Molecular characterization, spatio-temporal expression patterns of crtc2 gene and its immune roles in yellow catfish (Pelteobagrus fulvidraco).

cAMP response element binding (CREB) protein 2 (CRTC2) is a transcriptional coactivator of CREB and plays an important role in the immune system. Thus far, the physiological roles of Crtc2 in teleost are still poorly understood. In this study, the crtc2 gene was identified and characterized from yellow catfish (Pelteobagrus fulvidraco; therefore, the gene is termed as pfcrtc2), and its evolutionary and molecular characteristics as well as potential immunity-related roles were investigated. Our results showed that the open reading frame of pfcrtc2 was 2346 bp in length, encoding a protein with 781 amino acids. Gene structure analysis revealed its existence of 14 exons and 13 introns. A phylogenetic analysis proved that the tree of crtc2 was clustered into five groups, exhibiting a similar evolutionary topology with species evolution. Multiple protein sequences alignment demonstrated high conservation of the crtc2 in various vertebrates with similar structure. Syntenic and gene structural comparisons further established that crtc2 was highly conserved, implying its similar roles in diverse vertebrates. Tissue distribution pattern detected by quantitative real-time PCR showed that the pfcrtc2 gene was almost expressed in all detected tissues except for eyes, with the highest expression levels in the gonad, indicating that Crtc2 may play important roles in various tissues. In addition, pfcrtc2 was transcribed at all developmental stages in yellow catfish, showing the highest expression levels at 12 h after fertilization. Finally, the transcriptional profiles of crtc2 were significantly increased in yellow catfishes injected with Aeromonas hydrophila or Poly I:C, which shared a consistent change pattern with four immune-related genes including IL-17A, IL-10, MAPKp38, and NF-κBp65, suggesting pfCrtc2 may play critical roles in preventing both exogenous bacteria and virus invasion. In summary, our findings lay a solid foundation for further studies on the functions of pfcrtc2, and provide novel genetic loci for developing new strategies to control disease outbreak in teleost.

PHD2 shRNA-Modified Bone Marrow Mesenchymal Stem Cells Facilitate Periodontal Bone Repair in Response to Inflammatory Condition.

OBJECTIVE: To investigate whether bone marrow mesenchymal stem cells (BMMSCs) modulate periodontal bone repair through the hydroxylase domain-containing protein 2 (PHD2)/hypoxia- inducible factor-1 (HIF-1) signalling pathway in response to inflammatory conditions. METHODS: Osteogenic differentiation of PHD2 shRNA-modified BMMSCs and the possible mechanism were explored in an inflammatory microenvironment stimulated by porphyromonas gingivalis lipopolysaccharide (Pg-LPS) in vitro. The effect of PHD2 gene-modified BMMSCs on periodontal bone loss was evaluated with experimental periodontitis. RESULTS: Pg-LPS stimulation greatly impaired the osteogenic differentiation of BMMSCs, whereas the silence of PHD2 significantly enhanced the osteogenesis of BMMSCs. More importantly, increased level of vascular endothelial growth factor (VEGF) was detected under Pg-LPS stimulation, which was verified to be associated with the augmented osteogenesis. In experimental periodontitis, PHD2-modified BMMSCs transplantation elevated osteogenic parameters and the expression of VEGF in periodontal tissue. CONCLUSION: This study highlighted that PHD2 gene silencing could be a feasible approach to combat inflammatory bone loss by rescuing the dysfunction of seed cells.

Exploring the synergy of logistics, finance, and technology on innovation.

As global environmental challenges intensify, manufacturing firms face increasing pressure to innovate sustainably. Green innovation, characterized by the development of environmentally friendly products, processes, and technologies, has become essential for firms striving to remain competitive. This study aims to investigate the influence of key factors-green logistics, green finance, and green technology-on green innovation within manufacturing firms, while exploring the mediating role of green technology in these relationships. A multi-method approach was employed, combining partial least squares structural equation modeling, fuzzy-set qualitative comparative analysis, and necessity condition analysis. 447 responses were collected from manufacturing companies in Dhaka city, Bangladesh, using structured questionnaires. The analysis revealed that green logistics and green finance have a significant positive impact on green innovation, while the influence of the green work environment was found to be positive but statistically insignificant. Additionally, green technology was identified as a significant mediator in the relationships between green finance, green logistics, and green innovation. This study offers a comprehensive green innovation model while green technology is a mediator. Furthermore, this study advances the resource-based view theory by integrating green technology as a pivotal resource that enhances a firm's competitive advantage in sustainable markets. By adopting a multi-method approach, this research provides a rigorous examination of the research questions, offering a comprehensive understanding of the dynamic interactions between green finance, green logistics, and green technology in driving innovation. Thus, this research has thought provoking implications to prioritize investments in green finance, logistics, and technology, manufacturing firms can enhance their competitiveness, improve operational efficiency, and meet evolving environmental regulations and consumer preferences.

