Genotypic variation in the tolerance to moderate cadmium toxicity among 20 maize genotypes with contrasting root systems.

BACKGROUND: Cadmium (Cd) contamination in farmland is a serious environmental and safety issue affecting plant growth, crop productivity, and human health. This study aimed to investigate genotypic variation in root morphology and Cd accumulations under moderate Cd stress among diverse maize genotypes. Twenty maize genotypes with contrasting root systems were assessed for Cd tolerance 39 days after transplanting (V6, six-leaf stage) under 20 µmol L-1 CdCl2 using a semi-hydroponic phenotyping platform in a glasshouse. RESULTS: Cadmium stress significantly inhibited plant growth across all genotypes. Genotypic variation in response to Cd toxicity was apparent: shoot dry weight varied from 0.13 (genotype NS2020) to 0.35 g plant-1 (Dongke301) with deductions up to 63% compared with non-Cd treatment (CK). Root dry weight of 20 genotypes ranged from 0.06 (NS2020) to 0.18 g plant-1 (Dongke301) with a deduction up to 56%. Root length ranged from 2.21 (NS590b) to 9.22 m (Dongke301) with a maximal decline of 76%. Cadmium-treated genotypes generally had thicker roots and average diameter increased by 34% compared with CK. Genotypes had up to 3.25 and 3.50 times differences in shoot and root Cd concentrations, respectively. Principal component and cluster analyses assigned the 20 genotypes into Cd-tolerant (five genotypes) and Cd-sensitive (15 genotypes) groups. CONCLUSIONS: Maize genotypes varied significantly in response to moderate Cd stress. Cadmium-tolerant genotypes optimized root morphology and Cd accumulation and distribution. This study could assist in the selection and breeding of new cultivars with improved adaptation to Cd-contaminated soil for food and feed or land remediation purposes. © 2022 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Genome-wide identification of resistance genes and transcriptome regulation in yeast to accommodate ammonium toxicity.

BACKGROUND: Ammonium is an important raw material for biomolecules and life activities, and the toxicity of ammonium is also an important ecological and agricultural issue. Ammonium toxicity in yeast has only recently been discovered, and information on its mechanism is limited. In recent years, environmental pollution caused by nitrogen-containing wastewater has been increasing. In addition, the use of yeast in bioreactors to produce nitrogen-containing compounds has been developed. Therefore, research on resistance mechanisms that allow yeast to grow under conditions of high concentrations of ammonium has become more and more important. RESULTS: To further understand the resistance mechanism of yeast to grow under high concentration of ammonium, we used NH4Cl to screen a yeast non-essential gene-deletion library. We identified 61 NH4Cl-sensitive deletion mutants from approximately 4200 mutants in the library, then 34 of them were confirmed by drop test analysis. Enrichment analysis of these 34 genes showed that biosynthesis metabolism, mitophagy, MAPK signaling, and other pathways may play important roles in NH4Cl resistance. Transcriptome analysis under NH4Cl stress revealed 451 significantly upregulated genes and 835 significantly downregulated genes. The genes are mainly enriched in: nitrogen compound metabolic process, cell wall, MAPK signaling pathway, mitophagy, and glycine, serine and threonine metabolism. CONCLUSIONS: Our results present a broad view of biological pathways involved in the response to NH4Cl stress, and thereby advance our understanding of the resistance genes and cellular transcriptional regulation under high concentration of ammonium.

Nitrogen supply improved plant growth and Cd translocation in maize at the silking and physiological maturity under moderate Cd stress.

