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Abstract Radiation-induced gastrointestinal syndrome is a major complication and limiting factor for radiotherapy. Tumor suppressor p53 has a protective role in radiation-induced gastrointestinal toxicity. However, its underlying mechanism remains unclear. Here we report that regulating the IL12-p40/MHC class II signaling pathway is a critical mechanism by which p53 protects against radiation-induced gastrointestinal syndrome. p53 inhibits the expression of inflammatory cytokine IL12-p40, which in turn suppresses the expression of MHC class II on intestinal epithelial cells to suppress T cell activation and inflammation post-irradiation that causes intestinal stem cell damage. Anti-IL12-p40 neutralizing antibody inhibits inflammation and rescues the defects in intestinal epithelial regeneration post-irradiation in p53-deficient mice and prolongs mouse survival. These results uncover that the IL12-p40/MHC class II signaling mediates the essential role of p53 in ensuring intestinal stem cell function and proper immune reaction in response to radiation to protect mucosal epithelium, and suggest a potential therapeutic strategy to protect against radiation-induced gastrointestinal syndrome.

Abstract Cancer cachexia is a systemic metabolic syndrome characterized by involuntary weight loss, and muscle and adipose tissue wasting. Mechanisms underlying cachexia remain poorly understood. Leukemia inhibitory factor (LIF), a multi-functional cytokine, has been suggested as a cachexia-inducing factor. In a transgenic mouse model with conditional LIF expression, systemic elevation of LIF induces cachexia. LIF overexpression decreases de novo lipogenesis and disrupts lipid homeostasis in the liver. Liver-specific LIF receptor knockout attenuates LIF-induced cachexia, suggesting that LIF-induced functional changes in the liver contribute to cachexia. Mechanistically, LIF overexpression activates STAT3 to downregulate PPARα, a master regulator of lipid metabolism, leading to the downregulation of a group of PPARα target genes involved in lipogenesis and decreased lipogenesis in the liver. Activating PPARα by fenofibrate, a PPARα agonist, restores lipid homeostasis in the liver and inhibits LIF-induced cachexia. These results provide valuable insights into cachexia, which may help develop strategies to treat cancer cachexia.

Net primary production (NPP) serves as a critical proxy for monitoring changes in the global capacity for vegetation carbon sequestration. The assessment of the factors (i.e., human activities and climate changes) influencing NPP is of great value for the study of terrestrial systems. To investigate the influence of factors on grassland NPP, the ecologically vulnerable Qinghai–Tibet Plateau region was considered an appropriate study area for the period from 2000 to 2020. We innovated the use of the RICI index to quantitatively represent human activities and analyzed the effects of RICI and climatic factors on grassland NPP using the geographical detector. In addition, the future NPP was predicted through the integration of two modeling approaches: The Patch-Generating Land Use Simulation (PLUS) model and the Carnegie–Ames–Stanford Approach (CASA) model. The assessment revealed that the expanded grassland contributed 7.55 × 104 Gg C (Gg = 109 g) to the total NPP, whereas the deterioration of grassland resulted in a decline of 1.06 × 105 Gg C. The climatic factor was identified as the dominant factor in grassland restoration, representing 70.85% of the total NPP, as well as the dominant factor in grassland degradation, representing 92.54% of the total NPP. By subdividing the climate change and human activity factors into sub-factors and detecting them with a geographical detector, the results show that climate change and anthropogenic factors have significant ability to explain geographic variation in NPP to a considerable extent, and the effect on NPP is greater when the factors interact. The q-values of the Relative Impact Contribution Index (RICI) and the RICI of the land use change NPP are consistently greater than 0.6, with the RICI of the human management practices NPP and the evapotranspiration remaining at approximately 0.5. The analysis of the interaction between climate and human activity factors reveals an average impact of greater than 0.8. By 2030, the NPP of the natural development scenario, economic development scenario (ED), and ecological protection scenario (EP) show a decreasing trend due to climate change, the dominant factor, causing them to decrease. Human activities play a role in the improvement. The EP indicates a positive expansion in the growth rate of forests, water, and wetlands, while the ED reveals rapid urbanization. It is notable that this is accompanied by a temporary suspension of urban greening.

