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.

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.

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.

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.

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.

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.

Arbuscular Mycorrhizal Fungi Alleviate Low Phosphorus Stress in Maize Genotypes with Contrasting Root Systems.

Soil available phosphorus (P) is one of the main factors limiting plant growth and yield. This study aimed to determine the role of arbuscular mycorrhizal fungi (AMF) in P-use efficiency in two maize genotypes with contrasting root systems in response to low P stress. Maize genotypes small-rooted Shengrui 999 and large-rooted Zhongke 11 were grown in rhizoboxes that were inoculated with or without AMF (Funneliformis mosseae) under low P (no added P) or optimal P (200 mg kg-1) for 53 days. Low P stress significantly inhibited shoot and root growth, photosynthesis, tissue P content, and root P concentration in both genotypes. Shengrui 999 was more tolerant to P stress with less reduction of these traits compared to Zhongke 11. Shengrui 999 had a higher AMF infection rate than Zhongke 11 at both P levels. Under P deficit, inoculation with AMF significantly promoted plant growth and P uptake in both genotypes with more profound effects seen in Zhongke 11, whilst Shengrui 999 was more dependent on AMF under optimal P. Low P stress inhibited the growth and physiological attributes of both genotypes. The small-rooted Shengrui 999 was more tolerant to low P than Zhongke 11. Inoculation with AMF alleviates low P stress in both genotypes with a more profound effect on Zhongke 11 at low P and on Shengrui 999 at high P conditions.

The active functional microbes contribute differently to soil nitrification and denitrification potential under long-term fertilizer regimes in North-East China.

Nitrogen (N) cycling microorganisms mediate soil nitrogen transformation processes, thereby affecting agricultural production and environment quality. However, it is not fully understood how active N-cycling microbial community in soil respond to long-term fertilization, as well as which microorganisms regulate soil nitrogen cycling in agricultural ecosystem. Here, we collected the soils from different depths and seasons at a 29-year fertilization experimental field (organic/chemical fertilizer), and investigated the transcriptions of N-cycling functional genes and their contribution to potential nitrification and denitrification. We found that long-term fertilization exerted significant impacts on the transcript abundances of nitrifiers (AOA amoA, AOB amoA and hao) and denitrifiers (narG and nosZ), which was also notably influenced by season variation. The transcriptions of AOA amoA, hao, and narG genes were lowest in autumn, and AOB amoA and nosZ transcript abundances were highest in autumn. Compared to no fertilization, soil potential nitrification rate (PNR) was reduced in fertilization treatments, while soil potential denitrification rate (PDR) was significantly enhanced in organic combined chemical fertilizer treatment. Both PNR and PDR were highest in 0-20 cm among the tested soil depths. Path model indicated active nitrifiers and denitrifiers had significant impact on soil PNR and PDR, respectively. The transcriptions of AOA amoA and nxr genes were significantly correlated with soil PNR (Pearson correlation, r > 0.174, p < 0.05). Significant correlation of napA and nosZ transcriptions with soil PDR (Pearson correlation, r > 0.234, p < 0.05) was also revealed. Random forest analysis showed that SOC content and soil pH were the important factors explaining the total variance of active nitrifers and denitrifiers, respectively. Taken together, long-term fertilization regimes reduced soil PNR and enhanced PDR, which could be attributed to the different responses of active N-cycling microorganisms to soil environment variations. This work provides new insight into the nitrogen cycle, particularly microbial indicators in nitrification and denitrification of long-term fertilized agricultural ecosystems.

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 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.

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Long-term fertilization causes the differences in water, heat, nutrients and microbial activities between topsoil and deep soil, with consequences on the decomposition and turnover of straw carbon (C) in soils. At a long-term positioning experimental station in Shenyang Agricultural University, we mixed the topsoil (0-20 cm) and deep soil (40-60 cm) samples from different fertilization treatments with 13C-labeled straw for in-situ incubation. We analyzed the content of organic C and its δ13C value in soil aggregates, compared the difference in the distribution of straw C between topsoil and deep soil aggregates, and explored the effects of fertilization on the sequestration of straw C in soil aggregates. Compared with fertilization treatments (i.e., single chemical nitrogen fertilizer application and combination of organic manure with nitrogen fertilizer application), the treatment without fertilization increased the content of straw C of <0.053 mm aggregate in the topsoil by 106.7% and that of >0.25 mm aggregate in the deep soil by 34.2%. The contribution percentage of straw C to organic C of >0.053 mm aggregate in the deep soil was about two times of that in the topsoil. About 22.6% and 11.4% of straw C was distributed into the >0.25 mm and <0.25 mm aggregates of topsoil, and about 29.4% and 8.8% of straw C was distributed into the >0.25 mm and <0.25 mm aggregates of deep soil, respectively. In conclusion, straw addition promoted the regeneration and sequestration of carbon in deep soil macroaggregates and increased the carbon sequestration potential of deep soil.

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.

Influence of environmental factors on soil organic carbon in different soil layers for Chinese Mollisols under intensive maize cropping.

