GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas.

Extra-axial cavernous hemangiomas (ECHs) are complex vascular lesions mainly found in the spine and cavernous sinus. Their removal poses significant risk due to their vascularity and diffuse nature, and their genetic underpinnings remain incompletely understood. Our approach involved genetic analyses on 31 tissue samples of ECHs employing whole-exome sequencing and targeted deep sequencing. We explored downstream signaling pathways, gene expression changes, and resultant phenotypic shifts induced by these mutations, both in vitro and in vivo. In our cohort, 77.4% of samples had somatic missense variants in GNA14, GNAQ, or GJA4. Transcriptomic analysis highlighted significant pathway upregulation, with the GNAQ c.626A>G (p.Gln209Arg) mutation elevating PI3K-AKT-mTOR and angiogenesis-related pathways, while GNA14 c.614A>T (p.Gln205Leu) mutation led to MAPK and angiogenesis-related pathway upregulation. Using a mouse xenograft model, we observed enlarged vessels from these mutations. Additionally, we initiated rapamycin treatment in a 14-year-old individual harboring the GNAQ c.626A>G (p.Gln209Arg) variant, resulting in gradual regression of cutaneous cavernous hemangiomas and improved motor strength, with minimal side effects. Understanding these mutations and their pathways provides a foundation for developing therapies for ECHs resistant to current therapies. Indeed, the administration of rapamycin in an individual within this study highlights the promise of targeted treatments in treating these complex lesions.

Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations.

Current treatments of brain arteriovenous malformation (BAVM) are associated with considerable risks and at times incomplete efficacy. Therefore, a clinically consistent animal model of BAVM is urgently needed to investigate its underlying biological mechanisms and develop innovative treatment strategies. Notably, existing mouse models have limited utility due to heterogenous and untypical phenotypes of AVM lesions. Here we developed a novel mouse model of sporadic BAVM that is consistent with clinical manifestations in humans. Mice with BrafV600E mutations in brain ECs developed BAVM closely resembled that of human lesions. This strategy successfully induced BAVMs in mice across different age groups and within various brain regions. Pathological features of BAVM were primarily dilated blood vessels with reduced vascular wall stability, accompanied by spontaneous hemorrhage and neuroinflammation. Single-cell sequencing revealed differentially expressed genes that were related to the cytoskeleton, cell motility, and intercellular junctions. Early administration of Dabrafenib was found to be effective in slowing the progression of BAVMs; however, its efficacy in treating established BAVM lesions remained uncertain. Taken together, our proposed approach successfully induced BAVM that closely resembled human BAVM lesions in mice, rendering the model suitable for investigating the pathogenesis of BAVM and assessing potential therapeutic strategies.

Preconception folic acid supplementation for the prevention of birth defects: a prospective, population-based cohort study in mainland China.

BACKGROUND: Folic acid supplementation is recommended for reducing the risk of birth defects. We aimed to assess the protective association of periconception folic acid supplements with birth defects in real-world setting. METHODS: This prospective, population-based cohort study utilized national preconception registered data of married Chinese couples planning a pregnancy within 6 months between 2010 and 2012 in Mainland China. Participated women are freely provided folic acid starting 3 months before conception till 3 months after conception. Birth defects were self-reported at 42 days postpartumn followup. R software (v4.0.2) was applied for statistical analyses. RESULTS: Complete data of 567,547 couples with pregnancy outcomes and folic acid supplementation were extracted for final analysis. A total of 74.7% women were with folic acid supplementation, and 599 birth defects were self-reported. The odd of birth defects was lower among women taking folic acid compared to their counterparts not taking (0.102% vs 0.116%, P < 0.001). In the multiple logistic regression analyses, the odd of birth defects was lower among couples with maternal folic acid supplementation (OR = 0.78, 95%CI: 0.66-0.95, P = 0.011), especially decreased odd of neural tube defects (NTDs) (OR = 0.56, 95%CI: 0.39-0.82, P = 0.003). This association was confirmed by 1:4 and 1:10 case control analysis. Odds of birth defects were significantly lower among women with folic acid supplementation more than 3 months before pregnancy (P < 0.001), and moreover, the odds of cleft (P = 0.007) and NTDs (P = 0.007) were of notable decrease. CONCLUSION: This retrospective case cohort study provides programmatic evidence for public health strategy-making to for reducing the risk of NTDs and clefts.

