The Formation Mechanism of Carbonized Polymer Dots: Crosslinking-Induced Nucleation and Carbonization.

Carbon dots (CDs), as a kind of zero-dimensional nanomaterials, have been widely synthesized by bottom-up methods from various precursors. However, the formation mechanism is still unclear and controversial, which also brings difficulty to the regulation of structures and properties. Only some tentative formation processes were postulated by analyzing the products obtained at different reaction times and temperatures. Here, the effect of crosslinking on the formation of carbonized polymer dots (CPDs) is explored. Crosslinking-induced nucleation and carbonization (CINC) is proposed as the driving force for the formation of CPDs. Under hydrothermal synthesis, the precursors are initiated to polymerize and crosslink. The crosslinking brings higher hydrophobicity to generate the hydrophilic/hydrophobic microphase separation, which promotes dehydration and carbonization resulting in the formation of CPDs. Based on the principle of CINC, the influence factors of size are also revealed. Moreover, the dissipative particle dynamics (DPD) simulation is employed to support this formation mechanism. This concept of CINC will bring light to the formation process of CPDs, as well as facilitate the regulation of CPDs' size and photoluminescence.

A ribonuclease T2 protein FocRnt2 contributes to the virulence of Fusarium oxysporum f. sp. cubense tropical race 4.

Banana Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4), is a major disease of banana plants worldwide. Effector proteins play critical roles in banana-Foc TR4 interaction. Our previous studies highlighted a ribonuclease protein belonging to the T2 family (named as FocRnt2) in the Foc TR4 secretome, which was predicted to be an effector. However, its biological function in Foc TR4 infection is still unclear. Herein, we observed significant expression of FocRnt2 during the early stage of fungal infection in planta. A yeast signal sequence trap assay showed that FocRnt2 contained a functional signal peptide for secretion. FocRnt2 possessed ribonuclease activity that could degrade the banana total RNA in vitro. Subcellular localization showed that FocRnt2 was localized in the nucleus and cytoplasm of Nicotiana benthamiana leaves. Transient expression of FocRnt2 suppressed the expression of salicylic acid- and jasmonic acid-signalling marker genes, reactive oxygen species accumulation, and BAX-mediated cell death in N. benthamiana. FocRnt2 deletion limited fungal penetration, reduced fusaric acid biosynthesis in Foc TR4, and attenuated fungal virulence against banana plants, but had little effect on Foc TR4 growth and sensitivity to various stresses. Furthermore, FocRnt2 deletion mutants induced higher expression of the defence-related genes in banana plants. These results suggest that FocRnt2 plays an important role in full virulence of Foc TR4, further improving our understanding of effector-mediated Foc TR4 pathogenesis.

Identification of lncRNA-mRNA network linking ferroptosis and immune infiltration to colon adenocarcinoma suppression.

Background: Colon adenocarcinoma (COAD) is one of the most common malignant tumors. The interplay involving ferroptosis between tumor and immune cells plays a crucial in cancer progression. However, the biological basis of this interplay in COAD development remains elusive. Methods: Transcriptome data of COAD samples were obtained from The Cancer Genome Atlas and National Center for Biotechnology Information databases. Using single-sample gene set enrichment analysis, we calculated the ferroptosis score (FS) and immune cell infiltration levels for each sample, leveraging the expression levels of genes related to ferroptosis and various immune cell types. Samples with FSs greater than the 75th percentile were classified into the high-FS subgroup, while those below the 25th percentile were categorized as the low-FS subgroup. Moreover, tumor tissue samples and adjacent normal tissue samples were collected from twenty colon patients. Using real-time quantitative polymerase chain reaction, we validated the expression of certain genes in these samples. Results: The COAD samples with high FSs experienced favorable survival probability and heightened sensitivity to anticancer drugs, with FSs negatively associated with the pathological stages. Moreover, the up-regulated genes in high-FS subgroup exhibited enrichment in immune-related pathways, suggesting a correlation between immunity and ferroptosis. Importantly, we discovered a key lncRNA-mRNA co-expression network linking tumor cell ferroptosis and immune infiltration (e.g., neutrophil) in the progression and classification of COAD. Further analysis identified several ferroptosis-related lncRNAs (e.g., RP11-399O19.9) within this network, indicating their potential roles in COAD progression and deserving in-depth study. Conclusions: Our findings provide novel insights into the underlying biological basis, particularly involving lncRNAs, at gene expression level associated with ferroptosis in COAD and cancer therapy. Nevertheless, further analysis and validation are required to expand the findings.

