Understanding animal movement is a key challenge in ecology and conservation biology. Relocation data often represent a complex mixture of different movement behaviors, and reliably decomposing this ...mix into its component parts is an unresolved problem in movement ecology. Traditional approaches, such as composite random walk models, require that the timescales characterizing the movement are all similar to the usually arbitrary data-sampling rate. Movement behaviors such as long-distance searching and fine-scale foraging, however, are often intermixed but operate on vastly different spatial and temporal scales. An approach that integrates the full sweep of movement behaviors across scales is currently lacking. Here we show how the semivariance function (SVF) of a stochastic movement process can both identify multiple movement modes and solve the sampling rate problem. We express a broad range of continuous-space, continuous-time stochastic movement models in terms of their SVFs, connect them to relocation data via variogram regression, and compare them using standard model selection techniques. We illustrate our approach using Mongolian gazelle relocation data and show that gazelle movement is characterized by ballistic foraging movements on a 6-h timescale, fast diffusive searching with a 10-week timescale, and asymptotic diffusion over longer timescales.
Animal migration is a global phenomenon, but few studies have examined the substantial within‐ and between‐species variation in migration distances. We built a global database of 94 land migrations ...of large mammalian herbivore populations ranging from 10 to 1638 km. We examined how resource availability, spatial scale of resource variability and body size affect migration distance among populations. Resource availability measured as normalised difference vegetation index had a strong negative effect, predicting a tenfold difference in migration distances between low‐ and high‐resource areas and explaining 23% of the variation in migration distances. We found a weak, positive effect of the spatial scale of resource variability but no effect of body size. Resource‐poor environments are known to increase the size of mammalian home ranges and territories. Here, we demonstrate that for migratory populations as well, animals living in resource‐poor environments travel farther to fulfil their resource needs.
Of the nine confirmed transiting circumbinary planet systems, only Kepler-47 is known to contain more than one planet. Kepler-47 b (the "inner planet") has an orbital period of 49.5 days and a radius ...of about 3 R⊕. Kepler-47 c (the "outer planet") has an orbital period of 303.2 days and a radius of about 4.7 R⊕. Here we report the discovery of a third planet, Kepler-47 d (the "middle planet"), which has an orbital period of 187.4 days and a radius of about 7 R⊕. The presence of the middle planet allows us to place much better constraints on the masses of all three planets, where the 1 ranges are less than 26 M⊕, between 7-43 M⊕, and between 2-5 M⊕ for the inner, middle, and outer planets, respectively. The middle and outer planets have low bulk densities, with g cm−3 and outer < 0.26 g cm−3 at the 1 level. The two outer planets are "tightly packed," assuming the nominal masses, meaning no other planet could stably orbit between them. All of the orbits have low eccentricities and are nearly coplanar, disfavoring violent scattering scenarios and suggesting gentle migration in the protoplanetary disk.
Abstract
N-Glycanase 1 (NGLY1) deficiency is a rare and complex genetic disorder. Although recent studies have shed light on the molecular underpinnings of NGLY1 deficiency, a systematic ...characterization of gene and protein expression changes in patient-derived cells has been lacking. Here, we performed RNA-sequencing and mass spectrometry to determine the transcriptomes and proteomes of 66 cell lines representing four different cell types derived from 14 NGLY1 deficient patients and 17 controls. Although NGLY1 protein levels were up to 9.5-fold downregulated in patients compared with parents, residual and likely non-functional NGLY1 protein was detectable in all patient-derived lymphoblastoid cell lines. Consistent with the role of NGLY1 as a regulator of the transcription factor Nrf1, we observed a cell type-independent downregulation of proteasomal genes in NGLY1 deficient cells. In contrast, genes involved in ribosome biogenesis and mRNA processing were upregulated in multiple cell types. In addition, we observed cell type-specific effects. For example, genes and proteins involved in glutathione synthesis, such as the glutamate-cysteine ligase subunits GCLC and GCLM, were downregulated specifically in lymphoblastoid cells. We provide a web application that enables access to all results generated in this study at https://apps.embl.de/ngly1browser. This resource will guide future studies of NGLY1 deficiency in directions that are most relevant to patients.