Delivery of a Hepatitis C Virus Vaccine Encoding NS3 Linked to the MHC Class II Chaperone Protein Invariant Chain Using Bacterial Ghosts.

Efficient delivery of a DNA plasmid into antigen-presenting cells (APCs) is a potential strategy to enhance the immune responses of DNA vaccines. The bacterial ghost (BG) is a potent DNA vaccine delivery system that targets APCs. In the present work, we describe a new strategy of using E. coli BGs as carriers for an Ii-linked Hepatitis C Virus (HCV) NS3 DNA vaccine that improved both the transgene expression level and the antigen-presentation level in APCs. BGs were prepared from DH5α cells, characterized via electron microscopy and loaded with the DNA vaccine. The high transfection efficiency mediated using BGs was first evaluated in vitro, and then, the immune protective effect of the BG-Ii-NS3 vaccine was determined in vivo. It was found that the antibody titer in the sera of BG-Ii-NS3-challenged mice was higher than that of Ii-NS3-treated mice, indicating that the BGs enhanced the humoral immune activity of Ii-NS3. The cellular immune protective effect of the BG-Ii-NS3 vaccine was determined using long-term HCV NS3 expression in a mouse model in which luciferase was used as a reporter for HCV NS3 expression. Our results showed that the luciferase activity in BG-Ii-NS3-treated mice was significantly reduced compared with that in Ii-NS3-treated mice. The CTL assay results demonstrated that BG-Ii-NS3 induced a greater NS3-specific T-cell response than did Ii-NS3. In summary, our study demonstrated that BGs enhanced both the humoral and cellular immune response to the Ii-NS3 DNA vaccine and improved its immune protection against HCV infection.

Influence of Engineering Parameters on Fracture Vertical Propagation in Deep Shale Reservoir: A Numerical Study Based on FEM.

The geometry of hydraulic fractures in deep shale facies is significantly affected by the longitudinal inhomogeneity of rock physical properties and stresses. Numerous studies have been conducted on the influence of the longitudinal inhomogeneity of rocks on fracture morphology. However, there is still a lack of research that simultaneously considers the reservoir dip, bedding plane interface, and longitudinal inhomogeneity of the reservoir. To fill this gap, a three-dimensional (3D) numerical model of multireservoir hydraulic fracturing, which takes into account the bedding plane interface, was developed using the finite element method (FEM). The Drucker-Prager elastic-plasticity criterion was incorporated to accurately represent the plasticity of deep shale. The research revealed the influence of the formation dip angle on fracture morphology. Additionally, the perforation layer position and pump rate were optimized based on the actual geological parameters in North Jiangsu shale reservoir. The study findings indicate that reservoir fractures with a formation dip are easily detected by the interface. However, it is not necessarily true that the larger the formation dip, the easier it is for fluids to enter the interface. Fracturing from high-strength and stress reservoirs to lower reservoirs promotes the propagation of fracture height and the connectivity of multiple reservoirs. On the other hand, fractures initiated from low-strength and stress reservoirs tend to be confined to adjacent reservoirs more easily. The pump rate significantly affects the vertical propagation of fractures. At high interface strength, fractures with pump rate below 2.4 m3/min can only propagate at the perforation layer. The limited fracture height in shale reservoirs is likely due to substantial energy consumption by the fracturing fluid at the bedding plane interface. These studies offer theoretical guidance for understanding the vertical propagation of fractures in a deep multilayer reservoir.