The Chinese version of rating scale of pain expression during childbirth (ESVADOPA): reliability and validity assessment.

BACKGROUND: Childbirth pain is a physiological phenomenon during the delivery process, the intense pain of childbirth could bring harmful effects to pregnant women and their babies. Assessment of childbirth pain is the first step in childbirth pain intervention. Some pain assessment scales have shortcomings such as interfering in the birthing process and affecting pain perception during delivery, while the Rating Scale of Pain Expression during Childbirth (ESVADOPA) could be used as an auxiliary scale to compensate for these shortcomings. The purpose of this study was to introduce the ESVADOPA and adapt it among Chinese pregnant women to check on the psychometric properties of the translated version of ESVADOPA. METHODS: A new translation model based on Brislin's classical back translation model was used to translate and cross-cultural adapt the ESVADOPA. During June 2021 and June 2022, pregnant women at Shandong Provincial Hospital Affiliated to Shandong First Medical University were invited. In the stage of translation and cross-culturally adaptation, 18 midwives and 30 pregnant women were invited to participate in the first round of pre-experiment. And in the second round of pre-experiment, 15 midwives and 20 pregnant women were invited to participate. The Chinese version of ESVADOPA was tested on a group of pregnant women (N = 487). Construct validity was evaluated by exploratory factor analysis, confirmatory factor analysis and criterion-related validity. Reliability was assessed by Cronbach's α coefficient, McDonald Omega, Spearman-Brown split-half reliability and Guttman split-half reliability. RESULTS: The item statistical analysis and construct validity resulted in six items and one factor that explained 61.064% of the total variance. Confirmatory factor analysis showed that the data fit the one-factor structure. Criterion-related validity indicated that the scale is significantly and positively correlated with the Numeric Rating Scale (NRS). Cronbach's α coefficient, McDonald Omega, Spearman-Brown split-half reliability, and Guttman split-half reliability of the Chinese version of ESVADOPA were 0.868, 0.896, 0.845, 0.842, respectively. CONCLUSION: The Chinese version of the ESVADOPA with good reliability and validity data could be used to assess the pain rating of pregnant women during childbirth without interfering in the birthing process.

Nanocomposite Hydrogel Bioinks for 3D Bioprinting of Tumor Models.

In vitro tumor models were successfully constructed by 3D bioprinting; however, bioinks with proper viscosity, good biocompatibility, and tunable biophysical and biochemical properties are highly desirable for tumor models that closely recapitulated the main features of native tumors. Here, we developed a nanocomposite hydrogel bioink that was used to construct ovarian and colon cancer models by 3D bioprinting. The nanocomposite bioink was composed of aldehyde-modified cellulose nanocrystals (aCNCs), aldehyde-modified hyaluronic acid (aHA), and gelatin. The hydrogels possessed tunable gelation time, mechanical properties, and printability by controlling the ratio between aCNCs and gelatin. In addition, ovarian and colorectal cancer cells embedded in hydrogels showed high survival rates and rapid growth. By the combination of 3D bioprinting, ovarian and colorectal tumor models were constructed in vitro and used for drug screening. The results showed that gemcitabine had therapeutic effects on ovarian tumor cells. However, the ovarian tumor model showed drug resistance for oxaliplatin treatment.

Model experimental study on the mechanism of collapse induced by leakage of underground pipeline.

