Recent clinical trials using rapalogues in tuberous sclerosis complex show regression in volume of typically vascularised tumours including angiomyolipomas and subependymal giant cell astrocytomas. ...By blocking mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signalling, rapalogue efficacy is likely to occur, in part, through suppression of hypoxia-inducible factors (HIFs) and vascular endothelial growth factors (VEGFs). We show that rapamycin reduces HIF-1α protein levels, and to a lesser extent VEGF-A levels, in renal cystadenoma cells in a Tsc2+/- mouse model. We established that mTORC1 drives HIF-1α protein accumulation through enhanced transcription of HIF-1α mRNA, a process that is blocked by either inhibition or knockdown of signal transducer and activation of transcription 3 (STAT3). Furthermore, we demonstrated that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1α mRNA transcription. mTORC1 also regulates HIF-1α synthesis on a translational level via co-operative regulation of both initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase-1 (S6K1), whereas HIF-1α degradation remains unaffected. We therefore proposed that mTORC1 drives HIF-1α synthesis in a multifaceted manner through 4E-BP1/eIF4E, S6K1 and STAT3. Interestingly, we observed a disconnect between HIF-1α protein levels and VEGF-A expression. Although both S6K1 and 4E-BP1 regulate HIF-1α translation, VEGF-A is primarily under the control of 4E-BP1/eIF4E. S6K1 inhibition reduces HIF-1α but not VEGF-A expression, suggesting that mTORC1 mediates VEGF-A expression via both HIF-1α-dependent and -independent mechanisms. Our work has important implications for the treatment of vascularised tumours, where mTORC1 acts as a central mediator of STAT3, HIF-1α, VEGF-A and angiogenesis via multiple signalling mechanisms.
Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit ...the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.
•Reviews the impact of the USDA's soil health initiative on soil organic P pools.•Shows that promoting organic C stores increases organic P in agricultural soils.•Suggests that organic P is not ...adequately accounted for in soil testing methods.•Discusses the impact on organic P release in relation to water quality.•Concludes that sustainable P management must consider both inorganic and organic P.
Despite the large scale implementation of conservation schemes aimed at reducing phosphorus (P) loss from agricultural lands, significant improvements in water quality at the watershed scale remain elusive. Changes in land management influence the speciation and cycling of P within soils and recent promotion of conservation practices to improve soil health revolve around increasing soil carbon stores, thereby increasing the pool of soil organic P. Adopting conservation tillage, use of cover crops, strategic crop rotations, and use of manures can increase organic P by 3–180% and microbial biomass pool of P by 30–240%. The role of organic P in soil fertility has been largely ignored in current soil testing methods, which in many cases may explain the lack of crop response to recommended fertilizer inputs in a growing number of trials. Conversely, soil organic P is gaining recognition as a potential source of P to runoff. This review explores the impact of adopting widely promoted “soil health” conservation practices on the speciation and cycling of soil P, with particular focus on the organic pool and the biotic processes regulating its accumulation and mobilization. Large stores of organic P exist in arable and grassland soils and strategies that increase the plant availability of these P stores could reduce the reliance on external P inputs, creating more sustainable P use. However, more detailed, mechanistic knowledge of soil organic P cycling, especially through the microbial biomass, is required. Furthermore, caution is needed to ensure that increasing the availability of organic P does not increase P loss in runoff effectively turning P sinks into P sources.
Advances in microelectronics performance and density continue to be fueled by the engine of Moore's law. Although lately this engine appears to be running out of steam, recent developments in ...advanced technologies have brought about a number of challenges and opportunities for their use in radiation environments. For example, while many advanced CMOS technologies have generally shown improving total dose tolerance, single-event effects continue to be a serious concern for highly scaled technologies. In this paper, we examine the impact of recent developments and the challenges they present to the radiation effects community. Topics covered include the impact of technology scaling on radiation response and technology challenges for both total dose and single-event effects. We include challenges for hardening and mitigation techniques at the nanometer scale. Recent developments leading to hardness assurance challenges are covered. Finally, we discuss future radiation effects challenges as the electronics industry looks beyond Moore's law to alternatives to traditional CMOS technologies.