Phosphorus and nitrogen pollution from agricultural nonpoint sources heavily burden the water environment, and a scientific calculating system is needed to calculate the pollutant loads under the water pollution treatment. This study established a system to calculate the coefficients of agricultural nonpoint source pollutants into water bodies in the subregion in Poyang Lake basin in the middle reach of the Yangtze River combining with multiple driving factors. Validation results showed that the errors of the typical unit were 30.58% for total phosphorus (TP), 13.43% for total nitrogen (TN) and 33.93% for ammonia nitrogen (NH3-N), respectively. The errors of the subregion were 26.92% for TP, 31.83% for TN and 29.15% for NH3-N, respectively. Besides, there were higher TP and TN loads in the east area of subregion in both units and county scales, which indicated the heavy phosphorus and nitrogen burden on water environment. In contrast, higher NH3-N loads occurred in the north area of subregion. The establishment of coefficient system for agricultural pollutants into water bodies and the pollutant loads calculation would provide enlightenment for water pollution treatment and agricultural nonpoint source pollution controlling.

Serious ecological crises have emerged in the Asian Water Tower region (17 countries centered on the Qinghai-Tibetan Plateau), making it a major priority and challenge for Asian and even global ecological conservation efforts. Constructing a multi-leveled ecological security pattern (ESP) based on the synergies among multiple ecosystem services (ESs) for this region can enhance the structural integrity, functional stability, and spatial connectivity of ecosystems. Therefore, based on a series of GIS spatial analysis methods, the minimum cumulative resistance model, and the analytic hierarchy process, this study measured the importance of five key ESs focused by Sustainable Development Goal 15 (including water conservation, carbon sequestration, sand fixation, soil conservation, and biodiversity conservation); and took fishnet scale as data calculation unit to construct a hierarchical ESP (including three levels of ecological sources and corridors) to provide evidence-based support for identifying and prioritizing synergistic conservation actions across scales (regions, nations, and basins). Overall, the ESP included a total of 534 sources and 656 corridors. Some key conservation obstacles in the region (e.g., edge effects and several human activities) and corresponding priority actions are provided, such as integrating the ESPs into long-term planning, enhancing the conservation and the restoration of both the extent and the quality of forests (e.g., increasing tree species richness), and increasing collaboration across scales for resource mobilization and synergistic land use.

The lack of high-spectral and high-resolution remote sensing data is impeding the differentiation of various fruit tree species that share comparable spectral and spatial features, especially for evergreen broadleaf trees in tropical and subtropical areas. Here, we propose a novel decision tree approach to map the spatial distribution of fruit trees at a 10 m spatial resolution based on the growth stage features extracted from Sentinel-1A (S-1A) time-series synthetic aperture radar (SAR) data. This novel method was applied to map the spatial distribution of fruit trees in Maoming City, which is known for its vast cultivation of fruit trees, such as litchi, citrus, and longan. The results showed that the key to extracting information on the distribution of fruit trees lies in the fact that the fruit ripening and expansion period attenuates the information on the vegetation of fruit trees, a characteristic of the reproductive period. Under VH polarization, different fruit tree growth stage traits were more separable and easier to distinguish. The optimal features, such as Hv (high valley value of the 14 May, 26 May, and 7 June SAR data), Tb (difference between the 7 June and 14 January SAR data), Cr (high valley value of the 13 July, 25 July, and 6 August SAR data), and Lo (high valley value of the 23 September, 17 October, and 11 November SAR data), were constructed based on the optimal window. The thresholds for these features were set to 1, 1, 1.5, and 1, respectively. The classification model can effectively distinguish different fruit trees and extract distribution information with overall accuracy (OA) of 90.34% and a Kappa coefficient of 0.84. The proposed method extracts the spatial distribution information of different fruit trees more accurately and provides a reference for the extraction of more tropical and subtropical species.

Highlights 1. Effects of salinity, alkalinity and their combined impact were analysed with transcriptome and and proteomics methods in G. przewalskii. 2. The validity of transcriptome and proteome results in G. przewalskii was compared. 3. Hub genes in the adaptive responses to the combined impact of salinity and alkalinity were isolated. 4. Physiological regulation mechanisms regarding salinity, alkalinity, and salinity-alkalinity interactions were discussed.

