Serine/threonine-protein kinase D2-mediated phosphorylation of DSG2 threonine 730 promotes esophageal squamous cell carcinoma progression.

Desmoglein-2 (DSG2) is a transmembrane glycoprotein belonging to the desmosomal cadherin family, which mediates cell-cell junctions; regulates cell proliferation, migration, and invasion; and promotes tumor development and metastasis. We previously showed serum DSG2 to be a potential biomarker for the diagnosis of esophageal squamous cell carcinoma (ESCC), although the significance and underlying molecular mechanisms were not identified. Here, we found that DSG2 was increased in ESCC tissues compared with adjacent tissues. In addition, we demonstrated that DSG2 promoted ESCC cell migration and invasion. Furthermore, using interactome analysis, we identified serine/threonine-protein kinase D2 (PRKD2) as a novel DSG2 kinase that mediates the phosphorylation of DSG2 at threonine 730 (T730). Functionally, DSG2 promoted ESCC cell migration and invasion dependent on DSG2-T730 phosphorylation. Mechanistically, DSG2 T730 phosphorylation activated EGFR, Src, AKT, and ERK signaling pathways. In addition, DSG2 and PRKD2 were positively correlated with each other, and the overall survival time of ESCC patients with high DSG2 and PRKD2 was shorter than that of patients with low DSG2 and PRKD2 levels. In summary, PRKD2 is a novel DSG2 kinase, and PRKD2-mediated DSG2 T730 phosphorylation promotes ESCC progression. These findings may facilitate the development of future therapeutic agents that target DSG2 and DSG2 phosphorylation. © 2024 The Pathological Society of Great Britain and Ireland.

Structural basis of a two-step tRNA recognition mechanism for plastid glycyl-tRNA synthetase.

Two types of glycyl-tRNA synthetase (GlyRS) are known, the α2 and the α2ß2 GlyRSs. Both types of synthetase employ a class II catalytic domain to aminoacylate tRNAGly. In plastids and some bacteria, the α and ß subunits are fused and are designated as (αß)2 GlyRSs. While the tRNA recognition and aminoacylation mechanisms are well understood for α2 GlyRSs, little is known about the mechanisms for α2ß2/(αß)2 GlyRSs. Here we describe structures of the (αß)2 GlyRS from Oryza sativa chloroplast by itself and in complex with cognate tRNAGly. The set of structures reveals that the U-shaped ß half of the synthetase selects the tRNA in a two-step manner. In the first step, the synthetase engages the elbow and the anticodon base C35 of the tRNA. In the second step, the tRNA has rotated ∼9° toward the catalytic centre. The synthetase probes the tRNA for the presence of anticodon base C36 and discriminator base C73. This intricate mechanism enables the tRNA to access the active site of the synthetase from a direction opposite to that of most other class II synthetases.

CXCL12+ Tumor-associated Endothelial Cells Promote Immune Resistance in Hepatocellular Carcinoma.

BACKGROUND: The tumor microenvironment (TME) plays a crucial role in the limited efficacy of existing treatments for hepatocellular carcinoma (HCC), with tumor-associated endothelial cells (TECs) serving as fundamental TME components that substantially influence tumor progression and treatment efficacy. However, the precise roles and mechanisms of TECs in HCC remain inadequately understood. METHODS: We employed a multi-omics profiling strategy to investigate the single-cell and spatiotemporal evolution of TECs within the microenvironment of HCC tumors showcasing varied responses to immunotherapy. Through an analysis of a clinical cohort of HCC patients, we explored the correlation between TEC subpopulations and immunotherapy outcomes. The influence of TEC subsets on the immune microenvironment was confirmed through comprehensive in vitro and in vivo studies. To further explore the mechanisms of distinct TEC subpopulations in microenvironmental modulation and their impact on immunotherapy, we utilized TEC subset-specific knockout mouse models as well as humanized mouse models. RESULTS: In this research, we identified a new subset of CXCL12+ TECs that exert a crucial role in immune suppression within the HCC TME. Functionally, CXCL12+ TECs impede the differentiation of CD8+ naïve T cells into CD8+ cytotoxic T cells by secreting CXCL12. Furthermore, they attract myeloid-derived suppressor cells (MDSCs). A bispecific antibody was developed to target both CXCL12 and PD1 specifically, showing significant promise in bolstering anti-tumor immune responses and advancing HCC therapy. CONCLUSIONS: CXCL12+ TECs are pivotal in mediating immunosuppression within HCC microenvironment and targeting CXCL12+ TECs presents a promising approach to augment the efficacy of immunotherapies in HCC patients. IMPACT AND IMPLICATION: This investigation reveals a pivotal mechanism in the HCC TME, where CXCL12+ TECs emerge as crucial modulators of immune suppression. The discovery of CXCL12+ TECs as inhibitors of CD8+ naïve T cell activation and recruiters of MDSCs significantly advances our grasp of the dynamic between HCC and immune regulation. Moreover, the development and application of a bispecific antibody precisely targeting CXCL12 and PD1 has proven to enhance immune responses in a humanized mouse HCC model. This finding underscores a promising therapeutic direction for HCC, offering the potential to amplify the impact of current immunotherapies.