Regulatory effect of rapamycin on recruitment and function of myeloid-derived suppressor cells in heart failure.

BACKGROUND: Immune response and inflammation play important roles in the physiological and pathophysiological processes of heart failure (HF). In our previous study, myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells with anti-inflammatory and immunosuppressive functions, were shown to exert cardioprotective effects in HF. The pharmacological targeting of MDSCs using rapamycin may emerge as a promising strategy for the prevention and treatment of HF. However, the specific mechanisms underlying rapamycin-induced MDSC accumulation remain unclear. Our study aimed to clarify the effects of rapamycin on the recruitment and function of MDSCs in HF, exploring new therapeutic options for the prevention and treatment of HF. METHODS: We used transverse aortic constriction surgery and isoproterenol injection to establish HF models. Flow cytometry, reverse transcription polymerase chain reaction, transcriptomics and western blot were used to explore the regulation of rapamycin on recruitment and function of MDSCs in HF. Furthermore, rapamycin and granulocyte-macrophage colony-stimulating factor (GM-CSF) were combined to induce exogenous MDSCs from bone marrow cells. RESULTS: Rapamycin promotes the recruitment of MDSCs by inhibiting their maturation and differentiation via suppression of the Wnt signaling in HF mice and enhanced the immunosuppressive function of MDSCs via the NF-κB signaling. Furthermore, exogenous MDSCs induced by rapamycin and GM-CSF can significantly alleviate transverse aortic constriction-induced cardiac dysfunction. CONCLUSIONS: The pharmacological targeting of MDSCs using rapamycin is a promising strategy for the prevention and treatment of HF.

Transcriptomic analyses reveals a diverse venom composition in Agelena limbata (Araneae: Agelenaidae).

Spider venom is a natural source of diverse biomolecules, but due to technical limitations, only a small fraction has been studied. With the advancement of omics technologies, research on spider venom has broadened, greatly promoting systematic studies of spider venom. Agelena limbata is a common spider found in vegetation, known for constructing funnel-shaped webs, and feeding on insects such as Diptera and Homoptera. However, due to its small size and the difficulty in obtaining venom, the composition of Agelena limbata venom has never been studied. In this study, a transcriptomics approach was used to analyze the toxin components in the venom of Agelena limbata, resulting in the identification of 28 novel toxin-like sequences and 24 peptidases. Based on sequence similarity and differences in cysteine motifs, the 28-novel toxin-like sequences were classified into 10 superfamilies. According to the results annotated in the database, the 24 peptidases were divided into six distinct families, with the serine protease family being the most common. A phylogenetic tree was constructed using the toxin-like sequences of Agelena limbata along with Psechrus triangulus and Hippasa lycosina. An analysis of the structural domains and motifs of Agelena limbata was also conducted. The results indicated that Agelena limbata is more distantly related to the other two species of funnel-web spiders, and that the toxin superfamily IX has a unique function compared to the other superfamilies. This study reveals the components of the Agelena limbata venom, deepening our understanding of it, and through bioinformatics analysis, has identified unique functions of the toxin superfamilies, providing a scientific basis for the development of bioactive drugs in the future.

A study of somatization symptoms and low-frequency amplitude fluctuations of emotional memory in adolescent depression.

