TRIM21-mediated ubiquitylation of TAT suppresses liver metastasis in gallbladder cancer.

Liver metastasis is common in patients with gallbladder cancer (GBC), imposing a significant challenge in clinical management and serving as a poor prognostic indicator. However, the mechanisms underlying liver metastasis remain largely unknown. Here, we report a crucial role of tyrosine aminotransferase (TAT) in liver metastasis of GBC. TAT is frequently up-regulated in GBC tissues. Increased TAT expression is associated with frequent liver metastasis and poor prognosis of GBC patients. Overexpression of TAT promotes GBC cell migration and invasion in vitro, as well as liver metastasis in vivo. TAT knockdown has the opposite effects. Intriguingly, TAT promotes liver metastasis of GBC by potentiating cardiolipin-dependent mitophagy. Mechanistically, TAT directly binds to cardiolipin and leads to cardiolipin externalization and subsequent mitophagy. Moreover, TRIM21 (Tripartite Motif Containing 21), an E3 ubiquitin ligase, interacts with TAT. The histine residues 336 and 338 at TRIM21 are essential for this binding. TRIM21 preferentially adds the lysine 63 (K63)-linked ubiquitin chains on TAT principally at K136. TRIM21-mediated TAT ubiquitination impairs its dimerization and mitochondrial location, subsequently inhibiting tumor invasion and migration of GBC cells. Therefore, our study identifies TAT as a novel driver of GBC liver metastasis, emphasizing its potential as a therapeutic target.

Bridge-layered decompression technique for vertebral artery-involved hemifacial spasm: technical note.

BACKGROUND: Hemifacial spasm (HFS) is most effectively treated with microvascular decompression (MVD). However, there are certain challenges in performing MVD for HFS when the vertebral artery (VA) is involved in compressing the facial nerve (VA-involved). This study aimed to introduce a "bridge-layered" decompression technique for treating patients with VA-involved HFS and to evaluate its efficacy and safety to treat patients with HFS. METHODS: A single-center retrospective analysis was conducted on the clinical data of 62 patients with VA-involved HFS. The tortuous trunk of VA was lifted by a multi-point "bridge" decompression technique to avoid excessive traction of the cerebellum and reduce the risk of damage to the facial-acoustic nerve complex. To fully decompress all the responsible vessels, the branch vessels of VA were then isolated using the "layered" decompression technique. RESULTS: Among the 62 patients, 59 patients were cured immediately after the surgery, two patients were delayed cured after two months, and one had occasional facial muscle twitching after the surgery. Patients were followed up for an average of 19.5 months. The long-term follow-up results showed that all patients had no recurrence of HFS during the follow-up period, and no patients developed hearing loss, facial paralysis, or other permanent neurological damage complications. Only two patients developed tinnitus after the surgery. CONCLUSION: The "bridge-layered" decompression technique could effectively treat VA-involved HFS with satisfactory safety and a low risk of hearing loss. The technique could be used as a reference for decompression surgery for VA-involved HFS.

Effect of bending deformation on the electronic and optical properties of O atoms adsorbed by Be3N2.

CONTEXT: In this paper, the optimum coverage of 4.44% and the optimum adsorption sites were determined for the Be3N2 adsorption system of O atoms at different coverages based on density functional theory. The electronic and optical properties of the model were investigated by applying bending deformation to the model at these coverage and adsorption sites. Adsorption of O atoms disrupts the geometrical symmetry of Be3N2, resulting in orbital rehybridization and lowering its band gap. Bending deformation causes the band gap of the adsorbed O atom structure of Be3N2 to first increase and then decrease, resulting in the modulation of its band gap. With increasing bending deformation, the adsorbed system is redshifts, and the degree of redshift increases with increasing bending deformation. METHODS: All calculations in this paper were performed using the first-principles-based CASTEP module of Materials Studio (MS). The generalized gradient approximation (GGA) plane-wave pseudopotential method and the Perdew-Burke-Ernzerhof (PBE) Perdew et al. Phys Rev Lett 77:3865, 1996 generalized functional were used in the geometry optimization and calculation process to calculate the exchange-correlation potential between electrons. The effect of coverage on the electronic and optical properties of the Be3N2-adsorbed O atom system was investigated by adsorbing different numbers of O atoms on a monolayer of Be3N2. The Be3N2 protocell contains two N atoms and three Be atoms with a space community of P6/MMM (No.191). The original cell was expanded 3 times along the direction of the base vectors a and b in the Be3N2 plane to create a 3 × 3 × 1 monolayer Be3N2 supercell system. A vacuum layer of 15 Å is set in the direction of the crystal plane of the vertical monolayer Be3N2 supercell to eliminate interactions between adjacent layers. In the overall energy convergence test of the Be3N2 supercell, the plane wave truncation energy was set to 500 eV, and the energy difference between the calculations given in the literature Reyes-Serrato et al. J Phys Chem Solids 59:743-6, 1998 using 550 eV was less than 0.01 eV, verifying the reliability of the data at a truncation energy of 500 eV. The Monkhorst-Pack special k-point sampling method Monkhorst et al. Phys Rev B 13:5188, 1976 was used in the structural calculations, and the grid was set to 3 × 3 × 1. The geometric optimization parameters are set as follows: the self-consistent field iteration convergence criterion is 2.0 × 10-6 eV, and the iterative accuracy convergence value is not less than 1.0 × 10-5 eV/atom for the total force of each atom and less than 0.03 eV/Å for all atomic forces. In addition the high-symmetry k-point path is taken as Γ(0,0,0) → M(0,0.5,0) → K(- 1/3,2/3,0) → Γ(0,0,0) Chen et al, AIP Adv 8:105105, 2018.

