Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling.

Neurovascular coupling (NVC) is important for brain function and its dysfunction underlies many neuropathologies. Although cell-type specificity has been implicated in NVC, how active neural information is conveyed to the targeted arterioles in the brain remains poorly understood. Here, using two-photon focal optogenetics in the mouse cerebral cortex, we demonstrate that single glutamatergic axons dilate their innervating arterioles via synaptic-like transmission between neural-arteriolar smooth muscle cell junctions (NsMJs). The presynaptic parental-daughter bouton makes dual innervations on postsynaptic dendrites and on arteriolar smooth muscle cells (aSMCs), which express many types of neuromediator receptors, including a low level of glutamate NMDA receptor subunit 1 (Grin1). Disruption of NsMJ transmission by aSMC-specific knockout of GluN1 diminished optogenetic and whisker stimulation-caused functional hyperemia. Notably, the absence of GluN1 subunit in aSMCs reduced brain atrophy following cerebral ischemia by preventing Ca2+ overload in aSMCs during arteriolar constriction caused by the ischemia-induced spreading depolarization. Our findings reveal that NsMJ transmission drives NVC and open up a new avenue for studying stroke.

Development and Validation of a Novel Prognosis Model Based on a Panel of Three Immunogenic Cell Death-Related Genes for Non-Cirrhotic Hepatocellular Carcinoma.

Purpose: The accurate prediction of non-cirrhotic hepatocellular carcinoma (NCHCC) risk facilitates improved surveillance strategy and decreases cancer-related mortality. This study aimed to explore the correlation between immunogenic cell death (ICD) and NCHCC prognosis using The Cancer Genome Atlas (TCGA) datasets, and the potential prognostic value of ICD-related genes in NCHCC. Methods: Clinical and transcriptomic data of patients with NCHCC patients were retrieved from TCGA database. Weighted gene co-expression network analysis was performed to obtain the NCHCC phenotype-related module genes. Consensus clustering analysis was performed to classify the patients into two clusters based on intersection genes among differentially expressed genes (DEGs) between cancer and adjacent tissues, NCHCC phenotype-related genes, and ICD-related genes. NCHCC-derived tissue microarray was used to evaluate the correlation of the expression levels of key genes with NCHCC prognosis using immunohistochemical staining. Results: Cox regression analyses were performed to construct a prognostic risk score model comprising three genes (TMC7, GRAMD1C, and GNPDA1) based on DEGs between two clusters. The model stratified patients with NCHCC into two risk groups. The overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group. Univariable and multivariable Cox regression analyses revealed that these signature genes are independent predictors of OS. Functional analysis revealed differential immune status between the two risk groups. Next, a nomogram was constructed, which demonstrated the potent distinguishing ability of the developed model based on receiver operating characteristic curves. In vitro functional validation revealed that the migration and invasion abilities of HepG2 and Huh7 cells were upregulated upon GRAMD1C knockdown but downregulated upon TMC7 knockdown. Conclusion: This study developed a prognostic model comprising three genes, which can aid in predicting the survival of patients with NCHCC and guide the selection of drugs and molecular markers for NCHCC.

Signaling metabolite succinylacetone activates HIF-1α and promotes angiogenesis in GSTZ1-deficient hepatocellular carcinoma.

Aberrant angiogenesis in hepatocellular carcinoma (HCC) is associated with tumor growth, progression, and local or distant metastasis. Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a major role in regulating angiogenesis during adaptation of tumor cells to nutrient-deprived microenvironments. Genetic defects in Krebs cycle enzymes, such as succinate dehydrogenase and fumarate hydratase, result in elevation of oncometabolites succinate and fumarate, thereby increasing HIF-1α stability and activating the HIF-1α signaling pathway. However, whether other metabolites regulate HIF-1α stability remains unclear. Here, we reported that deficiency of the enzyme in phenylalanine/tyrosine catabolism, glutathione S-transferase zeta 1 (GSTZ1), led to accumulation of succinylacetone, which was structurally similar to α-ketoglutarate. Succinylacetone competed with α-ketoglutarate for prolyl hydroxylase domain 2 (PHD2) binding and inhibited PHD2 activity, preventing hydroxylation of HIF-1α, thus resulting in its stabilization and consequent expression of vascular endothelial growth factor (VEGF). Our findings suggest that GSTZ1 may serve as an important tumor suppressor owing to its ability to inhibit the HIF-1α/VEGFA axis in HCC. Moreover, we explored the therapeutic potential of HIF-1α inhibitor combined with anti-programmed cell death ligand 1 therapy to effectively prevent HCC angiogenesis and tumorigenesis in Gstz1-knockout mice, suggesting a potentially actionable strategy for HCC treatment.