The evolution and mechanism of ground collapse caused by underground water pipeline leakage have become increasingly significant as more urban areas experience collapses. Based on the principle of similarity, and considering the engineering context of road collapses in Anqing City, Anhui Province, this study designed a 3 m × 2 m × 2 m rupture-collapse model test device. Digital Image Correlation (DIC) technology was employed to investigate the erosion process and collapse mechanisms caused by underground pipeline leakage. The results indicate that groundwater seepage provides the driving force for collapses, combined with the migration space provided by defects, collectively triggering the collapses. When groundwater seepage is minimal, the cohesive forces between soil particles maintain soil stability. As groundwater seepage increases, the soil particle framework is eroded, leading to soil structure destabilization and collapse initiation. The depth of collapse significantly influences stress evolution: stress evolution intensity beneath and above the collapse pit is positively correlated with the distance from the collapse pit bottom, but negatively correlated with the distance from the defect. The research provides insights for the early warning and management of ground collapse.

Improving Quantitative Analysis with Cross Instrument-Sparse Bayesian Learning (CI-SBL) Raman Spectroscopy Analysis Algorithm.

Qualitative and quantitative analysis of Raman spectroscopy is a widely used nondestructive analytical technique in many fields. It utilizes the Raman scattering effect of lasers to obtain molecular vibration information on samples. By comparison with the Raman spectra of standard substances, qualitative and quantitative analyses can be achieved on unknown samples. However, current Raman spectroscopy analysis algorithms still have many drawbacks. They struggled to handle quantitative analysis between different instruments. Their prediction accuracy for concentration is generally low, with poor robustness. Therefore, this study addresses these deficiencies by designing the cross instrument-sparse Bayesian learning (CI-SBL) Raman spectroscopy analysis algorithm. CI-SBL can facilitate spectroscopic analysis between different instruments through the cross instrument module. CI-SBL converts data from portable instruments into data from scientific instruments, with high similarity between the converted spectrum and the spectrum from the scientific instruments reaching 98.6%. The similarity between the raw portable instrument spectrum and the scientific instrument spectrum is often lower than 90%. The cross instrument effect of the CI-SBL is remarkable. Moreover, CI-SBL employs sparse Bayesian learning (SBL) as the core module for analysis. Through multiple iterations, the SBL algorithm effectively identified various components within mixtures. In experiments, CI-SBL can achieve a qualitative accuracy of 100% for the majority of binary and multicomponent mixtures. On the other hand, the previous Raman spectroscopy analysis algorithms predominantly yield a qualitative accuracy below 80% for the same data. Additionally, CI-SBL incorporates a quantitative module to calculate the concentration of each component within the mixed samples. In the experiment, the quantification error for all substances was below 3%, with the majority of the substances exhibiting an error of approximately 1%. These experimental results illustrate that CI-SBL significantly enhances the accuracy of qualitative judgment of mixture spectra and the prediction of mixture concentrations compared with previous Raman spectroscopy analysis algorithms. Furthermore, the cross instrument module of CI-SBL allows for a flexible handling of data acquired from different instruments.

Astrocyte-specific activation of sigma-1 receptors in mPFC mediates the faster onset antidepressant effect by inhibiting NF-κB-induced neuroinflammation.

Major depressive disorder (MDD) is a global health burden characterized by persistent low mood, deprivation of pleasure, recurrent thoughts of death, and physical and cognitive deficits. The current understanding of the pathophysiology of MDD is lacking, resulting in few rapid and effective antidepressant therapies. Recent studies have pointed to the sigma-1 (σ-1) receptor as a potential rapid antidepressant target; σ-1 agonists have shown promise in a variety of preclinical depression models. Hypidone hydrochloride (YL-0919), an independently developed antidepressant by our institute with faster onset of action and low rate of side effects, has recently emerged as a highly selective σ-1 receptor agonist; however, its underlying astrocyte-specific mechanism is unknown. In this study, we investigated the effect of YL-0919 treatment on gene expression in the prefrontal cortex of depressive-like mice by single-cell RNA sequencing. Furthermore, we knocked down σ-1 receptors on astrocytes in the medial prefrontal cortex of mice to explore the effects of YL-0919 on depressive-like behavior and neuroinflammation in mice. Our results demonstrated that astrocyte-specific knockdown of σ-1 receptor resulted in depressive-like behavior in mice, which was reversed by YL-0919 administration. In addition, astrocytic σ-1 receptor deficiency led to activation of the NF-κB inflammatory pathway, and crosstalk between reactive astrocytes and activated microglia amplified neuroinflammation, exacerbating stress-induced neuronal apoptosis. Furthermore, the depressive-like behavior induced by astrocyte-specific knockdown of the σ-1 receptor was improved by a selective NF-κB inhibitor, JSH-23, in mice. Our study not only reaffirms the σ-1 receptor as a key target of the faster antidepressant effect of YL-0919, but also contributes to the development of astrocytic σ-1 receptor-based novel drugs.

