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Coupled protein quality control during nonsense-mediated mRNA decay
No full textTranslation of mRNAs containing premature termination codons (PTCs) results in truncated protein products with deleterious effects. Nonsense-mediated decay (NMD) is a surveillance pathway responsible for detecting PTC containing transcripts. Although the molecular mechanisms governing mRNA degradation have been extensively studied, the fate of the nascent protein product remains largely uncharacterized. Here, we use a fluorescent reporter system in mammalian cells to reveal a selective degradation pathway specifically targeting the protein product of an NMD mRNA. We show that this process is post-translational and dependent on the ubiquitin proteasome system. To systematically uncover factors involved in NMD-linked protein quality control, we conducted genome-wide flow cytometry-based screens. Our screens recovered known NMD factors but suggested that protein degradation did not depend on the canonical ribosome-quality control (RQC) pathway. A subsequent arrayed screen demonstrated that protein and mRNA branches of NMD rely on a shared recognition event. Our results establish the existence of a targeted pathway for nascent protein degradation from PTC containing mRNAs, and provide a reference for the field to identify and characterize required factors
A Thermodynamic Nonequilibrium Model for Preferential Infiltration and Refreezing of Melt in Snow
No full textThe transport of meltwater through porous snow is a fundamental process in hydrology that remains poorly understood but essential for more robust predictions of how the cryosphere will respond under climate change. Here, we propose a continuum model that resolves the nonlinear coupling of preferential melt flow and the nonequilibrium thermodynamics of ice-melt phase change at the Darcy scale. We assume that the commonly observed unstable melt infiltration is due to the gravity fingering instability and capture it using the modified Richards equation, which is extended with a higher-order term in saturation. Our model accounts for changes in porosity and the thermal budget of the snowpack caused by melt refreezing at the continuum scale, based on a mechanistic estimate of the ice-water phase change kinetics formulated at the pore scale. We validate the model in 1D against field data and laboratory experiments of infiltration in snow and find generally good agreement. Compared to existing theory of stable melt infiltration, our 2D simulation results show that preferential infiltration delivers melt faster to deeper depths, and as a result, changes in porosity and temperature can occur at deeper parts of the snow. The simulations also capture the formation of vertical low porosity annulus known as ice pipes, which have been observed in the field but lack mechanistic understanding to date. Our results demonstrate how melt refreezing and unstable infiltration reshape the porosity structure of snow and impacts thermal and mass transport in highly nonlinear ways that are not captured by simpler models
The Apertif Radio Transient System (ARTS): Design, commissioning, data release, and detection of the first five fast radio bursts
No full textFast radio bursts (FRBs) must be powered by uniquely energetic emission mechanisms. This requirement has eliminated a number of possible source types, but several remain. Identifying the physical nature of FRB emitters arguably requires good localisation of more detections, as well as broad-band studies enabled by real-time alerting. In this paper, we present the Apertif Radio Transient System (ARTS), a supercomputing radio-telescope instrument that performs real-time FRB detection and localisation on the Westerbork Synthesis Radio Telescope (WSRT) interferometer. It reaches coherent-addition sensitivity over the entire field of the view of the primary-dish beam. After commissioning results verified that the system performed as planned, we initiated the Apertif FRB survey (ALERT). Over the first 5 weeks we observed at design sensitivity in 2019, we detected five new FRBs, and interferometrically localised each of them to 0.4–10 sq. arcmin. All detections are broad band, very narrow, of the order of 1 ms in duration, and unscattered. Dispersion measures are generally high. Only through the very high time and frequency resolution of ARTS are these hard-to-find FRBs detected, producing an unbiased view of the intrinsic population properties. Most localisation regions are small enough to rule out the presence of associated persistent radio sources. Three FRBs cut through the halos of M31 and M33. We demonstrate that Apertif can localise one-off FRBs with an accuracy that maps magneto-ionic material along well-defined lines of sight. The rate of one every ~7 days ensures a considerable number of new sources are detected for such a study. The combination of the detection rate and localisation accuracy exemplified by the first five ARTS FRBs thus marks a new phase in which a growing number of bursts can be used to probe our Universe
Genetic Deletion of the LINC00520 Homolog in Mouse Aggravates Angiotensin II-Induced Hypertension
No full text(1) Background: Hypertension is a complex, multifactorial disease that is caused by genetic and environmental factors. Apart from genetic predisposition, the mechanisms involved in this disease have yet to be fully understood. We previously reported that LEENE (lncRNA enhancing endothelial nitric oxide expression, transcribed from LINC00520 in the human genome) regulates endothelial cell (EC) function by promoting the expression of endothelial nitric oxide synthase (eNOS) and vascular growth factor receptor 2 (VEGFR2). Mice with genetic deletion of the LEENE/LINC00520 homologous region exhibited impaired angiogenesis and tissue regeneration in a diabetic hindlimb ischemia model. However, the role of LEENE in blood pressure regulation is unknown.