Scattering-Based Light-Sheet Microscopy Imaging of Human Papillomavirus-Associated Squamous Lesions of the Anal Canal: A Proof-of-Principle Study.

Demand for anal cancer screening is expected to rise following the recent publication of the Anal Cancer-HSIL Outcomes Research trial, which showed that treatment of high-grade squamous intraepithelial lesions significantly reduces the rate of progression to anal cancer. While screening for human papillomavirus-associated squamous lesions in the cervix is well established and effective, this is less true for other sites in the lower anogenital tract. Current anal cancer screening and prevention rely on high-resolution anoscopy with biopsies. This procedure has a steep learning curve for providers and may cause patient discomfort. Scattering-based light-sheet microscopy (sLSM) is a novel imaging modality with the potential to mitigate these challenges through real-time, microscopic visualization of disease-susceptible tissue. Here, we report a proof-of-principle study that establishes feasibility of dysplasia detection using an sLSM device. We imaged 110 anal biopsy specimens collected prospectively at our institution's dysplasia clinic (including 30 nondysplastic, 40 low-grade squamous intraepithelial lesion, and 40 high-grade squamous intraepithelial lesion specimens) and found that these optical images are highly interpretable and accurately recapitulate histopathologic features traditionally used for the diagnosis of human papillomavirus-associated squamous dysplasia. A reader study to assess diagnostic accuracy suggests that sLSM images are noninferior to hematoxylin and eosin images for the detection of anal dysplasia (sLSM accuracy = 0.87; hematoxylin and eosin accuracy = 0.80; P = .066). Given these results, we believe that sLSM technology holds great potential to enhance the efficacy of anal cancer screening by allowing accurate sampling of diagnostic tissue at the time of anoscopy. While the current imaging study was performed on ex vivo biopsy specimens, we are currently developing a handheld device for in vivo imaging that will provide immediate microscopic guidance to high-resolution anoscopy providers.

Compensatory upregulation of MT2A alleviates neurogenic intermittent claudication through inhibiting activated p38 MAPK-mediated neuronal apoptosis.

Neurogenic intermittent claudication (NIC), a classic symptom of lumbar spinal stenosis (LSS), is associated with neuronal apoptosis. To explore the novel therapeutic target of NIC treatment, we constructed the rat model of NIC by cauda equina compression (CEC) method and collected dorsal root ganglion (DRG) tissues, a region responsible for sensory and motor function, for mRNA sequencing. Bioinformatic analysis of mRNA sequencing indicated that upregulated metallothionein 2A (MT2A), an apoptosis-regulating gene belonging to the metallothionein family, might participate in NIC progression. Activated p38 MAPK mediated motor dysfunction following LSS and it was also found in DRG tissues of rats with NIC. Therefore, we supposed that MT2A might affect NIC progression by regulating p38 MAPK pathway. Then the rat model of NIC was used to explore the exact role of MT2A. Rats at day 7 post-CEC exhibited poorer motor function and had two-fold MT2A expression in DRG tissues compared with rats with sham operation. Co-localization analysis showed that MT2A was highly expressed in neurons, but not in microglia or astrocytes. Subsequently, neurons isolated from DRG tissues of rats were exposed to hypoxia condition (3% O2, 92% N2, 5% CO2) to induce cell damage. Gain of MT2A function in neurons was performed by lentivirus-mediated overexpression. MT2A overexpression inhibited apoptosis by inactivating p38 MAPK in hypoxia-exposed neurons. Our findings indicated that high MT2A expression was related to NIC progression, and MT2A overexpression protected against NIC through inhibiting activated p38 MAPK-mediated neuronal apoptosis in DRG tissues.

