Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity.

Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles

A clumpy and anisotropic galaxy halo at z=1 from gravitational-arc tomography

Every star-forming galaxy has a halo of metal-enriched gas extending out to at least 100 kpc, as revealed by the absorption lines this gas imprints on the spectra of background quasars. However, quasars are sparse and typically probe only one narrow pencil beam through the intervening galaxy. Close quasar pairs and gravitationally lensed quasars have been used to circumvent this inherently one-dimensional technique, but these objects are rare and the structure of the circum-galactic medium remains poorly constrained. As a result, our understanding of the physical processes that drive the re-cycling of baryons across the lifetime of a galaxy is limited. Here we report integral-field (tomographic) spectroscopy of an extended background source -a bright giant gravitational arc. We can thus coherently map the spatial and kinematic distribution of Mg II absorption -a standard tracer of enriched gas- in an intervening galaxy system at redshift 0.98 (i.e., ~8 Gyr ago). Our gravitational-arc tomography unveils a clumpy medium in which the absorption-strength decreases with increasing impact parameter, in good agreement with the statistics towards quasars; furthermore, we find strong evidence that the gas is not distributed isotropically. Interestingly, we detect little kinematic variation over a projected area of ~600 kpc squared, with all line-of-sight velocities confined to within a few tens of km/s of each other. These results suggest that the detected absorption originates from entrained recycled material, rather than in a galactic outflow.Comment: Published online in Nature on 31 January 201

Fast Synthetic Dataset for Kitchen Object Segmentation in Deep Learning

Object recognition has been widely investigated in computer vision for many years. Currently, this process is carried out through neural networks, but there are very few public datasets available with mask and class labels of the objects for the training process in usual applications. In this paper, we address the problem of fast generation of synthetic datasets to train neural models because creating a handcraft labeled dataset with object segmentation is a very tedious and time-consuming task. We propose an efficient method to generate a synthetic labeled dataset that adequately combines background images with foreground segmented objects. The synthetic images can be created automatically with random positioning of the objects or, alternatively, the method can produce realistic images by keeping the realism in the scales and positions of the objects. Then, we employ Mask-RCNN deep learning model, to detect and segment classes of kitchen objects using images. In the experimental evaluation, we study both synthetic datasets, automatic or realistic, and we compare the results. We analyze the performance with the most widely used indexes and check that the realistic synthetic dataset, quickly created through our method, can provide competitive results and accurately classify the different objects

Fertility and survival of Swedish Red and White × Holstein crossbred cows and purebred Holstein cows

Swedish Red and White × Holstein (S×H) cows were compared with pure Holstein (HOL) cows for fertility and survival traits in 2 commercial dairy farms in central-southern Córdoba province, Argentina, over 6 years (2008–2013). The following traits were evaluated: first service conception rate (FSCR), overall conception rate (CR), number of services per conception (SC), days open (DO), mortality rate, culling rate, survival to subsequent calvings, and length of productive life (LPL). The data set consisted of 506 lactations from 240 S×H crossbred cows and 1,331 lactations from 576 HOL cows. The FSCR and CR were analyzed using logistic regression, DO and LPL were analyzed using a Cox's proportional hazards regression model, and differences of proportions were calculated for mortality rate, culling rate, and survival to subsequent calvings. The S×H cows were superior to HOL cows in overall lactations for all the fertility traits (+10.5% FSCR, +7.7% CR, −0.5 SC, and 35 fewer DO). During the first lactation, S×H cows were superior to HOL cows for all fertility traits (+12.8% FSCR, +8.0% CR, −0.4 SC, and 34 fewer DO). In the second lactation, S×H cows exhibited lower SC (−0.5) and 21 fewer DO than HOL cows. In the third or greater lactations, S×H cows showed higher FSCR (+11.0%) and CR (+12.2%), lower SC (−0.8), and 44 fewer DO than pure HOL cows. In addition, S×H cows had a lower mortality rate (−4.7%) and a lower culling rate (−13.7%) than HOL cows. Due to the higher fertility and lower mortality and culling rates, the S×H cows had higher survival to the second (+9.2%), third (+16.9%), and fourth (+18.7%) calvings than HOL cows. Because of these results, S×H cows had longer LPL (+10.3 mo) than HOL cows. These results indicate that S×H cows had higher fertility and survival than HOL cows on commercial dairy farms in Argentina.Fil: Pipino, D. F.. Universidad Nacional de Río Cuarto. Facultad de Agronomía y Veterinaria. Departamento de Producción Animal; ArgentinaFil: Piccardi, Mónica Belén. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias. Unidad de Fitopatología y Modelización Agrícola - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Fitopatología y Modelización Agrícola; ArgentinaFil: Lopez Villalobos, Nicolas. Massey University; Nueva ZelandaFil: Hickson, R. E.. Massey University; Nueva ZelandaFil: Vazquez, Maria Isabel. Universidad Nacional de Río Cuarto. Facultad de Agronomía y Veterinaria. Departamento de Producción Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentin

A low-mass planet candidate orbiting Proxima Centauri at a distance of 1.5 AU

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).Our nearest neighbor, Proxima Centauri, hosts a temperate terrestrial planet. We detected in radial velocities evidence of a possible second planet with minimum mass m c sin i c = 5.8 ± 1.9 M ⊕ and orbital period P c = 5.21 - 0.22 + 0.26 years. The analysis of photometric data and spectro-scopic activity diagnostics does not explain the signal in terms of a stellar activity cycle, but follow-up is required in the coming years for confirming its planetary origin. We show that the existence of the planet can be ascertained, and its true mass can be determined with high accuracy, by combining Gaia astrometry and radial velocities. Proxima c could become a prime target for follow-up and characterization with next-generation direct imaging instrumentation due to the large maximum angular separation of ~1 arc second from the parent star. The candidate planet represents a challenge for the models of super-Earth formation and evolution.Peer reviewedFinal Published versio

Comparative evaluation of solubility, cytotoxicity and photostability studies of resveratrol and oxyresveratrol loaded nanosponges

Resveratrol and oxyresveratrol are natural polyphenolic stilbenes with several important pharmacological activities. However, low solubility and aqueous instability are the major limitations in their drug delivery applications. In the present work, we demonstrated the encapsulation of resveratrol and oxyresveratrol with nanosponge to improve solubility and stability. Several characterization techniques were used to confirm the encapsulation of both drug molecules within the nanosponges. The high encapsulation efficiency of resveratrol (77.73%) and oxyresveratrol (80.33%) was achieved within the nanosponges. Transmission electron microscopy suggested uniform spherical size particles of resveratrol and oxyresveratrol loaded nanosponges. Compared to free drugs, better protection against UV degradation was observed for resveratrol-loaded nanosponge (2-fold) and oxyresveratrol-loaded nanosponge (3-fold). Moreover, a higher solubilization of resveratrol- and oxyresveratrol-loaded nanosponges lead to a better antioxidant activity compared to drug molecules alone. Cytotoxicity studies against DU-145 prostate cancer cell lines further suggested improved activity of both resveratrol and oxyresveratrol-loaded nanosponges without any significant toxicity of blank nanosponges

Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem.

Rap1 GTPases bind effectors, such as RIAM, to enable talin1 to induce integrin activation. In addition, Rap1 binds directly to the talin1 F0 domain (F0); however, this interaction makes a limited contribution to integrin activation in CHO cells or platelets. Here, we show that talin1 F1 domain (F1) contains a previously undetected Rap1-binding site of similar affinity to that in F0. A structure-guided point mutant (R118E) in F1, which blocks Rap1 binding, abolishes the capacity of Rap1 to potentiate talin1-induced integrin activation. The capacity of F1 to mediate Rap1-dependent integrin activation depends on a unique loop in F1 that has a propensity to form a helix upon binding to membrane lipids. Basic membrane-facing residues of this helix are critical, as charge-reversal mutations led to dramatic suppression of talin1-dependent activation. Thus, a novel Rap1-binding site and a transient lipid-dependent helix in F1 work in tandem to enable a direct Rap1-talin1 interaction to cause integrin activation