Soil cadmium (Cd) contamination is a serious problem on agricultural land. Adequate nitrogen (N) may help ameliorate plant fitness under Cd stress. This study examined the role of N application in improving maize tolerance to Cd stress. Two maize genotypes, Zhongke11 (larger root system) and Shengrui999 (smaller root system), were grown in a loessal soil amended with Cd (Cd0, no added Cd; Cd1, 20 mg kg-1 soil as CdCl2·2.5 H2O) and N (N0, no added N; N1, 100 mg kg-1 soil as urea) under greenhouse, and plants were assessed at silking and maturity stages. Maize plants exhibited moderate Cd stress with significantly reduced grain yield, especially under low N (N1). Roots accumulated more Cd than above-ground parts. Grain Cd concentration was the least (0.05-0.06 µg g-1) among all organs which is below the safety threshold. Leaf Cd concentrations (0.24-1.18 mg kg-1) were also under the toxicity threshold. Nitrogen addition significantly improved plant growth, chlorophyll content, photosynthesis traits, and tissue Cd contents, and reduced Cd concentration in soil compared to N0 treatment. Nitrogen promoted Cd bioconcentration and translocation factors in stem and leaves. Cadmium stress reduced N fertilizer agronomic efficiency at maturity. At maturity, root Cd content was positively correlated with root N and calcium accumulation, and stem Cd content was positively correlated with stem N content (both P ≤ 0.05). Genotypes with different root system size differed in response to Cd toxicity and / or N deficit. The small-rooted genotype Shengrui999 was more tolerant to moderate Cd stress than the large-rooted Zhongke11. Addition of N ameliorated Cd stress in both maize genotypes by improving plant growth performance, and regulating Cd translocations among plant organs.

Lateral root elongation enhances nitrogen-use efficiency in maize genotypes at the seedling stage.

BACKGROUND: Maize plants show great variation in root morphological response to nitrogen (N) deficit, and such alterations often determine N-use efficiency (NUE) plants. This study assessed genotypic variation in root morphology and NUE in selected 20 maize genotypes with contrasting root system size grown in a semi-hydroponic phenotyping system for 38 days under control (4 mmol L-1 NO3 - ) and low N (LN) (40 µmol L-1 ) for 38 days after transplanting. RESULTS: Maize genotypes exhibited different responses to LN stress in each of the 28 measured shoot and root traits. The 20 genotypes were assigned into one of the three groups: N-efficient (eight genotypes), medium (four genotypes), and N-inefficient (eight genotypes), based on shoot dry weight ratio (the ratio of shoot dry weight at LN and control) ± one standard error. In response to LN stress, the N-inefficient genotypes had significant reduction in biomass production by ~58% in shoots and ~64% in roots, while the N-efficient genotypes maintained their biomass. Under LN supply N-efficient genotypes showed a plasticity response that would result in both sparse lateral branching and increased root elongation as a whole or at each growth strata, and N efficiency positively correlated with lateral or axial root elongation and root elongation at different depths. CONCLUTSION: The total lateral root length was the main contributor to the improved N foraging and utilization in maize under LN conditions, followed by axial root length. Total lateral root length can be considered in breeding programs for producing maize cultivars with high NUE at the early seedling stage. © 2022 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Arbuscular mycorrhizal symbioses alleviating salt stress in maize is associated with a decline in root-to-leaf gradient of Na+/K+ ratio.

BACKGROUND: Inoculation of arbuscular mycorrhizal (AM) fungi has the potential to alleviate salt stress in host plants through the mitigation of ionic imbalance. However, inoculation effects vary, and the underlying mechanisms remain unclear. Two maize genotypes (JD52, salt-tolerant with large root system, and FSY1, salt-sensitive with small root system) inoculated with or without AM fungus Funneliformis mosseae were grown in pots containing soil amended with 0 or 100 mM NaCl (incrementally added 32 days after sowing, DAS) in a greenhouse. Plants were assessed 59 DAS for plant growth, tissue Na+ and K+ contents, the expression of plant transporter genes responsible for Na+ and/or K+ uptake, translocation or compartmentation, and chloroplast ultrastructure alterations. RESULTS: Under 100 mM NaCl, AM plants of both genotypes grew better with denser root systems than non-AM plants. Relative to non-AM plants, the accumulation of Na+ and K+ was decreased in AM plant shoots but increased in AM roots with a decrease in the shoot: root Na+ ratio particularly in FSY1, accompanied by differential regulation of ion transporter genes (i.e., ZmSOS1, ZmHKT1, and ZmNHX). This induced a relatively higher Na+ efflux (recirculating) rate than K+ in AM shoots while the converse outcoming (higher Na+ influx rate than K+) in AM roots. The higher K+: Na+ ratio in AM shoots contributed to the maintenance of structural and functional integrity of chloroplasts in mesophyll cells. CONCLUSION: AM symbiosis improved maize salt tolerance by accelerating Na+ shoot-to-root translocation rate and mediating Na+/K+ distribution between shoots and roots.