Global burden and trends of acute viral hepatitis among children and adolescents from 1990 to 2019: a systematic analysis of the Global Burden of Disease Study 2019.

BACKGROUND: Children and adolescents are at high risk for acute viral hepatitis (AVH), but epidemiological research focusing on them has been overshadowed by adult chronic B and C. We provide global, regional, and national estimates of the AVH burden and their trends on people under 20 years from 1990 to 2019. METHODS: AVH data from Global Burden of Disease Study (GBD) 2019 was used. Incidence and disability-adjusted life years (DALYs) were calculated, analyzing trends with estimated annual percentage change (EAPC) and Joinpoint regression. RESULTS: In 2019, 156.39 (95% uncertainty interval 145.20-167.16) million new cases of AVH were reported among children and adolescents globally, resulting in 1.98 (1.50-2.55) million DALYs. Incidence rates for young children (< 5 years), older children (5-9 years), and adolescents (10-19 years) were 12,799 (11,068-14,513), 5,108 (4829-5411), and 3020 (2724-3339) per 100,000 population, respectively. The global AVH incidence displayed a linear decline with an EAPC of - 0.66 (- 0.68 to - 0.65). High-incidence regions included sub-Saharan Africa, Oceania, South Asia, and Central Asia, with India, Pakistan, and Nigeria facing the greatest burden. Leading causes were hepatitis A, followed by hepatitis E, B, and C. All hepatitis types showed declining trends, especially hepatitis B. Furthermore, we confirmed the association between the AVH incidence and the socioeconomics, vaccine, and advanced liver diseases. CONCLUSION: Effective vaccines and treatments for hepatitis B and C offer eradication opportunities. Broadening diagnostic and therapeutic coverage is vital to address disparities in service provision for children and adolescents.

Computed Tomography-Based Radiomics to Predict FOXM1 Expression and Overall Survival in Patients with Clear Cell Renal Cell Carcinoma.

RATIONALE AND OBJECTIVES: To establish a computed tomography (CT)-based radiomics model to predict Fork head box M1(FOXM1) expression levels and develop a combined model for prognostic prediction in patients with clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: A total of 529 patients were utilized to assess the prognostic significance of FOXM1 expression and were subsequently categorized into low and high FOXM1 expression groups. 184 patients with CT images were randomly divided into training and validation cohorts. Radiomics signature (Rad-score) for predicting FOXM1 expression level was developed in the training cohort. The predictive performance was evaluated using receiver operating characteristic (ROC) curves. A clinical model based on clinical factors and a combined model incorporating clinical factors and Rad-score were developed to predict ccRCC prognosis using Cox regression analyses. The concordance index(C-index) was employed to assess and compare the predictive capabilities of the Rad-score, TNM stage, clinical model, and combined model. The likelihood ratio test was used to compare the models' performance. RESULTS: The Rad-score demonstrated high predictive accuracy for high FOXM1 expression with areas under the ROC curves of 0.713 and 0.711 in the training and validation cohorts. In the training cohort, the C-indexes for the Rad-score, TNM Stage, clinical model, and combined model were 0.657, 0.711, 0.737, and 0.741, respectively. Correspondingly, in the validation cohort, the C-indexes were 0.670, 0.712, 0.736, and 0.745. The combined model had the highest C-index, significantly outperforming the other models. CONCLUSION: The Rad-score accurately predicts FOXM1 expression levels and is an independent prognostic factor for ccRCC.

MX1 and UBE2L6 are potential metaflammation gene targets in both diabetes and atherosclerosis.