Abstract LIF, a multifunctional cytokine, is frequently overexpressed in many types of solid tumors, including breast cancer, and plays an important role in promoting tumorigenesis. Currently, how LIF promotes tumorigenesis is not well-understood. Metabolic reprogramming is a hallmark of cancer cells and a key contributor to cancer progression. However, the role of LIF in cancer metabolic reprogramming is unclear. In this study, we found that LIF increases glucose uptake and drives glycolysis, contributing to breast tumorigenesis. Blocking glucose uptake largely abolishes the promoting effect of LIF on breast tumorigenesis. Mechanistically, LIF overexpression enhances glucose uptake via activating the AKT/GLUT1 axis to promote glycolysis. Blocking the AKT signaling by shRNA or its inhibitors greatly inhibits glycolysis driven by LIF and largely abolishes the promoting effect of LIF on breast tumorigenesis. These results demonstrate an important role of LIF overexpression in glucose metabolism reprogramming in breast cancers, which contributes to breast tumorigenesis. This study also reveals an important mechanism underlying metabolic reprogramming of breast cancers, and identifies LIF and its downstream signaling as potential therapeutic targets for breast cancers, especially those with LIF overexpression.

Modeling and estimating the energy consumption of computer numerical control (CNC) milling systems have been recognized as essential ways to realize lean energy consumption management and improve energy efficiency performance. As the preparatory phase, considerable time and energy are consumed in the tool setting process. However, research on the tool setting process mainly focuses on accuracy and operational efficiency, and the energy consumption is usually ignored or simplified. Accurately estimating the energy consumption of the tool setting process is thus indispensable for reducing the energy consumption of CNC milling systems and improving their energy efficiency. To bridge this gap, an energy consumption estimation method for the tool setting process in CNC milling based on the modular arrangement of predetermined time standards (MODAPTS) is presented. It includes three steps: (i) operations decomposition and determination of the MODAPTS codes for the tool setting process, (ii) power modeling of the basic action elements of the machine tool, and (iii) energy consumption modeling of the tool setting process. Finally, a case study was conducted to illustrate the practicability of the proposed method via energy consumption modeling of the tool setting process using an XH714D CNC machine center with a square workpiece, in which the estimation values of the operating time and the energy consumption for the tool setting process were 210.786 s and 140,681.68 J, respectively. The proposed method can increase the transparency of energy consumption and help establish labor-hour quotas and energy consumption allowances in the tool setting process.

The tumor suppressor TP53 is the most frequently mutated gene in human cancers. Mutant p53 (mutp53) proteins often accumulate to very high levels in human cancers to promote cancer progression through the gain-of-function (GOF) mechanism. Currently, the mechanism underlying mutp53 accumulation and GOF is incompletely understood. Here, we identified TRIM21 as a critical E3 ubiquitin ligase of mutp53 by screening for specific mutp53-interacting proteins. TRIM21 directly interacted with mutp53 but not WT p53, resulting in ubiquitination and degradation of mutp53 to suppress mutp53 GOF in tumorigenesis. TRIM21 deficiency in cancer cells promoted mutp53 accumulation and GOF in tumorigenesis. Compared with p53R172H knockin mice, which displayed mutp53 accumulation specifically in tumors but not normal tissues, TRIM21 deletion in p53R172H knockin mice resulted in mutp53 accumulation in normal tissues, an earlier tumor onset, and a shortened life span of mice. Furthermore, TRIM21 was frequently downregulated in some human cancers, including colorectal and breast cancers, and low TRIM21 expression was associated with poor prognosis in patients with cancers carrying mutp53. Our results revealed a critical mechanism underlying mutp53 accumulation in cancers and also uncovered an important tumor-suppressive function of TRIM21 and its mechanism in cancers carrying mutp53.

p53 is a key tumor suppressor. As a transcription factor, p53 accumulates in cells in response to various stress signals and selectively transcribes its target genes to regulate a wide variety of cellular stress responses to exert its function in tumor suppression. In addition to tumor suppression, p53 is also involved in many other physiological and pathological processes, e.g. anti-infection, immune response, development, reproduction, neurodegeneration and aging. To maintain its proper function, p53 is under tight and delicate regulation through different mechanisms, particularly the posttranslational modifications. The tripartite motif (TRIM) family proteins are a large group of proteins characterized by the RING, B-Box and coiled-coil (RBCC) domains at the N-terminus. TRIM proteins play important roles in regulation of many fundamental biological processes, including cell proliferation and death, DNA repair, transcription, and immune response. Alterations of TRIM proteins have been linked to many diseases including cancer, infectious diseases, developmental disorders, and neurodegeneration. Interestingly, recent studies have revealed that many TRIM proteins are involved in the regulation of p53, and at the same time, many TRIM proteins are also regulated by p53. Here, we review the cross-talk between p53 and TRIM proteins, and its impact upon cellular biological processes as well as cancer and other diseases.