Phosphorus (P) runoff from agricultural land continues to receive attention due to a widespread lack of reduction in losses combined with a series of high profile P-induced harmful algal blooms. Many ...widely adopted conservation practices (CPs), aimed at reducing P loss, target particulate P (PP) through reductions in erosion or entrapment of P within the terrestrial landscape. However, there is increasing evidence that in time, these CPs may in fact increase dissolved P (DP) losses. We reviewed the effectiveness of current CPs promoted in the U.S., the results from long-term in-stream monitoring following implementation of conservation schemes and field studies investigating P loss from buffer zones designed to trap PP. These studies showed that different CPs are required to target different forms of P loss and the tendency for farmers to implement strategies targeting PP over DP resulted in an increase in dissolved reactive P export post-implementation of 37–250 % in three of the five catchment monitoring studies. Buffer zones, such as grass and vegetative filter strips, managed riparian zones and wetlands were found to accumulate labile forms of soil P over time and, in some studies, became significant sources of both inorganic and organic DP. Furthermore, often overlooked microbial processes appear to play a key role in P release. Consequently, to improve the effectiveness of future conservation schemes, practices need to specifically target DP losses in addition to PP and recognize that CPs trapping P within the landscape are at risk of becoming legacy P sources.
This document describes the radiation environments, physical mechanisms, and test philosophies that underpin radiation hardness assurance test methodologies. The natural space radiation environment ...is presented, including the contributions of both trapped and transient particles. The effects of shielding on radiation environments are briefly discussed. Laboratory radiation sources used to simulate radiation environments are covered, including how to choose appropriate sources to mimic environments of interest. The fundamental interactions of radiation with materials via direct and indirect ionization are summarized. Some general test considerations are covered, followed by in-depth discussions of physical mechanisms and issues for total dose and single-event effects testing. The purpose of this document is to describe why the test protocols we use are constructed the way they are. In other words, to answer the question: "Why do we test it that way"?
Time-domain science has undergone a revolution over the past decade, with tens of thousands of new supernovae (SNe) discovered each year. However, several observational domains, including SNe within ...days or hours of explosion and faint, red transients, are just beginning to be explored. Here we present the Young Supernova Experiment (YSE), a novel optical time-domain survey on the Pan-STARRS telescopes. Our survey is designed to obtain well-sampled griz light curves for thousands of transient events up to z 0.2. This large sample of transients with four-band light curves will lay the foundation for the Vera C. Rubin Observatory and the Nancy Grace Roman Space Telescope, providing a critical training set in similar filters and a well-calibrated low-redshift anchor of cosmologically useful SNe Ia to benefit dark energy science. As the name suggests, YSE complements and extends other ongoing time-domain surveys by discovering fast-rising SNe within a few hours to days of explosion. YSE is the only current four-band time-domain survey and is able to discover transients as faint as ∼21.5 mag in gri and ∼20.5 mag in z, depths that allow us to probe the earliest epochs of stellar explosions. YSE is currently observing approximately 750 deg2 of sky every 3 days, and we plan to increase the area to 1500 deg2 in the near future. When operating at full capacity, survey simulations show that YSE will find ∼5000 new SNe per year and at least two SNe within 3 days of explosion per month. To date, YSE has discovered or observed 8.3% of the transient candidates reported to the International Astronomical Union in 2020. We present an overview of YSE, including science goals, survey characteristics, and a summary of our transient discoveries to date.
We describe observations carried out by the MOA group of the Galactic bulge during 2000 that were designed to detect efficiently gravitational microlensing of faint stars in which the magnification ...is high and/or of short duration. These events are particularly useful for studies of extrasolar planets and faint stars. Approximately 17 deg2 were monitored at a sampling rate of up to six times per night. The images were analysed in real time using a difference imaging technique. 20 microlensing candidates were detected, of which eight were alerted to the microlensing community whilst in progress. Approximately half of the candidates had high magnifications (≳10), at least one had very high magnification (≳50), and one exhibited a clear parallax effect. The details of these events are reported here, together with details of the on-line difference imaging technique. Some nova-like events were also observed and these are described, together with one asteroid.