Complete chloroplast genome of the Malus baccata var. gracilis provides insights into the evolution and phylogeny of Malus species.

Malus baccata (L.) var. gracilis (Rehd.) has high ornamental value and breeding significance, and comparative chloroplast genome analysis was applied to facilitate genetic breeding for desired traits and resistance and provide insight into the phylogeny of this genus. Using data from whole-genome sequencing, a tetrameric chloroplast genome with a length of 159,992 bp and a total GC content of 36.56% was constructed. The M. baccata var. gracilis chloroplast genome consists of a large single-copy sequence (88,100 bp), a short single-copy region (19,186 bp), and two inverted repeat regions, IRa (26,353 bp) and IRb (26,353 bp). This chloroplast genome contains 112 annotated genes, including 79 protein-coding genes (nine multicopy), 29 tRNA genes (eight multicopy), and four rRNA genes (all multicopy). Calculating the relative synonymous codon usage revealed a total of 32 high-frequency codons, and the codons exhibited a biased usage pattern towards A/U as the ending nucleotide. Interspecific sequence comparison and boundary analysis revealed significant sequence variation in the vast single-copy region, as well as generally similar expansion and contraction of the SSC and IR regions for 10 analyzed Malus species. M. baccata var. gracilis and Malus hupehensis were grouped together into one branch based on phylogenetic analysis of chloroplast genome sequences. The chloroplast genome of Malus species provides an important foundation for species identification, genetic diversity analysis, and Malus chloroplast genetic engineering. Additionally, the results can facilitate the use of pendant traits to improve apple tree shape.

PTI-ETI synergistic signal mechanisms in plant immunity.

Plants face a relentless onslaught from a diverse array of pathogens in their natural environment, to which they have evolved a myriad of strategies that unfold across various temporal scales. Cell surface pattern recognition receptors (PRRs) detect conserved elicitors from pathogens or endogenous molecules released during pathogen invasion, initiating the first line of defence in plants, known as pattern-triggered immunity (PTI), which imparts a baseline level of disease resistance. Inside host cells, pathogen effectors are sensed by the nucleotide-binding/leucine-rich repeat (NLR) receptors, which then activate the second line of defence: effector-triggered immunity (ETI), offering a more potent and enduring defence mechanism. Moreover, PTI and ETI collaborate synergistically to bolster disease resistance and collectively trigger a cascade of downstream defence responses. This article provides a comprehensive review of plant defence responses, offering an overview of the stepwise activation of plant immunity and the interactions between PTI-ETI synergistic signal transduction.

Dietary Bacillus velezensis T23 fermented products supplementation improves growth, hepatopancreas and intestine health of Litopenaeus vannamei.

