c-Src regulates δ-secretase activation and truncated Tau production by phosphorylating the E3 ligase Traf6.

The accumulation of abnormal Tau protein is a common feature of various neurodegenerative diseases. Truncated Tau, resulting from cleavage by asparaginyl endopeptidase (AEP, δ-secretase), promotes its own phosphorylation and aggregation. Our study focused on understanding the regulatory mechanisms of AEP activation and its interaction with other proteins. We discovered that c-Src plays a critical role in mediating the activation and polyubiquitination of AEP in response to epidermal growth factor stimulation. In addition, we investigated the involvement of tumor necrosis factor receptor-associated factor 6 (Traf6), an E3 ligase, in the regulation of AEP levels and its interaction with c-Src. Knockdown of Traf6 effectively inhibited c-Src-induced AEP activation. To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src. By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation. Pharmacological inhibition of c-Src reduced the phosphorylation of Traf6 and inhibited AEP activation in neurons derived from human-induced pluripotent stem cells. Conditional knockout of Traf6 in neurons prevented c-Src-induced AEP activation and subsequent Tau truncation in vivo. Moreover, phosphorylation of Traf6 is highly correlated with AEP activation, Tau368 and pathological Tau (AT8) in Alzheimer's disease brain. Overall, our study elucidates the role of c-Src in regulating AEP-cleaved Tau through phosphorylating Traf6. Targeting the c-Src-Traf6 pathway may hold potential for the treatment of Alzheimer's disease and other tauopathies.

[Review on the Long-term and Short-term Effects of Biochar Addition on Soil Greenhouse Gas Emissions].

Increasing concentrations of greenhouse gases in the atmosphere caused by human activities are the main cause of climate warming. Global warming is a severe challenge confronted by human society today. Reducing greenhouse gas emissions and increasing carbon sinks are the keys to addressing climate warming. Biochar addition is considered to be a promising way to reduce greenhouse gas emissions and increase carbon sinks, due to its unique physical, chemical, and biological properties. Therefore, it is of great significance to study the effects of biochar on soil greenhouse gas emissions to mitigate the greenhouse effect and achieve "carbon neutrality." The long-term and short-term effects of biochar on soil greenhouse gas emissions and their influencing mechanism were reviewed. It was found that the effects of biochar on soil greenhouse gas emissions varied with the types of biochar feedstock, pyrolysis temperature, application ratio, and soil and vegetable types. In addition, due to the different aging times and modes and cultivation methods, the mitigation effect of aged biochar on soil greenhouse gas could be enhanced or weakened or even disappeared. Further, based on the deficiencies of the previous research, the direction and focus of future research on the effects of biochar on soil greenhouse gas emissions were analyzed and prospected. It was proposed to strengthen simultaneous research on the effects of biochar on CO2, N2O, and CH4 emissions; reducing greenhouse gas emissions and carbon sequestration; different aging modes and cultivation methods of biochar; and revealing the influencing mechanism at the process level, through exploring the effects of biochar on soil carbon and nitrogen dynamics and tracing the source of greenhouse gases using 13C and 15N tracer technology.

Greenhouse Gas Emissions from Soils Amended with Cornstalk Biochar at Different Addition Ratios.

Biochar addition has been recommended as a potential strategy for mitigating climate change. However, the number of studies simultaneously investigating the effects of biochar addition on CO2, N2O and CH4 emissions and sequentially global warming potential (GWP) is limited, especially concerning its effect on native soil organic carbon (SOC) mineralization. An incubation experiment was conducted to investigate soil physicochemical properties, CO2, N2O and CH4 emissions and GWP in the treatments with 0% (CK), 1% (BC1) and 4% (BC4) cornstalk biochar additions, and clarify the priming effect of biochar on native SOC mineralization by the 13C tracer technique. Generally, biochar addition increased soil pH, cation exchange capacity, SOC and total nitrogen, but decreased NH4+-N and NO3--N. Compared with CK, BC1 and BC4 significantly reduced CO2 emissions by 20.7% and 28.0%, and reduced N2O emissions by 25.6% and 95.4%, respectively. However, BC1 significantly reduced CH4 emission by 43.6%, and BC4 increased CH4 emission by 19.3%. BC1 and BC4 significantly reduced the GWP by 20.8% and 29.3%, but there was no significant difference between them. Biochar addition had a negative priming effect on native SOC mineralization, which was the reason for the CO2 emission reduction. The negative priming effect of biochar was attributed to the physical protection of native SOC by promoting microaggregate formation and preferentially using soluble organic carbon in biochar. The N2O emission decrease was rooted in the reduction of nitrification and denitrification substrates by promoting the microbial assimilation of inorganic nitrogen. The inconsistency of CH4 emissions was attributed to the different relative contributions of CH4 production and oxidation under different biochar addition ratios. Our study suggests that 1% should be a more reasonable biochar addition ratio for mitigating greenhouse gas emissions in sandy loam, and emphasizes that it is necessary to furtherly investigate nitrogen primary transformation rates and the relative contributions of CH4 production and oxidation by the 15N and 13C technique, which is helpful for comprehensively understanding the effect mechanisms of biochar addition on greenhouse gas emissions.

