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Tumor suppressor p53 plays a key role in tumor suppression. In addition to tumor suppression, p53 is also involved in many other biological and pathological processes, such as immune response, maternal reproduction, tissue ischemia/reperfusion injuries and neurodegenerative diseases. While it has been widely accepted that the role of p53 in regulation of cell cycle arrest, senescence and apoptosis contributes greatly to the function of p53 in tumor suppression, emerging evidence has implicated that p53 also exerts its tumor suppressive function through regulation of many other cellular processes, such as metabolism, anti-oxidant defense and ferroptosis. Ferroptosis is a unique iron-dependent form of programmed cell death driven by lipid peroxidation in cells. Ferroptosis has been reported to be involved in cancer, tissue ischemia/reperfusion injuries and neurodegenerative diseases. Recent studies have shown that ferroptosis can be regulated by p53 and its signaling pathway as well as tumor-associated mutant p53. Interestingly, the regulation of ferroptosis by p53 appears to be highly context-dependent. In this review, we summarize recent advances in the regulation of ferroptosis by p53 and its signaling pathway. Further elucidation of the role and molecular mechanism of p53 in ferroptosis regulation will yield new therapeutic strategies for cancer and other diseases, including neurodegenerative diseases and tissue ischemia/reperfusion injuries. [ABSTRACT FROM AUTHOR]

Leukemia stem cells (LSCs) are capable of limitless self-renewal and are responsible for the maintenance of leukemia. Because selective eradication of LSCs could offer substantial therapeutic benefit, there is interest in identifying the signaling pathways that control their development. We studied LSCs in mouse models of acute myelogenous leukemia (AML) induced either by coexpression of the Hoxa9 and Meis1a oncogenes or by the fusion oncoprotein MLL-AF9. We show that the Wnt/β-catenin signaling pathway is required for self-renewal of LSCs that are derived from either hematopoietic stem cells (HSC) or more differentiated granulocyte-macrophage progenitors (GMP). Because the Wnt/β-catenin pathway is normally active in HSCs but not in GMP, these results suggest that reactivation of β-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. β-catenin is not absolutely required for self-renewal of adult HSCs; thus, targeting the Wnt/β-catenin pathway may represent a new therapeutic opportunity in AML., Stem Cell and Regenerative Biology

The large-scale ingot of the 7xxx-series aluminum alloys fabricated by direct chill (DC) casting often suffers from foundry defects such as cracks and cold shut due to the formidable challenges in the precise controlling of casting parameters. In this manuscript, by using the integrated computational method combining numerical simulations with machine learning, we systematically estimated the evolution of multi-physical fields and grain structures during the solidification processes. The numerical simulation results quantified the influences of key casting parameters including pouring temperature, casting speed, primary cooling intensity, and secondary cooling water flow rate on the shape of the mushy zone, heat transport, residual stress, and grain structure of DC casting ingots. Then, based on the data of numerical simulations, we established a novel model for the relationship between casting parameters and solidification characteristics through machine learning. By comparing it with experimental measurements, the model showed reasonable accuracy in predicting the sump profile, microstructure evolution, and solidification kinetics under the complicated influences of casting parameters. The integrated computational method and predicting model could be used to efficiently and accurately determine the DC casting parameters to decrease the casting defects. [ABSTRACT FROM AUTHOR]

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 H v (high valley value of the 14 May, 26 May, and 7 June SAR data), T b (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 L o (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. [ABSTRACT FROM AUTHOR]

Gymnocypris przewalskii (Naked carp), a native teleost, plays an important role in maintaining the ecological balance of Lake Qinghai (altitude, 3.2 km), the largest saline lake in China. In this study, a new gill cell line from G. przewalskii was developed using the explant technique and named as GPG. This cell line was maintained in Dulbecco's Modified Eagle Medium (DMEM) (high glucose), supplemented with 15% fetal bovine serum (FBS), and was successfully subcultured up to 32 passages. Meanwhile, this cell line was also authenticated by sequencing the mitochondrial cytochrome C oxidase subunit I (COI) and 16S rRNA genes and by chromosome analysis. With the Cytomegalovirus (CMV) promoter, the GPG cell line could express green fluorescent protein (GFP) at about 5% transfection efficiency. MTT test showed that Clostridium botulinum toxin (BTX) was toxic to the cell line. After cryopreservation with 10% dimethyl sulfoxide (DMSO), this cell line could be successfully revived at an efficiency over 70%. This study revealed that the GPG cell line could be used as materials for physio‐chemical investigation of G. przewalskii and also provided a tool for gene function study and toxicological reaction in vitro. [ABSTRACT FROM AUTHOR]