Homoharringtonine inhibits the progression of hepatocellular carcinoma by suppressing the PI3K/AKT/GSK3ß/Slug signaling pathway.

Homoharringtonine (HHT), was first isolated from the bark of Cephalotaxus harringtonia (Knight ex J. Forbes) K. Koch and Cephalotaxus fortunei Hook trees. The bark extract is used to treat leukemia and in recent years has also been used in traditional Chinese medicine (TCM) to treat solid tumors. However, the inhibitory mechanism of HHT in the progression of hepatocellular carcinoma (HCC) is rarely studied. We aimed to evaluate the antitumor efficacy of HHT on HCC in vitro and in vivo and elucidate the underlying molecular mechanism(s). HCC cell lines, including HCCLM3, HepG2, and Huh7, were used to evaluate the antitumor efficacy of HHT in vitro. Cytotoxicity and proliferative ability were evaluated by MTT and colony formation assays. Cell cycle progression and apoptosis in HHT-treated HCC cells were evaluated by flow cytometry. To determine the migration and invasion abilities of HCC cells, wound-healing and Transwell assays were used. Finally, western blot analysis was used to reveal the proteins involved. We also established a xenograft nude mouse model for in vivo assessments of the preclinical efficacy of HHT, mainly using hematoxylin and eosin staining, immunohistochemistry, ultrasound imaging (USI), and magnetic resonance imaging (MRI). HHT suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells, and induced cell cycle arrest at the G2 phase and apoptosis. In the HCC xenograft model, HHT showed an obvious tumor-suppressive effect. Surprisingly, Slug expression was also decreased by HHT via the PI3K/AKT/GSK3ß signaling pathway at least partially suppressed the growth of HCC via the PI3K/AKT/GSK3ß/Slug signaling pathway.

Molecular mechanism of reward treatment ameliorating chronic stress-induced depressive-like behavior assessed by sequencing miRNA and mRNA in medial prefrontal cortex.

Chronic stress and lack of reward may reduce the function of the brain's reward circuits, leading to major depressive disorder. The effect of reward treatment on chronic stress-induced depression-like behaviors and its molecular mechanism in the brain remain unclear. In this study, companion communication was used as a reward to study the effect of reward on CUMS-induced depression-like behaviors, and mRNA and miRNA profiles in the medial prefrontal cortex harvested from mice with depression-like and resilient behaviors were established by high-throughput sequencing. The results showed that accompanying with companion ameliorated CUMS-induced depression-like behaviors in mice. Furthermore, 45 differentially expressed genes (DEGs) associated with depression-like behaviors, 8 DEGs associated with resilience and 59 DEGs associated with nature reward (companion) were identified, and 196 differentially expressed miRNAs were found to be associated with companion. Based on the differentially expressed miRNAs and DEGs data, miRNA-mRNA network was established to be associated with companion. Taken together, our data here provided a method to ameliorate depression-like behaviors, and numerous potential drug targets for the prevention or treatment of depression.

The transcription factor Krüppel-like factor 5 promotes cell growth and metastasis via activating PI3K/AKT/Snail signaling in hepatocellular carcinoma.