Background: The coexistence of diabetes mellitus (DM) and atherosclerosis (AS) is widespread, although the explicit metabolism and metabolism-associated molecular patterns (MAMPs) responsible for the correlation are still unclear. Methods: Twenty-four genetically wild-type male Ba-Ma mini pigs were randomly divided into five groups distinguished by different combinations of 90 mg/kg streptozotocin (STZ) intravenous injection and high-cholesterol/lipid (HC) or high-lipid (HL) diet feeding for 9 months in total. Pigs in the STZ+HC and STZ+HL groups were injected with STZ first and then fed the HC or HL diet for 9 months. In contrast, pigs in the HC+STZ and HL+STZ groups were fed the HC or HL diet for 9 months and injected with STZ at 3 months. The controls were only fed a regular diet for 9 months. The blood glucose and abdominal aortic plaque observed through oil red O staining were used as evaluation indicators for successful modelling of DM and AS. A microarray gene expression analysis of all subjects was performed. Results: Atherosclerotic lesions were observed only in the HC+STZ and STZ+HC groups. A total of 103 differentially expressed genes (DEGs) were identified as common between them. The most significantly enriched pathways of 103 common DEGs were influenza A, hepatitis C, and measles. The global and internal protein-protein interaction (PPI) networks of the 103 common DEGs consisted of 648 and 14 nodes, respectively. The top 10 hub proteins, namely, ISG15, IRG6, IRF7, IFIT3, MX1, UBE2L6, DDX58, IFIT2, USP18, and IFI44L, drive aspects of DM and AS. MX1 and UBE2L6 were the intersection of internal and global PPI networks. The expression of MX1 and UBE2L6 was 507.22 ± 342.56 and 96.99 ± 49.92 in the HC+STZ group, respectively, which was significantly higher than others and may be linked to the severity of hyperglycaemia-related atherosclerosis. Further PPI network analysis of calcium/micronutrients, including MX1 and UBE2L6, consisted of 58 and 18 nodes, respectively. The most significantly enriched KEGG pathways were glutathione metabolism, pyrimidine metabolism, purine metabolism, and metabolic pathways. Conclusions: The global and internal PPI network of the 103 common DEGs consisted of 648 and 14 nodes, respectively. The intersection of the nodes of internal and global PPI networks was MX1 and UBE2L6, suggesting their key role in the comorbidity mechanism of DM and AS. This inference was partly verified by the overexpression of MX1 and UBE2L6 in the HC+STZ group but not others. Further calcium- and micronutrient-related enriched KEGG pathway analysis supported that MX1 and UBE2L6 may affect the inflammatory response through micronutrient metabolic pathways, conceptually named metaflammation. Collectively, MX1 and UBE2L6 may be potential common biomarkers for DM and AS that may reveal metaflammatory aspects of the pathological process, although proper validation is still needed to determine their contribution to the detailed mechanism.

Mechanistic insight into glioma through spatially multidimensional proteomics.

Characterizing the tumor microenvironment at the molecular level is essential for understanding the mechanisms of tumorigenesis and evolution. However, the specificity of the blood proteome in localized region of the tumor and its linkages with other systems is difficult to investigate. Here, we propose a spatially multidimensional comparative proteomics strategy using glioma as an example. The blood proteome signature of tumor microenvironment was specifically identified by in situ collection of arterial and venous blood from the glioma region of the brain for comparison with peripheral blood. Also, by integrating with different dimensions of tissue and peripheral blood proteomics, the information on the genesis, migration, and exchange of glioma-associated proteins was revealed, which provided a powerful method for tumor mechanism research and biomarker discovery. The study recruited multidimensional clinical cohorts, allowing the proteomic results to corroborate each other, reliably revealing biological processes specific to gliomas, and identifying highly accurate biomarkers.

NONO promotes gallbladder cancer cell proliferation by enhancing oncogenic RNA splicing of DLG1 through interaction with IGF2BP3/RBM14.

Gallbladder cancer (GBC) is a highly malignant and rapidly progressing tumor of the human biliary system, and there is an urgent need to develop new therapeutic targets and modalities. Non-POU domain-containing octamer-binding protein (NONO) is an RNA-binding protein involved in the regulation of transcription, mRNA splicing, and DNA repair. NONO expression is elevated in multiple tumors and can act as an oncogene to promote tumor progression. Here, we found that NONO was highly expressed in GBC and promoted tumor cells growth. The dysregulation of RNA splicing is a molecular feature of almost all tumor types. Accordingly, mRNA-seq and RIP-seq analysis showed that NONO promoted exon6 skipping in DLG1, forming two isomers (DLG1-FL and DLG1-S). Furthermore, lower Percent-Spliced-In (PSI) values of DLG1 were detected in tumor tissue relative to the paraneoplastic tissue, and were associated with poor patient prognosis. Moreover, DLG1-S and DLG1-FL act as tumor promoters and tumor suppressors, respectively, by regulating the YAP1/JUN pathway. N6-methyladenosine (m6A) is the most common and abundant RNA modification involved in alternative splicing processes. We identified an m6A reader, IGF2BP3, which synergizes with NONO to promote exon6 skipping in DLG1 in an m6A-dependent manner. Furthermore, IP/MS results showed that RBM14 was bound to NONO and interfered with NONO-mediated exon6 skipping of DLG1. In addition, IGF2BP3 disrupted the binding of RBM14 to NONO. Overall, our data elucidate the molecular mechanism by which NONO promotes DLG1 exon skipping, providing a basis for new therapeutic targets in GBC treatment.