Abstract: Nano-sized ceramic particle reinforced aluminum matrix composites fabricated using conventional stir casting technique usually present poor distribution of nanoparticles within the matrix and high porosity. In this study, nano-Al2O3/2024 composites were prepared by solid–liquid mixed casting combined with ultrasonic treatment. The obtained composite exhibited fine grain microstructure, reasonable Al2O3 nanoparticles distribution in the matrix, and low porosity. Solid–liquid mixed casting technique was effective in inhibiting the agglomeration of nanoparticles in the matrix. The application of ultrasonic vibration on the composite melt during the solidification not only refined the grain microstructure of the matrix, but also improved the distribution of nano-sized reinforcement. Compared with the matrix, the ultimate tensile strength and yield strength of 1wt.% nano-Al2O3/2024 composite were enhanced by 37% and 81%, respectively. The better tensile properties were attributed to the uniform distribution of reinforcement and grain refinement of aluminum matrix. [Copyright &y& Elsevier]

Naked carp (Gymnocypris przewalskii) is a migratory fish endemic to the Qinghai Lake, the largest inland saline-alkaline lake in China. Based on our previous results of comparative transcriptome sequencing, we found that pathways related to regulation of actin cytoskeleton, plasma membrane damage, and inflammation-related signaling were significantly enriched during saline-alkaline stress, suggesting involvement of annexin (ANN) family proteins in stress adaption in naked carp. Herein, to explore the role of annexin family in naked carp under saline-alkaline stress, twenty GpANNs family members were identified at the genome-wide scale, and bioinformatics and expression analysis under saline-alkaline stress were performed. The predicted subcellular localization showed that most members of GpANNs were distributed in the cytoplasm, and the rest were localized in the cytoskeleton, nucleus, or mitochondria, respectively. GpANNs family proteins contained specific type II Ca2+-binding motifs, actin-binding motifs, GTP-binding motifs, etc. Phylogenetic tree analysis showed that the annexin homologues from naked carp, carp (Cyprinus carpio), zebrafish (Danio rerio), and chinese cavefish (Sinocyclocheilus rhinocerous) were divided into eight groups, i.e. ANN1 ∼ 6, ANN11 and ANN13. But homologues of ANN7 ∼ 10 groups were not found in these three fish species. Twenty-eight, nineteen and twenty-nine orthologous gene pairs were identified between naked carp and carp, zebrafish and chinese cavefish, respectively. Six paralogous gene pairs were identified in naked carp, all of which had a Ka/Ks ratio less than one, suggesting that the GpANNs family may have undergone purifying selection pressure during evolution. Expression of GpANN3 was significantly up-regulated in the kidney tissue under saline-alkaline stress, while GpANN2 was significantly down-regulated. Similar trends of protein expression were also observed by Western blot, suggesting involvement of GpANN3 and GpANN2 in stress response. Confocal microscopy revealed that GpANN2 was localized in both cytoplasm and nucleus, but GpANN3 was preferentially localized in the cytoplasm. Our study demonstrated the role of annexins in stress adaption, and provided the basic information required for further function analyses in naked carp. • The annexin family were comprehensively analyzed in G. przewalskii for the first time, but ANN7 ∼ 10 memebers were lacked. • GpANNs contain a variety of motifs which may be important sites for protein function under saline-alkaline conditions. • GpANNs exhibited differential expression patterns in 12 different tissues under saline-alkaline stress. • In kidney, GpANN2 and GpANN3 significantly responded to saline-alkaline stress at both mRNA and protein levels. [ABSTRACT FROM AUTHOR]