(2) Methods: We subjected mice with genetic ablation of leene and wild-type littermates to Angiotensin II (AngII) and monitored their blood pressure and examined their hearts and kidneys. We used RNA-sequencing to identify potential leene-regulated molecular pathways in ECs that contributed to the observed phenotype. We further performed in vitro experiments with murine and human ECs and ex vivo experiments with murine aortic rings to validate the select mechanism.
(3) Results: We identified an exacerbated hypertensive phenotype of leene-KO mice in the AngII model, evidenced by higher systolic and diastolic blood pressure. At the organ level, we observed aggravated hypertrophy and fibrosis in the heart and kidney. Moreover, the overexpression of human LEENE RNA, in part, restored the signaling pathways impaired by leene deletion in murine ECs. Additionally, Axitinib, a tyrosine kinase inhibitor that selectively inhibits VEGFR suppresses LEENE in human ECs.
(4) Conclusions: Our study suggests LEENE as a potential regulator in blood pressure control, possibly through its function in ECs
Helium isotope evidence for mixing of mantle-derived fluids and deeply penetrating surface waters in an obducted peridotite massif
No full textWe measured He and Ar in fresh peridotites from the Twin Sisters massif, Washington USA. ³He/⁴He ratios measured on >35 samples are highly variable (∼0.8 to ∼6 times the atmospheric ratio, RA). Step-heating of a subset of these samples in every case reveals a low ³He/⁴He component (∼1 R_A) released at 3 R_A) above that temperature, but these components are not effectively isolated by crushing and powder fusion analysis. He-Ar systematics indicate an intimate association of two fluid-inclusion hosted components in the peridotites. The first is a ∼6 R_A mantle component that is released at higher temperatures during step heating and is more abundant in dunite bands than surrounding harzburgites. The second component, released at low temperatures, has a ³He/⁴He ratio of 1.0 ± 0.5 R_A, atmospheric ⁴⁰Ar/³⁶Ar, and ⁴He/⁴⁰Ar far above atmospheric. It appears to be a mixture of mantle and radiogenic He sources introduced during obduction-related serpentinization, sometimes invisible, by surface-derived waters enriched with deeply-sourced helium.
These data indicate that mantle noble gas signatures can be retained in lithospheric peridotites against both diffusive loss and radiogenic ingrowth over at least 10⁸ year timescales, likely due to concentration and immobilization of He in fluid inclusions. However, the mantle signature can be greatly modified by pervasive and potentially cryptic fluid alteration during emplacement
Single-crystal UV/Vis optical absorption spectra of almandine-bearing and spessartine garnet: Part II. An analysis of the spin-forbidden bands of Fe²⁺, Mn²⁺, and Fe³⁺
No full textThe UV/Vis single-crystal absorption spectra of two almandine-bearing and several spessartine garnets were measured and their respective Fe²⁺ and Mn²⁺ spin-forbidden electronic transitions analyzed. Spin-forbidden bands of Fe³⁺ are also considered, because many aluminosilicate garnets contain some Fe³⁺. The spectra of the almandine-bearing garnets were recorded at room temperature between about 10 000 and 30 000 cm⁻¹. The spectrum of a nearly end-member spessartine (97 mol% Mn²⁺₃Al₂Si₃O₁₂) was measured between about 15 000 cm⁻¹ and 30 000 cm⁻¹ at room temperature and 78 K, the latter for the first time. The 78 K spectrum shows absorption features not observed at room temperature. Five additional spessartine-rich garnets with different Mn²⁺/(Mn²⁺ + Fe²⁺) ratios, and two with unusual chemistries, were recorded up to 26 000 cm⁻¹. The spectra of the two almandine-bearing garnets agree well with published results and show several overlapping Fe²⁺/³⁺ bands located between about 14 000 and 25 000 cm⁻¹. The spectra were deconvoluted to gain more insight into the electronic transition behavior. These results, together with an analysis of other measured spectra, reveal several absorption features that were previously unrecognized or misassigned. The spectrum of spessartine shows several Mn²⁺ bands, and most are clearly spaced from one another. A synthesis of various UV/Vis spectroscopic results is made and assignments for the Fe²⁺/³⁺ and Mn²⁺ bands are attempted. The intensities of the Mn²⁺, spin-forbidden bands and the ligand → metal charge edge observed in the various spessartine spectra are discussed. Spectra of almandine and spessartine have been interpreted using Tanabe-Sugano diagrams that are constructed for cations in octahedral coordination, point symmetry O_h. However, such analysis does not appear to be fully successful because Fe²⁺ and Mn²⁺ in garnet have triangular dodecahedral coordination with point symmetry D₂. The interpretation of the spectrum of spessartine is especially problematic. An analysis shows that published model calculations of Fe²⁺ electronic transition energies in garnet are not in good agreement with each other and are also not in full agreement with experimental spectra. First principles calculations are needed to better understand the spin-forbidden transitions of Fe²⁺, Fe³⁺, and Mn²⁺ in garnet