Association between regulatory T cells and ischemic heart disease: a Mendelian randomization study.

Background: An imbalance of innate and acquired immune responses is significantly involved in the pathophysiology of coronary atherosclerosis and the occurrence of ischemic heart disease (IHD). Regulatory T cells (Tregs) play an essential regulatory role in atherosclerotic plaque formation and maintenance; therefore, dysfunction of Tregs triggers the formation of atherosclerotic plaques and accelerates their progression. However, due to the inherent limitations of observational research, clinical evidence is limited concerning the relationship between the variation in peripheral Tregs and the risk of IHD, and the cause-and-effect relationship between these factors is unclear. Mendelian randomization (MR) uses genetic variation as a proxy for exposure and can be used to inferentially determine the causal effect of exposure on outcomes. We thus used MR analysis to investigate whether there is a causal relationship between the biomarkers of Tregs and IHD. Methods: Selected genetic variants (P<5.00E-08) from the summary data of a genome-wide association study (GWAS) were used to conduct a two-sample bidirectional MR analysis. The analysis included 51 extensive Treg subtypes involving 3,757 individuals from the general population. Summary statistics of IHD were obtained from the IEU open GWAS project, which contains 30,952 cases and 187,845 controls. The populations in both GWAS studies were of European ancestry. Results: We identified a set of 197 single-nucleotide polymorphisms (SNPs) that served as instrumental variables (IVs) for evaluating 51 Treg subtypes. Thirteen significant variables were found to be potentially associated with IHD. After false-discovery rate (FDR) adjustment, we identified four Treg subtypes to be causally protective for IHD risk: CD28 on activated & secreting CD4 Tregs [odds ratio (OR) =0.89; 95% confidence interval (CI): 0.82-0.96; P=3.10E-03; adjusted P=0.04], CD28 on activated CD4 Tregs (OR =0.87; 95% CI: 0.80-0.95; P=3.10E-03; adjusted P=0.04), CD28 on CD4 Tregs (OR =0.87; 95% CI: 0.80-0.96; P=3.41E-03; adjusted P=0.04), and CD28 on resting CD4 Treg cell (OR =0.91; 95% CI: 0.85-0.97; P=3.48E-03; adjusted P=0.04). Reverse MR analysis found eight potential causal variables, but these associations were nonsignificant after FDR correction (all adjusted P values >0.05). Conclusions: This study identified the significance of elevated CD28 expression on CD4 Tregs as a novel molecular modifier that may influence IHD occurrence, suggesting that targeting CD28 expression on CD4 Tregs could offer a promising therapeutic approach for IHD.

The positional consistency between guidewire and cannulated or solid screw in robot-assisted spinal internal fixation surgery.

BACKGROUND: This study aimed to investigate the positional consistency between the guidewire and the screw in spinal internal fixation surgery. METHODS: This study involved 64 patients who underwent robot-assisted thoracic or lumbar pedicle screw fixation surgery. Guidewires were inserted with the assistance of the Tirobot. Either cannulated screws or solid screws were inserted. Guidewire and screw accuracy was measured using CT images based on the Gertzbein and Robbins scale. The positional consistency between guidewire and screw was evaluated based on the fused CT images, which could graphically and quantitatively demonstrate the consistency. The consistency was evaluated based on a grading system that considered the maximum distance and angulation between the centerline of the guidewire and the screw in the region of the pedicle. RESULTS: A total of 322 screws were placed including 206 cannulated ones and 116 solid ones. Based on the Gertzbein and Robbins scale, 97.5% of the guidewires were grade A, and 94.1% of the screws were grade A. Based on our guidewire-screw consistency scale, 85% in cannulated group, and 69.8% in solid group, were grade A. Both solid and cannulated screws may alter trajectory compared to the guidewires. The positional accuracy and guidewire-screw consistency in the solid screw group is significantly worse than that in the cannulated screw group. The cortical bone of the pedicle has a positive guide effect on either solid or cannulated screws. CONCLUSION: The pedicle screws may alter trajectory despite the guidance of the guidewires. Solid screws show worse positional accuracy and guidewire-screw consistency compared with cannulated screws. Trial registration The study was retrospectively registered and approved by our center's institutional review board.