• A multi-leveled ESP was constructed to help with large-scale ecological conservation. • This ESP can enhance synergistic conservation across scales (regions, basins, and nations). • Five key ecosystem services focused by Sustainable Development Goal 15 were used to identify ecological sources. 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. [ABSTRACT FROM AUTHOR]

Mercury species distribution in the flue gas from three typical coal-fired power plants have been investigated using a C-5000 sampler for Ontario Hydro Method (OHM) to evaluate specified Hg emission inventories in the largest coal-production province of China, Inner Mongolia. The feed coal, bottom ash, fly ash and gypsum have also been sampled in the field. Mercury emissions are in the dominant form of Hg 0 (>85%). The Hg 2+ (<15%) and the Hg p (<2%) emissions are minor fractions of Hg t in the flue gas. The wet limestone flue gas desulfurization device (WLFGD) showed much higher removal efficiency for Hg 2+ (87–95%) than for the other two Hg species. The input Hg/output Hg varied from 92% to 115% for the tested 3 coal-fried utility boilers during sampling time. We obtained comprehensive Hg discharge factors, including direct atmospheric Hg emission factors and indirect discharge factors of Hg associated with bottom ash, fly ash and gypsum, to the environment, designating the fates of Hg in coal. We estimated the Hg discharges from coal-fired power plants in Inner Mongolia in 2008–2014 and expanded to China. The maximum of direct Hg emissions from coal-fired power plants of Inner Mongolia was 24 Mg in 2012. The Chinese coal-fired power plants emitted directly 100 Mg Hg to the atmosphere every year at the nationwide air control actions. The maximum discharges of Hg associated with fly ash and gypsum of Inner Mongolia was 81 Mg and 11 Mg in 2012, respectively. The national Hg discharges with fly ash and gypsum every year are respectively about 300 Mg and 82 Mg, majority of which may be reemitted to the atmosphere by the utilization industry. Therefore, mercury emissions from coal-fired power plants are not the largest single source of Hg to the atmosphere in normal operation of the current efficient denitrification, particles control and desulfurization devices. Instead, the utilization industry of fly ash and gypsum would be emitting more Hg to the atmosphere. [ABSTRACT FROM AUTHOR]

Tumor-suppressor p53 plays a key role in tumor prevention. As a transcription factor, p53 transcriptionally regulates its target genes to initiate different biological processes in response to stress, including apoptosis, cell cycle arrest or senescence, to exert its function in tumor suppression. Recent studies have revealed that metabolic regulation is a novel function of p53. Metabolic changes have been regarded as a hallmark of tumors and a key contributor to tumor development. p53 regulates many different aspects of metabolism, including glycolysis, mitochondrial oxidative phosphorylation, pentose phosphate pathway, fatty acid synthesis and oxidation, to maintain the homeostasis of cellular metabolism, which contributes to the role of p53 in tumor suppression. p53 is frequently mutated in human tumors. In addition to loss of tumor suppressive function, tumor-associated mutant p53 proteins often gain new tumorigenic activities, termed gain-of-function of mutant p53. Recent studies have shown that mutant p53 mediates metabolic changes in tumors as a novel gain-of-function to promote tumor development. Here we review the functions and mechanisms of wild-type and mutant p53 in metabolic regulation, and discuss their potential roles in tumorigenesis. [ABSTRACT FROM AUTHOR]

Summary: The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia. [Copyright &y& Elsevier]

Leukemia inhibitory factor (LIF) is a multi-functional cytokine of the interleukin-6 (IL-6) superfamily. Initially identified as a factor that inhibits the proliferation of murine myeloid leukemia cells, LIF displays a wide variety of important functions in a cell-, tissue- and context-dependent manner in many physiological and pathological processes, including regulating cell proliferation, pluripotent stem cell self-renewal, tissue/organ development and regeneration, neurogenesis and neural regeneration, maternal reproduction, inflammation, infection, immune response, and metabolism. Emerging evidence has shown that LIF plays an important but complex role in human cancers; while LIF displays a tumor suppressive function in some types of cancers, including leukemia, LIF is overexpressed and exerts an oncogenic function in many more types of cancers. Further, targeting LIF has been actively investigated as a novel strategy for cancer therapy. This review summarizes the recent advances in the studies on LIF in human cancers and its potential application in cancer therapy. A better understanding of the role of LIF in different types of cancers and its underlying mechanisms will help to develop more effective strategies for cancer therapy. [ABSTRACT FROM AUTHOR]

Competing Interests: Disclosure Statement None declared.