Graphical Abstract
Graphical Abstract
The cytoplasmic peptide:N-glycanase (Ngly1) is a de-N-glycosylating enzyme that cleaves N-glycans from misfolded glycoproteins and is involved in endoplasmic reticulum-associated degradation. The ...recent discovery of NGLY1-deficiency, which causes severe systemic symptoms, drew attention to the physiological function of Ngly1 in mammals. While several studies have been carried out to reveal the physiological necessity of Ngly1, the semi-lethal nature of Ngly1-deficient animals made it difficult to analyze its function in adults. In this study, we focus on the physiological function of Ngly1 in liver (hepatocyte)-specific Ngly1-deficient mice generated using the cre-loxP system. We found that hepatocyte-specific Ngly1-deficient mice showed abnormal hepatocyte nuclear size/morphology with aging but did not show other notable defects in unstressed conditions. This nuclear phenotype did not appear to be related to the function of the only gene currently reported to rescue Ngly1-deficient murine lethality so far, endo-β-N-acetylglucosaminidase. We also found that under a high fructose diet induced stress, the hepatocyte-specific Ngly1-deletion resulted in liver transaminases elevation and increased lipid droplet accumulation. We showed that the processing and localization of the transcription factor, nuclear factor erythroid 2-like 1 (Nfe2l1), was impaired in the Ngly1-deficient hepatocytes. Therefore, Nfe2l1, at least partially, contributes to the phenotypes observed in hepatocyte-specific Ngly1-deficient mice. Our results indicate that Ngly1 plays important roles in the adult liver impacting nuclear morphology and lipid metabolism. Hepatocyte-specific Ngly1-deficient mice could thus serve as a valuable animal model for assessing in vivo efficacy of drugs and/or treatment for NGLY1-deficiency.
•Ngly1 is important for hepatocyte nuclear morphology and liver lipid metabolism.•Nfe2l1 partially contributes to the Ngly1-deficient liver defects.•Nfe2l1 and ENGase contribute to the defects caused by Ngly1-deletion independently.•HFrD fed Alb-cre;Ngly1flox/flox mice show defects similar to NGLY1-deficiency.
Proteasome inhibitors are used to treat blood cancers such as multiple myeloma (MM) and mantle cell lymphoma. The efficacy of these drugs is frequently undermined by acquired resistance. One ...mechanism of proteasome inhibitor resistance may involve the transcription factor Nuclear Factor, Erythroid 2 Like 1 (NFE2L1, also referred to as Nrf1), which responds to proteasome insufficiency or pharmacological inhibition by upregulating proteasome subunit gene expression. This “bounce-back” response is achieved through a unique mechanism. Nrf1 is constitutively translocated into the ER lumen, N-glycosylated, and then targeted for proteasomal degradation via the ER-associated degradation (ERAD) pathway. Proteasome inhibition leads to accumulation of cytosolic Nrf1, which is then processed to form the active transcription factor. Here we show that the cytosolic enzyme N-glycanase 1 (NGLY1, the human PNGase) is essential for Nrf1 activation in response to proteasome inhibition. Chemical or genetic disruption of NGLY1 activity results in the accumulation of misprocessed Nrf1 that is largely excluded from the nucleus. Under these conditions, Nrf1 is inactive in regulating proteasome subunit gene expression in response to proteasome inhibition. Through a small molecule screen, we identified a cell-active NGLY1 inhibitor that disrupts the processing and function of Nrf1. The compound potentiates the cytotoxicity of carfilzomib, a clinically used proteasome inhibitor, against MM and T cell-derived acute lymphoblastic leukemia (T-ALL) cell lines. Thus, NGLY1 inhibition prevents Nrf1 activation and represents a new therapeutic approach for cancers that depend on proteasome homeostasis.