Influence of Narcissistic CEOs on Corporate Social Responsibility (CSR) Choices: The Moderating Role of the Legal Environment.

Purpose: During recent years, there has been a growing interest in CSR across disciplines. Various scholars document that Chief Executive Officer (CEO) narcissism is an important factor that should not be overlooked when analyzing CSR. Research on the relationship between CEO narcissism and CSR has treated CSR as a whole construct. However, little attention has been paid to its effect on different dimensions of CSR, especially the same psychological trait may have effects on charitable donations and employee welfare. The purpose of the study is to explore the relationship between CEO narcissism and charitable donations and employee welfare, while taking into account the moderating role of the legal environment. Methods: This study used the video survey method to measure CEO narcissism, the video information was obtained from Baidu.com and hao.360.com search engines. Other data were collected from Chinese Stock Market Research (CSMAR) database. We used OLS regression for data analysis and also used Tobit regression model to check the robustness of the estimation results. Meanwhile, all analyses will be performed with Stata 16.0 software. Results: Empirical analysis reveals that CEO narcissism has a positive and significant impact on charitable donations and has a negative and significant impact on employee welfare. Moreover, the legal environment will reduce the effect of CEO narcissism on charitable donations and employee welfare, indicating that a stronger legal environment could attenuate the effect of CEO personality traits, especially narcissism on charity donations and employee welfare. Conclusion: This study contributes to the behavioral finance theory and stakeholder theory to better understand the relationship between CEO narcissism and charitable donations and employee welfare. Meanwhile, this study is one of the few studies to investigate the patterns of CSR activities in China, an important emerging economy.

Vegetation structural shift tells environmental changes on the Tibetan Plateau over 40 years.

Structural information of grassland changes on the Tibetan Plateau is essential for understanding alterations in critical ecosystem functioning and their underlying drivers that may reflect environmental changes. However, such information at the regional scale is still lacking due to methodological limitations. Beyond remote sensing indicators only recognizing vegetation productivity, we utilized multivariate data fusion and deep learning to characterize formation-based plant community structure in alpine grasslands at the regional scale of the Tibetan Plateau for the first time and compared it with the earlier version of Vegetation Map of China for historical changes. Over the past 40 years, we revealed that (1) the proportion of alpine meadows in alpine grasslands increased from 50% to 69%, well-reflecting the warming and wetting trend; (2) dominances of Kobresia pygmaea and Stipa purpurea formations in alpine meadows and steppes were strengthened to 76% and 92%, respectively; (3) the climate factor mainly drove the distribution of Stipa purpurea formation, but not the recent distribution of Kobresia pygmaea formation that was likely shaped by human activities. Therefore, the underlying mechanisms of grassland changes over the past 40 years were considered to be formation dependent. Overall, the first exploration for structural information of plant community changes in this study not only provides a new perspective to understand drivers of grassland changes and their spatial heterogeneity at the regional scale of the Tibetan Plateau, but also innovates large-scale vegetation study paradigm.

Gluconeogenic enzyme PCK1 supports S-adenosylmethionine biosynthesis and promotes H3K9me3 modification to suppress hepatocellular carcinoma progression.