Studies have revealed that somatization symptoms are associated with emotional memory in adolescents with depressive disorders. This study investigated somatization symptoms and emotional memory among adolescents with depressive disorders using low-frequency amplitude fluctuations (ALFF). Participants were categorized into the somatization symptoms (FSS) group, non-FSS group and healthy control group (HC). The correctness of negative picture re-recognition was higher in the FFS and HC group than in the non-FSS group. The right superior occipital gyrus and right inferior temporal gyrus were significantly larger in the FSS group than those in the non-FSS and HC groups. Additionally, the ALFF in the superior occipital and inferior temporal gyrus were positively correlated with CSI score. Furthermore, the ALFF values in the temporal region positively correlated with correct negative image re-recognition. The negative image re-recognition rate was positively correlated with the ALFF in the left and right middle occipital gyri. These findings indicated that somatization symptoms in adolescent depression are associated with the superior occipital gyrus and inferior temporal gyrus. Notably, somatization symptoms play a role in memory bias within depressive disorders, with middle occipital and inferior temporal gyri potentially serving as significant brain regions.

The difference of functional MR imaging in evaluating outcome of patients with diffuse and compact brain arteriovenous malformation.

Microsurgical resection is an effective method to treat brain arteriovenous malformations (BAVMs). Functional magnetic resonance imaging (fMRI) can evaluate the spatial relationship of nidus and eloquent. Diffuse BAVMs are related to poor outcomes postoperatively. The role of fMRI in evaluating outcomes in patients with different nidus types remains unclear. BAVM patients received microsurgical resection were included from a prospective, multicenter cohort study. All patients underwent fMRI evaluation preoperatively and were regularly followed up postoperatively. Diffuse BAVM is radiologically identified as nidus containing normal brain tissue interspersing between malformed vessels. Lesion-to-eloquent distance (LED) was calculated based on the relationship between nidus and eloquent. The primary outcome was 180-day unfavorable neurological status postoperatively. The risk of primary outcome was investigated within different BAVM nidus types. The LED's performance to predict poor outcome was evaluated using area under curve (AUC). 346 BAVM patients were included in this study. 93 (26.9%) patients were found to have a 180-day unfavorable outcome. Multivariate logistic analysis demonstrated LED (odd ratio [OR], 0.44; 0.34-0.57; P < 0.001) and mRS at admission (OR, 2.59; 1.90-3.54; P < 0.001) as factors of unfavorable outcome. Subgroup analysis showed LED and mRS at admission as factors of unfavorable outcome for patients with compact BAVMs (all P < 0.05), but not for patients with diffuse BAVMs. Subsequent analysis showed that LED performed poorly to predict the unfavorable outcome for patients with diffuse BAVMs, compared with patients with compact BAVMs (AUC as 0.69 vs. 0.86, P < 0.05). A larger cutoff value of LED to unfavorable outcome was found in patients with diffuse BAVMs (15 mm) compared with patients with compact BAVMs (4.7 mm). Usage of LED to evaluate postoperative outcome of patients with diffuse BAVMs differs from its use in patients with compact BAVMs. Specific assessment strategy considering BAVM nidus types could help improve patients' outcome. MITASREAVM cohort (unique identifier: NCT02868008, https://clinicaltrials.gov/study/NCT02868008?term=NCT02868008&rank=1 ).

Pollution of four heavy metal elements in dried chili peppers in Guizhou Province and its health risk assessment.

This study aimed to evaluate arsenic (As), cadmium (Cd), chromium (Cr), and lead (Pb) levels in dried chili peppers from nine districts in Guizhou Province. These heavy metals, widely dispersed and capable of transferring to crops, pose potential health risks to humans. The assessment included modeling daily intake (EDI), target hazard quotient (THQ), total target hazard index (TTHQ), and target carcinogenic risk (TCR) to assess health risks across different population groups. Results showed chromium (0.9540 ± 0.301 mg/kg) and lead (0.8949 ± 0.266 mg/kg) had the highest concentrations, followed by arsenic (0.3287 ± 0.093 mg/kg) and cadmium (0.0627 ± 0.017 mg/kg). Children exhibited higher EDI values than adults, indicating greater health risks from dried chili pepper consumption at equivalent levels. THQ and TTHQ values were below 1 across all regions, indicating no significant health risks associated with dried chili pepper consumption. Similarly, TCR values were below 10-4 for all nine regions, indicating an acceptable level of carcinogenic risk. Overall, consuming dried chili peppers in Guizhou Province poses an acceptable health risk, but caution is advised, especially for children, to limit heavy metal exposure.

