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As one of the most successful pathogenic organisms, Vibrio cholerae (V. cholerae) has evolved sophisticated regulatory mechanisms to overcome host stress. During long-term colonization by V. cholerae in adult mice, many spontaneous nonmotile mutants (approximately 10% at the fifth day post-infection) were identified. These mutations occurred primarily in conserved regions of the flagellar regulator genes flrA, flrC, and rpoN, as shown by Sanger and next-generation sequencing, and significantly increased fitness during colonization in adult mice. Intriguingly, instead of key genes in DNA repair systems (mutS, nfo, xthA, uvrA) or ROS and RNS scavenging systems (katG, prxA, hmpA), which were generally thought to be associated with bacterial mutagenesis, we found that deletion of the cyclin gene dps significantly increased the mutation rate (up to 53% at the fifth day post-infection) in V. cholerae. We further determined that the dpsD65A and dpsF46E point mutants showed a similar mutagenesis profile as the Δdps mutant during long-term colonization in mice, which strongly indicated that the antioxidative function of Dps directly contributes to the development of V. cholerae nonmotile mutants. Methionine metabolism pathway may be one of the mechanism for ΔflrA, ΔflrC and ΔrpoN mutant increased colonization in adult mice. Our results revealed a new phenotype in which increased fitness of V. cholerae in the host gut via spontaneous production nonmotile mutants regulated by cyclin Dps, which may represent a novel adaptation strategy for directed evolution of pathogens in the host.

Sensing and resisting oxidative stress is critical for Vibrio cholerae to survive in either the aquatic environment or the gastrointestinal tract. Previous studies mainly focused on the mechanisms of oxidative stress response regulation that rely on enzymatic antioxidant systems, while functions of non-enzymatic antioxidants are rarely discussed in V. cholerae. For the first time, we investigated the role of hydrogen sulfide (H2S), the simplest thiol compound, in protecting V. cholerae against oxidative stress. We found that degradation of L-cysteine by putative cystathionine β-synthase (CBS) is the major source of endogenous H2S in V. cholerae. Our results indicate that intracellular H2S level has a positive correlation with cbs expression, while the enhanced H2S production can render V. cholerae cells less susceptible to H2O2 in vitro. Using proteome analysis and real-time qPCR assay, we found that cbs expression could stimulate the expression of several enzymatic antioxidants, including reactive oxygen species (ROS) detoxifying enzymes SodB, KatG and AhpC, the DNA protective protein DPS and the protein redox regulator Trx1. Assays of ROS detoxification capacities revealed that CBS-derived H2S could promote catalase activity at the post-translational level, especially for KatB, which serves as an important way that endogenous H2S participates in H2O2 detoxification. The enhancement of catalase activity by H2S is achieved through facilitating the uptake of iron. Adult mice experiments showed that cbs mutant has colonization defect, while either complementation of cbs or exogenous supplement of N-Acetyl-L-Cysteine restores its fitness in the host environment. Herein, we proposed that V. cholerae regulates CBS-dependent H2S production for better survival and proliferation under ROS stress.

The geo-hazards comprehensive evaluation index system was established in the early stage of the team, and the number, the number density, the volume and the volume density, which reflect the spatial dimension, are used to evaluate the development degree of geo-hazards, excluding the evaluation factors reflecting the time dimension. In this paper, disaster years reflecting the time dimension are introduced to enrich the development degree evaluation system of geo-hazards. The median logarithmic method and probability density distribution are respectively used to processing data of disaster years and volume, and the entropy weight is used to determine the weight of evaluation factors. The evaluation models are established and the evaluation results are divided into four levels by the slope method, reflecting the development status of disasters. The geo-hazards occurred in 31provinces in China (excluding Hong Kong, Macao and Taiwan) from 2011 to 2020 are taken as examples, the development degree of geo-hazards (landslide, collapse and debris flow) is evaluated and divided according to this method. The results show that the geo-hazards high development areas cover 323 counties in total, involving 19 provinces, mainly occurring in Southeast China, Southwest China and Northwest China. The sub-high development areas cover 566 counties in total, involving 25 provinces, mainly occurring in Southwest China, South Central China and Southeast China. The moderately development areascover 623 counties in total, involving 30 provinces, mainly occurring in Northwest China and North China. The low development areas cover 1336 counties in total, involving 30 provinces, mainly occurring in North China, Northeast China and East China. When compared with the national disaster prevention deployment situation or the geo-hazards distribution, the evaluation results are in good agreement with the reality. In addition, through field investigation, the evaluation results are more consistent with the actual situation.