Identifying functional domains and genetic regulatory mechanisms is essential for developing new therapies. Here the authors present sc-Tiling, single-cell high-density CRISPR tiling screening for functional domain characterization.

P53 is a well-known tumour suppressor, however its role in intestinal type 2 immunity is currently unclear. Here authors report that during parasitic infections, p53 triggers tuft cell Ca2+ influx and IL-25 release, and shows a regulatory role for p53 in intestinal type 2 immunity via transcriptional regulation of the Lrmp gene.

Changes in land use and landscape caused by human activities, rapid socioeconomic development and climate change disturb the water cycle process and impact the runoff. This study analyzed the runoff responses to different driving factors in a typical basin in the Beijing-Tianjin-Hebei region of North China combined with methods such as geographically and temporally weighted regression, landscape pattern indexes and Budyko theory. The results indicated that the runoff and runoff depth were higher in the central and south part and were lower in the northwest of the basin. Furthermore, the average runoff increased at the later stage of the study period. Artificial surface and land use intensity exerted positive impacts on runoff and runoff depth in most areas. The complex and diverse landscape with a high shape index blocked runoff to some extent. Moreover, runoff depth would increase by 0.724 mm or decrease by 0.069 mm when the rainfall or potential evaporation increased by 1 mm. In addition, population density and the economic development in both rural as well as urban areas put a heavy burden on runoff and water resource in this basin. From above it could be concluded that the impacts on runoff due to environmental change brought by human activities could not be neglected though the runoff was also greatly affected by climate change. This study reflected the runoff responses to driving factors in a typical basin of North China, which will provide reference for water resource protection and give enlightenment to water management.

Gas detection in enclosed cabins is a challenging concern in the industry to ensure the safety of cabin operations and personnel driving. There has been a growing development in the detection of safety in enclosed cabin operations based on volatile organic compounds, which have unique characteristics. The air pollution in closed cabins seriously affects the driver’s health, and the accuracy of the detection directly affects the operation safety of the cabin. However, until today, gas detection in enclosed cabins has relied on traditional methods that are expensive and time-consuming, and it cannot be detected in real time. This paper focuses on the potential and capability of electronic nose applications for gas detection in enclosed cabins. Since the electronic nose is a good substitute for the closed cabin, people’s attention to it has increased greatly. The characteristics of hazardous gas and warning gas in closed cabins are also discussed. In addition, this paper provides important insights into the challenges and future trends of the electronic nose, a low-cost, high-precision, and fast detection method, in more applications in closed compartments.

Hypoxia is a hallmark of solid tumors and plays a critical role in different steps of tumor progression, including proliferation, survival, angiogenesis, metastasis, metabolic reprogramming, and stemness of cancer cells. Activation of the hypoxia-inducible factor (HIF) signaling plays a critical role in regulating hypoxic responses in tumors. As a key tumor suppressor and transcription factor, p53 responds to a wide variety of stress signals, including hypoxia, and selectively transcribes its target genes to regulate various cellular responses to exert its function in tumor suppression. Studies have demonstrated a close but complex interplay between hypoxia and p53 signaling pathways. The p53 levels and activities can be regulated by the hypoxia and HIF signaling differently depending on the cell/tissue type and the severity and duration of hypoxia. On the other hand, p53 regulates the hypoxia and HIF signaling at multiple levels. Many tumor-associated mutant p53 proteins display gain-of-function (GOF) oncogenic activities to promote cancer progression. Emerging evidence has also shown that GOF mutant p53 can promote cancer progression through its interplay with the hypoxia and HIF signaling pathway. In this review, we summarize our current understanding of the interplay between the hypoxia and p53 signaling pathways, its impact upon cancer progression, and its potential application in cancer therapy.

