Nuclear export regulation of COP1 by 14-3-3σ in response to DNA damage

Mammalian constitutive photomorphogenic 1 (COP1) is a p53 E3 ubiquitin ligase involved in regulating p53 protein level. In plants, the dynamic cytoplasm/nucleus distribution of COP1 is important for its function in terms of catalyzing the degradation of target proteins. In mammalian cells, the biological consequence of cytoplasmic distribution of COP1 is not well characterized. Here, we show that DNA damage leads to the redistribution of COP1 to the cytoplasm and that 14-3-3σ, a p53 target gene product, controls COP1 subcellular localization. Investigation of the underlying mechanism suggests that COP1 S387 phosphorylation is required for COP1 to bind 14-3-3σ. Significantly, upon DNA damage, 14-3-3σ binds to phosphorylated COP1 at S387, resulting in COP1's accumulation in the cytoplasm. Cytoplasmic COP1 localization leads to its enhanced ubiquitination. We also show that N-terminal 14-3-3σ interacts with COP1 and promotes COP1 nuclear export through its NES sequence. Further, we show that COP1 is important in causing p53 nuclear exclusion. Finally, we demonstrate that 14-3-3σ targets COP1 for nuclear export, thereby preventing COP1-mediated p53 nuclear export. Together, these results define a novel, detailed mechanism for the subcellular localization and regulation of COP1 after DNA damage and provide a mechanistic explanation for the notion that 14-3-3σ's impact on the inhibition of p53 E3 ligases is an important step for p53 stabilization after DNA damage

Research on coal-geothermal collaborative exploration system in deep mines

Under the trend of deep mining of coal resources, the problem of high temperature heat damage in mines is becoming increasingly serious, the heat source that causes high temperature heat damage in mines is actually sustainably used geothermal energy, extracting and utilizing geothermal energy from deep mines while mining coal is an innovative way to build green mines and reduce mine carbon dioxide emission. This paper summarizes the current situation of deep mineral and geothermal energy collaborative exploration at China and abroad, analyzes the feasibility in terms of processes and key equipment and finally proposes a system of coal-geothermal collaborative exploration. The system adopts closed cycle mode, including ground heat utilization system and underground extracting system, drilling horizontal holes and installing coaxial casing heat exchangers at the coal to extract the heat, and utilization of the extracted low-grade geothermal energy through the heat pump on ground. Adhering to the principle of “mining heat first and then mining” in terms of time and space coordination, the thermal mining face is divided in front of the mining work in advance, and two modes of sequential and alternating thermal mining are proposed to ensure that the thermal mining process does not interfere with the coal mining process. Analyzed key technologies including spatial collaborative design, coal seam drilling, efficient heat extraction, and intelligent monitoring and control. Conducted underground spatial collaborative design for coal mining and geothermal energy extraction, proposed a coaxial casing heat exchanger layout process based on coal seam water injection. Multiple combinations of quick assembly coaxial casing heat exchangers can be used to achieve efficient heat extraction. Building an intelligent monitoring and control platform and proposed relevant optimization models, building a heat extraction calculation model and propose an intelligent control heat extraction method. Simplify the heat transfer process of coal formations, construct a heat transfer model for heat extraction from coal to calculate and evaluate the heat capacity of the mining face based on its actual situation and the outlet airflow parameters. According to the heat transfer model, the initial temperature of coal, the coal transportation volume, and the outlet air flow temperature through mining face are the key parameters that determine the heat extraction from the coal. The heat extraction is the maximum when the moisture content of the air flow of the working face remains unchanged and the equivalent temperature of the air flow at the outlet of the working face is not higher than 28 ℃. The application of this system will converting heat damage of deep mine to useful resources, which not only solves the problem of heat damage of coal mining, but also realizes the comprehensive utilization of geothermal energy in deep mine

PtoMYB031, the R2R3 MYB transcription factor involved in secondary cell wall biosynthesis in poplar