This study aimed to elucidate the effects of dietary fermented products of Bacillus velezensis T23 on the growth, immune response and gut microbiota in Pacific white shrimp (Litopenaeus vannamei). Shrimp were fed with diets containing fermentation products of B. velezensis T23 at levels of (0, 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5 g/kg) for 4 weeks, to assess the influence on shrimp growth. The results showed that 0.3 and 0.4 g/kg T23 supplementation improved shrimp growth and feed utilization. Based on these results we selected these three diets (Control, 0.3T23 and 0.4T23) to assess the effect on immune response and gut microbiota of shrimp. Compared with the control, the 0.3T23 and 0.4T23 groups enhanced lipase and α-amylase activities in the gut significantly. Moreover, the 0.4T23 group decreased TAG and MDA levels in hepatopancreas, ALT and AST levels of serum significantly (P < 0.05). In hepatopancreas, CAT and SOD activities were improved observably and the MDA content was reduced markedly in both T23 groups. The expressions of antimicrobial related genes, Cru and peroxinectin in the 0.3T23 group, and proPO and peroxinectin in the 0.4T23 group were up-regulated remarkably (P < 0.05). Moreover, hepatopancreas of shrimp fed with a diet amended with T23 showed a significant down-regulated expression of nf-kb and tnf-α genes, while expressions of tgf-ß was considerably up-regulated. Furthermore, serum LPS and LBP contents were reduced markedly in T23 groups. Intestinal SOD and CAT were noteworthy higher in T23 groups (P < 0.05). In the intestine of shrimp fed on the diet enriched with T23 the expression of nf-κb and tnf-α exhibited markedly down-regulated, whereas hif1α was up-regulated (P < 0.05). Besides, in the intestine of shrimp grouped under T23, Cru and peroxinectin genes were markedly up-regulated (P < 0.05). Dietary 0.3 g/kg T23 also upregulated the ratio of Rhodobacteraceae to Vibrionaceae in the gut of the shrimp. Taken together, the inclusion of B. velezensis T23 in the diet of shrimp enhanced the growth and feed utilization, enhanced hepatopancreas and intestine health.

Analyzing the safety and efficacy of pipeline embolization device in pediatric aneurysms: insight from a mul-ticenter cohort and pooled analysis.

BACKGROUND: Pediatric patients with intracranial aneurysms face high risks of spontaneous subarachnoid hemorrhages. Despite its approval for adults aged 22 and above, the Pipeline Embolization Device (PED, Covidien/Medtronic, Irvine, California, USA) is being considered for younger patients due to its efficacy. This study aims to assess the safety and effectiveness of using PEDs in pediatric aneurysm treatment. METHODS: A retrospective study across 14 institutions identified 25 patients (age ≤ 18) treated with PED from November 2014 to October 2019. A literature review included all published pediatric aneurysm cases treated with PED from 2007 to 2023. Analyzed data included patient demographics, aneurysm characteristics, treatment, clinical outcomes, and complications. RESULTS: We analyzed 81 pediatric patients, including 25 from the multi-center registry and 56 from 38 relevant literature. In the entire cohort of 81 patients, mean age of the patients was 11.9 ± 4.0 years (ranged from 9 months to 18 years), with 58.0% males. Ruptured aneurysms were observed in 7 patients (8.6%), whereas 43 patients (53.1%) harbored large/giant aneurysms. The aneurysm occlusion rate was 87.7% during the median 7 months follow-up. Complications occurred in 12.3% of patients, resulting in morbidity in 5 cases (6.1%) and mortality in 4 cases (4.9%). Patient age was not associated with the occurrence of aneurysm residual, complications, and mortality following PED treatment. CONCLUSIONS: PED can be effective for pediatric aneurysms, but morbidity and mortality can be substantial compared to the adults. Surgical timing should depend on clinical judgment and patient factors, without age-related delays.

A retrospective study on the relationship between serum electrolyte disorder and delayed cerebral infarction after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Delayed cerebral ischemia (DCI)-induced cerebral infarction is a major cause of adverse neurological outcomes following aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to investigate the relationship between postoperative serum electrolyte levels and DCI in patients with aSAH. MATERIALS AND METHODS: We analyzed the data of patients with aSAH between 2015 and 2022. The patients were classified into two groups according to whether they experienced DCI. Electrolyte levels were categorized into three groups based on the normal ranges for electrolytes. Logistic regression models were used to study the relationship between electrolyte levels and DCI. Another logistic regression analysis was conducted to explore the relationship between the different severity levels of statistically significant indicators and DCI. A restrictive cubic spline model was adopted to assess the potential linear relationship between electrolytes and DCI. Subsequently, sensitivity analysis was performed to assess the impact of collinearity among ions. Finally, subgroup analysis was performed. RESULTS: This study included 1,099 patients. Patients with hyperchloremia were more prone to DCI than those with normal chloride levels. Subsequently, excluding the population with hypochloremia, both mild and severe hyperchloremia were found to be associated with an increased risk of DCI compared with normal chloride levels. Within the framework of a restrictive cubic spline, our findings revealed an increased incidence of DCI (P for nonlinear = 0.735) as chloride levels increased. Sensitivity analysis revealed that patients with severe hyperchloremia were more susceptible to DCI. CONCLUSIONS: This study found that patients with aSAH and postoperative hyperchloremia are more prone to developing DCI.