A Rapid In Vivo Toxicity Assessment Method for Antimicrobial Peptides.

Antimicrobial peptides (AMPs) represent a promising antibiotic alternative to overcome drug-resistant bacteria by inserting into the membrane of bacteria, resulting in cell lysis. However, therapeutic applications of AMPs have been hindered by their ability to lyse eukaryotic cells. GF-17 is a truncated peptide of LL-37, which has perfect amphipathicity and a higher hydrophobicity, resulting in higher haemolytic activity. However, there is no significant difference in the cytotoxicity against human lung epithelial cells between the GF-17 and LL-37 groups, indicating that there are significant differences in the sensitivity of different human cells to GF-17. In this study, LL-37 and GF-17 were administered to mouse lungs via intranasal inoculation. Blood routine examination results showed that LL-37 did not affect the red blood cells, platelet, white blood cells and neutrophil counts, but GF-17 decreased the white blood cells and neutrophil counts with the increasing concentration of peptides. GF-17-treated mice suffer a body weight loss of about 2.3 g on average in 24 h, indicating that GF-17 is highly toxic to mice. The total cell counts in the bronchoalveolar lavage fluid from GF-17-treated mice were 4.66-fold that in the untreated group, suggesting that GF-17 treatment leads to inflammation in the lungs of mice. Similarly, the histological results showed the infiltration of neutrophils in the lungs of GF-17-treated mice. The results suggest that the administration of GF-17 in the lungs of mice does not affect the red blood cells and platelet counts in the blood but promotes neutrophil infiltration in the lungs, leading to an inflammatory response. Therefore, we established a mouse acute lung injury model to preliminarily evaluate the in vivo toxicity of AMPs. For AMPs with a clinical application value, systematic research is still needed to evaluate their acute and long-term toxicity.

MAC: Maximal Cliques for 3D Registration.

This paper presents a 3D registration method with maximal cliques (MAC) for 3D point cloud registration (PCR). The key insight is to loosen the previous maximum clique constraint and mine more local consensus information in a graph for accurate pose hypotheses generation: 1) A compatibility graph is constructed to render the affinity relationship between initial correspondences. 2) We search for maximal cliques in the graph, each representing a consensus set. 3) Transformation hypotheses are computed for the selected cliques by the SVD algorithm and the best hypothesis is used to perform registration. In addition, we present a variant of MAC if given overlap prior, called MAC-OP. Overlap prior further enhances MAC from many technical aspects, such as graph construction with re-weighted nodes, hypotheses generation from cliques with additional constraints, and hypothesis evaluation with overlap-aware weights. Extensive experiments demonstrate that both MAC and MAC-OP effectively increase registration recall, outperform various state-of-the-art methods, and boost the performance of deep-learned methods. For instance, MAC combined with GeoTransformer achieves a state-of-the-art registration recall of 95.7% / 78.9% on 3DMatch / 3DLoMatch. We perform synthetic experiments on 3DMatch-LIR / 3DLoMatch-LIR, a dataset with extremely low inlier ratios for 3D registration in ultra-challenging cases. Code will be available at: https://github.com/zhangxy0517/3D-Registration-with-Maximal-Cliques.

Hemodynamics in nutcracker syndrome: implications for diagnosis.

BACKGROUND: Nutcracker syndrome is a disease characterized by complex symptoms, making its diagnosis challenging and often delayed, often resulting in a painful experience for the patients. OBJECTIVE: This study aimed to investigate the pathogenesis of nutcracker syndrome through the perspective of hemodynamics by simulating blood flow with varying compression degrees of the left renal vein. METHODS: 3D patient-specific vascular models of the abdominal aorta, superior mesenteric artery and left renal vein were constructed based on CT images of patients suspected of having nutcracker syndrome. A hemodynamic simulation was then conducted using computational fluid dynamics to identify the correlation between alterations in hemodynamic parameters and varying degrees of compression. RESULTS: The study indicated the presence of an evident gradient in velocity distribution over the left renal vein with relatively high degrees of stenosis (α ≤ 50°), with maximum velocity in the central region of the stenosis. Additionally, when the compression degree of the left renal vein increases, the pressure distribution of the left renal vein presents an increasing number of gradient layers. Furthermore, the wall shear stress shows a correlation with the variation of blood flow velocity, i.e., the increase of wall shear stress correlates with the acceleration of the blood flow velocity. CONCLUSIONS: Using computational fluid dynamics as a non-invasive instrument to obtain the hemodynamic characteristics of nutcracker syndrome is feasible and could provide insights into the pathological mechanisms of the nutcracker syndrome supporting clinicians in diagnosis.