Convergence rates for ansatz‐free data‐driven inference in physically constrained problems
No full textWe study a Data-Driven approach to inference in physical systems in a measure-theoretic framework. The systems under consideration are characterized by two measures defined over the phase space: (i) A physical likelihood measure expressing the likelihood that a state of the system be admissible, in the sense of satisfying all governing physical laws; (ii) A material likelihood measure expressing the likelihood that a local state of the material be observed in the laboratory. We assume deterministic loading, which means that the first measure is supported on a linear subspace. We additionally assume that the second measure is only known approximately through a sequence of empirical (discrete) measures. We develop a method for the quantitative analysis of convergence based on the flat metric and obtain error bounds both for annealing and the discretization or sampling procedure, leading to the determination of appropriate quantitative annealing rates. Finally, we provide an example illustrating the application of the theory to transportation networks
The Road to High Data Rates in Space: Terahertz Versus Optical Wireless Communication
No full textWith the ultimate vision of ubiquitous egalitarian worldwide coverage, private companies are launching satellite constellations at unprecedented rates. The large projected traffic in orbital cross-link communication will demand more spectrum to suit more users and to satisfy higher data rates. In this article, terahertz and optical wireless communication technologies are explored as the two projected high-data-rate cross-link communication technologies and are compared in terms of device technology capabilities and wireless propagation properties. A performance analysis including a link budget directly compares the two technologies for space communication in low Earth orbit constellations. More importantly, a roadmap is provided paving the way to push both ultrabroadband wireless technologies forward
Long-exposure NuSTAR constraints on decaying dark matter in the Galactic halo
No full textWe present two complementary NuSTAR x-ray searches for keV-scale dark matter decaying to monoenergetic photons in the Milky Way halo. In the first, we utilize the known intensity pattern of unfocused stray light across the detector planes—the dominant source of photons from diffuse sources—to separate astrophysical emission from internal instrument backgrounds using ~7-Ms/detector deep blank-sky exposures. In the second, we present an updated parametric model of the full NuSTAR instrument background, allowing us to leverage the statistical power of an independent ~20-Ms/detector stacked exposures spread across the sky. Finding no evidence of anomalous x-ray lines using either method, we set limits on the active-sterile mixing angle sin² (2θ) for sterile-neutrino masses 6–40 keV. The first key result is that we strongly disfavor a ~7-keV sterile neutrino decaying into a 3.5-keV photon. The second is that we derive leading limits on sterile neutrinos with masses ~15-18 keV and ~25-40 KeV, reaching or extending below the big bang nucleosynthesis limit. In combination with previous results, the parameter space for the neutrino minimal standard model is now nearly closed
The Hydrogen-poor Superluminous Supernovae from the Zwicky Transient Facility Phase I Survey. II. Light-curve Modeling and Characterization of Undulations
No full textWe present analysis of the light curves (LCs) of 77 hydrogen-poor superluminous supernovae (SLSNe I) discovered during the Zwicky Transient Facility Phase I operation. We find that the majority (67%) of the sample can be fit equally well by both magnetar and ejecta–circumstellar medium (CSM) interaction plus ⁵⁶Ni decay models. This implies that LCs alone cannot unambiguously constrain the physical power sources for an SLSN I. However, 23% of the sample show inverted V-shape, steep-declining LCs or features of long rise and fast post-peak decay, which are better described by the CSM+Ni model. The remaining 10% of the sample favors the magnetar model. Moreover, our analysis shows that the LC undulations are quite common, with a fraction of 18%–44% in our gold sample. Among those strongly undulating events, about 62% of them are found to be CSM-favored, implying that the undulations tend to occur in the CSM-favored events. Undulations show a wide range in energy and duration, with median values (and 1σ errors) being as 1.7%^(+1.5%)_(-0.7%) E_(rad,total) and 28.8^(+14.1)_(-9.1) days, respectively. Our analysis of the undulation timescales suggests that intrinsic temporal variations of the central engine can explain half of the undulating events, while CSM interaction (CSI) can account for the majority of the sample. Finally, all of the well-observed He-rich SLSNe Ib either have strongly undulating LCs or the LCs are much better fit by the CSM+Ni model. These observations imply that their progenitor stars have not had enough time to lose all of the He-envelopes before supernova explosions, and H-poor CSM are likely to present in these events