R-spondin proteins strongly potentiate Wnt signalling and function as stem-cell growth factors. Despite the biological and therapeutic significance, the molecular mechanism of R-spondin action ...remains unclear. Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. Inhibition of ZNRF3 enhances Wnt/β-catenin signalling and disrupts Wnt/planar cell polarity signalling in vivo. Notably, R-spondin mimics ZNRF3 inhibition by increasing the membrane level of Wnt receptors. Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3. Our study provides new mechanistic insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a tractable target for therapeutic exploration.
Without transposon-silencing Piwi-interacting RNAs (piRNAs), transposition causes an ovarian atrophy syndrome in
called gonadal dysgenesis (GD).
(
) strains with
-elements cause severe GD in F1 ...daughters when
fathers mate with mothers lacking
-element-piRNAs (i.e.
strain). To address the mystery of why
induces severe GD, we bred hybrid
with
genomic fragments into the
background to create
lines that still cause
ysgenesis or are
on-dysgenic, respectively. In these lines, we discovered a highly truncated
-element variant we named '
' as the most frequent de novo insertion. Although
lines still contain full-length
-elements,
lines lost functional
-transposase but retained
's that when crossed back to
-transposase restores GD induction. Finally, we uncovered
-element-piRNA-directed repression on
transmitted paternally to suppress somatic transposition. The
short
and full-length
-elements relationship parallels the MITEs/DNA-transposase in plants and SINEs/LINEs in mammals.
Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) is a common molecular event in a variety of pathological settings, including genetic tumor syndromes, cancer, and obesity. ...However, the cell-intrinsic consequences of mTORC1 activation remain poorly defined. Through a combination of unbiased genomic, metabolomic, and bioinformatic approaches, we demonstrate that mTORC1 activation is sufficient to stimulate specific metabolic pathways, including glycolysis, the oxidative arm of the pentose phosphate pathway, and de novo lipid biosynthesis. This is achieved through the activation of a transcriptional program affecting metabolic gene targets of hypoxia-inducible factor (HIF1α) and sterol regulatory element-binding protein (SREBP1 and SREBP2). We find that SREBP1 and 2 promote proliferation downstream of mTORC1, and the activation of these transcription factors is mediated by S6K1. Therefore, in addition to promoting protein synthesis, mTORC1 activates specific bioenergetic and anabolic cellular processes that are likely to contribute to human physiology and disease.
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► Unbiased genomic and metabolomic approaches to reveal downstream functions of mTORC1 ► mTORC1 stimulates glucose uptake and glycolysis through HIF1 ► mTORC1 stimulates the pentose phosphate pathway and lipid biosynthesis through SREBP1 ► S6K1 regulates SREBP1 processing and transcriptional activation of target genes
•Integrated analysis of meteorological-soil-groundwater information based on two typical monitoring sites and the plain area of Jilin Province, China.•Reveals the prerequisite that groundwater levels ...are influenced by freeze–thaw processes.•The main influencing factors controlling water level fluctuations during freeze–thaw periods are revealed and their importance is quantified.
Studying the dynamic mechanism of water-level variations during the freeze–thaw period in seasonally frozen soil regions is an important premise and foundation for winter agricultural irrigation and groundwater resource assessment. Freezing and thawing-induced groundwater-level variations have been observed in regions with a shallow water table depth. However, whether the groundwater level is affected by the freeze–thaw process and the extent of this effect should be verified and discussed on a wider spatiotemporal scale. To this end, this study selected the plain area of Jilin Province, China as an example, and based on a comprehensive analysis of dynamic groundwater-level monitoring data from 114 monitoring wells, the distribution of the meteorological data and soil types and two typical experimental monitoring sites in the area, the dynamic characteristics and influencing factors of groundwater-level variations during the freeze–thaw period were identified. Combined with a multi-factor statistical analysis of the monitoring data at the regional scale of the plain area of Jilin Province, China, the response mechanism of the groundwater level to the freeze–thaw process in the seasonally frozen plain area was summarized. The results showed that: (1) The dynamic phenomenon where the groundwater level falls in the freezing period and rises in the thawing period due to the freeze–thaw process was widespread in seasonally frozen soil regions; (2) The depth threshold of the groundwater level affected by the freeze–thaw process was the sum of the maximum frozen soil depth and the maximum capillary rise height; (3) The main factors controlling the groundwater-level variation during the freeze–thaw period were the initial water-level depth and the maximum snow cover thickness; based on a random forest model, the groundwater-level variation during the freeze–thaw process could be accurately calculated with these main controlling factors; (4) The groundwater-level dynamics during the freeze–thaw process was mainly controlled by the exchange of water between the groundwater and the vadose zone system, and the rise in the water level was only partially replenished by the snowmelt water. The research results have an important guiding significance for winter agricultural irrigation and groundwater recharge resource evaluation.