Impacts of microplastic type on the fate of antibiotic resistance genes and horizontal gene transfer mechanism during anaerobic digestion.

Microplastics (MPs) and antibiotic resistance genes (ARGs) are important pollutants in waste activated sludge (WAS), but their interactions during anaerobic digestion (AD) still need to be further explored. This study investigated variations in ARGs, mobile genetic elements (MGEs), and host bacteria during AD under the pressure of polyamide (PA), polyethylene (PE), and polypropylene (PP). The results showed that the MPs increased methane production by 11.7-35.5%, and decreased ARG abundance by 5.6-24.6%. Correlation analysis showed that the decrease of MGEs (plasmid, prophage, etc.) promoted the decrease of the abundance of multidrug, aminoglycoside and tetracycline resistance genes. Metagenomic annotation revealed that the reduction of key host bacteria (Arenimonas, Lautropia, etc.) reduced the abundance of major ARGs (rsmA, rpoB2, etc.). Moreover, PP MPs contributed to a reduction in the abundance of functional genes related to the production of reactive oxygen species, ATP synthesis, and cell membrane permeability, which was conducive to reducing the potential for horizontal gene transfer of ARGs. These findings provide insights into the treatment of organic waste containing MPs.

A comprehensive analysis of patients with cerebral arteriovenous malformation with headache: assessment of risk factors and treatment effectiveness.

BACKGROUND: Due to the high mortality and disability rate of intracranial hemorrhage, headache is not the main focus of research on cerebral arteriovenous malformation (AVM), so research on headaches in AVM is still scarce, and the clinical understanding is shallow. This study aims to delineate the risk factors associated with headaches in AVM and to compare the effectiveness of various intervention treatments versus conservative treatment in alleviating headache symptoms. METHODS: This study conducted a retrospective analysis of AVMs who were treated in our institution from August 2011 to December 2021. Multivariable logistic regression analysis was employed to assess the risk factors for headaches in AVMs with unruptured, non-epileptic. Additionally, the effectiveness of different intervention treatments compared to conservative management in alleviating headaches was evaluated through propensity score matching (PSM). RESULTS: A total of 946 patients were included in the analysis of risk factors for headaches. Multivariate logistic regression analysis identified that female (OR 1.532, 95% CI 1.173-2.001, p = 0.002), supply artery dilatation (OR 1.423, 95% CI 1.082-1.872, p = 0.012), and occipital lobe (OR 1.785, 95% CI 1.307-2.439, p < 0.001) as independent risk factors for the occurrence of headaches. There were 443 AVMs with headache symptoms. After propensity score matching, the microsurgery group (OR 7.27, 95% CI 2.82-18.7 p < 0.001), stereotactic radiosurgery group(OR 9.46, 95% CI 2.26-39.6, p = 0.002), and multimodality treatment group (OR 8.34 95% CI 2.87-24.3, p < 0.001) demonstrate significant headache relief compared to the conservative group. However, there was no significant difference between the embolization group (OR 2.24 95% CI 0.88-5.69, p = 0.091) and the conservative group. CONCLUSIONS: This study identified potential risk factors for headaches in AVMs and found that microsurgery, stereotactic radiosurgery, and multimodal therapy had significant benefits in headache relief compared to conservative treatment. These findings provide important guidance for clinicians when developing treatment options that can help improve overall treatment outcomes and quality of life for patients.

Identification of WUSCHEL-related homeobox gene and truncated small peptides in transformation efficiency improvement in Eucalyptus.