In Situ Visualizing Carboxylesterase Activity in Type 2 Diabetes Mellitus Using an Activatable Endoplasmic Reticulum Targetable Proximity Labeling Far-Red Fluorescent Probe.

Carboxylesterase (CE), an enzyme widely present in organisms, is involved in various physiological and pathological processes. Changes in the levels of CEs in the liver may predict the presence of type 2 diabetes mellitus (T2DM). Here, a novel dicyanoisophorone (DCI)-based proximity-labeled far-red fluorescent probe DCI2F-Ac with endoplasmic reticulum targeting was proposed for real-time monitoring and imaging of the CEs activity. DCI2F-Ac featured very low cytotoxicity and biotoxicity and was highly selective and sensitive for CEs. Compared with traditional CEs probes, DCI2F-Ac was covalently anchored directly to CEs, thus effectively reducing the loss of in situ fluorescent signals due to diffusion. Through the "on-off" fluorescence signal readout, DCI2F-Ac was able to distinguish cell lines and screen for CEs inhibitors. In terms of endoplasmic reticulum (ER) stress, it was found that thapsigargin (Tg) induced upregulation of CEs levels but not tunicamycin (Tm), which was related to the calcium homeostasis of the ER. DCI2F-Ac could efficiently detect downregulated CEs in the livers of T2DM, and the therapeutic efficacy of metformin, acarbose, and a combination of these two drugs was assessed by tracking the fluctuation of CEs levels. The results showed that combining metformin and acarbose could restore CEs levels to near-normal levels with the best antidiabetic effect. Thus, the DCI2F-Ac probe provides a great opportunity to explore the untapped potential of CEs in liver metabolic disorders and drug efficacy assessment.

A Decision Tree Model to Help Treatment Decision-Making for Unruptured Intracranial Aneurysms: A Multi-center, Long-Term Follow-up Study in a Large Chinese Cohort.

Chinese population have a high prevalence of unruptured intracranial aneurysm (UIA). Clinical and imaging risk factors predicting UIA growth or rupture are poorly understood in the Chinese population due to the lack of large-scale longitudinal studies, and the treatment decision for UIA patients was challenging. Develop a decision tree (DT) model for UIA instability, and validate its performance in multi-center studies. Single-UIA patients from two prospective, longitudinal multicenter cohort studies were analyzed, and set as the development cohort and validation cohort. The primary endpoint was UIA instability (rupture, growth, or morphological change). A DT was established within the development cohort and validated within the validation cohort. The performance of clinicians in identifying unstable UIAs before and after the help of the DT was compared using the area under curve (AUC). The development cohort included 1270 patients with 1270 UIAs and a follow-up duration of 47.2 ± 15.5 months. Aneurysm instability occurred in 187 (14.7%) patients. Multivariate Cox analysis revealed hypertension (hazard ratio [HR], 1.54; 95%CI, 1.14-2.09), aspect ratio (HR, 1.22; 95%CI, 1.17-1.28), size ratio (HR, 1.31; 95%CI, 1.23-1.41), bifurcation configuration (HR, 2.05; 95%CI, 1.52-2.78) and irregular shape (HR, 4.30; 95%CI, 3.19-5.80) as factors of instability. In the validation cohort (n = 106, 12 was unstable), the DT model incorporating these factors was highly predictive of UIA instability (AUC, 0.88 [95%CI, 0.79-0.97]), and superior to existing UIA risk scales such as PHASES and ELAPSS (AUC, 0.77 [95%CI, 0.67-0.86] and 0.76 [95%CI, 0.66-0.86], P < 0.001). Within all 1376 single-UIA patients, the use of the DT significantly improved the accuracy of junior neurosurgical clinicians to identify unstable UIAs (AUC from 0.63 to 0.82, P < 0.001). The DT incorporating hypertension, aspect ratio, size ratio, bifurcation configuration and irregular shape was able to predict UIA instability better than existing clinical scales in Chinese cohorts. CLINICAL TRIAL REGISTRATION: IARP-CP cohort were included (unique identifier: ChiCTR1900024547. Published July 15, 2019. Completed December 30, 2020), with 100-Project phase-I cohort (unique identifier: NCT04872842, Published May 5, 2021. Completed November 8, 2022) as the development cohort. The 100-Project phase-II cohort (unique identifier: NCT05608122. Published November 8, 2022) as the validation cohort.

