Plasmopara viticola effector PvCRN11 induces disease resistance to downy mildew in grapevine.

The downy mildew of grapevine (Vitis vinifera L.) is caused by Plasmopara viticola and is a major production problem in most grape-growing regions. The vast majority of effectors act as virulence factors and sabotage plant immunity. Here, we describe in detail one of the putative P. viticola Crinkler (CRN) effector genes, PvCRN11, which is highly transcribed during the infection stages in the downy mildew-susceptible grapevine V. vinifera cv. 'Pinot Noir' and V. vinifera cv. 'Thompson Seedless'. Cell death-inducing activity analyses reveal that PvCRN11 was able to induce spot cell death in the leaves of Nicotiana benthamiana but did not induce cell death in the leaves of the downy mildew-resistant V. riparia accession 'Beaumont' or of the downy mildew-susceptible 'Thompson Seedless'. Unexpectedly, stable expression of PvCRN11 inhibited the colonization of P. viticola in grapevine and Phytophthora capsici in Arabidopsis. Both transgenic grapevine and Arabidopsis constitutively expressing PvCRN11 promoted plant immunity. PvCRN11 is localized in the nucleus and cytoplasm, whereas PvCRN11-induced plant immunity is nucleus-independent. The purified protein PvCRN11Opt initiated significant plant immunity extracellularly, leading to enhanced accumulations of reactive oxygen species, activation of MAPK and up-regulation of the defense-related genes PR1 and PR2. Furthermore, PvCRN11Opt induces BAK1-dependent immunity in the apoplast, whereas PvCRN11 overexpression in intracellular induces BAK1-independent immunity. In conclusion, the PvCRN11 protein triggers resistance against P. viticola in grapevine, suggesting a potential for the use of PvCRN11 in grape production as a protectant against downy mildew.

PABPN1 aggregation is driven by Ala expansion and poly(A)-RNA binding, leading to CFIm25 sequestration that impairs alternative polyadenylation.

Poly(A)-binding protein nuclear 1 (PABPN1) is an RNA-binding protein localized in nuclear speckles, while its alanine (Ala)-expanded variants accumulate as intranuclear aggregates in oculopharyngeal muscular dystrophy. The factors that drive PABPN1 aggregation and its cellular consequences remain largely unknown. Here, we investigated the roles of Ala stretch and poly(A) RNA in the phase transition of PABPN1 using biochemical and molecular cell biology methods. We have revealed that the Ala stretch controls its mobility in nuclear speckles, and Ala expansion leads to aggregation from the dynamic speckles. Poly(A) nucleotide is essential to the early-stage condensation that thereby facilitates speckle formation and transition to solid-like aggregates. Moreover, the PABPN1 aggregates can sequester CFIm25, a component of the pre-mRNA 3'-UTR processing complex, in an mRNA-dependent manner and consequently impair the function of CFIm25 in alternative polyadenylation. In conclusion, our study elucidates a molecular mechanism underlying PABPN1 aggregation and sequestration, which will be beneficial for understanding PABPN1 proteinopathy.

Interaction of age and CYP2C19 genotypes on voriconazole steady-state trough concentration in Chinese patients.

OBJECTIVES: Both age and CYP2C19 genotypes affect voriconazole plasma concentration; the interaction of age and CYP2C19 genotypes on voriconazole plasma concentration remains unknown. This study aims to investigate the combined effects of age and CYP2C19 genotypes on voriconazole plasma concentration in Chinese patients. METHODS: A total of 480 patients who received voriconazole treatment were recruited. CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893) polymorphisms were genotyped. Patients were divided into the young and the elderly groups by age of 60 years old. Influence of CYP2C19 genotype on steady-state trough concentration (C ss-min ) in overall patients and in age subgroups was analyzed. RESULTS: Voriconazole C ss-min correlated positively with age, and mean voriconazole C ss-min was significantly higher in the elderly group ( P  < 0.001). CYP2C19 poor metabolizers showed significantly increased mean voriconazole C ss-min in the young but not the elderly group. The percentage of patients with subtherapeutic voriconazole C ss-min (<1.0 mg/l) was higher in the young group and that of supratherapeutic voriconazole C ss-min (>5.5 mg/l) was higher in the elderly patients. When the average C ss-min in the CYP2C19 normal metabolizer genotype was regarded as a reference, CYP2C19 genotypes showed greater impact on voriconazole C ss-min in the young group, while the influence of age on voriconazole C ss-min exceeded CYP2C19 genotypes in the elderly. CONCLUSION: CYP2C19 genotypes affects voriconazole exposure is age dependent. Influence of CYP2C19 poor metabolizer genotype on increased voriconazoleexposure is prominent in the young, while age is a more important determinant factor for increased voriconazole exposure in the elderly patients.