Deciphering the crosstalk between metabolic reprogramming and epigenetic regulation is a promising strategy for cancer therapy. In this study, we discovered that the gluconeogenic enzyme PCK1 fueled the generation of S-adenosylmethionine (SAM) through the serine synthesis pathway. The methyltransferase SUV39H1 catalyzed SAM, which served as a methyl donor to support H3K9me3 modification, leading to the suppression of the oncogene S100A11. Mechanistically, PCK1 deficiency-induced oncogenic activation of S100A11 was due to its interaction with AKT1, which upregulated PI3K/AKT signaling. Intriguingly, the progression of hepatocellular carcinoma (HCC) driven by PCK1 deficiency was suppressed by SAM supplement or S100A11 KO in vivo and in vitro. These findings reveal the availability of the key metabolite SAM as a bridge connecting the gluconeogenic enzyme PCK1 and H3K9 trimethylation in attenuating HCC progression, thus suggesting a potential therapeutic strategy against HCC.

Reclamation intensifies the positive effects of warming on N2O emission in an alpine meadow.

Climatic warming can alter grassland nitrous oxide (N2O) emissions due to soil property alterations. However, how the reclamation affect grassland N2O flux under warming conditions remains unclear in alpine meadow ecosystems. We conducted a long-term manipulative warming experiment in a natural alpine meadow and a cultivated grassland on the Qinghai-Tibetan Plateau to explore the separate and interactive effects of warming and reclamation on the soil N2O emission flux. N2O fluxes were measured under four treatments including control (CK), warming (W), reclamation (R) and warming under reclamation (WR) from August 2018 to July 2019. We measured the content of soil C, N nutrients and 5 enzymatic activities in 2018 and 2019. Correlation analysis and structural equation modeling were used to clarify how soil N availability and soil enzyme activities affect N2O emission. Our results indicated that compared to the ambient conditions for the growing and non-growing seasons, soil N2O flux was significantly increased 59.1% and 152.0% by warming and 28.4% and 142.4% by reclamation, respectively. Compared with W, WR significantly increased N2O flux by 18.9% and 81.1% during the growing and non-growing seasons, respectively. Soil moisture was negatively correlated to enzymatic activity and N2O flux. Both warming and reclamation promoted soil nitrification by increasing related enzymatic activities that acted to increase the N2O flux. Reclamation resulted in a greater sensitivity of the activity of ammonia monooxygenase and hydroxylamine oxidoreductase to warming, thus enhancing the effects of warming on increasing the N2O flux. Our research indicated that reclamation can additionally increase the effects of warming on N2O emissions for alpine meadows. Therefore, excessive expansion of arable land should be avoided, and new reclamation sites should be planned scientifically, as warming is expected to intensify in the future.

Chairman Narcissism and Social Responsibility Choices: The Moderating Role of Analyst Coverage.

Chairman narcissism has received extensive attention in social psychology and organizational behavior, but the relationship between chairman narcissism and social responsibility has not yet received much attention. The purpose of this study is to investigate the effect of chairman narcissism on various dimensions of CSR and the moderating roles of analyst coverages. Based on upper echelons theory and stakeholder theory, we distinguished internal corporate social responsibility (internal CSR) and external corporate social responsibility (external CSR) according to whether there was a formal contractual relationship. This study used a narcissism index of chairmen of Chinese listed companies to examine the relationship between chairman narcissism and internal CSR, external CSR, and the data were analyzed using Stata16.0. The results showed that there was a positive correlation between chairman narcissism and external CSR, and there was a negative correlation between chairman narcissism and internal CSR. That is, the higher the Chairman's narcissism degree is, the more external CSR and less internal CSR the firm makes. Further research showed that analyst coverage has weakened the impact of chairman narcissism on internal and external CSR. This paper enriches and expands the research on chairman narcissism and CSR and provides new ideas for selecting corporate managers and improving corporate governance.

O-GlcNAcylation of YTHDF2 promotes HBV-related hepatocellular carcinoma progression in an N6-methyladenosine-dependent manner.

Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), but its pathogenic mechanism remains to be explored. The RNA N6-methyladenosine (m6A) reader, YTH (YT521-B homology) domain 2 (YTHDF2), plays a critical role in the HCC progression. However, the function and regulatory mechanisms of YTHDF2 in HBV-related HCC remain largely elusive. Here, we discovered that YTHDF2 O-GlcNAcylation was markedly increased upon HBV infection. O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of YTHDF2 on serine 263 enhanced its protein stability and oncogenic activity by inhibiting its ubiquitination. Mechanistically, YTHDF2 stabilized minichromosome maintenance protein 2 (MCM2) and MCM5 transcripts in an m6A-dependent manner, thus promoting cell cycle progression and HBV-related HCC tumorigenesis. Moreover, targeting YTHDF2 O-GlcNAcylation by the OGT inhibitor OSMI-1 significantly suppressed HCC progression. Taken together, our findings reveal a new regulatory mechanism for YTHDF2 and highlight an essential role of YTHDF2 O-GlcNAcylation in RNA m6A methylation and HCC progression. Further description of the molecular pathway has the potential to yield therapeutic targets for suppression of HCC progression due to HBV infection.

Effects of water levels on plant traits and nitrogen use efficiency in monoculture and intercropped artificial grasslands.

Water availability is the main factor affecting the forage productivity of artificial grasslands, particularly in semi-arid regions. Generally, intercropping of gramineous grass and leguminous grass can achieve high productivity. However, how different water availability levels affect the productivity of intercropping system remains unclear. Here, we conducted a 3-year (2015-2017) study by manipulating the water conditions (CK equivalent to the annual precipitation, +50% treatment equivalent to 50% increase over the average precipitation, and -50% treatment equivalent to 50% decrease over the average precipitation) to explore the responses of plant traits, nitrogen use efficiency, and biomass of the monoculture of Medicago sativa (a leguminous grass, M.s), monoculture of Elymus nutans (a gramineous grass, E.n), and intercropping of M.s and E.n in a semi-arid region in Inner Mongolia, China. The results showed that the biomass obtained by intercropping of M.s and E.n decreased by 24.4% in -50% treatment compared to the CK treatment, while that of the monoculture of M.s decreased by 34.4% under the -50% treatment compared to the CK treatment. However, there was no significant difference in the biomass between intercropping artificial grassland and monoculture M. sativa under +50% treatment. Compared to monoculture, M.s can obtain more nitrogen by biological nitrogen fixation and decrease the proportion of nitrogen absorbed from soils under intercropping in the same water conditions. Under the intercropping system, the proportions of nitrogen absorbed from soils by M.s were 87.4%, 85.1, and 76.9% in -50%, CK, and +50% treatments, respectively. Under monoculture, these proportions were 91.9, 89.3, and 82.3% in -50%, CK, and +50% treatments, respectively. Plant trait, but not soil nitrogen content, was the main regulator for the productivity responses to water level changes. Our results highlight that intercropping can achieve higher productivity in both dry and wet conditions. Therefore, considering the fluctuating rainfall events in the future, it might be useful to alter the proportions of intercropped forage species in an artificial grassland to obtain optimal productivity by reducing the limitations of nitrogen availability. However, the economic viability of intercropping M. sativa and E. nutans should be evaluated in the future.

Dysregulated glucuronic acid metabolism exacerbates hepatocellular carcinoma progression and metastasis through the TGFß signalling pathway.