Intention detection and slot filling are two major subtasks in building a spoken language understanding (SLU) system. These two tasks are closely related to each other, and information from one will ...influence the other, establishing a bidirectional contributory relationship. Existing studies have typically modeled the two-way connection between these two tasks simultaneously in a unified framework. However, these studies have merely contributed to the research direction of fully using the correlations between feature information of the two tasks, without sufficient focusing on and utilizing native textual semantics. In this article, we propose a semantic guidance (SG) framework, enabling enhancing the understanding of textual semantics by dynamically gating the information from both tasks to acquire semantic features, ultimately leading to higher joint task accuracy. Experimental results on two widely used public datasets show that our model achieves state-of-the-art performance.
Genetic mechanisms that repress transposable elements (TEs) in young animals decline during aging, as reflected by increased TE expression in aged animals. Does increased TE expression during aging ...lead to more genomic TE copies in older animals? To address this question, we quantified TE Landscapes (TLs) via whole genome sequencing of young and aged Drosophila strains of wild-type and mutant backgrounds. We quantified TLs in whole flies and dissected brains and validated the feasibility of our approach in detecting new TE insertions in aging Drosophila genomes when small RNA and RNA interference (RNAi) pathways are compromised. We also describe improved sequencing methods to quantify extra-chromosomal DNA circles (eccDNAs) in Drosophila as an additional source of TE copies that accumulate during aging. Lastly, to combat the natural progression of aging-associated TE expression, we show that knocking down PAF1, a conserved transcription elongation factor that antagonizes RNAi pathways, may bolster suppression of TEs during aging and extend lifespan. Our study suggests that in addition to a possible influence by different genetic backgrounds, small RNA and RNAi mechanisms may mitigate genomic TL expansion despite the increase in TE transcripts during aging.
Antibiotics, antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) are ubiquitous in the reclaimed water, posing a potential threat to human and ecological health. Nowadays, the ...reuse technology of reclaimed water has been widely concerned, but the removal of antibiotics, ARB and ARGs in reclaimed water has not been sufficiently studied. This study used TiO2 nanotube arrays (TNTs) decorated with Ag/SnO2-Sb nanoparticles (TNTs-Ag/SnO2-Sb) as the anode and Ti-Pd/SnO2-Sb as the cathode to construct an efficient photoelectrocatalytic (PEC) system. In this system, 99.9% of ARB was inactivated in 20 min, meanwhile, ARGs was removed within 30 min, and antibiotics were almost completely degraded within 1 h. Furthermore, the effects of system parameters on the removals of antibiotics, ARB and ARGs were also studied. The redox performance of the system was verified by adding persulfate. Escherichia coli, as a representative microorganism in aquatic environments, was used to evaluate the ecotoxicity of PEC treated chloramphenicol (CAP) solution. The ecotoxicity of CAP solution was significantly reduced after being treated by PEC. In addition, transformation intermediates of CAP were identified using liquid chromatography-tandems mass spectrometry (LC-MS/MS) and the possible degradation pathways were proposed. This study could provide a potential alternative method for controlling antibiotic resistance and protecting the quality of reclaimed water.
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•A novel PEC system was constructed to synergistically remove CAP and ARB.•DNA/ARGs were destroyed in PEC and the mechanism involved the generation of ROS.•The ecotoxicity of PEC treated CAP solution was significantly reduced.•Possible degradation pathways of CAP were proposed.
In the rapidly evolving domain of question answering systems, the ability to integrate machine comprehension with relational reasoning stands paramount. This paper introduces a novel architecture, ...the Dependent Syntactic Semantic Augmented Graph Network (DSSAGN), designed to address the intricate challenges of multi-hop question answering. By ingeniously leveraging the synergy between syntactic structures and semantic relationships within knowledge graphs, DSSAGN offers a breakthrough in interpretability, scalability, and accuracy. Unlike previous models that either fall short in handling complex relational paths or lack transparency in reasoning, our framework excels by embedding a sophisticated mechanism that meticulously models multi-hop relations and dynamically prioritizes the syntactic–semantic context.
Abstract
Because the signal amplitude corresponding to the phase of BPSK modulation is ±1, it’s autocorrelation function is shaped like a mountain peak. The fuzzy function of BPSK-LFM is multiplied ...by two parts, the left part is the fuzzy function of the standard LFM signal, and the right part is the autocorrelation function of the BPSK communication symbol, which won’t change with the random change of the communication symbol. Therefore, the fuzzy function performance of BPSK-LFM signal is better than that of LFM signal, but the transmission rate of communication is low. The shape of the fuzzy function will change with the change of random communication symbol in QPSK-LFM and 8PSK-LFM modulation. OFDM multi-carrier modulation can improve spectrum efficiency and communication transmission rate. MIMO technology can multiply channel capacity and spectrum efficiency without increasing signal bandwidth B. As a result, the integrated radar communication signal designed in this paper is a centralized MIMO-OFDM-BPSK-LFM signal. The distance between receiving antennas and transmitting antennas is very small in centralized MIMO radars, which is easy to place together.
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