The transcription factor Krüppel-like factor 5 (KLF5) is highly expressed in many cancers and serves as a prognostic factor. However, the function of KLF5 in hepatocellular carcinoma (HCC) is unclear. In this study, we found that KLF5 was significantly overexpressed in HCC cell lines and specimens, and high KLF5 expression predicted a poor prognosis for HCC patients. Then, we studied the effects of KLF5 on the proliferation, apoptosis, migration and invasion of HCC cells in vitro and vivo. The inhibition of KLF5 markedly inhibited HCC growth and metastasis, while KLF5 overexpression promoted these processes. In addition, we observed that KLF5 could promote the epithelial-mesenchymal transition (EMT) in HCC via the PI3K/AKT/Snail signaling pathway. The silencing of KLF5 in HCC cell lines downregulated the expression of N-cadherin, Vimentin and Snail and increased the expression of the epithelial marker E-cadherin. The expression of MMP2 and MMP9 was also decreased in KLF5-silenced HCC cells. However, opposite results were observed in the KLF5-overexpressing group. These results indicate that KLF5 plays a significant role in HCC progression and metastasis and induces EMT via activating PI3K/AKT/Snail signaling, and the inhibition of KLF5 may be a potential treatment modality for patients with HCC.

Bioassay-guided isolation of a Mycobacterium tuberculosis bioflim inhibitor from Arisaema sinii Krause.

Mycobacterium tuberculosis biofilms harbour drug-tolerant bacteria. Identification of drugs that inhibit biofilm formation could enable the dramatic shortening of tuberculosis treatments using standard antibiotics. Arisaema sinii Krause is used to treat pulmonary and lymphatic tuberculosis by Dong People of China. Current study was aimed to purify the active components against M. tuberculosis biofilms from Arisaema sinii extract by using bioassay-guided isolation. (E)-2-(methyl (phenyl) amino) ethyl 2-(2-hydroxyundecanamido)-7, 11-dimethyl-3-oxotetradec-4-enoate, compound 1, was identified as the active component. It could inhibit mycobacterial biofilm formation, disperse the preformed biofilms, and disrupt the mature biofilms at concentration of 4, 8, and 32 µg/ml, respectively. At the dose of 32 µg/ml, it could potentiate the bactericidal activity of isoniazid against M. tuberculosis in mature biofilms. The results of this study indicate that compound 1 might be a novel lead compound against mycobacterial biofilm formation.

Integrin ß1-Mediated Cell⁻Cell Adhesion Augments Metformin-Induced Anoikis.

Cell⁻cell adhesion plays an important role in regulation of cell proliferation, migration, survival, and drug sensitivity. Metformin, a first line drug for type 2 diabetes, has been shown to possess anti-cancer activities. However, whether cell⁻cell adhesion affects metformin anti-cancer activity is unknown. In this study, Microscopic and FACS analyses showed that metformin induced cancer cell⁻cell adhesion exemplified by cell aggregation and anoikis under glucose restriction. Furthermore, western blot and QPCR analyses revealed that metformin dramatically upregulated integrin ß1 expression. Silencing of integrin ß1 significantly disrupted cell aggregation and reduced anoikis induced by metformin. Moreover, we showed that p53 family member ΔNp63α transcriptionally suppressed integrin ß1 expression and is responsible for metformin-mediated upregulation of integrin ß1. In summary, this study reveals a novel mechanism for metformin anticancer activity and demonstrates that cell⁻cell adhesion mediated by integrin ß1 plays a critical role in metformin-induced anoikis.

Fast Dynamic Visualizations in Microfluidics Enabled by Fluorescent Carbon Nanodots.