BACKGROUND: Glucuronic acid metabolism participates in cellular detoxification, extracellular matrix remodeling and cell adhesion and migration. Here, we aimed to explore the crosstalk between dysregulated glucuronic acid metabolism and crucial metastatic signalling in glutathione S-transferase zeta 1 (GSTZ1)-deficient hepatocellular carcinoma (HCC). METHODS: Transwell, HCC xenograft and Gstz1-/- mouse models were used to examine the role of GSTZ1 in HCC metastasis. Non-targeted and targeted metabolomics and global transcriptomic analyses were performed to screen significantly altered metabolic and signalling pathways in GSTZ1 overexpressing hepatoma cells. Further, RNA-binding protein immunoprecipitation, Biotin-RNA pull-down, mRNA decay assays and luciferase reporter assays were used to explore the interaction between RNA and RNA-binding proteins. RESULTS: GSTZ1 was universally silenced in both human and murine HCC cells, and its deficiency contributed to HCC metastasis in vitro and in vivo. UDP-glucose 6-dehydrogenase (UGDH)-mediated UDP-glucuronic acid (UDP-GlcUA) accumulation promoted hepatoma cell migration upon GSTZ1 loss. UDP-GlcUA stabilized TGFßR1 mRNA by enhancing its binding to polypyrimidine tract binding protein 3, contributing to the activation of TGFß/Smad signalling. UGDH or TGFßR1 blockade impaired HCC metastasis. In addition, UGDH up-regulation and UDP-GlcUA accumulation correlated with increased metastatic potential and decreased patient survival in GSTZ1-deficient HCC. CONCLUSIONS: GSTZ1 deficiency and subsequent up-regulation of the glucuronic acid metabolic pathway promotes HCC metastasis by increasing the stability of TGFßR1 mRNA and activating TGFß/Smad signalling. UGDH and a key metabolite, UDP-GlcUA, may serve as prognostic markers. Targeting UGDH might be a promising strategy for HCC therapy.

Nitrogen Addition Affects Ecosystem Carbon Exchange by Regulating Plant Community Assembly and Altering Soil Properties in an Alpine Meadow on the Qinghai-Tibetan Plateau.

Nitrogen (N) deposition can affect the global ecosystem carbon balance. However, how plant community assembly regulates the ecosystem carbon exchange in response to the N deposition remains largely unclear, especially in alpine meadows. In this study, we conducted a manipulative experiment to examine the impacts of N (ammonium nitrate) addition on ecosystem carbon dioxide (CO2) exchange by changing the plant community assembly and soil properties at an alpine meadow site on the Qinghai-Tibetan Plateau from 2014 to 2018. The N-addition treatments were N0, N7, N20, and N40 (0, 7, 20, and 40 kg N ha-1year-1) during the plant growing season. The net ecosystem CO2 exchange (NEE), gross ecosystem productivity (GEP), and ecosystem respiration (ER) were measured by a static chamber method. Our results showed that the growing-season NEE, ER and GEP increased gradually over time with increasing N-addition rates. On average, the NEE increased significantly by 55.6 and 65.2% in N20 and N40, respectively (p < 0.05). Nitrogen addition also increased forage grass biomass (GB, including sedge and Gramineae) by 74.3 and 122.9% and forb biomass (FB) by 73.4 and 51.4% in N20 and N40, respectively (p < 0.05). There were positive correlations between CO2 fluxes (NEE and GEP) and GB (p < 0.01), and the ER was positively correlated with functional group biomass (GB and FB) and soil available N content (NO3 --N and NH4 +-N) (p < 0.01). The N-induced shift in the plant community assembly was primarily responsible for the increase in NEE. The increase in GB mainly contributed to the N stimulation of NEE, and FB and the soil available N content had positive effects on ER in response to N addition. Our results highlight that the plant community assembly is critical in regulating the ecosystem carbon exchange response to the N deposition in alpine ecosystems.

Grazing Changed Plant Community Composition and Reduced Stochasticity of Soil Microbial Community Assembly of Alpine Grasslands on the Qinghai-Tibetan Plateau.

