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Key Points The essential amino acid tryptophan is degraded to several neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. These metabolites, collectively termed 'kynurenines', directly target important neurotransmitter receptors and affect redox processes, and thus influence brain physiology. In the mammalian brain, the catabolic cascade responsible for the neosynthesis of kynurenines — the kynurenine pathway — is physically segregated into two branches. One, leading to the neuroprotective agent kynurenic acid, is contained in astrocytes, whereas the other, leading to the neurotoxins 3-hydroxykynurenine and quinolinic acid, is present in microglial cells. Brain kynurenines are not autonomous but are linked to, and affected by, the peripheral kynurenine pathway. As the pathway is stimulated by a host of cytokines and other intercellular signalling molecules, both peripheral and central functions of kynurenines are influenced by infections and other inflammatory conditions. Dysregulations of the pathway, causing hyper- or hypofunction of active metabolites, are associated with neurodegenerative and other neurological disorders, as well as psychiatric diseases such as depression and schizophrenia. Recently developed pharmacological agents make it increasingly possible to selectively influence the kynurenine pathway in the periphery and in the brain. Targeted interventions with such specific 'kynurenergic' drugs can now be used to influence brain physiology. This approach is also envisaged to normalize pathophysiologically relevant imbalances in cerebral kynurenines and thus provide novel treatments for a host of brain diseases. Tryptophan metabolism along the kynurenine pathway generates several neuroactive metabolites. Schwarcz and colleagues discuss the regulation of this pathway in the normal brain and in neurological and psychiatric disorders, and consider the potential therapeutic opportunities of targeting this pathway. The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper- or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.

China has more patients with traumatic brain injury (TBI) than most other countries in the world, making this condition a major public health concern. Population-based mortality of TBI in China is estimated to be approximately 13 cases per 100 000 people, which is similar to the rates reported in other countries. The implementation of various measures, such as safety legislation for road traffic, establishment of specialised neurosurgical intensive care units, and the development of evidence-based guidelines, have contributed to advancing prevention and care of patients with TBI in China. However, many challenges remain, which are augmented further by regional differences in TBI care. High-level care, such as intracranial pressure monitoring, is not universally available yet. In the past 30 years, the quality of TBI research in China has substantially improved, as evidenced by an increasing number of clinical trials done. The large number of patients with TBI and specialised trauma centres offer unique opportunities for TBI research in China. Furthermore, the formation and development of research collaborations between China and international groups are considered essential to advancing the quality of TBI care and research in China, and to improve quality of life in patients with this condition.

Accumulating evidence indicates that mitochondrial dysfunction and oxidative stress play a pivotal role in the initiation and progression of nonalcoholic fatty liver disease (NAFLD). In this study, we found that blueberry-derived exosomes-like nanoparticles (BELNs) could ameliorate oxidative stress in rotenone-induced HepG2 cells and high-fat diet (HFD)-fed C57BL/6 mice. Preincubation with BELNs decreased the level of reactive oxygen species (ROS), increased the mitochondrial membrane potential, and prevented cell apoptosis by inducing the expression of Bcl-2 and heme oxygenase-1 (HO-1) and decreasing the content of Bax in rotenone-treated HepG2 cells. We also found that preincubation with BELNs accelerated the translocation of Nrf2, an important transcription factor of antioxidative proteins, from the cytoplasm to the nucleus in rotenone-treated HepG2 cells. Moreover, administration of BELNs improved insulin resistance, ameliorated the dysfunction of hepatocytes, and regulated the expression of detoxifying/antioxidant genes by affecting the distribution of Nrf2 in the cytoplasm and nucleus of hepatocytes of HFD-fed mice. Furthermore, BELNs supplementation prevented the formation of vacuoles and attenuated the accumulation of lipid droplets by inhibiting the expression of fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1), the two key transcription factors for de novo lipogenesis in the liver of HFD-fed mice. These findings suggested that BELNs can be used for the treatment of NAFLD because of their antioxidative activity.

