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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. ZNRF3 and RNF43 are identified as negative feedback regulators of Wnt signalling; the stem-cell growth factor R-spondin is shown to potentiate Wnt signalling by inhibiting ZNRF3. ZNRF3 protein inhibits Wnt signalling The R-spondin proteins are secreted molecules that function as stem-cell growth factors and potentiate Wnt signalling by binding LGR4 family receptors, but their precise mechanism of action remains unclear. Here, the transmembrane E3 ubiquitin ligase ZNRF3 is identified as an inhibitor of Wnt signalling that acts by promoting the turnover of Wnt receptors. R-spondin potentiates Wnt signalling by inhibiting ZNRF3 in a mechanism dependent on LGR4, resulting in the accumulation of Wnt receptors. Given the importance of Wnt signalling in cancer, ZNRF3 may be a target for therapeutic intervention.

Without transposon-silencing Piwi-interacting RNAs (piRNAs), transposition causes an ovarian atrophy syndrome in Drosophila called gonadal dysgenesis (GD). Harwich (Har) strains with P-elements cause severe GD in F1 daughters when Har fathers mate with mothers lacking P-element-piRNAs (i.e. ISO1 strain). To address the mystery of why Har induces severe GD, we bred hybrid Drosophila with Har genomic fragments into the ISO1 background to create HISR-D or HISR-N lines that still cause Dysgenesis or are Non-dysgenic, respectively. In these lines, we discovered a highly truncated P-element variant we named ‘Har-P’ as the most frequent de novo insertion. Although HISR-D lines still contain full-length P-elements, HISR-N lines lost functional P-transposase but retained Har-P’s that when crossed back to P-transposase restores GD induction. Finally, we uncovered P-element-piRNA-directed repression on Har-P’s transmitted paternally to suppress somatic transposition. The Drosophila short Har-P’s and full-length P-elements relationship parallels the MITEs/DNA-transposase in plants and SINEs/LINEs in mammals. DNA provides the instructions needed for life, a role that relies on it being a very stable and organized molecule. However, some sections of DNA are able to move from one place in the genome to another. When these “mobile genetic elements” move they may disrupt other genes and cause disease. For example, a mobile section of DNA known as the P-element causes a condition called gonadal dysgenesis in female fruit flies, leading to infertility. Only certain strains of fruit flies carry P-elements and the severity of gonadal dysgenesis in their daughters varies. For example, when male fruit flies of a strain known as Harwich (or Har for short) is crossed with female fruit flies that do not contain P-elements, all of their daughters develop severe gonadal dysgenesis and are infertile. However, if the cross is done the other way around, and female Har flies mate with males that do not contain P-elements, the daughters are fertile because the Har mothers provide their daughters with protective molecules that silence the P-elements. But it was a mystery as to why the P-elements from the Har fathers always caused such severe gonadal dysgenesis in all the daughters. Here, Srivastav et al. bred fruit flies to create offspring that had different pieces of Har DNA in a genetic background that was normally free from P-elements; they then analyzed the ‘hybrid’ offspring to identify which pieces of the Har genome caused gonadal dysgenesis in the daughter flies. These experiments showed that Har flies possess a very short variant of the P-element (named “Har-P”) that is more mobile than other variants. However, the Har-P variants still depended on an enzyme known as P-transposase encoded by the full-length P-elements to move around the genome. Further experiments showed that other strains of fruit flies that cause severe gonadal dysgenesis also had very short P-element variants that were almost identical to Har-P. These findings may explain why Har and some other strains of fruit flies drive severe gonadal dysgenesis. In the future, it may be possible to transfer P-transposase and Har-P into mosquitoes, ticks and other biting insects to make them infertile and help reduce the spread of certain diseases in humans.