Saccharopolyspora mangrovi sp. nov., a novel mangrove soil actinobacterium with distinct metabolic potential revealed by comparative genomic analysis.

A novel mangrove soil-derived actinomycete, strain S2-29T, was found to be most closely related to Saccharopolyspora karakumensis 5K548T based on 16 S rRNA sequence (99.24% similarity) and genomic phylogenetic analyses. However, significant divergence in digital DNA-DNA hybridization, average nucleotide identity, and unique biosynthetic gene cluster possession distinguished S2-29T as a distinct Saccharopolyspora species. Pan genome evaluation revealed exceptional genomic flexibility in genus Saccharopolyspora, with > 95% accessory genome content. Strain S2-29T harbored 718 unique genes, largely implicated in energetic metabolisms, indicating different metabolic capacities from its close relatives. Several uncharacterized biosynthetic gene clusters in strain S2-29T highlighted the strain's untapped capacity to produce novel functional compounds with potential biotechnological applications. Designation as novel species Saccharopolyspora mangrovi sp. nov. (type strain S2-29T = JCM 34,548T = CGMCC 4.7716T) was warranted, expanding the known Saccharopolyspora diversity and ecology. The discovery of this mangrove-adapted strain advances understanding of the genus while highlighting an untapped source of chemical diversity.

LncRNA DCRT Protects Against Dilated Cardiomyopathy by Preventing NDUFS2 Alternative Splicing by Binding to PTBP1.

BACKGROUND: Dilated cardiomyopathy is characterized by left ventricular dilation and continuous systolic dysfunction. Mitochondrial impairment is critical in dilated cardiomyopathy; however, the underlying mechanisms remain unclear. Here, we explored the cardioprotective role of a heart-enriched long noncoding RNA, the dilated cardiomyopathy repressive transcript (DCRT), in maintaining mitochondrial function. METHODS: The DCRT knockout (DCRT-/-) mice and DCRT knockout cells were developed using CRISPR-Cas9 technology. Cardiac-specific DCRT transgenic mice were generated using α-myosin heavy chain promoter. Chromatin coimmunoprecipitation, RNA immunoprecipitation, Western blot, and isoform sequencing were performed to investigate the underlying mechanisms. RESULTS: We found that the long noncoding RNA DCRT was highly enriched in the normal heart tissues and that its expression was significantly downregulated in the myocardium of patients with dilated cardiomyopathy. DCRT-/- mice spontaneously developed cardiac dysfunction and enlargement with mitochondrial impairment. DCRT transgene or overexpression with the recombinant adeno-associated virus system in mice attenuated cardiac dysfunction induced by transverse aortic constriction treatment. Mechanistically, DCRT inhibited the third exon skipping of NDUFS2 (NADH dehydrogenase ubiquinone iron-sulfur protein 2) by directly binding to PTBP1 (polypyrimidine tract binding protein 1) in the nucleus of cardiomyocytes. Skipping of the third exon of NDUFS2 induced mitochondrial dysfunction by competitively inhibiting mitochondrial complex I activity and binding to PRDX5 (peroxiredoxin 5) and suppressing its antioxidant activity. Furthermore, coenzyme Q10 partially alleviated mitochondrial dysfunction in cardiomyocytes caused by DCRT reduction. CONCLUSIONS: Our study revealed that the loss of DCRT contributed to PTBP1-mediated exon skipping of NDUFS2, thereby inducing cardiac mitochondrial dysfunction during dilated cardiomyopathy development, which could be partially treated with coenzyme Q10 supplementation.

Mitochondrial GPX4 acetylation is involved in cadmium-induced renal cell ferroptosis.