Dihydroartemisinin breaks the immunosuppressive tumor niche during cisplatin treatment in Hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma, characterized by high mortality rates, often exhibits limited responsiveness to conventional treatments such as surgery, radiotherapy, and chemotherapy. Therefore, identifying a sensitizer for cisplatin has become crucial. Dihydroartemisinin, known for its potent role of tumor treatment, arises as a prospective candidate for cisplatin sensitization in clinical settings. METHODS: A mouse model of liver tumor was established through chemical induction of DEN/TCPOBOP. Upon successful model establishment, ultrasound was employed to detect tumors, Hematoxylin and eosin staining was conducted for observation of liver tissue pathology, and ELISA was utilized to assess cytokine changes (IFN-γ, IL-2, IL-4, IL-10, TGF-ß, IL-1ß, CCL2, and CCL21) in peripheral blood, para-tumor tissues, and tumor tissues. The infiltration of CD8+T cells and macrophages in tumor tissue sections was detected by immunofluorescence. RESULTS: Dihydroartemisinin combined with cisplatin obviously restrained the growth of liver tumors in mice and improved the weight and spleen loss caused by cisplatin. Cisplatin treatment of liver tumor mice increased the content of CCL2 and the number of macrophages in tumor tissues and promoted the formation of an immunosuppressive microenvironment. The combination therapy decreased the content of TGF-ß in tumor tissues while increasing CCL2 levels in para-tumor tissues. Both combination therapy and cisplatin alone increased the number of CD8+T cells in tumor tissue, but there was no difference between them. CONCLUSION: Dihydroartemisinin combined with cisplatin obviously prevented the deterioration of liver tumor in hepatocellular carcinoma mice and improve the therapeutic effect of cisplatin by improving the immunosuppressive microenvironment induced by cisplatin. Our findings provide a theoretical basis for considering dihydroartemisinin as an adjuvant drug for cisplatin in the treatment of hepatocellular carcinoma in the future.

[Single mini-incision combined with honeycomb titanium plate in treatment of acute acromioclavicular joint dislocation].

