P.E., and T.A.E. conceived and designed the experiment; C.L.P., P.E., and T.A.E. established the experimental plots; H.M.G., L.A.A., and P.E. collected the data; H.M.G., L.A.A., P.E., and R.K.D. analyzed the data; C.S.V., F.H., and H.S.T. carried out laboratory analysis; H.M.G. and L.A.A. led the writing of the manuscript with significant input from C.L.P., P.E., R.K.D., and Y.A.T. Competing interests: None declared. Data and materials availability: Data have been deposited in the NERC Environmental Information Data Centre (37).Peer reviewedPostprin

The impact of logging on vertical canopy structure across a gradient of tropical forest degradation intensity in Borneo

Forest degradation through logging is pervasive throughout the world's tropical forests, leading to changes in the three-dimensional canopy structure that have profound consequences for wildlife, microclimate and ecosystem functioning. Quantifying these structural changes is fundamental to understanding the impact of degradation, but is challenging in dense, structurally complex forest canopies. We exploited discrete-return airborne LiDAR surveys across a gradient of logging intensity in Sabah, Malaysian Borneo, and assessed how selective logging had affected canopy structure (Plant Area Index, PAI, and its vertical distribution within the canopy). LiDAR products compared well to independent, analogue models of canopy structure produced from detailed ground-based inventories undertaken in forest plots, demonstrating the potential for airborne LiDAR to quantify the structural impacts of forest degradation at landscape scale, even in some of the world's tallest and most structurally complex tropical forests. Plant Area Index estimates across the plot network exhibited a strong linear relationship with stem basal area (R2 = 0.95). After at least 11–14 years of recovery, PAI was ~28% lower in moderately logged plots and ~52% lower in heavily logged plots than that in old-growth forest plots. These reductions in PAI were associated with near-complete lack of trees >30-m tall, which had not been fully compensated for by increasing plant area lower in the canopy. This structural change drives a marked reduction in the diversity of canopy environments, with the deep, dark understorey conditions characteristic of old-growth forests far less prevalent in logged sites. Full canopy recovery is likely to take decades. Synthesis and applications. Effective management and restoration of tropical forests requires detailed monitoring of the forest and its environment. We demonstrate that airborne LiDAR can effectively map the canopy architecture of the complex tropical forests of Borneo, capturing the three-dimensional impact of degradation on canopy structure at landscape scales, therefore facilitating efforts to restore and conserve these ecosystems

Reconstruction of the equation of state for the cyclic universes in homogeneous and isotropic cosmology

We study the cosmological evolutions of the equation of state (EoS) for the universe in the homogeneous and isotropic Friedmann-Lema\^{i}tre-Robertson-Walker (FLRW) space-time. In particular, we reconstruct the cyclic universes by using the Weierstrass and Jacobian elliptic functions. It is explicitly illustrated that in several models the universe always stays in the non-phantom (quintessence) phase, whereas there also exist models in which the crossing of the phantom divide can be realized in the reconstructed cyclic universes.Comment: 29 pages, 8 figures, version accepted for publication in Central European Journal of Physic

The influence of feature selection methods on accuracy, stability and interpretability of molecular signatures

Motivation: Biomarker discovery from high-dimensional data is a crucial problem with enormous applications in biology and medicine. It is also extremely challenging from a statistical viewpoint, but surprisingly few studies have investigated the relative strengths and weaknesses of the plethora of existing feature selection methods. Methods: We compare 32 feature selection methods on 4 public gene expression datasets for breast cancer prognosis, in terms of predictive performance, stability and functional interpretability of the signatures they produce. Results: We observe that the feature selection method has a significant influence on the accuracy, stability and interpretability of signatures. Simple filter methods generally outperform more complex embedded or wrapper methods, and ensemble feature selection has generally no positive effect. Overall a simple Student's t-test seems to provide the best results. Availability: Code and data are publicly available at http://cbio.ensmp.fr/~ahaury/

Reverse electrowetting as a new approach to high-power energy harvesting

Over the last decade electrical batteries have emerged as a critical bottleneck for portable electronics development. High-power mechanical energy harvesting can potentially provide a valuable alternative to the use of batteries, but, until now, a suitable mechanical-to-electrical energy conversion technology did not exist. Here we describe a novel mechanical-to-electrical energy conversion method based on the reverse electrowetting phenomenon. Electrical energy generation is achieved through the interaction of arrays of moving microscopic liquid droplets with novel nanometer-thick multilayer dielectric films. Advantages of this process include the production of high power densities, up to 103 W m−2; the ability to directly utilize a very broad range of mechanical forces and displacements; and the ability to directly output a broad range of currents and voltages, from several volts to tens of volts. These advantages make this method uniquely suited for high-power energy harvesting from a wide variety of environmental mechanical energy sources

Bitter Melon (Momordica charantia) Extract Inhibits Tumorigenicity and Overcomes Cisplatin-Resistance in Ovarian Cancer Cells Through Targeting AMPK Signaling Cascade

OBJECTIVE: Acquired chemoresistance is a major obstacle in the clinical management of ovarian cancer. Therefore, searching for alternative therapeutic modalities is urgently needed. Bitter melon (Momordica charantia) is a traditional dietary fruit, but its extract also shows potential medicinal values in human diabetes and cancers. Here, we sought to investigate the extract of bitter melon (BME) in antitumorigenic and cisplatin-induced cytotoxicity in ovarian cancer cells. METHODS: Three varieties of bitter melon were used to prepare the BME. Ovarian cancer cell lines, human immortalized epithelial ovarian cells (HOSEs), and nude mice were used to evaluate the cell cytotoxicity, cisplatin resistance, and tumor inhibitory effect of BME. The molecular mechanism of BME was examined by Western blotting. RESULTS: Cotreatment with BME and cisplatin markedly attenuated tumor growth in vitro and in vivo in a mouse xenograft model, whereas there was no observable toxicity in HOSEs or in nude mice in vivo. Interestingly, the antitumorigenic effects of BME varied with different varieties of bitter melon, suggesting that the amount of antitumorigenic substances may vary. Studies of the molecular mechanism demonstrated that BME activates AMP-activated protein kinase (AMPK) in an AMP-independent but CaMKK (Ca2+/calmodulin-dependent protein kinase)-dependent manner, exerting anticancer effects through activation of AMPK and suppression of the mTOR/p70S6K and/or the AKT/ERK/FOXM1 (Forkhead Box M1) signaling cascade. CONCLUSION: BME functions as a natural AMPK activator in the inhibition of ovarian cancer cell growth and might be useful as a supplement to improve the efficacy of cisplatin-based chemotherapy in ovarian cancer.published_or_final_versio