This paper provides an exploratory study about data quality evaluation index system of geological hazard. To serve geological hazard research and national geological hazard prevention, select five dimensions of completeness, timeliness, accuracy, consistency, and standardization as first-level indicators, which contains 10 secondary indicators and 28 tertiary indicators. Take the geological hazard database of a province in central China as an example, conduct data quality evaluation with Delphi method, the results show that is good the overall situation of the province's geological hazard database quality. This quality evaluation of geological hazard data is an exploratory research that integrates science and practicability, it is of great significance for improving the data quality to support geological hazard research and national geological hazard prevention.

Summary: In addition to acting as building blocks for biosynthesis, amino acids might serve as signaling regulators in various physiological and pathological processes. However, it remains unknown whether amino acid levels affect the activities of hematopoietic stem cells (HSCs). By using a genetically encoded fluorescent sensor of the intracellular levels of branched-chain amino acids (BCAAs), we could monitor the dynamics of BCAA metabolism in HSCs. A mitochondrial-targeted 2C-type Ser/Thr protein phosphatase (PPM1K) promotes the catabolism of BCAAs to maintain MEIS1 and p21 levels by decreasing the ubiquitination-mediated degradation controlled by the E3 ubiquitin ligase CDC20. PPM1K deficiency led to a notable decrease in MEIS1/p21 signaling to reduce the glycolysis and quiescence of HSCs, followed by a severe impairment in repopulation activities. Moreover, the deletion of Ppm1k dramatically extended survival in a murine leukemia model. These findings will enhance the current understanding of nutrient signaling in metabolism and function of stem cells. : Liu et al. show that the dynamics of BCAA metabolism in hematopoietic stem cells (HSCs) and leukemia-initiating cells (LICs) can be monitored by a genetically encoded fluorescent sensor. PPM1K promotes BCAA catabolism and maintains the glycolysis and quiescence of HSCs/LICs through the downregulation of CDC20-mediated ubiquitination of MEIS1 and p21. Keywords: branched-chain amino acids, PPM1K, ubiquitination, CDC20, MEIS1/p21, hematopoietic stem cells, leukemia-initiating cells

Abstract Background The adipocyte remodeling, including of the morphological change, might indicate special pathological function. Our previous study found that the morphological remodeling of larger marrow adipocytes into small marrow adipocytes correlates with a poor prognosis for acute myeloid leukemia (AML) patients. However, the mechanisms contributed to the marrow adipocyte remodeling are still poorly understood. Methods GDF15 expression was analyzed by RT-qPCR and western blotting assays in the leukemic cells. The enhancing and antibody neutralization tests in vitro were employed to evaluate the effect of GDF15 on the morphology of mature adipocytes. CCK8 test was used to detect the proliferation of leukemic cells after co-cultivation with small marrow adipocytes. Flow cytometry was used to analysis the proportion of cell cycle of leukemic cells. Immunofluorescence staining and linear analysis were applied to verify the GDF15 expression and the relationship between GDF15 and small marrow adipocytes in AML patients. Results In this study, we found that leukemic cell lines not only expressed significantly higher growth differentiation factor 15 (GDF15) than the other three cytokines associated with adipocyte differentiation in RNA level but also secreted GDF15 factor. Furthermore, the in vitro experiments demonstrated that GDF15 was involved in the conversion of small marrow adipocytes from larger marrow adipocytes. Correspondingly, the leukemic cells proliferated more rapidly through regulating the cell cycle when co-cultured with GDF15-induced small marrow adipocytes. The immunofluorescence staining on the bone marrow sections of AML patients further exhibited that GDF15 was partly produced by leukemic cells. The positive correlation between the concentration of GDF15 in the marrow aspirates and the number and the volume of small marrow adipocytes might suggest the contribution of GDF15 in AML patients (r = 0.72, r = 0.67). Conclusions GDF15 secreted by leukemic cells was involved in the morphological remodeling of marrow adipocytes, which can in turn promote leukemic cell growth, indicating that GDF15 may be a promising treatment target for AML patients.

Reservoir landslide is a type of commonly seen geological hazards in reservoir area and could potentially cause significant risk to the routine operation of reservoir and hydropower station. It has been accepted that reservoir landslides are mainly induced by periodic variations of reservoir water level during the impoundment and drawdown process. In this study, to better understand the deformation characters and controlling factors of the reservoir landslide, a multiparameter-based monitoring program was conducted on a reservoir landslide—the Hongyanzi landslide located in Pubugou reservoir area in the southwest of China. The results indicated that significant deformation occurred to the landslide during the drawdown period; otherwise, the landslide remained stable. The major reason of reservoir landslide deformation is the generation of seepage water pressure caused by the rapidly growing water level difference inside and outside of the slope. The influences of precipitation and earthquake on the slope deformation of the Hongyanzi landslide were insignificant.