OBJECTIVE: To explore clinical effect of single small incision with honeycomb titanium plate in treating acute acromioclavicular dislocation. METHODS: The clinical data of 40 patients with acute acromioclavicular dislocation admitted from December 2019 to December 2021 were retrospectively analyzed and divided into two groups according to different surgical methods. Among them, 20 patients were fixed with single small incision with honeycomb titanium plate (titanium plate group), including 11 males and 9 females, aged from 23 to 65 years old with an average of (47.40±12.58) years old;12 patients on the left side, 8 patients on the right side;11 patients with type Ⅲ, 3 patients with type Ⅳ, and 6 patients with type Ⅴ according to Rockwood classification. Twenty patients were fixed with clavicular hook plate (clavicular hook group), including 8 males and 12 females, aged from 24 to 65 years old with an average of (48.40±12.08) years old;12 patients on the left side, 8 patients on the right side;10 patients with type Ⅲ, 2 patients with type Ⅳ, and 8 patients with type Ⅴ according to Rockwood classification. Operative time, incision length, intraoperative blood loss, hospital stay, visual analogue scale (VAS) and Constant-Murley score of shoulder joint function were compared between two groups. Anteroposterior radiographs of the affected shoulder joint were recorded before, immediately and 6 months after surgery, and the coracoclavicular distance was measured and compared. RESULTS: Both groups of patients were successfully completed operation without serious complications. All patients were followed up for 6 to 15 months with an average of (11.9±4.8) months. There were no incisional infection, internal plant fracture or failure, bone tunnel fracture and other complications occurred. The incision length of titanium plate group (35.90±3.14) mm was significantly shorter than that of clavicular hook group (49.30±3.79) mm (P<0.05). There were no significant difference in operative time, intraoperative blood loss and hospital stay between two groups (P>0.05). At 1 and 3 months after operation, VAS of titanium plate group was lower than that of clavicular hook group (P<0.05). Connstant-Murley scores in titanium plate group at 1, 3 and 6 months after operation were (86.80±1.36), (91.60±2.32) and (94.90±2.22), respectively;and in clavicular hook group were (78.45±5.47), (85.55±2.01) and (90.25±1.92), which were higher than that of clavicular hook group (P<0.05). There was no significant difference in coracoclavicular distance between two groups immediately and 6 months after operation(P>0.05). CONCLUSION: For the treatment of acute acromioclavicular joint dislocation, single small incision combined with honeycomb titanium plate have advantages of shorter incision, fast recovery of shoulder joint function without the second operation, and has good satisfaction of patient.

A Selective FGFR1/2 PROTAC Degrader with Antitumor Activity.

The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.

Optimal design and analysis of a space lightweight mirror with a directionally oriented 2.5D-CVT structure.

Reflective mirrors are the key imaging components of space-borne telescopes, which require a high lightweight ratio integrated with excellent optical properties. In this context, a novel, to our knowledge, 2.5D centroidal Voronoi tessellation (CVT) generation methodology is proposed for designing and optimizing a lightweight mirror structure. Firstly, the initial designs are obtained combining global sensitivity factor mapping and local distribution optimization. Then, the optimal model is selected through multi-objective optimization and decision making. Subsequently, the FEA (finite element analysis) results indicate that, under the same mass, the proposed design exhibits better optomechanical performance. Finally, in practical applications, the approach presented in this paper outperforms the traditional design for each technological requirement, including a 62% reduction in RMS and a higher lightweight ratio. This method offers a kind of novel design and optimization process for space-based optomechanical lightweight structures.

Chronic Neuropathic Pain and Comorbid Depression Syndrome: From Neural Circuit Mechanisms to Treatment.

Chronic neuropathic pain and comorbid depression syndrome (CDS) is a major worldwide health problem that affects the quality of life of patients and imposes a tremendous socioeconomic burden. More than half of patients with chronic neuropathic pain also suffer from moderate or severe depression. Due to the complex pathogenesis of CDS, there are no effective therapeutic drugs available. The lack of research on the neural circuit mechanisms of CDS limits the development of treatments. The purpose of this article is to provide an overview of the various circuits involved in CDS. Notably, activating some neural circuits can alleviate pain and/or depression, while activating other circuits can exacerbate these conditions. Moreover, we discuss current and emerging pharmacotherapies for CDS, such as ketamine. Understanding the circuit mechanisms of CDS may provide clues for the development of novel drug treatments for improved CDS management.

Ergothioneine Protects Against UV-Induced Oxidative Stress Through the PI3K/AKT/Nrf2 Signaling Pathway.