Summary: Repair of DNA double-stranded breaks (DSBs) during lymphocyte development is essential for V(D)J recombination and forms the basis of immunoglobulin variable region diversity. Understanding of this process in lymphogenesis has historically been centered on the study of RAG1/2 recombinases and a set of classical non-homologous end-joining factors. Much less has been reported regarding the role of chromatin modifications on this process. Here, we show a role for the non-redundant histone H3 lysine methyltransferase, Setd2, and its modification of lysine-36 trimethylation (H3K36me3), in the processing and joining of DNA ends during V(D)J recombination. Loss leads to mis-repair of Rag-induced DNA DSBs, especially when combined with loss of Atm kinase activity. Furthermore, loss reduces immune repertoire and a severe block in lymphogenesis as well as causes post-mitotic neuronal apoptosis. Together, these studies are suggestive of an important role of Setd2/H3K36me3 in these two mammalian developmental processes that are influenced by double-stranded break repair. : Biological Sciences; Molecular Biology; Immunology; Cell Biology Subject Areas: Biological Sciences, Molecular Biology, Immunology, Cell Biology

Abstract The mutation of the Parkin gene is a cause of familial Parkinson’s disease. A growing body of evidence suggests that Parkin also functions as a tumor suppressor. Parkin is an ubiquitin E3 ligase, and plays important roles in a variety of cellular processes implicated in tumorigenesis, including cell cycle, cell proliferation, apoptosis, metastasis, mitophagy and metabolic reprogramming. Here we review the role and mechanism of Parkin in cancer.

Parkin is an E3 ubiquitin ligase involved in Parkinson’s disease. Parkin has also been linked to cancer suppression but the mechanisms are unclear. Here the authors show that Parkin regulates HIF-1α through ubiquitin-dependent degradation, thus inhibiting metastasis of breast cancer cells.

Tumor suppressor p53 prevents early death due to cancer development. However, the role of p53 in aging process and longevity has not been well-established. In humans, single nucleotide polymorphism (SNP) with either arginine (R72) or proline (P72) at codon 72 influences p53 activity; the P72 allele has a weaker p53 activity and function in tumor suppression. Here, employing a mouse model with knock-in of human TP53 gene carrying codon 72 SNP, we found that despite increased cancer risk, P72 mice that escape tumor development display a longer lifespan than R72 mice. Further, P72 mice have a delayed development of aging-associated phenotypes compared with R72 mice. Mechanistically, P72 mice can better retain the self-renewal function of stem/progenitor cells compared with R72 mice during aging. This study provides direct genetic evidence demonstrating that p53 codon 72 SNP directly impacts aging and longevity, which supports a role of p53 in regulation of longevity.

Glutaminase (GLS) isoenzymes GLS1 and GLS2 are key enzymes for glutamine metabolism. Interestingly, GLS1 and GLS2 display contrasting functions in tumorigenesis with elusive mechanism; GLS1 promotes tumorigenesis, whereas GLS2 exhibits a tumor-suppressive function. In this study, we found that GLS2 but not GLS1 binds to small GTPase Rac1 and inhibits its interaction with Rac1 activators guanine-nucleotide exchange factors, which in turn inhibits Rac1 to suppress cancer metastasis. This function of GLS2 is independent of GLS2 glutaminase activity. Furthermore, decreased GLS2 expression is associated with enhanced metastasis in human cancer. As a p53 target, GLS2 mediates p53’s function in metastasis suppression through inhibiting Rac1. In summary, our results reveal that GLS2 is a novel negative regulator of Rac1, and uncover a novel function and mechanism whereby GLS2 suppresses metastasis. Our results also elucidate a novel mechanism that contributes to the contrasting functions of GLS1 and GLS2 in tumorigenesis.

Tumor suppressor p53 is the most frequently mutated gene in tumors. Many mutant p53 (mutp53) proteins promote tumorigenesis through the gain-of-function (GOF) mechanism. Mutp53 proteins often accumulate to high levels in tumors, which is critical for mutp53 GOF. Its underlying mechanism is poorly understood. Here, we found that BAG2, a protein of Bcl-2 associated athanogene (BAG) family, promotes mutp53 accumulation and GOF in tumors. Mechanistically, BAG2 binds to mutp53 and translocates to the nucleus to inhibit the MDM2-mutp53 interaction, and MDM2-mediated ubiquitination and degradation of mutp53. Thus, BAG2 promotes mutp53 accumulation and GOF in tumor growth, metastasis and chemoresistance. BAG2 is frequently overexpressed in tumors. BAG2 overexpression is associated with poor prognosis in patients and mutp53 accumulation in tumors. These findings revealed a novel and important mechanism for mutp53 accumulation and GOF in tumors, and also uncovered an important role of BAG2 in tumorigenesis through promoting mutp53 accumulation and GOF.