ABSTRACT We report the discovery of a new Kepler transiting circumbinary planet (CBP). This latest addition to the still-small family of CBPs defies the current trend of known short-period planets ...orbiting near the stability limit of binary stars. Unlike the previous discoveries, the planet revolving around the eclipsing binary system Kepler-1647 has a very long orbital period (∼1100 days) and was at conjunction only twice during the Kepler mission lifetime. Due to the singular configuration of the system, Kepler-1647b is not only the longest-period transiting CBP at the time of writing, but also one of the longest-period transiting planets. With a radius of 1.06 0.01 RJup, it is also the largest CBP to date. The planet produced three transits in the light curve of Kepler-1647 (one of them during an eclipse, creating a syzygy) and measurably perturbed the times of the stellar eclipses, allowing us to measure its mass, 1.52 0.65 MJup. The planet revolves around an 11-day period eclipsing binary consisting of two solar-mass stars on a slightly inclined, mildly eccentric (ebin = 0.16), spin-synchronized orbit. Despite having an orbital period three times longer than Earth's, Kepler-1647b is in the conservative habitable zone of the binary star throughout its orbit.
We present the discovery of Kepler-453 b, a 6.2 R sub(+ in circle) planet in a low-eccentricity, 240.5 day orbit about an eclipsing binary. The binary itself consists of a 0.94 and 0.195 M sub(middot ...in circle) pair of stars with an orbital period of 27.32 days. The plane of the planet's orbit is rapidly precessing, and its inclination only becomes sufficiently aligned with the primary star in the latter portion of the Kepler data. Thus three transits are present in the second half of the light curve, but none of the three conjunctions that occurred during the first half of the light curve produced observable transits. The precession period is ~103 years, and during that cycle, transits are visible only ~8.9% of the time. This has the important implication that for every system like Kepler-453 that we detect, there are ~11.5 circumbinary systems that exist but are not currently exhibiting transits. The planet's mass is too small to noticeably perturb the binary, and consequently its mass is not measurable with these data; however, our photodynamical model places a 1sigma upper limit of 16 M sub(middot in circle). With a period 8.8 times that of the binary, the planet is well outside the dynamical instability zone. It does, however, lie within the habitable zone of the binary, making it the third of 10 Kepler circumbinary planets to do so.
The relative proximity of Al atoms substituted in zeolite lattices is an important parameter that influences both hydrothermal stability and catalytic function, but the underlying chemistry that ...governs Al site proximity is not well understood. Here, we examine relationships between exchanged countercations and different Al–Al arrangements in a chabazite (SSZ-13) zeolite lattice. We report periodic supercell density functional theory (DFT) calculations for structures and energies of SSZ-13 lattices with systematically enumerated and varied Al–Al proximity, both charge-uncompensated and charge-compensated by either proton pairs (H+/H+) or divalent copper cations (Cu2+). Al–Al interactions are electrostatically repulsive without charge compensation, but the relative energies of certain Al–Al site arrangements change upon compensation by countercations. Al–Al interactions are uniformly attractive when compensated by H+/H+ pairs but are attractive at long and repulsive at short Al–Al distances when compensated by Cu2+, highlighting the role of the countercation in stabilizing different Al–Al arrangements. Through descriptor analysis, we find that the Cu2+ energy landscape can be described by models consisting of electrostatics and a binary term that specifies whether or not Cu2+ resides in the six-membered ring (6MR). The H+/H+ and Cu2+ energy landscapes together imply that Cu2+ prefers to reside at 6MR Al–Al pairs. These results shed light on how countercations influence Al distribution and rearrangement during synthesis and postsynthetic treatments of the SSZ-13 zeolite, which potentially influences its susceptibility to dealumination during hydrothermal aging. The systematic DFT computation workflow and descriptor analysis reported here are promising approaches that can be applied generally to examine other combinations of ions and zeotypes of interest.
PDF