BACKGROUND: The WUSCHEL-related Homeobox (WOX) genes, which encode plant-specific homeobox (HB) transcription factors, play crucial roles in regulating plant growth and development. However, the functions of WOX genes are little known in Eucalyptus, one of the fastest-growing tree resources with considerable widespread cultivation worldwide. RESULTS: A total of nine WOX genes named EgWOX1-EgWOX9 were retrieved and designated from Eucalyptus grandis. From the three divided clades marked as Modern/WUS, Intermediate and Ancient, the largest group Modern/WUS (6 EgWOXs) contains a specific domain with 8 amino acids: TLQLFPLR. The collinearity, cis-regulatory elements, protein-protein interaction network and gene expression analysis reveal that the WUS proteins in E. grandis involve in regulating meristems development and regeneration. Furthermore, by externally adding of truncated peptides isolated from WUS specific domain, the transformation efficiency in E. urophylla × E. grandis DH32-29 was significant enhanced. The transcriptomics data further reveals that the use of small peptides activates metabolism pathways such as starch and sucrose metabolism, phenylpropanoid biosynthesis and flavonoid biosynthesis. CONCLUSIONS: Peptides isolated from WUS protein can be utilized to enhance the transformation efficiency in Eucalyptus, thereby contributing to the high-efficiency breeding of Eucalyptus.

A scheme for rapid evaluation of the intermolecular three-body polarization effect in water clusters.

The ability to accurately and rapidly evaluate the intermolecular many-body polarization effect of the water system is very important for computer simulations of biomolecule in aqueous. In this paper, a scheme is proposed based on the polarizable dipole-dipole interaction model and used to rapidly estimate the intermolecular many-body polarization effect in water clusters. We use a bond-dipole-based polarization function to evaluate the polarization energy. We regard two OH bonds of a water molecule as two bond-dipoles and set the permanent OH bond-dipole moment of a water molecule to be 1.51 Debye. We estimate the induced OH bond-dipole moment via a simple formula in which only one correction factor is needed. This scheme is then applied to tens of water clusters to calculate the three- and four-body interaction energies. The three-body interaction energies of 93 water clusters produced by our scheme are compared with those produced by the counterpoise-corrected CCSD(T)/aug-cc-pVDZ, MP2/aug-cc-pVDZ, M06-2X/jul-cc-pVTZ methods, by the AMOEBApro13, iAMOEBA, AMOEBA+, AMOEBA+(CF) methods, and by the MB-pol method. The four-body interaction energies of 47 water clusters yielded by our scheme are compared with those yielded by the counterpoise-corrected MP2/aug-cc-pVDZ and M06-2X/ jul-cc-pVTZ methods, by the AMOEBApro13, AMOEBA+, AMOEBA+(CF) methods, and by the MB-pol method. The comparison results show that the scheme proposed in this paper can reproduce the counterpoise-corrected CCSD(T)/aug-cc-pVDZ three-body interaction energies and reproduce the counterpoise-corrected MP2/aug-cc-pVDZ four-body interaction energies both accurately and efficiently. We anticipate the scheme proposed here can be useful for computer simulations of liquid water and aqueous solutions.

Cost-Effectiveness of [99mTc]Tilmanocept Relative to [99mTc]Sulfur Colloid for Sentinel Lymph Node Biopsy in Early Stage Oral Cavity Cancer.

BACKGROUND: Several studies have demonstrated varying rates of efficacy, reliability, and sensitivity of sentinel lymph node biopsy (SLNB) in identifying occult nodal disease for early stage oral cavity squamous cell carcinoma (OCSCC) depending on the radionuclide agent utilized. No head-to-head comparison of cost or clinical outcomes of SLNB when utilizing [99mTc]tilmanocept versus [99mTc]sulfur colloid has been performed. The goal of this study was to develop a decision model to compare the cost-effectiveness of [99mTc]tilmanocept versus [99mTc]sulfur colloid in early stage OCSCC. PATIENTS AND METHODS: A decision model of disease and treatment as a function of SLNB was created. Patients with a negative SLNB entered a Markov model of the natural history of OCSCC parameterized with published data to simulate five states of health and iterated over a 30-year time horizon. Treatment costs and quality-adjusted life-years (QALYs) for each health state were included. The incremental cost-effectiveness ratio (ICER) was then estimated using $100,000 per additional QALY as the threshold for determining cost-effectiveness. RESULTS: The base case cost-effectiveness analysis suggested [99mTc]tilmanocept was more effective than [99mTc]sulfur colloid by 0.12 QALYs (7.06 versus 6.94 QALYs). [99mTc]Tilmanocept was more costly, with a lifetime cost of $84,961 in comparison with $84,264 for sulfur colloid, however, the overall base case ICER was $5859 per additional QALY, well under the threshold for cost-effectiveness. Multiple one-way sensitivity analyses were performed, and demonstrated the model was robust to alternative parameter values. CONCLUSION: Our analysis showed that while [99mTc]tilmanocept is more costly upfront, these costs are worth the additional QALYs gained by the use of [99mTc]tilmanocept.