Gentulizumab, a novel anti-CD47 antibody with potent antitumor activity and demonstrates a favorable safety profile.

BACKGROUND: Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells. METHODS: In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059. RESULTS: GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile. CONCLUSION: GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer.

Plasmopara viticola effector PvCRN20 represses the import of VvDEG5 into chloroplasts to suppress immunity in grapevine.

Chloroplasts play a crucial role in plant defense against pathogens, making them primary targets for pathogen effectors that suppress host immunity. This study characterizes the Plasmopara viticola CRN-like effector, PvCRN20, which interacts with DEG5 in the cytoplasm but not with its interacting protein, DEG8, which is located in the chloroplast. By transiently overexpressing in tobacco leaves, we show that PvCRN20 could inhibit INF1- and Bax-triggered cell death. Constitutive expression of PvCRN20 suppresses the accumulation of reactive oxygen species (ROS) and promotes pathogen colonization. PvCRN20 reduces DEG5 entry into chloroplasts, thereby disrupting DEG5 and DEG8 interactions in chloroplasts. Overexpression of VvDEG5 and VvDEG8 induces ROS accumulation and enhances grapevine resistance to P. viticola, whereas knockout of VvDEG8 represses ROS production and promotes P. viticola colonization. Consistently, ectopic expression of VvDEG5 and VvDEG8 in tobacco promotes chloroplast-derived ROS accumulation, whereas co-expression of PvCRN20 counteracted this promotion by VvDEG5. Therefore, DEG5 is essential for the virulence function of PvCRN20. Although PvCRN20 is located in both the nucleus and cytoplasm, only cytoplasmic PvCRN20 suppresses plant immunity and promotes pathogen infection. Our results reveal that PvCRN20 dampens plant defenses by repressing the chloroplast import of DEG5, thus reducing host ROS accumulation and facilitating pathogen colonization.

GAS5 promotes cytarabine induced myelosuppression via inhibition of hematopoietic stem cell differentiation.

Cytarabine (Ara-C) is widely used in the induction chemotherapy for acute myeloid leukemia (AML). Association between LncRNA GAS5 genetic polymorphism and the recovery of hematopoietic function after Ara-C-based chemotherapy is observed. This study aimed to identify whether intervention of GAS5 expression and GAS5 genotype affect Ara-C-induced inhibition of hematopoietic stem cells (HSCs) differentiation. In this study, cord blood-derived CD34+ cells were cultured in vitro, and a cell model of myelosuppression was established by treatment of CD34+ cells with Ara-C. The effect of GAS5 overexpression, Ara-C treatment, and GAS5 rs55829688 genotype on the hematopoietic colony-forming ability of CD34+ cells was assessed using methylcellulose-based colony forming unit assay. GAS5 overexpression slowed down the proliferation of cord blood-derived CD34+ cells significantly (p < 0.05) and decreased their ability to form hematopoietic colonies in vitro. Ara-C significantly reduced the hematopoietic colony-forming ability of CD34+ cells in vitro (p < 0.0001), and overexpressing GAS5 further decreased the number of hematopoietic colonies. GAS5 expression was higher in CD34+ cells than in CD34- cells, and positively correlated with GATA1 mRNA expression in CD34+ cells in vitro culture. However, GAS5 genotype had no effect on the total number of hematopoietic colonies formed from cord blood-derived CD34+ cells. In conclusion, our study highlights that GAS5 inhibited the in vitro proliferation and reduced the hematopoietic colony-forming ability of cord blood-derived CD34+ cells, with the most pronounced effect observed on CFU-GEMM formation. GAS5 also enhanced the inhibitory effect of Ara-C on the in vitro hematopoietic ability of CD34+ HSCs.

Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage.