A nomogram based on clinical multivariate factors predicts delayed cure after microvascular decompression for hemifacial spasm.

BACKGROUND: The course of disease after microvascular decompression (MVD) in patients with hemifacial spasm (HFS) is variable. The purpose of this study was to develop and validate a nomogram to predict the probability of delayed cure after microvascular decompression in patients with hemifacial spasms based on clinical multivariate factors. METHODS: A retrospective data collection was performed on 290 patients with HFS undergoing MVD at our center from January 2017 to January 2022. The patients were randomly assigned to the training cohort (n = 232) and validation cohort (n = 58) at a ratio of 8:2. Retrospective analysis was performed of information on clinical, radiological, and intraoperative findings and clinical outcomes. Univariate and multivariate analyses were performed in the training cohort, and a nomogram was constructed using a stepwise logistic regression approach. The receiver operating characteristic (ROC) was calculated to evaluate the reliability of the nomogram model. Decision curve analysis (DCA) was used to assess the clinical application value of the nomogram model. RESULTS: In the training cohorts, 73 patients (73/232) had a delayed cure. In the validation cohorts, 18 patients (18/58) had a delayed cure. We developed a novel nomogram model to predict the risk of delayed cure after MVD in HFS patients based on the presence of vertebral artery compression, venous compression, absence of LSR, degree of facial nerve indentation, degree of neurovascular compression, and internal auditory canal vascular looThe area under the curve (AUC) of the nomogram model was 0.9483 in the training cohort and 0.9382 in the validation cohort. The calibration curve showed good correspondence between the predicted and actual probabilities in the training and validation groups. The decision curve showed that the nomogram model had good performance in clinical applications. CONCLUSIONS: We developed and validated a preoperative and intraoperative multivariate factors nomogram to predict the possibility of delayed cure after MVD in HFS patients, which may help clinicians in the comprehensive management of HFS.

MicroRNA-218-5p-Ddx41 axis restrains microglia-mediated neuroinflammation through downregulating type I interferon response in a mouse model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Microglia-mediated neuroinflammation has been largely considered one of main factors to the PD pathology. MicroRNA-218-5p (miR-218-5p) is a microRNA that plays a role in neurodevelopment and function, while its potential function in PD and neuroinflammation remains unclear. METHODS: We explore the involvement of miR-218-5p in the PD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model. The miR-218-5p agomir used for overexpression was delivered into the substantia nigra (SN) by bilateral stereotaxic infusions. The loss of dopaminergic (DA) neurons and microglial inflammation in the SN was determined using Western blotting and immunofluorescence. Motor function was assessed using the rotarod test. RNA sequencing (RNA-seq) was performed to explore the pathways regulated by miR-218-5p. The target genes of miR-218-5p were predicted using TargetScan and confirmed using dual luciferase reporter assays. The effects of miR-218-5p on microglial inflammation and related pathways were verified in murine microglia-like BV2 cells. To stimulate BV2 cells, SH-SY5Y cells were treated with 1-methyl-4-phenylpyridinium (MPP+) and the conditioned media (CM) were collected. RESULTS: MiR-218-5p expression was reduced in both the SN of MPTP-induced mice and MPP+-treated BV2 cells. MiR-218-5p overexpression significantly alleviated MPTP-induced microglial inflammation, loss of DA neurons, and motor dysfunction. RNA sequence and gene set enrichment analysis showed that type I interferon (IFN-I) pathways were upregulated in MPTP-induced mice, while this upregulation was reversed by miR-218-5p overexpression. A luciferase reporter assay verified that Ddx41 was a target gene of miR-218-5p. In vitro, miR-218-5p overexpression or Ddx41 knockdown inhibited the IFN-I response and expression of inflammatory cytokines in BV2 cells stimulated with MPP+-CM. CONCLUSIONS: MiR-218-5p suppresses microglia-mediated neuroinflammation and preserves DA neurons via Ddx41/IFN-I. Hence, miR-218-5p-Ddx41 is a promising therapeutic target for PD.