Grazing is a substantial threat to the sustainability of grassland ecosystems, while it is uncertain about the variety of plant and soil microbial community and the linkages between them limit the comprehensive understanding of grazing ecology. We conducted an experiment on the effects of the grazing regimes rotational grazing (RG), continuous grazing (CG), and grazing exclusion (GE) on an alpine meadow in Qinghai-Tibetan Plateau. The differences of plant community composition, soil microbial community assembly mechanism, and taxonomic and functional composition between grazing regimes were examined, and the relationship between plant species and the soil microbes was assessed by constructing a co-occurrence network. The results showed that the plant community composition varied with the grazing regimes, while the soil microbial community composition did not vary with the grazing regimes. The soil bacterial functional composition was similar under RG and CG, while the soil fungal functional composition was similar under GE and RG. The soil microbial community under all grazing regimes was assembled mainly according to stochastic rather than deterministic mechanisms, and RG and CG reduced the relative importance of the stochastic ratio. At the microbial phylum level, CG and GE increased the relative abundance of Acidobacteria and Armatimonadetes and CG and RG increased the relative abundance of Elusimicrobia. In the network of plant species and soil microbial classes, plants and bacteria themselves were mainly positively linked (symbiosis and promotion), while plants and soil microbes were mainly negatively linked (competition). There were five microbial generalists in the network, which connected with many microbes, and four showed no difference in their abundance among the grazing regimes. Overall, the stable key microbes in the network and the fact that many of the plants are unconnected with microbes weakened the impact of grazing-induced changes in the plant community on soil microbes, probably resulting in the stable soil microbial community composition. Moreover, there was still a dominant and tolerant plant species, Kobresia pygmaea, that connected the plant and microbial communities, implying that the dominant plant species not only played a crucial role in the plant community but also acted as a bridge between the plants and soil microbes; thus, its tolerance and dominance might stabilize the soil microbial community.

Warming and spring precipitation addition change plant growth pattern but have minor effects on growing season mean gross ecosystem productivity in an alpine meadow.

Gross ecosystem productivity (GEP) plays an important role in global carbon cycling. However, how plant phenology and growth rate regulate GEP under climate change is unclear. Based on an in situ manipulative experiment using open top chambers from 2015 to 2018, we measured whole year warming and spring precipitation addition effects on plant phenology, plant growth rate and GEP. Our results showed that warming delayed plant green up (4 days) and withering (5 days), while spring precipitation addition advanced green up 13 days and did not change withering. Warming delayed the timing of the fast-growing phase 7 days, shortened length of the fast-growing phase 7 days and marginally increased the growth rate. Spring precipitation addition advanced the timing of the fast-growing phase 6 days, but did not change the length of the fast-growing phase or the growth rate. Both whole year warming and spring precipitation addition have not significantly affected growing season mean GEP. GEP is positively correlated with plant growth rate and negatively correlated with the length of the fast-growing phase. We provide an evidence that although warming did not change growing season mean productivity, it delayed plant fast-growing phase. Our findings suggest that management approaches for increasing water availability before the fast-growing phase should be intensified to increase ecosystem carbon uptake and grass supply for animal husbandry in spring.

Potent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants.

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.

O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis.

Aberrant glucose metabolism and elevated O-linked ß-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 (PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pathway (HBP)-mediated protein O-GlcNAcylation in hepatoma cell and promotes cell growth and proliferation. However, whether PCK1 deficiency and hyper O-GlcNAcylation can induce HCC metastasis is largely unknown. Here, gain- and loss-of-function studies demonstrate that PCK1 suppresses HCC metastasis in vitro and in vivo. Specifically, lysine acetyltransferase 5 (KAT5), belonging to the MYST family of histone acetyltransferases (HAT), is highly modified by O-GlcNAcylation in PCK1 knockout hepatoma cells. Mechanistically, PCK1 depletion suppressed KAT5 ubiquitination by increasing its O-GlcNAcylation, thereby stabilizing KAT5. KAT5 O-GlcNAcylation epigenetically activates TWIST1 expression via histone H4 acetylation, and enhances MMP9 and MMP14 expression via c-Myc acetylation, thus promoting epithelial-mesenchymal transition (EMT) in HCC. In addition, targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice. Collectively, our findings demonstrate that PCK1 depletion increases O-GlcNAcylation of KAT5, epigenetically induces TWIST1 expression and promotes HCC metastasis, and link metabolic enzyme, post-translational modification (PTM) with epigenetic regulation.

[Tracing the sources of sedimentary organic matter in Nanyue small watershed based on 13C, 15N and C/N]. / 基于13C、15N和C/N识别南岳小流域沉积有机质的来源.