Endoplasmic reticulum (ER) stress is observed in many human diseases, often associated with inflammation. ER stress can trigger inflammation through nucleotide-binding domain and leucine-rich repeat containing (NLRP3) inflammasome, which might stimulate inflammasome formation by association with damaged mitochondria. How ER stress triggers mitochondrial dysfunction and inflammasome activation is ill defined. Here we have used an infection model to show that the IRE1α ER stress sensor regulates regulated mitochondrial dysfunction through an NLRP3-mediated feed-forward loop, independently of ASC. IRE1α activation increased mitochondrial reactive oxygen species, promoting NLRP3 association with mitochondria. NLRP3 was required for ER stress-induced cleavage of caspase-2 and the pro-apoptotic factor, Bid, leading to subsequent release of mitochondrial contents. Caspase-2 and Bid were necessary for activation of the canonical inflammasome by infection-associated or general ER stress. These data identify an NLRP3-caspase-2-dependent mechanism that relays ER stress to the mitochondria to promote inflammation, integrating cellular stress and innate immunity.

GluR2 can Drive Neuroinflammation and Cognitive Impairments Following Peripherally Repeated Lipopolysaccharide Exposures.

Neuroinflammation is being increasingly recognized as a vital factor in the development of various neurological and neuropsychiatric diseases. Lipopolysaccharides (LPS), an outer membrane component of gram-negative bacteria, can trigger innate immune responses, resulting in neuroinflammation and subsequent cognitive deficits. The expression of glutamate receptors (GluRs) on glial cells can induce glial activation. Therefore, we hypothesized that repeated LPS exposure can increase GluR levels, promoting microglial activation and ultimately affecting synaptic plasticity and cognitive function. In this study, C57/BL6 mice were repeatedly exposed to LPS to construct a neuroinflammation animal model. The levels of GluRs, inflammatory cytokines, ionized calcium-binding adaptor molecule 1, postsynaptic density protein 95, synaptophysin 38, NMDA receptor 2 A, and NMDA receptor 2B (GluN2B) were measured in the hippocampi. Furthermore, dendritic spine density in the CA1 hippocampal region was determined. Repeated LPS exposure induced cognitive impairments and microglial activation and increased GluR1 and GluR2 levels. This was accompanied by a significant decrease in GluN2B expression and dendritic spine density in the hippocampi. However, CFM-2, an α-amino-3- hydroxy-5-methyl-4-isoxazolepropionate receptor antagonist, reversed these anomalies. Furthermore, minocycline, a microglial inhibitor, reversed these anomalies and downregulated GluR2 but not GluR1 expression. In summary, we demonstrated that GluR2 plays an essential role in microglia-induced neuroinflammation, resulting in synaptic plasticity and cognitive impairment induced by repeated exposure to LPS.

A radiomics-based interpretable model to predict the pathological grade of pancreatic neuroendocrine tumors.

OBJECTIVES: To develop a computed tomography (CT) radiomics-based interpretable machine learning (ML) model to predict the pathological grade of pancreatic neuroendocrine tumors (pNETs) in a non-invasive manner. METHODS: Patients with pNETs who underwent contrast-enhanced abdominal CT between 2010 and 2022 were included in this retrospective study. Radiomics features were extracted, and five radiomics-based ML models, namely logistic regression (LR), random forest (RF), support vector machine (SVM), XGBoost, and GaussianNB, were developed. The performance of these models was evaluated using a time-independent testing set, and metrics such as sensitivity, specificity, accuracy, and the area under the receiver operating characteristic curve (AUC) were calculated. The accuracy of the radiomics model was compared to that of needle biopsy. The Shapley Additive Explanation (SHAP) tool and the correlation between radiomics and biological features were employed to explore the interpretability of the model. RESULTS: A total of 122 patients (mean age: 50 ± 14 years; 53 male) were included in the training set, whereas 100 patients (mean age: 48 ± 13 years; 50 male) were included in the testing set. The AUCs for LR, SVM, RF, XGBoost, and GaussianNB were 0.758, 0.742, 0.779, 0.744, and 0.745, respectively, with corresponding accuracies of 73.0%, 70.0%, 77.0%, 71.9%, and 72.9%. The SHAP tool identified two features of the venous phase as the most significant, which showed significant differences among the Ki-67 index or mitotic count subgroups (p < 0.001). CONCLUSIONS: An interpretable radiomics-based RF model can effectively differentiate between G1 and G2/3 of pNETs, demonstrating favorable interpretability. CLINICAL RELEVANCE STATEMENT: The radiomics-based interpretable model developed in this study has significant clinical relevance as it offers a non-invasive method for assessing the pathological grade of pancreatic neuroendocrine tumors and holds promise as an important complementary tool to traditional tissue biopsy. KEY POINTS: • A radiomics-based interpretable model was developed to predict the pathological grade of pNETs and compared with preoperative needle biopsy in terms of accuracy. • The model, based on CT radiomics, demonstrated favorable interpretability. • The radiomics model holds potential as a valuable complementary technique to preoperative needle biopsy; however, it should not be considered a replacement for biopsy.