Transcriptomic Signature of 3D Hierarchical Porous Chip Enriched Exosomes for Early Detection and Progression Monitoring of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly lethal malignant tumor, and the current non-invasive diagnosis method based on serum markers, such as α-fetoprotein (AFP), and des-γ-carboxy-prothrombin (DCP), has limited efficacy in detecting it. Therefore, there is a critical need to develop novel biomarkers for HCC. Recent studies have highlighted the potential of exosomes as biomarkers. To enhance exosome enrichment, a silicon dioxide (SiO2) microsphere-coated three-dimensional (3D) hierarchical porous chip, named a SiO2-chip is designed. The features of the chip, including its continuous porous 3D scaffold, large surface area, and nanopores between the SiO2 microspheres, synergistically improved the exosome capture efficiency. Exosomes from both non-HCC and HCC subjects are enriched using an SiO2-chip and performed RNA sequencing to identify HCC-related long non-coding RNAs (lncRNAs) in the exosomes. This study analysis reveales that LUCAT-1 and EGFR-AS-1 are two HCC-related lncRNAs. To further detect dual lncRNAs in exosomes, quantitative real time polymerase chain reaction (qRT-PCR) is employed. The integration of dual lncRNAs with AFP and DCP significantly improves the diagnostic accuracy. Furthermore, the integration of dual lncRNAs with DCP effectively monitors the prognosis of patients with HCC and detects disease progression. In this study, a liquid biopsy-based approach for noninvasive and reliable HCC detection is developed.

[Application of metronidazole combined with minocycline in reducing infection after dental implant in patients with localized periodontitis].

PURPOSE: To explore the value of metronidazole combined with minocycline in reducing infection after dental implant in patients with localized periodontitis. METHODS: A total of 120 patients with localized periodontitis who underwent dental implantation in the Department of Stomatological, Shanghai Pudong New Area People's Hospital from August 2021 to September 2022 were selected. According to the way of postoperative infection prevention, the patients were divided into control group and experimental group, with 60 patients in each group. The control group was orally given roxithromycin capsules, and the experimental group was locally coated with minocycline hydrochloride ointment and metronidazole gel. The incidence of postoperative infection and complications was compared between the two groups. The modified gingival creval bleeding index (mSBI), periodontal probing depth (PD) and modified plaque index (mPLI) of the patients were examined by periodontal probe. Serum C-reactive protein (CRP) level was determined by immunoturbidimetry and tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) level was determined by ELISA. SPSS 25.0 software package was used for statistical analysis of the data. RESULTS: Good healing rate of the experimental group was 91.67% higher than that of the control group 73.33%, postoperative infection rate was 8.33% and complication rate was 6.67% in the experimental group, significantly lower than that of the control group (26.67% and 20.00%), respectively (P＜0.05). After treatment, the level of CRP, TNF-α and IL-6 in the experimental group were significantly lower than those in the control group (P＜0.05). At 3 and 6 months after treatment, mSBI, mPLI and PD in the experimental group were significantly lower than those in the control group(P＜0.05). CONCLUSIONS: The administration of minocycline hydrochloride and metronidazole in patients with localized periodontitis undergoing implantation can reduce oral inflammatory response, reduce postoperative infection and other complications, and improve periodontal health.