As urbanization accelerates, urban greenery, particularly street greenery, emerges as a vital strategy for enhancing residents’ quality of life, demanding attention for its alignment with pedestrian flows to foster sustainable urban development and ensure urban dwellers’ wellbeing. The advent of diverse urban data has significantly advanced this area of study. Focusing on Chengdu’s central urban district, this research assesses street greening metrics against pedestrian flow indicators, employing spatial autocorrelation techniques to investigate the interplay between street greenery and pedestrian flow over time and space. Our findings reveal a prevalent negative spatial autocorrelation between street greenery and pedestrian flow within the area, underscored by temporal disparities in greenery demands across various urban functions during weekdays versus weekends. This study innovatively incorporates mobile phone signal-based population heat maps into the mismatch analysis of street greenery for the first time, moving beyond the conventional static approach of space syntax topology in assessing pedestrian flow. By leveraging dynamic pedestrian flow data, it enriches our understanding of the disconnect between street greening plans and pedestrian circulation, highlighting the concept of urban flow and delving into the intricate nexus among time, space, and human activity. Moreover, this study meticulously examines multiple street usage scenarios, reflecting diverse behavior patterns, with the objective of providing nuanced and actionable strategies for urban renewal initiatives aimed at creating more inviting and sustainable urban habitats.

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.

A quarter of the human population is infected with Mycobacterium tuberculosis , but less than 10% of those infected develop pulmonary TB. We developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: the development of necrotic lung granulomas and determined that the sst1-susceptible phenotype was driven by the aberrant macrophage activation. This study demonstrates that the aberrant response of the sst1-susceptible macrophages to prolonged stimulation with TNF is primarily driven by conflicting Myc and antioxidant response pathways leading to a coordinated failure (1) to properly sequester intracellular iron and (2) to activate ferroptosis inhibitor enzymes. Consequently, iron-mediated lipid peroxidation fueled superinduction of Ifnβ and sustained the type I interferon (IFN-I) pathway hyperactivity that locked the sst1-susceptible macrophages in a state of unresolving stress and compromised their resistance to Mtb. The accumulation of the aberrantly activated, stressed, macrophages within the granuloma microenvironment led to the local failure of anti-tuberculosis immunity and tissue necrosis. The upregulation of the Myc pathway in peripheral blood cells of human TB patients was significantly associated with poor outcomes of TB treatment. Thus, Myc dysregulation in activated macrophages results in an aberrant macrophage activation and represents a novel target for host-directed TB therapies.

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.

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.

Taking a lead and zinc plant plot in Yunnan as the research object, the land use status and planting types of the region were investigated, the original enterprise distribution area and crop growing area of the plot were defined, and 67 surface soil samples and 14 columnar soil samples were systematically arranged in the plot for monitoring. Combined with the monitoring results and analysis, it is concluded that there is no definite basis that the high arsenic content in soil in the region is caused by the enterprise production, and the high arsenic content in the region may be caused by the background value. Based on the monitoring and investigation results, the risk assessment of the area was carried out. The results showed that the non-carcinogenic risk and carcinogenic hazard index of arsenic exceeded the prescribed acceptable level when the area was developed as the second type of construction land, and soil remediation should be carried out. At the same time, the collaborative distribution monitoring of regional crops showed that the arsenic content of crops was low, which met the requirements of food standards, possibly because the cultivated crops did not have strong adsorption and enrichment effects on the arsenic occurrence form in the regional soil.

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. Author summary Transposable elements, also called transposons, are genetic parasites found in all animal genomes. Normally, transposons are compacted away in silent chromatin in young animals. But, as animals age and transposon-silencing defense mechanisms break down, transposon RNAs accumulate to significant levels in old animals like fruit flies. An open question is whether the increased levels of transposon RNAs in older animals also correspond to increased genomic copies of transposons. This study approached this question by sequencing the whole genomes of young and old wild-type and mutant flies lacking a functional RNA interference (RNAi) pathway, which naturally silences transposon RNAs. Although the wild-type flies with intact RNAi activity had little new accumulation of transposon copies, the sequencing approach was able to detect several transposon accumulation occurrences in some RNAi mutants. In addition, we found that some fly transposon families can also accumulate as extra-chromosomal circular DNA copies. Lastly, we showed that genetically augmenting the expression of RNAi factors can counteract the rising transposon RNA levels in aging and promote longevity. This study improves our understanding of the animal host genome relationship with transposons during natural aging processes.