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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 (NH 3 -N), respectively. The errors of the subregion were 26.92% for TP, 31.83% for TN and 29.15% for NH 3 -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 NH 3 -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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

RAB11 small GTPases and associated recycling endosome have been localized to mitotic spindles and implicated in regulating mitosis. However, the physiological significance of such regulation has not been observed in mammalian tissues. We have used newly engineered mouse models to investigate intestinal epithelial renewal in the absence of single or double isoforms of RAB11 family members: Rab11a and Rab11b. Comparing with single knockouts, mice with compound ablation demonstrate a defective cell cycle entry and robust mitotic arrest followed by apoptosis, leading to a total penetrance of lethality within 3 days of gene ablation. Upon Rab11 deletion ex vivo, enteroids show abnormal mitotic spindle formation and cell death. Untargeted proteomic profiling of Rab11a and Rab11b immunoprecipitates has uncovered a shared interactome containing mitotic spindle microtubule regulators. Disrupting Rab11 alters kinesin motor KIF11 function and impairs bipolar spindle formation and cell division. These data demonstrate that RAB11A and RAB11B redundantly control mitotic spindle function and intestinal progenitor cell division, a mechanism that may be utilized to govern the homeostasis and renewal of other mammalian tissues., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

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.

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine of the interleukin-6 (IL-6) superfamily. LIF was initially discovered as a factor to induce the differentiation of myeloid leukemia cells and thus inhibit their proliferation. Subsequent studies have highlighted the multi-functions of LIF under a wide variety of physiological and pathological conditions in a highly cell-, tissue-, and context-dependent manner. Emerging evidence has demonstrated that LIF plays an essential role in the stem cell niche, where it maintains the homeostasis and regeneration of multiple somatic tissues, including intestine, neuron, and muscle. Further, LIF exerts a crucial regulatory role in immunity and functions as a protective factor against many immunopathological diseases, such as infection, inflammatory bowel disease (IBD), and graft-verse-host disease (GVHD). It is worth noting that while LIF displays a tumor-suppressive function in leukemia, recent studies have highlighted the oncogenic role of LIF in many types of solid tumors, further demonstrating the complexities and context-dependent effects of LIF. In this review, we summarize the recent insights into the roles and mechanisms of LIF in stem cell homeostasis and regeneration, immunity, and cancer, and discuss the potential therapeutic options for human diseases by modulating LIF levels and functions., Competing Interests: Declaration of interests Authors declare no competing interests., (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Natural vegetation has been proved to promote water purification in previous studies, while the relevant laws has not been excavated systematically. This research explored the relationships between vegetation cover and water quality indexes in Liaohe River Basin in China combined with self-organizing map (SOM) and geographically and temporally weighted regression (GTWR) innovatively and systematically based on the distributing heterogeneity of water quality conditions. Results showed that the central and northeast regions of the study area had serious organic and nutrient pollution, which needed targeted treatment. And SOM verified that high vegetation coverage with retention potential of organic and inorganic pollutants as well as nutrients improved water quality to some degree, while the excessive discharges of pollutants still had serious threats to nearby water environment despite the purification function of vegetation. GTWR indicated that the waterside vegetation was beneficial for dissolved oxygen increasing and contributed to the decreasing of organic pollutants and inorganic pollutants with reducibility. Natural vegetation also obsorbed nutrients like TN and TP to some degree. However, the retential potential of nitrogen and organic pollutants became not obvious when there were heavy pollution, which demonstrated that pollution sources should be controlled despite the purification function of vegetation. This study implied that natural vegetation purified water quality to some degree, while this function could not be revealed when there was too heavy pollution. These findings underscore that the pollutant discharge should be controlled though the natural vegetation in ecosystem promoted the purification of water bodies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The glycolytic enzyme lactate dehydrogenase A (LDHA) is frequently overexpressed in cancer, which promotes glycolysis and cancer. The oncogenic effect of LDHA has been attributed to its glycolytic enzyme activity. Here we report an unexpected noncanonical oncogenic mechanism of LDHA; LDHA activates small GTPase Rac1 to promote cancer independently of its glycolytic enzyme activity. Mechanistically, LDHA interacts with the active form of Rac1, Rac1-GTP, to inhibit Rac1-GTP interaction with its negative regulator, GTPase-activating proteins, leading to Rac1 activation in cancer cells and mouse tissues. In clinical breast cancer specimens, LDHA overexpression is associated with higher Rac1 activity. Rac1 inhibition suppresses the oncogenic effect of LDHA. Combination inhibition of LDHA enzyme activity and Rac1 activity by small-molecule inhibitors displays a synergistic inhibitory effect on breast cancers with LDHA overexpression. These results reveal a critical oncogenic mechanism of LDHA and suggest a promising therapeutic strategy for breast cancers with LDHA overexpression., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Gymnocypris przewalskii (naked carp), a native teleost, plays an important role in the ecosystem of Qinghai Lake (altitude, 3.2 km) on the Qinghai-Tibet Plateau in China. We developed a new cell line from the muscle of G. przewalskii using the explant technique and named the cell line GPM. This cell line was maintained in DMEM medium (high glucose) supplemented with 15% fetal bovine serum (FBS). The cell line was successfully subcultured up to 32 passages and was authenticated by immunofluorescence assay, sequencing the mitochondrial cytochrome C oxidase subunit I (COI) and 16S rRNA genes, and by chromosome analysis. In the medium containing 15% FBS, the cell line could be passaged stably at 25 °C. The GPM cell line could express green fluorescent protein (GFP) with a CMV promoter with about 5% transfection efficiency. MTT tests showed that Clostridium botulinum toxin (BTX) was toxic to the cell line. The cell line could be successfully cryopreserved in liquid nitrogen with a revival efficiency of over 70%. This study demonstrated that the GPM cell line can be used as an important tool for understanding the physiological characteristics of G. przewalskii, and it can provide a resource for studying gene function and toxicological reactions in vitro., (© 2022. The Society for In Vitro Biology.)