Imatinib facilitates gemcitabine sensitivity by targeting epigenetically activated PDGFC signaling in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.

Klebsiella pneumoniae increases invasion in intestinal epithelial cells by disrupting the cytoskeleton.

Klebsiella pneumoniae is an opportunistic pathogen and it can cause human mucosal lesions through the intestine, leading to bacteremia and abscess formation in liver and spleen. Previous studies have shown that K. pneumoniae can enter or cross cells through the intestinal epithelium, but the mechanism is unknown. In this study, we treated the intestinal epithelial cell line Caco-2 with KP1195, a clinically isolated strain with high adhesion and invasion of intestinal epithelial cells. The results showed that the treatment of K. pneumoniae could increase the expression of integrin gene and further disrupt the changes of cytoskeleton. Treating Caco-2 with cytoskeletal inhibitor cytorelaxin D can significantly increase the efficiency of K. pneumoniae invading Caco-2 cells. These data suggest that disruption of the cytoskeleton through integrins may be one of the mechanisms by which K. pneumoniae increases intracellular invasion. This study provides a theoretical basis for further understanding of the mechanism of K. pneumoniae entering intestinal epithelial cells.

Vitamin D nutritional status in early pregnancy and its relationship with periconceptional multiple micronutrients supplementation.

BACKGROUND AND OBJECTIVES: To assess the vitamin D nutritional status (VDN) of pregnant women in early pregnancy and investigate the effects of periconceptional supplementation with multiple micronutrients (MMs) on this status. METHODS AND STUDY DESIGN: Data were taken from the Pregnancy Health Care System and Hospital Information System in 2018 in Beijing. Vitamin D nutritional status in early pregnancy was evaluated among 4,978 pregnant women, and 4,540 women who took folic acid only (FA) or multiple mi-cronutrients supplements (MM) during the periconceptional period, were include to estimate the associations between periconceptional supplementation with MM and prevalence of vitamin D deficiency or insufficiency with logistic regression model. RESULTS: The mean early-pregnancy vitamin D concentration was 18.6 (±7.5) ng/mL, and the rates of deficiency and insufficiency were 31.6% and 60.5%, respectively. Compared to the FA group, the adjusted odds ratio (aOR, 95%confidence interval, CI) for insufficiency or deficiency of the MM group were 0.25(0.18-0.34), and the aOR (95%CI) for deficiency of the MM group were 0.17 (0.12-0.23). Women who took MMs for a longer period of time, at higher frequencies, and with higher compliance scores had lower rates of deficiency and insufficiency. In winter, spring, and autumn, taking MMs could reduce deficiency by about 70%; in summer, there was little effect. CONCLUSIONS: Among women in Beijing, serum concentrations of vitamin D in early pregnancy are relatively low, and the rates of deficiency and insufficiency are high. Taking MMs during the periconceptional period could improve this situation.

New cembranoid with potent anti-inflammatory effect isolated from Boswellia sacra by inactivating the NF-κB signaling pathway.

Boswellia sacra has the properties of activating blood circulation, fixing pain, subduing swelling and promoting muscle growth. However, the anti-inflammatory active ingredients and molecular mechanisms of Boswellia sacra are still not clearly explored. Boswellia sacra was grounded and extracted using 95% ethanol, the extracts were separated by column chromatography preparation to give compounds. Spectral analysis and quantum calculations confirmed the structures of compounds and identified compound 1 as a new compound. Compounds 1-3 showed potent inhibitory activities and their effects on inflammatory mediator NO and inflammatory cytokines were examined by ELISA assay. Furthermore, their modulatory mechanism on inflammatory signal pathways was explored.

An RxLR effector from Plasmopara viticola suppresses plant immunity in grapevine by targeting and stabilizing VpBPA1.