Molecular dynamics study of the mechanical properties of hydrated calcium silicate enhanced by functionalized carbon nanotubes.

CONTEXT: The incorporation of functionalized carbon nanotubes can enhance the mechanical properties of cement-based materials. However, the types of functional groups and their roles in composite materials are not yet clear. In this study, molecular dynamics (MD) simulation methods were employed to investigate the mechanical performance of hybridized calcium silicate hydrate gel reinforced with pure carbon nanotubes, epoxy-coated carbon nanotubes, carboxylated carbon nanotubes, and hydroxylated carbon nanotubes. The results indicate that the addition of all four types of nanotubes can enhance the mechanical properties of hydrated calcium silicate gel compared to pure C-S-H. Tensile loading results show that carbon nanotubes can act as bridges for microcracks in the composite material, and functionalized nanotubes exhibit a better reinforcing effect than pure carbon nanotubes. Under tensile stress, hydroxylated nanotubes are more effective in increasing the toughness of the composite material, while carboxylated nanotubes tend to enhance the strength of the composite material. The compressive loading results indicate that the compressive strength of cement-based materials is higher than their tensile strength. Overall, carboxylated nanotubes show particularly remarkable performance in enhancing the mechanical properties of cement-based materials. Compared to pure C-S-H gel, the tensile and compressive elastic moduli of carboxylated nanotube/C-S-H composite material increased by 18.13% and 34.78%, respectively. Its tensile and compressive strengths also increased by 30.40% and 40.23%, respectively. METHOD: All molecular dynamics simulations were performed on the classical computational simulation platform LAMMPS. In this paper, the parameters in the ClayFF force field are chosen to simulate calcium hydrated silicate (/C-S-H), and the ClayFF-CVFF combined force field is used to simulate the mechanical properties of the CNT/C-S-H molecular model structure.

Pedicle screw path planning for multi-level vertebral fixation.

BACKGROUND: For the spinal internal fixation procedures, connecting rods to the pedicle screws are commonly used in all spinal segments from the cervical to sacral spine. So far, we have only seen single vertebral screw trajectory planning methods in literatures. Joint screw placements in multi-level vertebrae with the constraint of an ipsilateral connecting rod are not considered. PURPOSE: In this paper, a screw trajectory planning method that considers screw-rod joint system with both multi-level vertebral constraints and individual vertebral safety tolerance are proposed. METHODS: The proposed method addresses three challenging constraints jointly for multi-level vertebral fixation with pedicle screws. First, a cylindrical screw safe passage model is suggested instead of a unique mathematical optimal trajectory for a single pedicle. Second, the flexible screw cap accessibility model is also included. Third, the connecting rod is modeled to accommodate the spine contour and support the needed gripping capacity. The retrospective clinical data of relative normal shape spines from Beijing Jishuitan hospital were used in the testing. The screw trajectories from the existing methods based on single vertebra and the proposed method based on multi-level vertebrae optimization are calculated and compared. RESULTS: The results showed that the calculated screw placements by the proposed method can achieve 88% success rate without breaking the pedicle cortex and 100% in clinical class A quality (allow less than 2 mm out of the pedicle cortex) compared to 86.1% and 99.1%, respectively, with the existing methods. Expert evaluation showed that the screw path trajectories and the connecting rod calculated by the new method satisfied the clinical implantation requirements. CONCLUSIONS: The new screw planning approach that seeks an overall optimization for multi-level vertebral fixation is feasible and more advantageous for clinical use than the single vertebral approaches.

Synaptic-like transmission between neural axons and arteriolar smooth muscle cells drives cerebral neurovascular coupling.

Neurovascular coupling (NVC) is important for brain function and its dysfunction underlies many neuropathologies. Although cell-type specificity has been implicated in NVC, how active neural information is conveyed to the targeted arterioles in the brain remains poorly understood. Here, using two-photon focal optogenetics in the mouse cerebral cortex, we demonstrate that single glutamatergic axons dilate their innervating arterioles via synaptic-like transmission between neural-arteriolar smooth muscle cell junctions (NsMJs). The presynaptic parental-daughter bouton makes dual innervations on postsynaptic dendrites and on arteriolar smooth muscle cells (aSMCs), which express many types of neuromediator receptors, including a low level of glutamate NMDA receptor subunit 1 (Grin1). Disruption of NsMJ transmission by aSMC-specific knockout of GluN1 diminished optogenetic and whisker stimulation-caused functional hyperemia. Notably, the absence of GluN1 subunit in aSMCs reduced brain atrophy following cerebral ischemia by preventing Ca2+ overload in aSMCs during arteriolar constriction caused by the ischemia-induced spreading depolarization. Our findings reveal that NsMJ transmission drives NVC and open up a new avenue for studying stroke.