IntroductionThe biosynthesis of the secondary cell wall (SCW) is orchestrated by an intricate hierarchical transcriptional regulatory network. This network is initiated by first-layer master switches, SCW-NAC transcription factors, which in turn activate the second-layer master switches MYBs. These switches play a crucial role in regulating xylem specification and differentiation during SCW formation. However, the roles of most MYBs in woody plants are yet to be fully understood.MethodsIn this study, we identified and isolated the R2R3-MYB transcription factor, PtoMYB031, from Populus tomentosa. We explored its expression, mainly in xylem tissues, and its role as a transcriptional repressor in the nucleus. We used overexpression and RNA interference techniques in poplar, along with Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays, to analyze the regulatory effects of PtoMYB031.ResultsOverexpression of PtoMYB031 in poplar significantly reduced lignin, cellulose, and hemicellulose content, and inhibited vascular development in stems, resulting in decreased SCW thickness in xylem tissues. Gene expression analysis showed that structural genes involved in SCW biosynthesis were downregulated in PtoMYB031-OE lines. Conversely, RNA interference of PtoMYB031 increased these compounds. Additionally, PtoMYB031 was found to recruit the repressor PtoZAT11, forming a transcriptional inhibition complex.DiscussionOur findings provide new insights into how PtoMYB031, through its interaction with PtoZAT11, forms a complex that can suppress the expression of key regulatory genes, PtoWND1A and PtoWND2B, in SCW biosynthesis. This study enhances our understanding of the transcriptional regulation involved in SCW formation in poplar, highlighting the significant role of PtoMYB031

Anti-angiogenic therapy or immunotherapy? A real-world study of patients with advanced non-small cell lung cancer with EGFR/HER2 exon 20 insertion mutations

BackgroundFor patients with EGFR/HER2 exon20 insertions, platinum-containing double-drug chemotherapy is still the standard treatment method. First-generation TKIs have almost no therapeutic activity against EGFR exon 20 insertions. The efficacy of second-and third-generation TKIs is still controversial. Immunotherapy research is scarce, and there is an urgent need for more evidence and new treatment options for this group of patients.MethodsWe reviewed patients with advanced NSCLC with EGFR/HER2 exon 20 insertion mutations treated in Shanghai Chest Hospital and Shanghai Pulmonary Hospital from 2015 to 2022 and assessed the efficacy of receiving chemotherapy, anti-angiogenic therapy and immunotherapy, including objective response rate (ORR) and disease control rate (DCR), and compared progression-free survival (PFS) and overall survival (OS).ResultsOf the 126 patients included in the study, 51 patients had EGFR20ins mutations and 7 5 patients had HER2-20ins mutations. In the first-line treatment, bevacizumab + chemotherapy (Beva+Chemo), ICI+chemotherapy (ICI+Chemo), compared with chemotherapy alone (Chemo), ORR: 40% vs 33.3% vs 15% (p=0.0168); DCR: 84% vs 80.9% vs 67.5% (p=0.1817); median PFS: 8.3 vs 7.0 vs 4.6 months (p=0.0032), ICI+Chemo has a trend of benefiting on OS. Stratified analysis showed that compared with chemotherapy, ICI+Chemo was more effective for EGFR20ins mutation with median PFS: 10.3 vs. 6.3m (P=0.013); Beva+Chemo was more effective for HER2-20ins mutation, with a median PFS: 6.6 vs. 4.3m (p=0.030). In the second-line treatment of EGFR20ins mutation, bevacizumab + chemotherapy has a significant advantage in PFS compared with targeted therapy, median PFS:10.8 vs 4.0 months (P=0.016).ConclusionFor patients with EGFR20ins mutation, compared to chemotherapy, ICI+Chemo prolongs PFS, and after chemotherapy progression, bevacizumab combined with chemotherapy seems better than Furmonertinib-based targeted therapy on PFS. For HER2-20ins mutation, Beva+Chemo may be a better choice

Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling

SummaryMany signals must be integrated to maintain self-renewal and pluripotency in embryonic stem cells (ESCs) and to enable induced pluripotent stem cell (iPSC) reprogramming. However, the exact molecular regulatory mechanisms remain elusive. To unravel the essential internal and external signals required for sustaining the ESC state, we conducted a short hairpin (sh) RNA screen of 104 ESC-associated phosphoregulators. Depletion of one such molecule, aurora kinase A (Aurka), resulted in compromised self-renewal and consequent differentiation. By integrating global gene expression and computational analyses, we discovered that loss of Aurka leads to upregulated p53 activity that triggers ESC differentiation. Specifically, Aurka regulates pluripotency through phosphorylation-mediated inhibition of p53-directed ectodermal and mesodermal gene expression. Phosphorylation of p53 not only impairs p53-induced ESC differentiation but also p53-mediated suppression of iPSC reprogramming. Our studies demonstrate an essential role for Aurka-p53 signaling in the regulation of self-renewal, differentiation, and somatic cell reprogramming

Altered presynaptic function and number of mitochondria in the medial prefrontal cortex of adult Cyfip2 heterozygous mice