Microfluidic systems have become a superior platform for explorations of fascinating fluidic physics at microscale as well as applications in biomedical devices, chemical reactions, drug delivery, etc. Exploitations of this platform are built upon the fundamental techniques of flow visualizations. However, the currently employed fluorescent materials for microfluidic visualization are far from satisfaction, which severely hinders their widespread applications. Here fluorescent carbon nanodots are documented as a game-changer, applicable in versatile fluidic environment for the visualization in microfluidics with unprecedented advantages. One of the fastest fluorescent imaging speeds up to 2500 frames per second under a normal contionous wave (CW) laser line is achieved by adopting carbon nanodots in microfluidics. Besides better visualizations of the fluid or interface, fluorescent carbon nanodots-based microparticles enable quantitative studies of high speed dynamics in fluids at microscale with a more than 90% lower cost, which is inaccessible by traditionally adopted fluorescent dye based seeding particles. The findings hold profound influences to microfluidic investigations and may even lead to revolutionary changes to the relevant industries.

Histone deacetylase 3-specific inhibitor RGFP966 attenuates oxidative stress and inflammation after traumatic brain injury by activating the Nrf2 pathway.

Background: Oxidative stress (OS) and inflammatory reactions play pivotal roles in secondary brain injury after traumatic brain injury (TBI). Histone deacetylase 3 (HDAC3) controls the acetylation of histones and non-histones, which has a significant impact on the central nervous system's reaction to damage. This research determined the implications of RGFP966, a new and specific inhibitor of HDAC3, for the antioxidant (AO) systems mediated by nuclear factor erythroid2-related factor 2 (Nrf2) and the Nod-like receptor protein 3 (NLRP3) inflammasome in TBI. The study also studied the underlying mechanisms of RGFP966's actions. Our objective was to examine the impacts and underlying RGFP966 mechanisms in TBI. Methods: In vitro, a rat cortical neuron OS model was induced by H2O2, followed by the addition of RGFP966 to the culture medium. Neurons were collected after 24 h for western blot (WB), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and 2'-7'-dichlorodihydrofluorescein diacetate staining. In vivo, RGFP966 (10 mg/kg) was administered post-TBI. Brain tissue water content and modified neurological severity scores were assessed 72 h post-injury. Cortical tissues surrounding the focal injury were subjected to western blot, TUNEL staining, Nissl staining and immunofluorescence/immunohistochemistry staining, and malondialdehyde level, hindered glutathione content and superoxide dismutase activity were measured. Serum was collected for the enzyme-linked immunosorbent assay. Nrf2-specific shRNA lentivirus was injected into the lateral ventricle of rats for 7 days, and cerebral cortex tissue was analyzed by WB and real-time polymerase chain reaction. Results: During in vitro and in vivo experiments, RGFP966 suppressed HDAC3 expression, promoted Nrf2 nuclear translocation, activated downstream AO enzymes, mitigated excessive reactive oxygen species production and alleviated nerve cell apoptosis. RGFP966 effectively reduced brain edema and histological damage and enhanced neurological and cognitive function in rats with TBI. RGFP966 markedly inhibited NLRP3 inflammasome activation mediated by high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4). Nrf2 knockdown in TBI rats attenuated the AO and anti-inflammatory, neuroprotective impacts of RGFP966. Conclusions: Overall, our findings demonstrate that RGFP966 can mitigate the first brain damage and neurological impairments in TBI. The underlying mechanism involves triggering the Nrf2-mediated AO system and negatively regulating the HMGB1/TLR4-mediated NLRP3 inflammasome pathway.

Comparative analysis of CRASH and IMPACT in predicting the outcome of 340 patients with traumatic brain injury.