Graft-versus-host disease (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation, a widely used therapy for hematologic malignancies and blood disorders. Here, we report an unexpected role of cytokine leukemia inhibitory factor (LIF) in protecting against GVHD development. Administrating recombinant LIF protein (rLIF) protects mice from GVHD-induced tissue damage and lethality without compromising the graft-versus-leukemia activity, which is crucial to prevent tumor relapse. We found that rLIF decreases the infiltration and activation of donor immune cells and protects intestinal stem cells to ameliorate GVHD. Mechanistically, rLIF downregulates IL-12-p40 expression in recipient dendritic cells after irradiation through activating STAT1 signaling, which results in decreased major histocompatibility complex II levels on intestinal epithelial cells and decreased donor T-cell activation and infiltration. This study reveals a previously unidentified protective role of LIF for GVHD-induced tissue pathology and provides a potential effective therapeutic strategy to limit tissue pathology without compromising antileukemic efficacy., (© 2022 by The American Society of Hematology.)

Exploring the responses of greenhouse gas (GHG) emissions to land use conversion or reversion is significant for taking effective land use measures to alleviate global warming. A global meta-analysis was conducted to analyze the responses of carbon dioxide (CO 2 ), methane (CH 4 ), and nitrous oxide (N 2 O) emissions to land use conversion or reversion, and determine their temporal evolution, driving factors, and potential mechanisms. Our results showed that CH 4 and N 2 O responded positively to land use conversion while CO 2 responded negatively to the changes from natural herb and secondary forest to plantation. By comparison, CH 4 responded negatively to land use reversion and N 2 O also showed negative response to the reversion from agricultural land to forest. The conversion of land use weakened the function of natural forest and grassland as CH 4 sink and the artificial nitrogen (N) addition for plantation increased N source for N 2 O release from soil, while the reversion of land use could alleviate them to some degree. Besides, soil carbon would impact CO 2 emission for a long time after land use conversion, and secondary forest reached the CH 4 uptake level similar to that of primary forest after over 40 years. N 2 O responses had negative relationships with time interval under the conversions from forest to plantation, secondary forest, and pasture. In addition, meta-regression indicated that CH 4 had correlations with several environmental variables, and carbon-nitrogen ratio had contrary relationships with N 2 O emission responses to land use conversion and reversion. And the importance of driving factors displayed that CO 2 , CH 4 , and N 2 O response to land use conversion and reversion was easily affected by NH 4 + and soil moisture, mean annual temperature and NO 3 - , total nitrogen and mean annual temperature, respectively. This study would provide enlightenments for scientific land management and reduction of GHG emissions., (© 2022 John Wiley & Sons Ltd.)