Grapevine downy mildew, caused by Plasmopara viticola, is one of the most devastating diseases in viticulture. Plasmopara viticola secretes RxLR effectors to modulate immune responses in grapevine. Here, we report an RxLR effector RxLR50253 from P. viticola that can interfere with plant immune response and thus promote pathogen colonization. RxLR50253 was induced at an early stage of P. viticola infection and could suppress elicitor (INF1 and Bax)-triggered cell death. RxLR50253 promote pathogen colonization in both tobacco and grapevine leaves. VpBPA1 was found to be the host target of RxLR50253 by yeast two-hybrid screening, and interaction between RxLR50253 and VpBPA1 was confirmed by multiple in vivo and in vitro assays. Further analysis revealed that VpBPA1 promoted pathogen colonization and decreased H2 O2 accumulation in transgenic tobacco and grapevine, while there was enhanced resistance and H2 O2 accumulation in NbBPA1-silenced Nicotiana benthamiana leaves. Moreover, transient expression of VpBPA1 in NbBPA1-silenced N. benthamiana leaves could reduce the accumulation of H2 O2 . Experiments in vivo demonstrated that RxLR50253 inhibits degradation of VpBPA1. Taken together, our findings showed that RxLR50253 targets and stabilizes VpBPA1 to attenuate plant immunity through decreasing H2 O2 accumulation during pathogen infection.

The mechanistic basis of sodium exclusion in Puccinellia tenuiflora under conditions of salinity and potassium deprivation.

Soil salinity is a significant threat to global agriculture. Understanding salt exclusion mechanisms in halophyte species may be instrumental in improving salt tolerance in crops. Puccinellia tenuiflora is a typical salt-excluding halophytic grass often found in potassium-deprived saline soils. Our previous work showed that P. tenuiflora possesses stronger selectivity for K+ than for Na+ ; however, the mechanistic basis of this phenomenon remained elusive. Here, P. tenuiflora PutHKT1;5 was cloned and the functions of PutHKT1;5 and PutSOS1 were characterized using heterologous expression systems. Yeast assays showed that PutHKT1;5 possessed Na+ transporting capacity and was highly selective for Na+ over K+ . PutSOS1 was located at the plasma membrane and operated as a Na+ /K+ exchanger, with much stronger Na+ extrusion capacity than its homolog from Arabidopsis. PutHKT2;1 mediated high-affinity K+ and Na+ uptake and its expression levels were upregulated by mild salinity and K+ deprivation. Salinity-induced changes of root PutHKT1;5 and PutHKT1;4 transcript levels matched the expression pattern of root PutSOS1, which was consistent with root Na+ efflux. The transcript levels of root PutHKT2;1 and PutAKT1 were downregulated by salinity. Taken together, these findings demonstrate that the functional activity of PutHKT1;5 and PutSOS1 in P. tenuiflora roots is fine-tuned under saline conditions as well as by operation of other ion transporters/channel (PutHKT1;4, PutHKT2;1, and PutAKT1). This leads to the coordination of radial Na+ and K+ transport processes, their loading to the xylem, or Na+ retrieval and extrusion under conditions of mild salinity and/or K+ deprivation.

Astrocytic connexin 43 deletion ameliorates SNI-induced neuropathic pain by reducing microglia activation.

Neuropathic pain (NP) is a chronic disease caused by damage to the peripheral or central nervous system. Connexin 43 (Cx43), the primary connexin expressed by astrocytes, has been reported to be significantly increased in NP. However, the roles and mechanisms of Cx43 in the development and maintenance of NP remain largely unknown, while microglia activation has been commonly regarded as a key factor of NP. In the present study, we found that Cx43 deletion significantly ameliorated spared nerve injury (SNI)-induced NP and suppressed SNI induced c-Fos expression in the spinal cord. Notably, Cx43 deletion led to much less SNI-induced microglia activation in the spinal cord. These results suggest that astrocyte Cx43 may play a significant role in regulating microglial activation and NP.

HMGB1 mediates synaptic loss and cognitive impairment in an animal model of sepsis-associated encephalopathy.

BACKGROUND: Microglial activation-mediated neuroinflammation is one of the essential pathogenic mechanisms of sepsis-associated encephalopathy (SAE). Mounting evidence suggests that high mobility group box-1 protein (HMGB1) plays a pivotal role in neuroinflammation and SAE, yet the mechanism by which HMGB1 induces cognitive impairment in SAE remains unclear. Therefore, this study aimed to investigate the mechanism of HMGB1 underlying cognitive impairment in SAE. METHODS: An SAE model was established by cecal ligation and puncture (CLP); animals in the sham group underwent cecum exposure alone without ligation and perforation. Mice in the inflachromene (ICM) group were continuously injected with ICM intraperitoneally at a daily dose of 10 mg/kg for 9 days starting 1 h before the CLP operation. The open field, novel object recognition, and Y maze tests were performed on days 14-18 after surgery to assess locomotor activity and cognitive function. HMGB1 secretion, the state of microglia, and neuronal activity were measured by immunofluorescence. Golgi staining was performed to detect changes in neuronal morphology and dendritic spine density. In vitro electrophysiology was performed to detect changes in long-term potentiation (LTP) in the CA1 of the hippocampus. In vivo electrophysiology was performed to detect the changes in neural oscillation of the hippocampus. RESULTS: CLP-induced cognitive impairment was accompanied by increased HMGB1 secretion and microglial activation. The phagocytic capacity of microglia was enhanced, resulting in aberrant pruning of excitatory synapses in the hippocampus. The loss of excitatory synapses reduced neuronal activity, impaired LTP, and decreased theta oscillation in the hippocampus. Inhibiting HMGB1 secretion by ICM treatment reversed these changes. CONCLUSIONS: HMGB1 induces microglial activation, aberrant synaptic pruning, and neuron dysfunction in an animal model of SAE, leading to cognitive impairment. These results suggest that HMGB1 might be a target for SAE treatment.