Characteristics of amino acid metabolism in preterm infants in Guangxi, China. / å¹¿è¥¿åœ°åŒºæ—©äº§å„¿æ°¨åŸºé ¸ä»£è°¢ç‰¹ç‚¹ç ”ç©¶.

OBJECTIVES: To study the characteristics of amino acid metabolism in preterm infants in Guangxi, China. METHODS: A retrospective analysis was performed on the medical data of 30 757 neonates who underwent the screening for inherited metabolic diseases and had negative results in Guangxi Neonatal Disease Screening Center from 2018 to 2020. Among these neonates, there were 28 611 normal full-term infants (control group) and 2 146 preterm infants (preterm birth group). According to gestational age, the preterm infants were further divided into four groups: very preterm (n=209), moderately preterm (n=307), and late preterm group (n=1 630). According to birth weight, they were divided into three groups: very low birth weight group (n=161), low birth weight group (n=1 085), and normal birth weight group (n=900). According to blood collection time, they were divided into three groups: 3-7 days group (n=1 664), 8-14 days group (n=314) and 15-28 days group (n=168). Tandem mass spectrometry was performed to measure the levels of 11 amino acids in dried blood spots, which were then compared between groups. RESULTS: After adjustment for confounding factors, there were significant differences in the levels of 11 amino acids among different gestational age groups (P<0.05), and significant differences were observed in the levels of the 11 amino acids between the control group and the various preterm groups (except for citrulline and methionine in the late preterm group). There were significant differences in the levels of 11 amino acids among different birth weight groups (P<0.05). Except for ornithine, there were significant differences in the levels of other amino acids among the different blood collection time groups (P<0.05). CONCLUSIONS: Gestational age, birth weight and blood collection time all affect amino acid metabolism in preterm infants in Guangxi, China. This provides a basis for the laboratory to establish the reference standard and clinical interpretation of blood amino acid levels in preterm infants, and to improve the nutritional metabolism of preterm infants.

[Analysis of metabolic profile and genetic variants for newborns with primary carnitine deficiency from Guangxi].

OBJECTIVE: To analyze the metabolic profile and genetic variants for newborns with primary carnitine deficiency (PCD) from Guangxi, China. METHODS: From January 2014 to December 2019, 400 575 newborns from the jurisdiction of Guangxi Zhuang Autonomous Region Newborn Screening Center were subjected to tandem mass spectrometry (MS/MS) analysis. Newborns with positive results for PCD and their mothers were recalled for retesting. Those who were still positive were subjected to sequencing of the SLC22A5 gene. RESULTS: Twenty-two newborns and 9 mothers were diagnosed with PCD, which gave a prevalence rate of 1/18 208. Sequencing of 18 newborns and 4 mothers have identified 14 types of SLC22A5 gene variants, with the common ones including c.51C>G (10/44, 22.7%), c.1195C>T (9/44, 20.5%) and c.1400C>G (7/44, 15.9%), The c.517delC(p.L173Cfs*3) and c.1031C>T(p.T344I) were unreported previously and predicted to be pathogenic (PVS1+PM2_supporting+PM3+PP4) and likely pathogenic (PM1+PM2_supporting+PM3+PP3+PP4) based on the American College of Medical Genetics and Genomics standards and guidelines. CONCLUSION: c.51C>G, c.1195C>T and c.1400C>G are the most common variants underlying PCD in Guangxi.