The micro-pathological characteristics in cerebral arteriovenous malformations(cAVMs).

BACKGROUND: Rupture and hemorrhage is the most serious complication of cerebral arteriovenous malformation(cAVMs), and have a significant impact on quality of life. OBJECTIVES: We investigated the hematoxylin and eosin staining and ultrastructural features of cAVMs and characterized the abnormal vascular structure of cAVMs. METHODS: Light and electron microscopy were performed on a series of pathological specimens obtained from 12 patients with cAVMs who underwent surgical resection for the first time without radiosurgery or embolization therapy. RESULTS: In tunica intima, we found that the vascular endothelial cells of cAVMs were damaged, and the lysis of the cell body occurred in multiple regions. In tunica media, the arrangement of the elastic layer was disordered, and the thickness was uneven. Part of the structure of the elastic lamina was missing. The part of tunica adventitia was fractured and discontinuous. In addition, we also observed the phenomenon that different blood vessels share the same vascular wall. Macrophage phagocytosis and lymphocyte infiltration in the adventitial region of ruptured cAVMs. Abnormal lipid deposition in vascular endothelial cells and smooth muscle cells. CONCLUSIONS: The structural incompleteness of cAVMs may be an important cause of hemorrhage.

Dietary cultured supernatant mixture of Cetobacterium somerae and Lactococcus lactis improved liver and gut health, and gut microbiota homeostasis of zebrafish fed with high-fat diet.

Postbiotics have the ability to improve host metabolic disorders and immunity. In order to explore whether the postbiotics SWFC (cultured supernatant mixture of Cetobacterium somerae and Lactococcus lactis) repaired the adverse effects caused by feeding of high-fat diet (HFD), zebrafish were selected as the experimental animal and fed for 6 weeks, with dietary HFD as the control group, and HFD containing 0.3 g/kg and 0.4 g/kg SWFC as the treatment groups. The results indicated that addition of SWFC in the diet at a level of 0.3 and 0.4 g/kg didn't affect the growth performance of zebrafish (P > 0.05). Supplementation of dietary SWFC0.3 relieved lipid metabolism disorders through significant increasing in the expression of pparα and cpt1, and decreasing the expression of cebpα, pparγ, acc1 and dgat-2 genes (P < 0.05). Moreover, the content of triacylglycerol was markedly lower in the liver of zebrafish grouped under SWFC0.3 (P < 0.05). Dietary SWFC0.3 also improved the antioxidant capacity via increasing the expression level of ho-1, sod and gstr genes, and significant inducing malondialdehyde content in the liver of zebrafish (P < 0.05). Besides, dietary SWFC0.3 also notably improved the expression level of lysozyme, c3a, defbl1 and defbl2 (P < 0.05). The expression level of pro-inflammatory factors (nf-κb, tnf-α, and il-1ß) were significantly decreased and the expression level of anti-inflammatory factor (il-10) was markedly increased in the postbiotics 0.3 g/kg group (P < 0.05). Feeding with SWFC0.3 supplemented diet for 6 weeks improved the homeostasis of gut microbiota and increased the survival rate of zebrafish after challenged with Aeromonus veronii Hm091 (P < 0.01). It was worth noting that the positive effect of dietary SWFC at a level of 0.3 g/kg was considerably better than that of 0.4 g/kg. This may imply that the effectiveness and use of postbiotics is limited by dosage.

The positive effects of postbiotic (SWF concentration®) supplemented diet on skin mucus, liver, gut health, the structure and function of gut microbiota of common carp (Cyprinus carpio) fed with high-fat diet.