Background Iron (Fe) deficiency is a common problem in citrus production. As the second largest superfamily of transcription factors (TFs), the basic/helix-loop-helix (bHLH) proteins have been shown to participate in the regulation of Fe homeostasis and a series of other biological and developmental processes in plants. However, this family of members in citrus and their functions in citrus Fe deficiency are still largely unknown. Results In this study, we identified a total of 128 CgbHLHs from pummelo ( Citrus grandis ) genome that were classified into 18 subfamilies by phylogenetic comparison with Arabidopsis thaliana bHLH proteins. All of these CgbHLHs were randomly distributed on nine known (125 genes) and one unknown (3 genes) chromosomes, and 12 and 47 of them were identified to be tandem and segmental duplicated genes, respectively. Sequence analysis showed detailed characteristics of their intron-exon structures, bHLH domain and conserved motifs. Gene ontology (GO) analysis suggested that most of CgbHLHs were annotated to the nucleus, DNA-binding transcription factor activity, response to abiotic stimulus, reproduction, post-embryonic development, flower development and photosynthesis. In addition, 27 CgbHLH proteins were predicted to have direct or indirect protein-protein interactions. Based on GO annotation, RNA sequencing data in public database and qRT-PCR results, several of CgbHLHs were identified as the key candidates that respond to iron deficiency. Conclusions In total, 128 CgbHLH proteins were identified from pummelo, and their detailed sequence and structure characteristics and putative functions were analyzed. This study provides comprehensive information for further functional elucidation of CgbHLH genes in citrus.

Immunotherapy of malignant tumor is a verified and crucial anti-tumor strategy to help patients with cancer for prolonging prognostic survival. It is a novel anticancer tactics that activates the immune system to discern and damage cancer cells, thereby prevent them from proliferating. However, immunotherapy still faces many challenges in view of clinical efficacy and safety issues. Various nanomaterials, especially gold nanoparticles (AuNPs), have been developed not only for anticancer treatment but also for delivering antitumor drugs or combining other treatment strategies. Recently, some studies have focused on AuNPs for enhancing cancer immunotherapy. In this review, we summarized how AuNPs applicated as immune agents, drug carriers or combinations with other immunotherapies for anticancer treatment. AuNPs can not only act as immune regulators but also deliver immune drugs for cancer. Therefore, AuNPs are candidates for enhancing the efficiency and safety of cancer immunotherapy.

A reliable projection of precipitation over the Tibetan Plateau (TP) is crucial for climate adaptation activities in this climate‐sensitive region, but existing studies show a large spread in magnitude. Based on Coupled Model Intercomparison Project Phase 6 models, we investigate the TP summer precipitation projection and understand the sources of uncertainty. The results show that the TP exhibits a profound wetting trend throughout the 21st century, with precipitation increasing by 0.64 ± 0.06 mm day−1 during 2050–2099 under the SSP5–8.5 scenario. The moisture budget analysis indicates that the thermodynamical response to global warming determines the precipitation increase. However, both the thermodynamical and dynamical components contribute to the uncertainty of precipitation projection. The inter‐model spread of the thermodynamic term arises from divergent global mean warming, which is closely related to model climate sensitivity. The uncertainty of the dynamic component is driven by model‐dependent circulation changes induced by different equatorial Pacific warming rates. Plain Language Summary The precipitation over the Tibetan Plateau (TP) is crucial for local and downstream ecosystems, influencing millions of people. An accurate projection of future precipitation change is a prerequisite for climate change adaptation activities. Current existing studies show a large spread in the future changes of precipitation over the TP, but the reasons remain inconclusive. Here, we unravel the diversity of climate models in the precipitation projection over the TP by quantifying the contributions of the thermodynamical process related to global warming and the dynamical process related to atmospheric circulation change. While the enhancement of precipitation in the multi‐model ensemble mean is dominated by the thermodynamical response, both the thermodynamical and dynamical components are found to be responsible for the uncertainty of precipitation projection. The thermodynamical uncertainty is due to divergent global mean warming, which is closely associated with climate sensitivity, implying that models projecting a warmer climate also tend to project a stronger thermodynamical change. The uncertainty of the dynamic component is driven by air circulation changes induced by the equatorial Pacific warming pattern, which further affects the water vapor transport to the TP. Key Points Future projection of the Tibetan Plateau (TP) summer precipitation exhibits a large inter‐model spread in the magnitude of moistening trend The uncertainty of precipitation projection arises from both the thermodynamical and dynamical process The thermodynamical uncertainty is related to climate sensitivity, while the dynamical spread is driven by the equatorial Pacific warming

Patients with Philadelphia chromosome‐like acute lymphoblastic leukaemia (Ph‐like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL‐3‐independent cell proliferation through activation of the p‐PDGFRB and p‐STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell‐derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs).