Variants of the cytoplasmic FMR1-interacting protein (CYFIP) gene family, CYFIP1 and CYFIP2, are associated with numerous neurodevelopmental and neuropsychiatric disorders. According to several studies, CYFIP1 regulates the development and function of both pre- and post-synapses in neurons. Furthermore, various studies have evaluated CYFIP2 functions in the postsynaptic compartment, such as regulating dendritic spine morphology; however, no study has evaluated whether and how CYFIP2 affects presynaptic functions. To address this issue, in this study, we have focused on the presynapses of layer 5 neurons of the medial prefrontal cortex (mPFC) in adult Cyfip2 heterozygous (Cyfip2+/−) mice. Electrophysiological analyses revealed an enhancement in the presynaptic short-term plasticity induced by high-frequency stimuli in Cyfip2+/− neurons compared with wild-type neurons. Since presynaptic mitochondria play an important role in buffering presynaptic Ca2+, which is directly associated with the short-term plasticity, we analyzed presynaptic mitochondria using electron microscopic images of the mPFC. Compared with wild-type mice, the number, but not the volume or cristae density, of mitochondria in both presynaptic boutons and axonal processes in the mPFC layer 5 of Cyfip2+/− mice was reduced. Consistent with an identification of mitochondrial proteins in a previously established CYFIP2 interactome, CYFIP2 was detected in a biochemically enriched mitochondrial fraction of the mouse mPFC. Collectively, these results suggest roles for CYFIP2 in regulating presynaptic functions, which may involve presynaptic mitochondrial changes.This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government Ministry of Science and ICT (NRF-2018R1C1B6001235, NRF-2018M3C7A1024603, NRF-2017M3C7A1048086, and NRF-2020R1A2C3011464) and the KBRI Basic Research Programs (20-BR01-08 and 20-BR-04-01)

Correlation between Spatial-Temporal Changes in Landscape Patterns and Habitat Quality in the Yongding River Floodplain, China

The watershed habitat, especially floodplains, is often impacted by the interaction between the natural environment and human activities, and the fragile ecological balance is easily disturbed. Therefore, the study of the changes in habitat quality in floodplains is significant for the reconstruction of damaged habitats. In this study, the landscape patterns and habitat quality in the Yongding River floodplain from 1967 to 2018 were evaluated. We employed spatial analysis to explore the characteristics and correlation of its spatio-temporal pattern change. Our results show that, first, the overall landscape pattern of the Yongding River floodplain was dominated by arable land and forestland while the construction land expanded. Second, the landscape pattern tended toward fragmentation, and the degree of landscape complexity increased. Third, the habitat quality was generally above the medium level. However, the low-quality area continued to increase. Furthermore, there was a strong correlation between habitat quality and the Aggregation Index, Diversity Index, and the area of water and forestland. In this context, the protection of the integrity and diversity of the landscape, reducing or even prohibiting the loss of water and forestland habitats, and restoring the ecological river, should be strengthened. The contribution of this paper provides a scientific reference to the comprehensive management and ecological restoration of river ecosystems

Historical Spatial Radiation Range of the Yongding River Corridor in Beijing Plain Section: Implications for Landscape Patterns and Ecological Restoration

The radiation range of the corridor effect holds great significance for the ecological restoration, planning, and sustainable development of river corridors. This study focuses on the Beijing plain section of the Yongding River, which has been cut off for half a century, and improves the research methodology. Utilizing land use data from 1967 and 1980, ArcGIS and Fragstats were employed to establish 5 km buffer zones on both sides of the Yongding River corridor. The buffer zone analysis method was then applied to investigate landscape pattern changes. Through SPSS correlation analysis and curve fitting, sensitive landscape indices were identified, and their change characteristics were analyzed to unveil the historical spatial radiation range and characteristics of the Yongding River corridor. The findings of this research are as follows: First, as the buffer width increases, the landscape pattern changes, showing a decrease in heterogeneity, an increase in aggregation and spread, and a good connection between dominant patches. Forest land exhibited higher levels of fragmentation and dispersion, cultivated land demonstrated improved dominance, and construction land became more regular and dispersed. Second, the spatial radiation range of the landscape level within the river corridor was approximately 4 km. The inflection point for the radiation range on forest land was found at 3.5–4 km, while for construction land, it occurred at 4.5 km. The outcomes of this study can be utilized to evaluate the impact of river corridors on landscape patterns in the period of good historical ecology. They also provide more targeted measures and scientific basis for landscape pattern protection and river ecological restoration planning after the restoration of water flow in the Yongding River plain