Postbiotics are an emerging research interest in recent years, which shows that metabolites, lysate extracts, cell wall components and even culture supernatants of probiotics can also exhibit significant prebiotic effects. In this study postbiotic stress worry free concentration® (SWFC) were prepared from the composition of culture supernatant of Cetobacterium somerae and Lactococcus lactis. The positive effects of SWFC supplemented diets on the growth performance, skin mucus, liver and gut health, and intestinal microbiota profile of Cyprinus carpio fed with high fat diets were investigated. 180 C. carpio with an average body weight of (3.01 ± 0.01) g were selected and randomly divided into three groups. They were fed with one of the three experimental diets supplemented with SWFC of 0 (control), 0.2 and 0.3 g/kg for 98 days, afterwards indexes were detected. The results revealed that, addition of SWFC had no significant effect on growth performance of C. carpio, while it can improve the health of the fish remarkably. In addition, SWFC improved mucosal C3, T-AOC, SOD activities, and decreased lipid peroxidation product MDA level, which were notably better than those in the control group (P < 0.05). In terms of the liver health systems, C. carpio fed on the diet supplemented with 0.2 g/kg of SWFC, showed significant improvement of the liver injured by HFD and reduce the contents of serum ALT and AST, and liver TAG (P < 0.05; P < 0.01). The expression of inflammation-related and lipid synthesis genes revealed that SWFC0.2 group could noteworthy enhance antioxidant capacity, reduced the expression of pro-inflammatory factors (TNF-α, IL-1ß) and lipid synthesis genes (ACC, FAS, PPAR-ß, PPAR-γ), and up-regulated the expression of anti-inflammatory factors (TGF-ß). Additionally, intestinal morphology arose inflammatory cell infiltration, while intestinal integrity was better in SWFC groups compared with the control. Furthermore, the contents of serum LPS and LBP were remarkably lower in the SWFC0.2 group compared with the control (P < 0.01). The mRNA expression of genes related to gut health indicated that SWFC supplementation noteworthy up-regulated the expression of antioxidant (Nrf2, CAT, GPX), immune (Hepcidin, IL-10) and tight junction protein-related (ZO-1, Occludin). Simultaneously, the results of GF-zebrafish showed that the relative expression of anti-inflammatory genes (IL-1ß, TGF-ß) and antioxidant related genes (Nrf2, HO-1) were significantly up-regulated in SWFC groups. Data on intestinal microbiota profile verified that, at the phylum level, the abundance of Fusobacteria was remarkably elevated in the SWFC groups (P < 0.05), whereas the abundance of Firmicutes was declined noteworthy in SWFC0.2 and SWFC0.3 compared to the control group (P < 0.05; P < 0.01) respectively. At the genus level, the abundance of Cetobacterium in the SWFC groups were notably higher than those in the control group (P < 0.05), while the Vibrio content in the SWFC groups was significantly decreased (P < 0.05). PCoA result indicated that the intestinal microflora of SWFC0.2 group was abundant and diverse. Our results elucidate that dietary supplementation of SWFC protects C. carpio from HFD induced inflammatory response and oxidative stress, ameliorate skin mucus, liver and gut health, and improve the gut microbiota balance. Therefore, SWFC could be considered as an improving-fish-health additive, when supplemented to aquatic animal feed. With regards to how SWFC regulates the immunity and inflammatory responses and which signal transductions are involved remains unclear and more scientific evidences are needed to address these issues.

From bonds to interactions: comprehensive molecular characterization via polarizable bond-dipole approach.

Accurately characterizing molecular interactions stands as a pivotal requirement for ensuring the reliability of molecular dynamics simulations. In line with our bond-dipole-based interaction model proposed by Gao et al. [X.-C. Gao, Q. Hao and C.-S. Wang, J. Chem. Theory Comput., 2017, 13, 2730-2741.], we have implemented an efficient and concise approach to compute electrostatic potential. This methodology capitalizes on the polarizable nature of chemical bond dipoles, resulting in a model of remarkable simplicity. In this study, we have revised the polarizable bond-dipole-based force field (PBFF) through the meticulous curation of quantum chemical data sets. These data sets encompass a comprehensive collection of 40 000 conformations, including those of water, methylamine, methanol, and N-methylacetamide. Additionally, we incorporate 520 hydrogen-bonded dimers into our data sets. In pursuit of enhanced accuracy in molecular dynamics simulations and a more faithful representation of potential energy landscapes, we undertook the re-optimization of the nonbonded parameters within the PBFF framework. Concurrently, we intricately fine-tuned the bonded parameters. The results of our comprehensive evaluation denote that this newly optimized force field method adeptly and efficiently computes structural characteristics, harmonic frequencies, and interaction energies. Overall, this study provides further validation for the applicability of PBFF in molecular dynamics simulations.