Background: Both the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) and the Corticosteroid randomization after significant head injury (CRASH) models are globally acknowledged prognostic algorithms for assessing traumatic brain injury (TBI) outcomes. The aim of this study is to externalize the validation process and juxtapose the prognostic accuracy of the CRASH and IMPACT models in moderate-to-severe TBI patients in the Chinese population. Methods: We conducted a retrospective study encompassing a cohort of 340 adult TBI patients (aged > 18 years), presenting with Glasgow Coma Scale (GCS) scores ranging from 3 to 12. The data were accrued over 2 years (2020-2022). The primary endpoints were 14-day mortality rates and 6-month Glasgow Outcome Scale (GOS) scores. Analytical metrics, including the area under the receiver operating characteristic curve for discrimination and the Brier score for predictive precision were employed to quantitatively evaluate the model performance. Results: Mortality rates at the 14-day and 6-month intervals, as well as the 6-month unfavorable GOS outcomes, were established to be 22.06, 40.29, and 65.59%, respectively. The IMPACT models had area under the curves (AUCs) of 0.873, 0.912, and 0.927 for the 6-month unfavorable GOS outcomes, with respective Brier scores of 0.14, 0.12, and 0.11. On the other hand, the AUCs associated with the six-month mortality were 0.883, 0.909, and 0.912, and the corresponding Brier scores were 0.15, 0.14, and 0.13, respectively. The CRASH models exhibited AUCs of 0.862 and 0.878 for the 6-month adverse outcomes, with uniform Brier scores of 0.18. The 14-day mortality rates had AUCs of 0.867 and 0.87, and corresponding Brier scores of 0.21 and 0.22, respectively. Conclusion: Both the CRASH and IMPACT algorithms offer reliable prognostic estimations for patients suffering from craniocerebral injuries. However, compared to the CRASH model, the IMPACT model has superior predictive accuracy, albeit at the cost of increased computational intricacy.

The role of arbuscular mycorrhizal fungi in the alleviation of cadmium stress in cereals: A multilevel meta-analysis.

The symbiotic relationships between crop species and arbuscular mycorrhizal fungi (AMF) are crucial for plant health, productivity, and environmental sustainability. The roles of AMF in reducing crop stress caused by cadmium (Cd) toxicity and in the remediation of Cd-contaminated soil are not fully understood. Here we report on a meta-analysis that sought to identify the functions of AMF in cereals under Cd stress. A total of 54 articles published between January 1992 and September 2022 were used to create the dataset, which provided 7216 data sets on mycorrhizal cereals under Cd stress examined. AMF effects on colonization rate, biomass, physiological level, nutritional level, and plant Cd level were measured using the logarithmic response ratio (Ln R). The results showed that AMF overall greatly reduced 5.14 - 33.6 % Cd stress on cereals in greenhouse experiments under controlled conditions. AMF colonization significantly stimulated crop biomass by 65.7 %, boosted the formation of photosynthetic pigments (23.2 %), and greatly increased plant nitrogen (24.8 %) and phosphorus (58.4 %) uptake. The dilution effect of mycorrhizal plants made the Cd concentration decline by 25.2 % in AMF plants compared to non-mycorrhizal ones. AMF also alleviated Cd stress by improving osmotic regulators (soluble protein, sugar, and total proline, from 14.8 to 36.0 %) and lowering the membrane lipid peroxidation product (MDA, 12.9 %). Importantly, the results from the random forest and model selection analysis demonstrated that crop type, soil characteristics, chemical form, and Cd levels were the main factors determining the function of AMF in alleviating Cd stress. Additionally, there was a significant interaction between AMF colonization rate and Cd addition, but their interactive effect was less than the colonization rate alone. This meta-analysis demonstrated that AMF inoculation could be considered as a promising strategy for mitigation of Cd stress in cereals.

Changes in the volatile compounds and characteristic aroma during liquid-state fermentation of instant dark tea by Eurotium cristatum.

Instant dark tea (IDT) was prepared by liquid-state fermentation inoculating Eurotium cristatum. The changes in the volatile compounds and characteristic aroma of IDT during fermentation were analyzed using gas chromatography-mass spectrometry by collecting fermented samples after 0, 1, 3, 5, 7, and 9 days of fermentation. Components with high odor activity (log2FD ≥ 5) were verified by gas chromatography-olfactometry. A total of 107 compounds showed dynamic changes during fermentation over 9 days, including 17 alcohols, 7 acids, 10 ketones, 11 esters, 8 aldehydes, 37 hydrocarbons, 4 phenols, and 13 other compounds. The variety of flavor compounds increased gradually with time within the early stage and achieved a maximum of 79 compounds on day 7 of fermentation. ß-Damascenone showed the highest odor activity (log2FD = 9) in the day 7 sample, followed by linalool and geraniol. These results indicate that fungal fermentation is critical to the formation of these aromas of IDT.