Increasing evidences demonstrate that environmental stressors are important inducers of acute kidney injury (AKI). This study aimed to investigate the impact of exposure to Cd, an environmental stressor, on renal cell ferroptosis. Transcriptomics analyses showed that arachidonic acid (ARA) metabolic pathway was disrupted in Cd-exposed mouse kidneys. Targeted metabolomics showed that renal oxidized ARA metabolites were increased in Cd-exposed mice. Renal 4-HNE, MDA, and ACSL4, were upregulated in Cd-exposed mouse kidneys. Consistent with animal experiments, the in vitro experiments showed that mitochondrial oxidized lipids were elevated in Cd-exposed HK-2 cells. Ultrastructure showed mitochondrial membrane rupture in Cd-exposed mouse kidneys. Mitochondrial cristae were accordingly reduced in Cd-exposed mouse kidneys. Mitochondrial SIRT3, an NAD+-dependent deacetylase that regulates mitochondrial protein stability, was reduced in Cd-exposed mouse kidneys. Subsequently, mitochondrial GPX4 acetylation was elevated and mitochondrial GPX4 protein was reduced in Cd-exposed mouse kidneys. Interestingly, Cd-induced mitochondrial GPX4 acetylation and renal cell ferroptosis were exacerbated in Sirt3-/- mice. Conversely, Cd-induced mitochondrial oxidized lipids were attenuated in nicotinamide mononucleotide (NMN)-pretreated HK-2 cells. Moreover, Cd-evoked mitochondrial GPX4 acetylation and renal cell ferroptosis were alleviated in NMN-pretreated mouse kidneys. These results suggest that mitochondrial GPX4 acetylation, probably caused by SIRT3 downregulation, is involved in Cd-evoked renal cell ferroptosis.

CircNSD1 promotes cardiac fibrosis through targeting the miR-429-3p/SULF1/Wnt/ß-catenin signaling pathway.

Cardiac fibrosis is a detrimental pathological process, which constitutes the key factor for adverse cardiac structural remodeling leading to heart failure and other critical conditions. Circular RNAs (circRNAs) have emerged as important regulators of various cardiovascular diseases. It is known that several circRNAs regulate gene expression and pathological processes by binding miRNAs. In this study we investigated whether a novel circRNA, named circNSD1, and miR-429-3p formed an axis that controls cardiac fibrosis. We established a mouse model of myocardial infarction (MI) for in vivo studies and a cellular model of cardiac fibrogenesis in primary cultured mouse cardiac fibroblasts treated with TGF-ß1. We showed that miR-429-3p was markedly downregulated in the cardiac fibrosis models. Through gain- and loss-of-function studies we confirmed miR-429-3p as a negative regulator of cardiac fibrosis. In searching for the upstream regulator of miR-429-3p, we identified circNSD1 that we subsequently demonstrated as an endogenous sponge of miR-429-3p. In MI mice, knockdown of circNSD1 alleviated cardiac fibrosis. Moreover, silence of human circNSD1 suppressed the proliferation and collagen production in human cardiac fibroblasts in vitro. We revealed that circNSD1 directly bound miR-429-3p, thereby upregulating SULF1 expression and activating the Wnt/ß-catenin pathway. Collectively, circNSD1 may be a novel target for the treatment of cardiac fibrosis and associated cardiac disease.

Unveiling the role of HP1α-HDAC1-STAT1 axis as a therapeutic target for HP1α-positive intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICCA) is a heterogeneous group of malignant tumors characterized by high recurrence rate and poor prognosis. Heterochromatin Protein 1α (HP1α) is one of the most important nonhistone chromosomal proteins involved in transcriptional silencing via heterochromatin formation and structural maintenance. The effect of HP1α on the progression of ICCA remained unclear. METHODS: The effect on the proliferation of ICCA was detected by experiments in two cell lines and two ICCA mouse models. The interaction between HP1α and Histone Deacetylase 1 (HDAC1) was determined using Electrospray Ionization Mass Spectrometry (ESI-MS) and the binding mechanism was studied using immunoprecipitation assays (co-IP). The target gene was screened out by RNA sequencing (RNA-seq). The occupation of DNA binding proteins and histone modifications were predicted by bioinformatic methods and evaluated by Cleavage Under Targets and Tagmentation (CUT & Tag) and Chromatin immunoprecipitation (ChIP). RESULTS: HP1α was upregulated in intrahepatic cholangiocarcinoma (ICCA) tissues and regulated the proliferation of ICCA cells by inhibiting the interferon pathway in a Signal Transducer and Activator of Transcription 1 (STAT1)-dependent manner. Mechanistically, STAT1 is transcriptionally regulated by the HP1α-HDAC1 complex directly and epigenetically via promoter binding and changes in different histone modifications, as validated by high-throughput sequencing. Broad-spectrum HDAC inhibitor (HDACi) activates the interferon pathway and inhibits the proliferation of ICCA cells by downregulating HP1α and targeting the heterodimer. Broad-spectrum HDACi plus interferon preparation regimen was found to improve the antiproliferative effects and delay ICCA development in vivo and in vitro, which took advantage of basal activation as well as direct activation of the interferon pathway. HP1α participates in mediating the cellular resistance to both agents. CONCLUSIONS: HP1α-HDAC1 complex influences interferon pathway activation by directly and epigenetically regulating STAT1 in transcriptional level. The broad-spectrum HDACi plus interferon preparation regimen inhibits ICCA development, providing feasible strategies for ICCA treatment. Targeting the HP1α-HDAC1-STAT1 axis is a possible strategy for treating ICCA, especially HP1α-positive cases.