Exosome-transmitted circCABIN1 promotes temozolomide resistance in glioblastoma via sustaining ErbB downstream signaling.

Although temozolomide (TMZ) provides significant clinical benefit for glioblastoma (GBM), responses are limited by the emergence of acquired resistance. Here, we demonstrate that exosomal circCABIN1 secreted from TMZ-resistant cells was packaged into exosomes and then disseminated TMZ resistance of receipt cells. CircCABIN1 could be cyclized by eukaryotic translation initiation factor 4A3 (EIF4A3) and is highly expressed in GBM tissues and glioma stem cells (GSCs). CircCABIN1 is required for the self-renewal maintenance of GSCs to initiate acquired resistance. Mechanistically, circCABIN1 regulated the expression of olfactomedin-like 3 (OLFML3) by sponging miR-637. Moreover, upregulation of OLFML3 activating the ErbB signaling pathway and ultimately contributing to stemness reprogramming and TMZ resistance. Treatment of GBM orthotopic mice xenografts with engineered exosomes targeting circCABIN1 and OLFML3 provided prominent targetability and had significantly improved antitumor activity of TMZ. In summary, our work proposed a novel mechanism for drug resistance transmission in GBM and provided evidence that engineered exosomes are a promising clinical tool for cancer prevention and therapy.

Diffuse pigmented villonodular synovitis treated with arthroscopic total synovial peel.

BACKGROUND: Diffuse pigmented villonodular synovitis (PVNS) is prone to recurrence after surgery, and it is difficult to achieve a long-term complete cure. OBJECTIVE: To reduce the recurrence rate of PVNS, the author pioneered the arthroscopic total synovial peel (ATSP). METHODS: From March 2014 to July 2020, a total of 19 patients (6 males and 13 females) with diffuse PVNS of the knee were treated in our department and underwent ATSP. It's 'peel' rather than simple excision. This method is similar to peeling bark. Relapse rates and functional scores were determined, with follow-ups ranging from 12 to 72 months, on average 36 months. RESULTS: Treatment efficacy was assessed by imaging and functional scores. Imaging results indicated a recurrence rate of 10.5%. In patients without recurrence, the visual analog score (VAS) decreased from 4.76 ± 2.02 preoperatively to 1.56 ± 1.15 postoperatively. The Tegner-Lysholm knee function score (TLS) score increased from 67.76 ± 15.64 preoperatively to 90.32 ± 8.32 postoperatively. Compared with the literature, ATSP significantly reduces the postoperative recurrence rate of diffuse PVNS. The preliminarily findings suggest that this approach could greatly reduce the recurrence rate of postoperative PVNS in follow-up studies. CONCLUSION: This approach may be a viable option for treating diffuse PVNS via arthroscopy and is worthy of clinical consideration.

A Mannose Receptor from Litopenaeus vannamei Involved in Innate Immunity by Pathogen Recognition and Inflammation Regulation.

Mannose receptor, as a member of the C-type lectin superfamily, is a non-canonical pattern recognition receptor that can internalize pathogen-associated ligands and activate intracellular signaling. Here, a mannose receptor gene, LvMR, was identified from the Pacific white shrimp Litopenaeus vannamei. LvMR encoded a signal peptide, a fibronectin type II (FN II) domain, and two carbohydrate-recognition domains (CRDs) with special EPS and FND motifs. LvMR transcripts were mainly detected in the hepatopancreas, and presented a time-dependent response after pathogen challenge. The recombinant LvMR (rLvMR) could bind to various PAMPs and agglutinate microorganisms in a Ca2+-dependent manner with strong binding ability to D-mannose and N-acetyl sugars. The knockdown of LvMR enhanced the expression of most NF-κB pathway genes, inflammation and redox genes, while it had no obvious effect on the transcription of most phagocytosis genes. Moreover, the knockdown of LvMR caused an increase in reactive oxygen species (ROS) content and inducible nitric oxide synthase (iNOS) activity in the hepatopancreas after Vibrio parahaemolyticus infection. All these results indicate that LvMR might perform as a PRR in immune recognition and a negative regulator of inflammation during bacterial infection.