Comprehensive efficiency analysis of wastewater treatment plants (WWPTs) in the alpine region with harsh environment and poor techniques as well as managing experience could provide targeted and effective improvement evidences for local wastewater treatment industry and help to improve the water quality of downstream reaches. In this paper, slack-based data envelopment analysis (SBM-DEA) was adopted to assess the operating efficiencies of WWPTs in northeast Qinghai-Tibet Plateau (QTP). Results showed that the average efficiency score for all WWPTs was 0.608, and 32.5% of WWPTs were efficient. Some WWPTs had large improvement potentials in operating costs and pollutant removal rates. Lowering expenditures and promoting facility construction for WWPTs to overcome the climate difficulties and improve management level was necessary according to their improvement potentials. In addition, the relative importance of the quantitative influential factors to efficiencies scores calculated by random forest regression (RFR) indicated that design capacity and temperature were important quantitative factors affecting the performance of WWPTs. Furthermore, geographical location and design capacity also had significant influence on the comprehensive efficiency of WWPTs verified by Kruskal-Wallis test. Our results highlight the importance of facilities upgrading, scientific management for WWPTs. And the relative improvement suggestions on overcoming the high and cold environment should also be considered for the efficient operations of WWTPs as well as the protection the aquatic environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Gymnocypris przewalskii is the only high-land endemic teleost living in Qinghai Lake, the largest saline-alkaline lake in China. Its osmoregulatory physiology remains elusive due to a lack of precise identification of the response proteins. In the present study, DIA/SWATH was used to identify differentially expressed proteins (DEPs) under alkaline (pH = 10.1, carbonate buffer), saline (12‰, sodium chloride), and saline-alkaline [carbonate buffer (pH = 10.1) plus 11‰ sodium chloride] stresses. A total of 66,056 unique peptides representing 7,150 proteins and 230 DEPs [the false discovery rate (FDR) ≤ 0.05, fold change (FC) ≥ 1.5] were identified under different stresses. Comparative analyses of the proteome and transcriptome indicated that over 86% of DEPs did not show consistent trends with mRNA. In addition to consistent enrichment results under different stresses, the specific DEPs involved in saline-alkaline adaptation were primarily enriched in functions of homeostasis, hormone synthesis and reactions of defense response, complement activation and reproductive development. Meanwhile, a protein-protein interaction (PPI) network analysis of these specific DEPs indicated that the hub genes were ITGAX, MMP9, C3, F2, CD74, BTK, ANXA1, NCKAP1L, and CASP8. This study accurately isolated the genes that respond to stress, and the results could be helpful for understanding the physiological regulation mechanisms regarding salinity, alkalinity, and salinity-alkalinity interactions., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

The tumor suppressor p53 gene is mutated in approximately 50% of all human tumors. Many tumor-associated mutant p53 proteins misfold into a common, denatured conformation and accumulate to high levels in human tumors. In such tumors, these mutant forms of p53 provide a "gain of function" to promote tumor progression. Therefore, targeting mutant p53 has become an attractive approach for cancer therapy. In this issue, the study by Lu and colleagues supports the premise that certain forms of mutant p53 are temperature sensitive in conformation; these forms of p53 are mutant in conformation at physiologic temperature, but can refold into a normal, or "wild-type" conformation at lower temperature (32°C to 34°C). Notably, these temperature-sensitive mutants account for up to 7.5% of all human tumors that carry mutant p53, so this fraction of patients is estimated to be quite significant. Results from this study show that employing therapeutic hypothermia to reduce the core temperature of mice bearing tumors with these temperature-sensitive mutant forms of p53 (ts mutant p53) causes ts mutant p53 to switch to a wild-type conformation in tumors, inhibiting tumor growth. Moreover, combining hypothermia with chemotherapy leads to durable remission of such tumors, with no obvious toxicity to normal tissues. See related article by Lu et al., p. 3905 ., (©2021 American Association for Cancer Research.)