Background: Ergothioneine (EGT) is an antioxidant, which could be detected in human tissues, and human skin cells could utilize EGT and play an anti-oxidative role in keratinocytes. And in this study we are going to elucidate whether EGT could protect the skin from photoaging by Ultraviolet (UV) exposure in mice and its molecule pathway. Methods: Histological analysis was performed for evaluating the skin structure change. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured with biological assay for evaluating oxidative and antioxidative ability of skin exposed to UV light. And the level of marker molecules in mouse skin were detected by hydroxyproline (Hyp) assay, immunohistochemical analysis, Western blot, and quantitative real-time PCR (qRT-PCR). The markers of skin aging and cell death were tested by cell culture and treatment, Western blot and qRT-PCR. Results: EGT decreased the levels of inflammatory factors induced by UV exposure in mouse skin. MDA and SOD activity detection showed that EGT decreased MDA levels, increased SOD activity, and upregulated PI3K/Akt/Nrf2 signals in mouse skin exposed to UV, which further activated Nrf2 in the nucleus and enhanced the expression of Nrf2 target genes. In the cell model, we revealed that EGT could inhibit the increase in senescence-associated ß-galactosidase-positive cells and p16 and γ-H2A.X positive cells induced by etoposide and activate PI3K/Akt/Nrf2 signaling. Moreover, a PI3K inhibitor blocked EGT protection against etoposide-induced cell death. Conclusion: The study showed EGT may play an important protective role against cell damage or death through the PI3K/Akt/Nrf2 signaling pathway in skin.

Efficacy and Safety of Neoadjuvant Subcutaneous Envafolimab in dMMR/MSI-H Locally Advanced Colon Cancer.

BACKGROUND: Neoadjuvant immunotherapy with programmed death-ligand 1 blockade for colon cancer, especially for mismatch repair-deficient (dMMR)/high microsatellite instability (MSI-H) colon cancer, has gained considerable attention recently. OBJECTIVE: This study aimed to assess the safety and efficacy of neoadjuvant subcutaneous envafolimab in patients with dMMR/MSI-H locally advanced colon cancer. METHODS: Patients with dMMR/MSI-H locally advanced colon cancer treated with envafolimab at Sun Yat-sen University Cancer Center and Yunnan Cancer Hospital from October 2021 to July 2023 were retrospectively reviewed and analyzed. The primary endpoint was the pathological complete response (CR) rate, and secondary endpoints were treatment-related adverse events and complete clinical response rate. RESULTS: Overall, 15 patients were analyzed. After neoadjuvant immunotherapy with envafolimab, six patients achieved a CR, with five partial responses, and four stable disease. Three patients achieving a complete clinical response chose to accept a "watch and wait" strategy, and surgery was performed in 12 patients. Postoperative pathology results revealed seven patients achieved pathological CRs, and five patients achieved tumor regression grade 2, with 66.7% of the total CR rate. The most common treatment-related adverse events were pruritus and rash (40%), with no severe cases. No recurrences occurred over a 7.9-month follow-up. CONCLUSIONS: Envafolimab yielded promising surgical outcomes and safety in dMMR/MSI-H locally advanced colon cancer, representing a promising treatment modality for this population.

Morphological variation in Schizothorax oconnori, Schizothorax waltoni (Teleostei: Cyprinidae: Schizothoracinae), and their natural hybrids from the middle Yarlung Zangbo River, Tibet.

The morphological variation in Schizothorax oconnori, Schizothorax waltoni, and their natural hybrids was examined using conventional and image-based analysis approaches. In total, 38 specimens of S. oconnori, 35 of S. waltoni, and 37 natural hybrids were collected from the Shigatse to the Lhasa section of the Yarlung Zangbo River during June and July 2021. A total of 21 morphometric, 4 meristic, and 27 truss variables were employed for the classification of S. oconnori, S. waltoni, and natural hybrids. Principal component analysis (PCA) and factor analysis (FA), as well as discriminant function analysis (DFA) and cluster analysis (CA), were conducted to identify differences based on traditional and truss measurements. Four principal components explained 75.92% of the variation among the morphometric characters, while five principal components accounted for 79.69% of the variation among the truss distances. FA results showed that factor 1 was associated with head shape, and factor 2 was associated with fins based on morphometric characters. Among the truss characters, factor 1 was related to head shape, and factor 2 was related to chest shape. In DFA, morphometric measurements achieved higher accuracy (100%) compared to truss distances (94.55%). The head morphology of hybrids exhibited intermediate traits between S. oconnori and S. waltoni. Both morphometry-based and truss-based clustering indicated that the morphology of natural hybrids leaned toward S. oconnori. In conclusion, the combination of morphometric and truss analysis is beneficial for classifying S. oconnori, S. waltoni, and their natural hybrids. The presence of natural hybrids could be considered an evolutionary response to the differentiation of nutritional and spatial niches in the middle Yarlung Zangbo River.