Variability in cadmium stress tolerance among four maize genotypes: Impacts on plant physiology, root morphology, and chloroplast microstructure.

Cadmium (Cd) is detrimental to both plants and humans. Maize (Zea mays L.) genotypes exhibit variations in Cd accumulations. This study examined variations in Cd accumulation and tolerance among four maize genotypes with contrasting root morphology. The four maize genotypes were cultivated in a semi-hydroponic system with three Cd concentrations (0, 10, 20 µmol L-1). The effects of Cd on plant growth and physiology were assessed 39 days after transplanting. Results showed that root characteristics were positively correlated with root Cd accumulation and the bioconcentration factor under Cd20 treatment. Genotypes Shengrui999 and Zhengdan958 exhibited higher total Cd content than Xundan29 and Zhongke11 under Cd20 conditions. Cd toxicity led to membrane degradation of chloroplast mesophyll cells, loosening and swelling of grana lamella, and reduced starch reserves. The greater tolerance of Shengrui999 and Zhengdan958 was contributed to factors such as root biomass, shallower root depth, higher Cd content, accumulation of osmolyte such as soluble protein, antioxidant activities such as catalase (CAT), and the presence of phytohormone gibberellic acid. The study establishes a link between root morphology, Cd accumulation, and tolerance in maize plants, as demonstrated by the higher Cd accumulation and shallower root system in Cd-tolerant genotypes. This research provides a foundation for breeding maize cultivars better suited for adaptation to moderate Cd-contaminated environments.

BRCA1 Insufficiency Induces a Hypersialylated Acidic Tumor Microenvironment That Promotes Metastasis and Immunotherapy Resistance.

Cancer metastasis is an extremely complex process affected by many factors. An acidic microenvironment can drive cancer cell migration toward blood vessels while also hampering immune cell activity. Here, we identified a mechanism mediated by sialyltransferases that induces an acidic tumor-permissive microenvironment (ATPME) in BRCA1-mutant and most BRCA1-low breast cancers. Hypersialylation mediated by ST8SIA4 perturbed the mammary epithelial bilayer structure and generated an ATPME and immunosuppressive microenvironment with increased PD-L1 and PD1 expressions. Mechanistically, BRCA1 deficiency increased expression of VEGFA and IL6 to activate TGFß-ST8SIA4 signaling. High levels of ST8SIA4 led to accumulation of polysialic acid (PSA) on mammary epithelial membranes that facilitated escape of cancer cells from immunosurveillance, promoting metastasis and resistance to αPD1 treatment. The sialyltransferase inhibitor 3Fax-Peracetyl Neu5Ac neutralized the ATPME, sensitized cancers to immune checkpoint blockade by activating CD8 T cells, and inhibited tumor growth and metastasis. Together, these findings identify a potential therapeutic option for cancers with a high level of PSA. SIGNIFICANCE: BRCA1 deficiency generates an acidic microenvironment to promote cancer metastasis and immunotherapy resistance that can be reversed using a sialyltransferase inhibitor.

Comparative genomic in situ hybridization (cGISH) analysis of the genomic relationships among Sinapis arvensis, Brassica rapa and Brassica nigra.