The Mollisol region of Northeast China has a large soil organic carbon (SOC) storage which is important for maintaining soil fertility. SOC is susceptible to various environmental factors; however, the responses of SOC content to environmental factors in different soil layers of cropland remain unclear, particularly in deep soil layers. In this study, we collected 138 soil samples from the surface, subsurface, and subsoil layers among 46 sample sites with monocropping maize and intensive conventional tillage in this region. We assessed the relative importance and effect paths of 12 environmental factors (including geography, climate, and soil properties) on SOC content in different layers using redundancy analysis (RDA), structural equation model (SEM), and variation partitioning analysis (VPA). The VPA results showed that SOC content was mainly affected by climatic factors that explained 68% and 57% for the surface and subsurface layers, respectively. However, SOC content in the subsoil layer was greatly affected by soil properties that explained 27%. Furthermore, the SEMs results suggested that geographical factors indirectly affected SOC content by influencing the climatic factors. Mean annual temperature was the most important factor affecting SOC content directly or indirectly, and its negative effects significantly diminished with soil depth, as it explained 63%, 52%, and 17% of the variation in SOC content for the surface, subsurface and subsoil layers, respectively. In addition, the effects of soil water-holding capacity on SOC content also decreased with soil depth, whereas pH and clay content showed a contrasting pattern. This implies that pH and clay content play important roles in the sequestration of SOC in deep soil layers. Moreover, the organic C content within >53 µm aggregates was more sensitive to environmental factors. This study can be useful for forecasting SOC dynamics and establishing reasonable C management strategies under climate change conditions.

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.

S100A9-CXCL12 activation in BRCA1-mutant breast cancer promotes an immunosuppressive microenvironment associated with resistance to immunotherapy.

Immune checkpoint blockade (ICB) is a powerful approach for cancer therapy although good responses are only observed in a fraction of cancer patients. Breast cancers caused by deficiency of breast cancer-associated gene 1 (BRCA1) do not have an improved response to the treatment. To investigate this, here we analyze BRCA1 mutant mammary tissues and tumors derived from both BRCA1 mutant mouse models and human xenograft models to identify intrinsic determinants governing tumor progression and ICB responses. We show that BRCA1 deficiency activates S100A9-CXCL12 signaling for cancer progression and triggers the expansion and accumulation of myeloid-derived suppressor cells (MDSCs), creating a tumor-permissive microenvironment and rendering cancers insensitive to ICB. These oncogenic actions can be effectively suppressed by the combinatory treatment of inhibitors for S100A9-CXCL12 signaling with αPD-1 antibody. This study provides a selective strategy for effective immunotherapy in patients with elevated S100A9 and/or CXCL12 protein levels.

ATP11B inhibits breast cancer metastasis in a mouse model by suppressing externalization of nonapoptotic phosphatidylserine.

Cancer metastasis is the cause of the majority of cancer-related deaths. In this study, we demonstrated that no expression or low expression of ATP11B in conjunction with high expression of PTDSS2, which was negatively regulated by BRCA1, markedly accelerates tumor metastasis. Further analysis revealed that cells with low ATP11B expression and high PTDSS2 expression (ATP11BloPTDSS2hi cells) were associated with poor prognosis and enhanced metastasis in breast cancer patients in general. Mechanistically, an ATP11BloPTDSS2hi phenotype was associated with increased levels of nonapoptotic phosphatidylserine (PS) on the outer leaflet of the cell membrane. This PS increase serves as a global immunosuppressive signal to promote breast cancer metastasis through an enriched tumor microenvironment with the accumulation of myeloid-derived suppressor cells and reduced activity of cytotoxic T cells. The metastatic processes associated with ATP11BloPTDSS2hi cancer cells can be effectively overcome by changing the expression phenotype to ATP11BhiPTDSS2lo through a combination of anti-PS antibody with either paclitaxel or docetaxel. Thus, blocking the ATP11BloPTDSS2hi axis provides a new selective therapeutic strategy to prevent metastasis in breast cancer patients.

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.

Retromer Complex and PI3K Complex II-Related Genes Mediate the Yeast (Saccharomyces cerevisiae) Sodium Metabisulfite Resistance Response.

Sodium metabisulfite (Na2S2O5) is widely used as a preservative in the food and wine industry. However, it causes varying degrees of cellular damage to organisms. In order to improve our knowledge regarding its cyto-toxicity, a genome-wide screen using the yeast single deletion collection was performed. Additionally, a total of 162 Na2S2O5-sensitive strains and 16 Na2S2O5-tolerant strains were identified. Among the 162 Na2S2O5 tolerance-related genes, the retromer complex was the top enriched cellular component. Further analysis demonstrated that retromer complex deletion leads to increased sensitivity to Na2S2O5, and that Na2S2O5 can induce mislocalization of retromer complex proteins. Notably, phosphatidylinositol 3-monophosphate kinase (PI3K) complex II, which is important for retromer recruitment to the endosome, might be a potential regulator mediating retromer localization and the yeast Na2S2O5 tolerance response. Na2S2O5 can decrease the protein expressions of Vps34, which is the component of PI3K complex. Therefore, Na2S2O5-mediated retromer redistribution might be caused by the effects of decreased Vps34 expression levels. Moreover, both pharmaceutical inhibition of Vps34 functions and deletions of PI3K complex II-related genes affect cell tolerance to Na2S2O5. The results of our study provide a global picture of cellular components required for Na2S2O5 tolerance and advance our understanding concerning Na2S2O5-induced cytotoxicity effects.