A study on expression of GRP78 and CHOP in neutrophil endoplasmic reticulum and their relationship with neutrophil apoptosis in the development of sepsis.

We investigated the relationship between neutrophil apoptosis and endoplasmic reticulum stress (ERS) in sepsis and its mechanism. A prospective cohort study was conducted by recruiting a total of 58 patients with sepsis. Peripheral blood samples were collected on 1, 3, 5 and 7 days after admission to the ICU. The expressions of endoplasmic reticulum specific glucose regulatory protein 78 (GRP78), C/EBP homologous protein (CHOP), apoptosis signal-regulating kinase 1 (ASK1), Bcl-2-like 11 (BIM), death receptor 5 (DR5), c-Jun N-terminal kinases (JNK) and p38 were detected by Western blot and PCR. The subcellular location of CHOP and GRP78 was observed by immunofluorescence analysis. Spearman correlation was used to analyze the correlation between the expression of chop protein and the apoptosis rate of peripheral blood neutrophils. Healthy volunteers in the same period were selected as the healthy control group. The expression of GRP78 protein was significantly elevated on the first day of ICU admission and showed a decreasing trend on the third, fifth and seventh day, but was significantly higher than the corresponding healthy control group. The expression of CHOP protein reached the highest level on the third day. The expression of chop protein in each group was significantly higher than that in the corresponding healthy control group. Immunofluorescence staining clearly showed that the CHOP protein accumulated in the nucleus, with an elevation in the intensity of GRP78. The neutrophil apoptosis rate of sepsis patients on the 1st, 3rd, 5th and 7th day of ICU stay was significantly higher than that of the healthy control group, with the highest apoptosis rate on the 3rd day, and then decreased gradually. CHOP protein expression level was significantly positively correlated with neutrophil apoptosis rate in sepsis patients. Endoplasmic reticulum stress occurs in neutrophils during the development of sepsis. GRP78 protein and CHOP protein may be involved in the pathological process of neutrophil apoptosis in sepsis.

Psilocybin promotes neuroplasticity and induces rapid and sustained antidepressant-like effects in mice.

BACKGROUND: Psilocybin offers new hope for treating mood disorders due to its rapid and sustained antidepressant effects, as standard medications require weeks or months to exert their effects. However, the mechanisms underlying this action of psilocybin have not been identified. AIMS: To investigate whether psilocybin has rapid and sustained antidepressant-like effects in mice and investigate whether its potential mechanisms of action are related to promoted neuroplasticity. METHODS: We first examined the antidepressant-like effects of psilocybin in normal mice by the forced swimming test and in chronic corticosterone (CORT)-exposed mice by the sucrose preference test and novelty-suppressed feeding test. Furthermore, to explore the role of neuroplasticity in mediating the antidepressant-like effects of psilocybin, we measured structural neuroplasticity and neuroplasticity-associated protein levels in the prefrontal cortex (PFC) and hippocampus. RESULTS: We observed that a single dose of psilocybin had rapid and sustained antidepressant-like effects in both healthy mice and chronic CORT-exposed mice. Moreover, psilocybin ameliorated chronic CORT exposure-induced inhibition of neuroplasticity in the PFC and hippocampus, including by increasing neuroplasticity (total number of dendritic branches and dendritic spine density), synaptic protein (p-GluA1, PSD95 and synapsin-1) levels, BDNF-mTOR signalling pathway activation (BDNF, TrkB and mTOR levels), and promoting neurogenesis (number of DCX-positive cells). CONCLUSIONS: Our results demonstrate that psilocybin elicits robust, rapid and sustained antidepressant-like effects which is accompanied by the promotion of neuroplasticity in the PFC and hippocampus.