[Mechanism of Jiaotai Pills in treatment of depression by UHPLC-TOF-MS combined with network pharmacology and experimental validation].

This study aims to analyze the constituents of Jiaotai Pills migrating to the blood in normal rats by UHPLC-TOF-MS technique and reveal the underlying mechanism of Jiaotai Pills in the treatment of depression by network pharmacology and animal experiments. UHPLC-TOF-MS technique was used to detect the constituents of Jiaotai Pills in the blood of rats after intragastric administration. The intersection target of the constituents and depression was screened by DisGeNET and SwissTargetPrediction database, and the protein-protein interaction(PPI) network was constructed. Key targets were imported into the DAVID platform for Gene Ontology(GO) analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway annotation. Combined with constituents, targets, and pathways, the "constituent-target-pathway" network was constructed by Cytoscape 3.9.1 software, through which the key targets and pathways of Jiaotai Pills against depression were predicted. The depression model of chronic unpredictable mild stress(CUMS) was established on rats. After that, behavioral experiments were conducted. The expression of inflammatory factors in serum and the neurotransmitters in the brain were detected by ELISA, and the expression of key targets in the hippocampus was detected by Western blot. The results showed that a total of 17 constituents of Jiaotai Pills were identified in the blood, including 10 alkaloids. There were 124 intersection targets between constituents of Jiaotai Pills and depression disorder. A total of 52 core targets were screened according to PPI results, including NLRP3 and caspase-1, etc. KEGG enrichment analysis mainly involved 15 typical pathways such as NOD-like receptor pathway. The results of animal experiments showed that Jiaotai Pills significantly improved the depression-like behavior of CUMS depressive model on rats, decreased the levels of IL-1ß, TNF-α and IL-6 in serum, and increased the expression of neurotransmitters such as 5-hydroxytryptamine(5-HT), dopamine(DA), and norepinephrine(NE) in the brain. Besides, Jiaotai Pills also down-regulated the expression of NLRP3 and caspase-1 proteins in the hippocampus and inhibited the NLRP3-mediated NOD-like receptor signaling pathway. In conclusion, Jiaotai Pills may play a role in the treatment of depression by inhibiting the NLRP3 inflammasome and the NOD-like receptor pathway mediated by NLRP3.

CXCL9 Overexpression Predicts Better HCC Response to Anti-PD-1 Therapy and Promotes N1 Polarization of Neutrophils.

Background: Anti-programmed death-1 (PD1) antibodies have changed the treatment landscape for hepatocellular carcinoma (HCC) and exhibit promising treatment efficacy. However, the majority of HCCs still do not respond to anti-PD-1 therapy. Methods: We analyzed the expression of CXCL9 in blood samples from patients who received anti-PD-1 therapy and evaluated its correlation with clinicopathological characteristics and treatment outcomes. Based on the results of Cox regression analysis, a nomogram was established for predicting HCC response to anti-PD-1 therapy. qRT‒PCR and multiple immunofluorescence assays were utilized to analyze the proportions of N1-type neutrophils in vitro and in tumor samples, respectively. Results: The nomogram showed good predictive efficacy in the training and validation cohorts and may be useful for guiding clinical treatment of HCC patients. We also found that HCC cell-derived CXCL9 promoted N1 polarization of neutrophils in vitro and that AMG487, a specific CXCR3 inhibitor, significantly blocked this process. Moreover, multiple immunofluorescence (mIF) showed that patients with higher serum CXCL9 levels had greater infiltration of the N1 phenotype of tumor-associated neutrophils (TANs). Conclusion: Our study highlights the critical role of CXCL9 as an effective biomarker of immunotherapy efficacy and in promoting the polarization of N1-type neutrophils; thus, targeting the CXCL9-CXCR3 axis could represent a novel pharmaceutical strategy to enhance immunotherapy for HCC.