River catchments worldwide are heavily fragmented by anthropogenic barriers, reducing their longitudinal connectivity and contributing to the decline of migratory fish populations. Direct impacts of ...individual barriers on migratory fish are well-established, but barrier impacts on onward migration are poorly understood, despite their relevance to evidence-based, catchment-scale, management of threatened species. This study investigated the upstream spawning migration of 352 acoustic tagged river lamprey (Lampetra fluviatilis), translocated upstream of two key barriers (R2: n = 60 & 59; R3: n = 59 & 52) compared to a control group (R1: n = 61 & 59), across two contrasting (dry and wet, n = 180 and 172) years in the River Yorkshire Ouse, England, to reveal the impact of barriers on the onward migration of upstream migrating fish. Release further upstream increased the degree of catchment penetration, with median distance upstream of R1 56.1% and 68.6% greater for lamprey released at R2 and R3 respectively. Median delays at the two downstream-most main river barriers by the control group were 23.8 and 5.4 days (2018/19) and 9.3 and 11.4 days (2019/20). However, impacts of delay were only observed on the time to reach spawning habitat, time to reach final assumed spawning location and speed of movement in one upper catchment tributary during 2019/20 whilst they were only observed on time to reach spawning habitat during 2018/19 and on assumed spawning location distance during 2019/20 in the other. Ultimately, limited impacts of delay at barriers on onward fish migration post-passage were observed but median catchment penetration was increased with consecutive release upstream. This study demonstrated the importance of a true understanding of barrier impacts to inform catchment-wide planning, evidence vital for management worldwide. Although the findings of this study do support the use of trap and transport as a measure to remediate barrier impacts on migration, fish passage engineering improvements or barrier removal, at structures shown to be the most inhibiting to fish migration should be considered the best and most sustainable option to improve barrier passage.
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•The impact of two river barriers on onward fish migration compared to controls.•Anadromous river lamprey (n = 352) tracked in two contrasting years (dry and wet).•Translocation past downstream-most barriers increased catchment penetration.•Migration delays at downstream-most barriers increased during dry conditions.•Limited impacts of delay on onward fish migration post-passage were observed.
Abstract
We present panchromatic observations and modeling of calcium-strong supernovae (SNe) 2021gno in the star-forming host-galaxy NGC 4165 and 2021inl in the outskirts of elliptical galaxy NGC ...4923, both monitored through the Young Supernova Experiment transient survey. The light curves of both, SNe show two peaks, the former peak being derived from shock cooling emission (SCE) and/or shock interaction with circumstellar material (CSM). The primary peak in SN 2021gno is coincident with luminous, rapidly decaying X-ray emission (
L
x
= 5 × 10
41
erg s
−1
) detected by Swift-XRT at
δ
t
= 1 day after explosion, this observation being the second-ever detection of X-rays from a calcium-strong transient. We interpret the X-ray emission in the context of shock interaction with CSM that extends to
r
< 3 × 10
14
cm. Based on X-ray modeling, we calculate a CSM mass
M
CSM
= (0.3−1.6) × 10
−3
M
⊙
and density
n
= (1−4) × 10
10
cm
−3
. Radio nondetections indicate a low-density environment at larger radii (
r
> 10
16
cm) and mass-loss rate of
M
̇
<
10
−
4
M
⊙
yr
−1
. SCE modeling of both primary light-curve peaks indicates an extended-progenitor envelope mass
M
e
= 0.02−0.05
M
⊙
and radius
R
e
= 30−230
R
⊙
. The explosion properties suggest progenitor systems containing either a low-mass massive star or a white dwarf (WD), the former being unlikely given the lack of local star formation. Furthermore, the environments of both SNe are consistent with low-mass hybrid He/C/O WD + C/O WD mergers.
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