Background Recent studies have shown that near-infrared (NIR) fluorescence imaging using Indocyanine green (ICG) may improve the efficiency of sentinel lymph node biopsy (SLNB). This study aimed to assess the effectiveness of the combination of ICG and methylene blue (MB) in breast cancer patients undergoing SLNB. Patients and method We evaluated ICG plus MB (ICG + MB) identification effectiveness with MB alone using retrospective analysis. From 2016 to 2020, we collected data on 300 eligible breast cancer patients who got SLNB treatment in our institution by ICG + MB or MB alone. By comparing the distribution of clinicopathological characteristics, the detection rate of sentinel lymph nodes (SLNs) and metastatic SLNs, as well as the total number of SLNs in the two groups, we were able to assess the imaging efficiency. Results Fluorescence imaging allowed 131 out of 136 patients in the ICG + MB group to find SLNs. ICG + MB group and MB group had detection rates of 98.5% and 91.5% ( P  = 0.007, χ 2  = 7.352), respectively. Besides, the ICG + MB approach was able to produce improved recognition outcomes. What’s more, compared with the MB group, the ICG + MB group can identify more lymph nodes (LNs) (3.1 to 2.6, P  = 0.000, t = 4.447). Additionally, in the ICG + MB group, ICG could identify more LNs than MB (3.1 vs 2.6, P  = 0.004, t = 2.884). Conclusion ICG has high detection effectiveness for SLNs, and when paired with MB, the detection efficiency can be increased even further. Furthermore, the ICG + MB tracing mode does not involve radioisotopes, which has a lot of promise for clinical use and can take the place of conventional standard detection methods.

Background Prostate cancer threatens the health of men over sixty years old, and its incidence ranks first among all urinary tumors among men. Enzalutamide remains the first-line drug for castration-resistant prostate cancer, however, tumors inevitably become resistant to enzalutamide. Hence, it is of great importance to investigate the mechanisms that induce enzalutamide resistance in prostate cancer cells. Methods Bioinformatic analyzing approaches were used to identified the over-expressed genes in prostate cancer tumor tissues from three GEO datasets. qRT-PCR, western blotting and immunochemistry/In situ hybridization staining assays were performed to assess the expression of SNHG4, RRM2, TK1, AURKA, EZH2 and RREB1. Cell cycle was measured by flow cytometry. CCK-8, plate colony formation and EdU assays were performed to assess the cell proliferation. Senescence-associated β-Gal assay was used to detect the cell senescence level. γ-H2AX staining assay was performed to assess the DNA damages of PCa cells. Luciferase reporter assay and RNA immunoprecipitation assay were performed to verify the RNA-RNA interactions. Chromatin immunoprecipitation assay was performed to assess the bindings between protein and genomic DNA. Results We found that RRM2 and NUSAP1 are highly expressed in PCa tumors and significantly correlated with poor clinical outcomes in PCa patients. Bioinformatic analysis as well as experimental validation suggested that SNHG4 regulates RRM2 expression via a let-7 miRNA-mediated ceRNA network. In addition, SNHG4 or RRM2 knockdown significantly induced cell cycle arrest and cell senescence, and inhibited DNA damage repair and cell proliferation, and the effects can be partially reversed by let-7a knockdown or RRM2 reoverexpression. In vitro and in vivo experiments showed that SNHG4 overexpression markedly enhanced cell resistance to enzalutamide. RREB1 was demonstrated to transcriptionally regulate SNHG4, and RREB1 was also validated to be a target of let-7a and thereby regulated by the SNHG4/let-7a feedback loop. Conclusion Our study uncovered a novel molecular mechanism of lncRNA SNHG4 in driving prostate cancer progression and enzalutamide resistance, revealing the critical roles and therapeutic potential of RREB1, SNHG4, RRM2 and let-7 miRNAs in anticancer therapy.

Bacterial vaginosis (BV) is a prevalent cause of vaginal symptoms in women of reproductive age. With the widespread of heavy metal pollutants and their harmful function on women’s immune and hormonal systems, it is necessary to explore the association between heavy metal exposure and BV. This study investigates the potential relationship between serum heavy metals and bacterial vaginosis in a cohort of American women. The present study employed a cross-sectional analysis of 2,493 women participating in the 2001–2004 National Health and Nutrition Examination Survey (NHANES). Multivariable logistic regression models were utilized in the study to assess the correlation between these variables. A stratified analysis was performed to investigate the relationship among different population groups further, and smooth curve fittings were conducted to intuitively evaluate the correlation. According to the current cross-sectional study results, a significant correlation was identified between the high levels of lead and cadmium in the serum and the likelihood of developing bacterial vaginosis. We found that serum lead (OR = 1.35, 95% CI: 1.06–1.72, p = 0.016) and serum cadmium (OR = 1.41, 95% CI: 1.01–1.98, p = 0.047) increased the risk of bacterial vaginosis by 35% and 41%, respectively, in the highest level group in comparison to the lowest level group in the fully adjusted model. Furthermore, the research discovered no statistically significant association between the levels of total mercury in the serum and a heightened susceptibility to bacterial vaginosis (OR = 0.96, 95% CI: 0.75–1.23, p = 0.763). Results of our study indicated an inverse association between serum heavy metals and bacterial vaginosis risk, including lead and cadmium. Reducing exposure to heavy metals could be vital to preventing and managing bacterial vaginosis.