Characterization of three lamp genes from largemouth bass (Micropterus salmoides): molecular cloning, expression patterns, and their transcriptional levels in response to fast and refeeding strategy.

Lysosomes-associated membrane proteins (LAMPs), a family of glycosylated proteins and major constituents of the lysosomal membranes, play a dominant role in various cellular processes, including phagocytosis, autophagy and immunity in mammals. However, their roles in aquatic species remain poorly known. In the present study, three lamp genes were cloned and characterized from Micropterus salmoides. Subsequently, their transcriptional levels in response to different nutritional status were investigated. The full-length coding sequences of lamp1, lamp2 and lamp3 were 1251bp, 1224bp and 771bp, encoding 416, 407 and 256 amino acids, respectively. Multiple sequence alignment showed that LAMP1-3 were highly conserved among the different fish species, respectively. 3-D structure prediction, genomic survey, and phylogenetic analysis were further confirmed that these genes are widely existed in vertebrates. The mRNA expression of the three genes was ubiquitously expressed in all selected tissues, including liver, brain, gill, heart, muscle, spleen, kidney, stomach, adipose and intestine, lamp1 shows highly transcript levels in brain and muscle, lamp2 displays highly expression level in heart, muscle and spleen, but lamp3 shows highly transcript level in spleen, liver and kidney. To analyze the function of the three genes under starvation stress in largemouth bass, three experimental treatment groups (fasted group and refeeding group, control group) were established in the current study. The results indicated that the expression of lamp1 was significant induced after starvation, and then returned to normal levels after refeeding in the liver. The expression of lamp2 and lamp3 exhibited the same trend in the liver. In addition, in the spleen and the kidney, the transcript level of lamp1 and lamp2 was remarkably increased in the fasted treatment group and slightly decreased in the refed treatment group, respectively. Collectively, our findings suggest that three lamp genes may have differential function in the immune and energetic organism in largemouth bass, which is helpful in understanding roles of lamps in aquatic species.

Knowledge, attitudes and practice towards postoperative nursing of patients with digit replantation and skin flap transplantation among new nurses in Beijing: a cross-sectional survey.

OBJECTIVE: To explore the knowledge, attitudes and practice (KAP) towards the postoperative nursing of patients with digit replantation and skin flap transplantation among new nurses. DESIGN: Cross-sectional survey. SETTING: Two tertiary medical centres in Beijing, China. PARTICIPANTS: New nurses with working experience within 2 years. PRIMARY AND SECONDARY OUTCOME MEASURES: The demographic characteristics of the nurses and their KAP towards the postoperative nursing of patients with digit replantation and skin flap transplantation were collected using a self-administered questionnaire. The primary outcome was the KAP scores towards the postoperative nursing of patients with digit replantation and skin flap transplantation. The secondary outcomes were the factors associated with the KAP scores and how the KAP dimensions interacted among them. RESULTS: A total of 206 valid questionnaires were collected. The mean KAP scores were 7.72±3.28 (total score 13; 59.3%), 37.95±6.05 (total score 50; 75.9%) and 38.23±6.12 (total score 45; 84.9%), indicating poor knowledge, moderately favourable attitudes and active practice. The structural equation model analysis showed that knowledge directly influences attitudes (ß=0.82, 95%CI 0.60 to 1.05, p<0.001) and that attitudes directly influence practices (ß=0.72, 95%CI 0.62 to 0.83, p<0.001). Knowledge had no direct influence on practices (ß=0.10, 95%CI -0.09 to 0.29, p=0.313), but the indirect influence was significant (ß=0.60, 95%CI 0.41 to 0.78, p<0.001). CONCLUSION: The lack of sufficient knowledge towards the postoperative nursing of patients with digit replantation and skin flap transplantation among nurses with <2 years of experience and the correlation among the KAP dimensions suggested the importance of proper training.