Diosmin ameliorates LPS-induced depression-like behaviors in mice: Inhibition of inflammation and oxidative stress in the prefrontal cortex.

Diosmin is a flavone glycoside with a confirmed therapeutic effectiveness on the chronic venous disorders. In this paper, the classical mouse depression model induced by LPS was established to explore the effect of Diosmin on depression. Firstly, we found that Diosmin could inhibit the inflammation and neuronal damage in the prefrontal cortex (PFC) of mice, and thus alleviating the LPS-induced depressive-like behaviors. Specifically, Diosmin treatment significantly suppressed the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1ß), reduced the activation of microglia, and inhibited the expression of NLRP3 inflammasome and its downstream effector caspase-1 in both PFC of mice and BV2 microglial cells exposed to LPS. Then, we demonstrated that pretreatment with Diosmin dramatically suppressed the LPS-induced oxidative stress in the PFC of mice, manifested in the decrease of reactive oxygen species and malondialdehyde while increase of catalase activity. Consistently, Diosmin also alleviated the oxidative stress in BV2 cells exposed to LPS. Finally, we confirmed that Diosmin effectively suppressed the activation of NF-κB signaling pathway in the PFC of LPS-treated mice. Further in vitro experiments also verified that Diosmin could prevent the p65 transposition to nucleus in LPS-treated BV2 cells, suggesting that the antidepressant effects of Diosmin are partially mediated by blocking of NF-κB signaling. Taken together, this study proposes the potential antidepressant effect of Diosmin, which provides useful support to the development of new therapies for depression.

Grafting a Polymer Coating Layer onto Li1.2 Ni0.13 Co0.13 Mn0.54 O2 Cathode by Benzene Diazonium Salts to Facilitate the Cycling Performance and High-Voltage Stability.

Li-rich Mn-based cathodes have been regarded as promising cathodes for lithium-ion batteries because of their low cost of raw materials (compared with Ni-rich layer structure and LiCoO2 cathodes) and high energy density. However, for practical application, it needs to solve the great drawbacks of Li-rich Mn-based cathodes like capacity degradation and operating voltage decline. Herein, an effective method of surface modification by benzene diazonium salts to build a stable interface between the cathode materials and the electrolyte is proposed. The cathodes after modification exhibit excellent cycling performance (the retention of specific capacity is 84.2% after 350 cycles at the current density of 1 C), which is mainly attributed to the better stability of the structure and interface. This work provides a novel way to design the coating layer with benzene diazonium salts for enhancing the structural stability under high voltage condition during cycling.

Enhanced heterogeneous interface to construct intelligent conductive hydrogel gas sensor for individualized treatment of infected wounds.

In this study, we developed an enhanced heterogeneous interface intelligent conductive hydrogel NH3 sensor for individualized treatment of infected wounds. The sensor achieved monitoring, self-diagnosis, and adaptive gear adjustment functions. The PPY@PDA/PANI(3/6) sensor had a minimum NH3 detection concentration of 50 ppb and a response value of 2.94 %. It also had a theoretical detection limit of 49 ppt for infected wound gas. The sensor exhibited a fast response time of 23.2 s and a recovery time of 42.9 s. Tobramycin (TOB) was encapsulated in a self-healing QCS/OD hydrogel formed by quaternized chitosan (QCS) and oxidized dextran (OD), followed by the addition of polydopamine-coated polypyrrole nanowires (PPY@PDA) and polyaniline (PANI) to prepare electrically conductive drug-loaded PPY@PDA/PANI hydrogels. The drug-loaded PPY@PDA/PANI hydrogel was combined with a PANI/PVDF membrane to form an enhanced heterogeneous interfacial PPY@PDA/PANI/PVDF-based sensor, which could adaptively learn the individual wound ammonia response and adjust the speed of drug release from the PPY@PDA/PANI hydrogel with electrical stimulation. Drug release and animal studies demonstrated the efficacy of the PPY@PDA/PANI hydrogel in inhibiting infection and accelerating wound healing. In conclusion, the gas-sensitive conductive hydrogel sensing system is expected to enable intelligent drug delivery and provide personalized treatment for complex wound management.