Identification of novel functional domains and characterization of detailed regulatory mechanisms in cancer-driving genes is critical for advanced cancer therapy. To date, CRISPR gene editing has primarily been applied to defining the role of individual genes. Recently, high-density mutagenesis via CRISPR tiling of gene-coding exons has been demonstrated to identify functional regions in genes. Furthermore, breakthroughs in combining CRISPR library screens with single-cell droplet RNA sequencing (sc-RNAseq) platforms have revealed the capacity to monitor gene expression changes upon genetic perturbations at single-cell resolution. Here, we present "sc-Tiling," which integrates a CRISPR gene-tiling screen with single-cell transcriptomic and protein structural analyses. Distinct from other reported single-cell CRISPR screens focused on observing gene function and gene-to-gene/enhancer-to-gene regulation, sc-Tiling enables the capacity to identify regulatory mechanisms within a gene-coding region that dictate gene activity and therapeutic response.

The role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such as Tritrichomonas muris and Nippostrongylus brasiliensis. Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca 2+ influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Liu, Wang, Zhang, Xu, Hu and Feng.)

p53 is the most frequently mutated gene in human cancers. Li-Fraumeni syndrome patients inheriting heterozygous p53 mutations often have a much-increased risk to develop cancer(s) at early ages. Recent studies suggest that some individuals inherited p53 mutations do not have the early onset or high frequency of cancers. These observations suggest that other genetic, environmental, immunological, epigenetic, or stochastic factors modify the penetrance of the cancerous mutant Tp53 phenotype. To test this possibility, this study explored dominant genetic modifiers of Tp53 mutations in heterozygous mice with different genetic backgrounds. Both genetic and stochastic effects upon tumor formation were observed in these mice. The genetic background of mice carrying Tp53 mutations has a strong influence upon the tissue type of the tumor produced and the number of tumors formed in a single mouse. The onset age of a tumor is correlated with the tissue type of that tumor, although identical tumor tissue types can occur at very different ages. These observations help to explain the great diversity of cancers in different Li-Fraumeni patients over lifetimes., (© 2020 Chan et al.)

p53 is a key tumor suppressor, and loss of p53 function is frequently a prerequisite for cancer development. The p53 gene is the most frequently mutated gene in human cancers; p53 mutations occur in >50% of all human cancers and in almost every type of human cancers. Most of p53 mutations in cancers are missense mutations, which produce the full-length mutant p53 (mutp53) protein with only one amino acid difference from wild-type p53 protein. In addition to loss of the tumor-suppressive function of wild-type p53, many mutp53 proteins acquire new oncogenic activities independently of wild-type p53 to promote cancer progression, termed gain-of-function (GOF). Mutp53 protein often accumulates to very high levels in cancer cells, which is critical for its GOF. Given the high mutation frequency of the p53 gene and the GOF activities of mutp53 in cancer, therapies targeting mutp53 have attracted great interest. Further understanding the mechanisms underlying mutp53 protein accumulation and GOF will help develop effective therapies treating human cancers containing mutp53. In this review, we summarize the recent advances in the studies on mutp53 regulation and GOF as well as therapies targeting mutp53 in human cancers., (© The Author(s) (2020). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.)