Undirected singing rate as a non-invasive tool for welfare monitoring in isolated male zebra finches

Research on the songbird zebra finch (Taeniopygia guttata) has advanced our behavioral, hormonal, neuronal, and genetic understanding of vocal learning. However, little is known about the impact of typical experimental manipulations on the welfare of these birds. Here we explore whether the undirected singing rate can be used as an indicator of welfare. We tested this idea by performing a post hoc analysis of singing behavior in isolated male zebra finches subjected to interactive white noise, to surgery, or to tethering. We find that the latter two experimental manipulations transiently but reliably decreased singing rates. By contraposition, we infer that a high-sustained singing rate is suggestive of successful coping or improved welfare in these experiments. Our analysis across more than 300 days of song data suggests that a singing rate above a threshold of several hundred song motifs per day implies an absence of an acute stressor or a successful coping with stress. Because singing rate can be measured in a completely automatic fashion, its observation can help to reduce experimenter bias in welfare monitoring. Because singing rate measurements are non-invasive, we expect this study to contribute to the refinement of the current welfare monitoring tools in zebra finches.Fil: Yamahachi, Homare. Universitat Zurich; SuizaFil: Zai, Anja T.. Universitat Zurich; SuizaFil: Tachibana, Ryosuke O.. Universitat Zurich; SuizaFil: Stepien, Anna E.. Universitat Zurich; SuizaFil: Rodrigues, Diana I.. Universitat Zurich; SuizaFil: Cavé Lopez, Sophie. Universitat Zurich; SuizaFil: Lorenz, Corinna. Universite Paris Saclay; Francia. Universitat Zurich; SuizaFil: Arneodo, Ezequiel Matías. Universitat Zurich; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Giret, Nicolas. Universite Paris Saclay; FranciaFil: Hahnloser, Richard H. R.. Universitat Zurich; Suiz

PACIFIC-R: First real-world study of patients with unresectable, stage III NSCLC treated with durvalumab after chemoradiotherapy

n/

Dissecting a 30 kpc galactic outflow at z∼z \sim 1.7

We present the spatially resolved measurements of a cool galactic outflow in the gravitationally lensed galaxy RCS0327 at $z \approx 1.703$ using VLT/MUSE IFU observations. We probe the cool outflowing gas, traced by blueshifted Mg II and Fe II absorption lines, in 15 distinct regions of the same galaxy in its image-plane. Different physical regions, 5 to 7 kpc apart within the galaxy, drive the outflows at different velocities ($V_{out} \sim$ $-161$ to $-240$ km s$^{-1}$), and mass outflow rates ($\dot{M}_{out} \sim$ 183 to 527 $M_{\odot}\ yr^{-1}$). The outflow velocities from different regions of the same galaxy vary by 80 km s$^{-1}$, which is comparable to the variation seen in a large sample of star-burst galaxies in the local Universe. Using multiply lensed images of RCS0327, we probe the same star-forming region at different spatial scales (0.5 kpc$^2$-25 kpc$^2$), we find that outflow velocities vary between$ \sim $$-120$to$-242$km s$^{-1}$, and the mass outflow rates vary between$\sim$37 to 254$M_{\odot}\ yr^{-1}$. The outflow momentum flux in this galaxy is$\geq$100regions, and outflow energy flux is$\approx$ 10% of the total energy flux provided by star-formation. These estimates suggest that the outflow in RCS0327 is energy driven. This work shows the importance of small scale variations of outflow properties due to the variations of local stellar properties of the host galaxy in the context of galaxy evolution.Comment: 24 pages, 15 figures, 6 tables, submitted to MNRA