Losses of organic matter in agricultural watersheds result in eutrophication and land degra-dation, which not only threaten water quality and food security, but also lead to environmental problems such as the greenhouse gases emission. We used 13C, 15N and C/N as fingerprint markers to trace the sources of sedimentary organic matter at the outlet in the Nanyue small watershed. We analyzed the spatial distribution in watershed sedimentary organic matter and soils of typical land use types, including forest, paddy field, and vegetable fields. The Bayesian stable isotope mixing model was used to quantitatively estimate the contribution of different sources. The results showed that there was significant spatial variation of δ13C. The δ13C of sediment organic matter (-22.6‰±0.53‰) and forest soil (-23.13‰±1.71‰) was significantly higher than that of paddy soil (-25.24‰±1.4‰). The differences of δ15N among the sources were not significant, with sediment having the maximum (4.37±0.83)‰ and forest soil having the minimum (2.38±1.97)‰. Forest soil had the highest C/N of 16.66±7.18, while paddy soil had the lowest C/N of 11.95±0.92. The results of the Bayesian stable isotope mixture model showed that the contribution rates of forest land, paddy fields and vegetable fields to the organic matter deposited at the outlet in the watershed were 19.6%, 15.7%, and 64.7%, respectively. Paddy filed and vegetable field had a combined contribution rate of 80.4%. It was concluded that, soils of agricultural land were the main sources of organic matter deposited in the Nanyue small watershed, and that nutrient loss in the watershed would be effectively controlled by optimizing farmland management.

GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis.

Increasing evidence supports that ferroptosis plays an important role in tumor growth inhibition. Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, has been shown to induce ferroptosis in hepatocellular carcinoma (HCC). However, some hepatoma cell lines are less sensitive to sorafenib-induced ferroptotic cell death. Glutathione S-transferase zeta 1 (GSTZ1), an enzyme in the catabolism of phenylalanine, suppresses the expression of the master regulator of cellular redox homeostasis nuclear factor erythroid 2-related factor 2 (NRF2). This study aimed to investigate the role and underlying molecular mechanisms of GSTZ1 in sorafenib-induced ferroptosis in HCC. GSTZ1 was significantly downregulated in sorafenib-resistant hepatoma cells. Mechanistically, GSTZ1 depletion enhanced the activation of the NRF2 pathway and increased the glutathione peroxidase 4 (GPX4) level, thereby suppressing sorafenib-induced ferroptosis. The combination of sorafenib and RSL3, a GPX4 inhibitor, significantly inhibited GSTZ1-deficient cell viability and promoted ferroptosis and increased ectopic iron and lipid peroxides. In vivo, the combination of sorafenib and RSL3 had a synergic therapeutic effect on HCC progression in Gstz1-/- mice. In conclusion, this finding demonstrates that GSTZ1 enhanced sorafenib-induced ferroptosis by inhibiting the NRF2/GPX4 axis in HCC cells. Combination therapy of sorafenib and GPX4 inhibitor RSL3 may be a promising strategy in HCC treatment.

A Rapid and Efficient Screening System for Neutralizing Antibodies and Its Application for SARS-CoV-2.

After the pandemic of COVID-19, neutralizing antibodies (NAbs) against SARS-CoV-2 have been developed for the prophylactic and therapeutic purposes. However, few methodologies are described in detail on how to rapidly and efficiently generate effective NAbs to SARS-CoV-2. Here, we integrated and optimized a strategically screening method for NAbs, which has enabled us to obtain SARS-CoV-2 receptor-binding domain (RBD) specific NAbs within 6 days, followed by additional 9 days for antibody production and function analysis. Using this method, we obtained 198 specific Abs against SARS-CoV-2 RBD from the blood samples of COVID-19 convalescent patients, and 96 of them showed neutralizing activity. At least 20% of these NAbs exhibited advanced neutralizing potency and high affinity, with the top two NAbs showing half-maximal inhibitory concentration (IC50) to block authentic SARS-CoV-2 at 9.88 and 11.13 ng/ml, respectively. Altogether, our study provides an effective methodology with high applicable value for discovering potential preventative and therapeutic NAbs for the emerging infectious diseases.