Leukemia inhibitory factor (LIF) is a cytokine essential for maintaining pluripotency of mouse embryonic stem cells. However, its role in adult intestinal stem cells (ISCs) is unclear. The adult intestinal epithelium has a high self-renewal rate driven by ISCs in crypts. Here, we find that LIF is present in the ISC niche in crypts and critical for the function of ISCs in maintaining the intestinal epithelial homeostasis and regeneration. Mechanistically, LIF maintains β-catenin activity through the AKT/GSK3β signaling to regulate ISC functions. LIF deficiency in mice impairs the renewal of the intestinal epithelium under the physiological condition. Further, LIF deficiency in mice impairs the regeneration of intestinal epithelium in response to radiation and shortens the lifespan of mice after high doses of radiation due to gastrointestinal (GI) syndrome, which can be rescued by administering recombinant LIF (rLIF). Importantly, LIF exhibits a radioprotective role in wild-type (WT) mice by protecting mice from lethal radiation-induced GI syndrome; administering rLIF promotes intestinal epithelial regeneration and prolongs survival in WT mice after radiation. These results reveal a previously unidentified and a crucial role of LIF in ensuring ISC function, promoting regeneration of the intestinal epithelium in response to radiation and protecting against radiation-induced GI syndrome.

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., (© 2020 Chongqing Medical University. Production and hosting by Elsevier B.V.)

Purpose: To examine associations of KRAS mutation with tumor deposit status and overall survival in colorectal cancer (CRC) patients., Methods: This retrospective cohort study included patients with incidental CRC diagnosed during 2010-2014 and recorded statuses of KRAS and tumor deposit in the National Cancer Database of the USA. Multivariable logistic regression and time-varying Cox regression analyses were used., Results: We included 45,761 CRC patients with KRAS status (24,027 [52.5%] men, 24,240 [53.0%] < 65 years old, 17,338 [37.9%] with KRAS mutation). Adjusted for microsatellite instability, age, pathologic stage and tumor grade, KRAS mutation (versus wild type) was associated with tumor deposit presence (odds ratio = 1.11, 95% CI 1.02-1.20). KRAS mutation was also linked to worse overall survival of CRC patients regardless of tumor deposit status (adjusted Hazard ratio [HR] = 1.20, 95% CI 1.07-1.33 for CRC with tumor deposits, and adjusted HR = 1.24, 95% CI 1.14-1.35 or CRC without) or tumor stage (adjusted HR = 1.32, 95% CI 1.14-1.54 for early-stage and adjusted HR = 1.18, 95% CI 1.10-1.27 for late-stage). Microsatellite instability was associated with better overall survival in CRC without tumor deposit (adjusted HR = 0.89, 95% CI 0.79-0.99), but not in CRC with tumor deposit (adjusted HR = 1.12, 95% CI 0.97-1.30)., Conclusion: KRAS mutation is independently associated with tumor deposit presence and a worse overall survival in CRC patients.

Phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme of serine synthesis, is frequently overexpressed in human cancer. PHGDH overexpression activates serine synthesis to promote cancer progression. Currently, PHGDH regulation in normal cells and cancer is not well understood. Parkin, an E3 ubiquitin ligase involved in Parkinson's disease, is a tumor suppressor. Parkin expression is frequently downregulated in many types of cancer, and its tumor-suppressive mechanism is poorly defined. Here, we show that PHGDH is a substrate for Parkin-mediated ubiquitination and degradation. Parkin interacted with PHGDH and ubiquitinated PHGDH at lysine 330, leading to PHGDH degradation to suppress serine synthesis. Parkin deficiency in cancer cells stabilized PHGDH and activated serine synthesis to promote cell proliferation and tumorigenesis, which was largely abolished by targeting PHGDH with RNA interference, CRISPR/Cas9 KO, or small-molecule PHGDH inhibitors. Furthermore, Parkin expression was inversely correlated with PHGDH expression in human breast cancer and lung cancer. Our results revealed PHGDH ubiquitination by Parkin as a crucial mechanism for PHGDH regulation that contributes to the tumor-suppressive function of Parkin and identified Parkin downregulation as a critical mechanism underlying PHGDH overexpression in cancer.

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., Competing Interests: Declaration of Interests S.A.A. has been a consultant and/or shareholder for Epizyme Inc, Imago Biosciences, Cyteir Therapeutics, C4 Therapeutics, Syros Pharmaceuticals, OxStem Oncology, Accent Therapeutics, and Mana Therapeutics. S.A.A. has received research support from Janssen, Novartis, and AstraZeneca. S.H.C. is currently an employee at Beam Therapeutics. The authors have no additional financial interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.