To further understand the relationships between the SS genome of Sinapis arvensis and the AA, BB genomes in Brassica, genomic DNA of Sinapis arvensis was hybridized to the metaphase chromosomes of Brassica nigra (BB genome), and the metaphase chromosomes and interphase nucleus of Brassica rapa (AA genome) by comparative genomic in situ hybridization (cGISH). As a result, every chromosome of B. nigra had signals along the whole chromosomal length. However, only half of the condensed heterochromatic areas in the interphase nucleus and the chromosomes showed rich signals in Brassica rapa. Interphase nucleus and the metaphase chromosomes of S. arvensis were simultaneously hybridized with digoxigenin-labeled genomic DNA of B. nigra and biotin-labeled genomic DNA of B. rapa. Signals of genomic DNA of B. nigra hybridized throughout the length of all chromosomes and all the condensed heterochromatic areas in the interphase nucleus, except chromosome 4, of which signals were weak in centromeric regions. Signals of the genomic DNA of B. rapa patterned the most areas of ten chromosomes and ten condensed heterochromatic areas, others had less signals. The results showed that the SS genome had homology with AA and BB genomes, but the homology between SS genome and AA genome was clearly lower than that between the SS genome and BB genome.

Development and Verification of Prognostic Prediction Models for Patients with Brain Trauma Based on Coagulation Function Indexes.

Objective: To assess the effect of adding coagulation indices to the currently existing prognostic prediction models of traumatic brain injury (TBI) in the prediction of outcome. Methods: A total of 210 TBI patients from 2017 to 2019 and 131 TBI patients in 2020 were selected for development and internal verification of the new model. The primary outcomes include death at 14 days and Glasgow Outcome Score (GOS) at 6 months. The performance of each model is evaluated by means of discrimination (area under the curve (AUC)), calibration (Hosmer-Lemeshow (H-L) goodness-of-fit test), and precision (Brier score). Results: The IMPACT Core model showed better prediction ability than the CRASH Basic model. Adding one coagulation index at a time to the IMPACT Core model, the new combined models IMPACT Core+FIB and IMPACT Core+APTT are optimal for the 6-month unfavorable outcome and 6-month mortality, respectively (AUC, 0.830 and 0.878). The new models were built based on the regression coefficients of the models. Internal verification indicated that for the prediction of 6-month unfavorable outcome and 6-month mortality, both the IMPACT Core+FIB model and the IMPACT Core+APTT model show better discrimination (AUC, 0.823 vs. 0.818 and 0.853 vs. 0.837), better calibration (HL, p = 0.114 and p = 0.317) and higher precision (Brier score, 0.148 vs. 0.141 and 0.147 vs. 0.164), respectively, than the original models. Conclusion: Our research shows that the combination of the traumatic brain injury prognostic models and coagulation indices can improve the 6-month outcome prediction of patients with TBI.

Genome-Wide Identification of Cellular Pathways and Key Genes That Respond to Sodium Bicarbonate Stress in Saccharomyces cerevisiae.

Sodium bicarbonate (NaHCO3) is an important inorganic salt. It is not only widely used in industrial production and daily life, but is also the main stress in alkaline saline soil. NaHCO3 has a strong ability to inhibit the growth of fungi in both natural environment and daily application. However, the mechanism by which fungi respond to NaHCO3 stress is not fully understood. To further clarify the toxic mechanisms of NaHCO3 stress and identify the specific cellular genes and pathways involved in NaHCO3 resistance, we performed genome-wide screening with NaHCO3 using a Saccharomyces cerevisiae deletion mutant library. A total of 33 deletion mutants with NaHCO3 sensitivity were identified. Compared with wild-type strains, these mutants had significant growth defects in the medium containing NaHCO3. Bioinformatics analysis found that the corresponding genes of these mutants are mainly enriched in the cell cycle, mitophagy, cell wall integrity, and signaling pathways. Further study using transcriptomic analysis showed that 309 upregulated and 233 downregulated genes were only responded to NaHCO3 stress, when compared with yeast transcriptomic data under alkaline and saline stress. Upregulated genes were mainly concentrated in amino acid metabolism, steroid biosynthesis, and cell wall, while downregulated genes were enriched in various cellular metabolisms. In summary, we have identified the cellular pathways and key genes that respond to NaHCO3 stress in the whole genome, providing resource and direction for understanding NaHCO3 toxicity and cellular resistance mechanisms.