The Role of Extracellular Vesicles in Liver Pathogenesis.

Extracellular vesicles (EVs) are generated by cells in the form of exosomes, microvesicles, and apoptotic bodies. They can be taken up by neighboring cells, and their contents can have functional impact on the cells that engulf them. As the mediators of intercellular communication, EVs can play important roles in both physiological and pathologic contexts. In addition, early detection of EVs in different body fluids may offer a sensitive diagnostic tool for certain diseases, such as cancer. Furthermore, targeting specific EVs may also become a promising therapeutic approach. This review summarizes the latest findings of EVs in the field of liver research, with a focus on the different contents of the EVs and their impact on liver function and on the development of inflammation, fibrosis, and tumor in the liver. The goal of this review is to provide a succinct account of the various molecules that can mediate the function of EVs so the readers may apply this knowledge to their own research.

A novel proxy to examine interspecific phosphorus facilitation between plant species.

Resource complementarity can contribute to enhanced ecosystem functioning in diverse plant communities, but the role of facilitation in the enhanced complementarity is poorly understood. Here, we use leaf manganese concentration ([Mn]) as a proxy for rhizosheath carboxylate concentration to explore novel mechanisms of complementarity mediated by phosphorus (P) facilitation. In pot experiments, we showed that mixtures involving Carex korshinskyi, an efficient P-mobilizing species, exhibited greater biomass and relative complementarity effect than combinations without C. korshinskyi on P-deficient soils. Compared with monocultures, leaf [Mn] and [P] of species that are inefficient at P mobilization increased by 27% and 21% when grown with C. korshinskyi (i.e. interspecific P facilitation via carboxylates) rather than next to another inefficient P-mobilizing species. This experimental result was supported by a meta-analysis including a range of efficient P-mobilizing species. Phosphorus facilitation enhanced the relative complementarity effect in low-P environments, related to a greater change in several facilitated species of their root morphological traits relative to those in monoculture. Using leaf [Mn] as a proxy, we highlight a vital mechanism of interspecific P facilitation via belowground processes and provide evidence for the pivotal role of P facilitation mediated by the plasticity of root traits in biodiversity research.

Hydraulic vulnerability segmentation in compound-leaved trees: Evidence from an embolism visualization technique.

The hydraulic vulnerability segmentation (HVS) hypothesis implies the existence of differences in embolism resistance between plant organs along the xylem pathway and has been suggested as an adaptation allowing the differential preservation of more resource-rich tissues during drought stress. Compound leaves in trees are considered a low-cost means of increasing leaf area and may thus be expected to show evidence of strong HVS, given the tendency of compound-leaved tree species to shed their leaf units during drought. However, the existence and role of HVS in compound-leaved tree species during drought remain uncertain. We used an optical visualization technique to estimate embolism occurrence in stems, petioles, and leaflets of shoots in two compound-leaved tree species, Manchurian ash (Fraxinus mandshurica) and Manchurian walnut (Juglans mandshurica). We found higher (less negative) water potentials corresponding to 50% loss of conductivity (P50) in leaflets and petioles than in stems in both species. Overall, we observed a consistent pattern of stem > petiole > leaflet in terms of xylem resistance to embolism and hydraulic safety margins (i.e. the difference between mid-day water potential and P50). The coordinated variation in embolism vulnerability between organs suggests that during drought conditions, trees benefit from early embolism and subsequent shedding of more expendable organs such as leaflets and petioles, as this provides a degree of protection to the integrity of the hydraulic system of the more carbon costly stems. Our results highlight the importance of HVS as an adaptive mechanism of compound-leaved trees to withstand drought stress.