DNA methylation regulator-mediated modification patterns and risk of intracranial aneurysm: a multi-omics and epigenome-wide association study integrating machine learning, Mendelian randomization, eQTL and mQTL data.

BACKGROUND: Intracranial aneurysms (IAs) pose a significant and intricate challenge. Elucidating the interplay between DNA methylation and IA pathogenesis is paramount to identify potential biomarkers and therapeutic interventions. METHODS: We employed a comprehensive bioinformatics investigation of DNA methylation in IA, utilizing a transcriptomics-based methodology that encompassed 100 machine learning algorithms, genome-wide association studies (GWAS), Mendelian randomization (MR), and summary-data-based Mendelian randomization (SMR). Our sophisticated analytical strategy allowed for a systematic assessment of differentially methylated genes and their implications on the onset, progression, and rupture of IA. RESULTS: We identified DNA methylation-related genes (MRGs) and associated molecular pathways, and the MR and SMR analyses provided evidence for potential causal links between the observed DNA methylation events and IA predisposition. CONCLUSION: These insights not only augment our understanding of the molecular underpinnings of IA but also underscore potential novel biomarkers and therapeutic avenues. Although our study faces inherent limitations and hurdles, it represents a groundbreaking initiative in deciphering the intricate relationship between genetic, epigenetic, and environmental factors implicated in IA pathogenesis.

Development and validation of a deep learning model for prediction of intracranial aneurysm rupture risk based on multi-omics factor.

OBJECTIVE: The clinical ability of radiomics to predict intracranial aneurysm rupture risk remains unexplored. This study aims to investigate the potential uses of radiomics and explore whether deep learning (DL) algorithms outperform traditional statistical methods in predicting aneurysm rupture risk. METHODS: This retrospective study included 1740 patients with 1809 intracranial aneurysms confirmed by digital subtraction angiography at two hospitals in China from January 2014 to December 2018. We randomly divided the dataset (hospital 1) into training (80%) and internal validation (20%). External validation was performed using independent data collected from hospital 2. The prediction models were developed based on clinical, aneurysm morphological, and radiomics parameters by logistic regression (LR). Additionally, the DL model for predicting aneurysm rupture risk using integration parameters was developed and compared with other models. RESULTS: The AUCs of LR models A (clinical), B (morphological), and C (radiomics) were 0.678, 0.708, and 0.738, respectively (all p < 0.05). The AUCs of the combined feature models D (clinical and morphological), E (clinical and radiomics), and F (clinical, morphological, and radiomics) were 0.771, 0.839, and 0.849, respectively. The DL model (AUC = 0.929) outperformed the machine learning (ML) (AUC = 0.878) and the LR models (AUC = 0.849). Also, the DL model has shown good performance in the external validation datasets (AUC: 0.876 vs 0.842 vs 0.823, respectively). CONCLUSION: Radiomics signatures play an important role in predicting aneurysm rupture risk. DL methods outperformed conventional statistical methods in prediction models for the rupture risk of unruptured intracranial aneurysms, integrating clinical, aneurysm morphological, and radiomics parameters. KEY POINTS: • Radiomics parameters are associated with the rupture risk of intracranial aneurysms. • The prediction model based on integrating parameters in the deep learning model was significantly better than a conventional model. • The radiomics signature proposed in this study could guide clinicians in selecting appropriate patients for preventive treatment.

Contrast-induced encephalopathy following endovascular treatment for intracranial aneurysms-risk factors analysis and clinical strategy.

PURPOSE: Contrast-induced encephalopathy (CIE) was defined as new onset of neurological deficits after exposure to contrast media, which could be observed after the endovascular treatment for intracranial aneurysms. METHODS: We enrolled a consecutive cohort of patients who underwent endovascular treatment for unruptured intracranial aneurysms. CIE was defined as a reversible neuropathic syndrome that occurred after interventional therapy, accompanied by imaging abnormalities and excluding other diseases. Multivariable Poisson regression analysis was performed to show risk factors by incidence rate ratio (IRR) and a clinical strategy was proposed. RESULTS: Among the 579 patients who underwent interventional therapy for intracranial aneurysms, the crude incidence rate of CIE was 2.4% (95% CI, 1.2-3.6%) at our center. Headache, hemiplegia, and disorientation could be initial symptoms, and cortical blindness was the most common localized deficit. Cerebral edema and sulci effacement on CT were observed, and re-revaluation after treatments on CT/MRI showed absent lesions. The risk factors were history of stroke (IRR, 7.752; P = 0.007), history of hypertension (IRR, 1.064; P = 0.042), posterior circulation aneurysms (IRR, 9.412; P = 0.004) and higher dosage of contrast agents (IRR, 1.018; P = 0.007). After the strategy of accelerating excretion of contrast agents, reduction of intracranial pressure and anti-inflammation/vasospasm therapy, the prognosis was favorable with most patients fully recovered within 72 h. CONCLUSION: History of stroke and posterior circulation aneurysms were main risk factors for CIE. A higher dosage of contrast agents might induce CIE, and the history of hypertension should be considered as well.

Pial arteriovenous fistula resembling the vein of Galen aneurysmal malformation, treated with staged endovascular embolization: a case report.

A 41-month-old boy was presented to our hospital because of an intracranial mass suspected of cerebrovascular malformation. He was admitted and received cerebral angiography. The angiography result confirmed the intracranial mass was the dilated vein of Galen resulting from a pial arteriovenous fistula, which quite resembling the vein of Galen aneurysmal malformation. Considering one-time embolization of the fistula may greatly change the distribution of intracranial blood flow, we decided to perform staged embolization. In the first stage, we partially embolized the fistula, resulting in a sharp decrease in blood flow to the lesion. The second intervention was performed one month later, and completely embolized the fistula. The boy recoverd well and returned to normal childhood without any neurological deficits. Follow-up MR images obtained at 10 months after the last procedure showing total obliteration of the pAVF, gradually shrinking of the varix, and remodeling of the vein of Galen.

Controllable Synthesis, Formation Process, and Luminescence Performances of Diverse Yttrium Compounds with Hollow Structures.

Hollow spherical Y2O3 and YBO3 have been prepared by a facile template-directed strategy using phenol-formaldehyde (PF) resin spheres as templates. The PF@Y(OH)CO3 precursor can be fabricated by a simple precipitation route. The Y2O3 hollow spheres are obtained via a direct annealing process, and the hollow spherical YBO3 are fabricated via a hydrothermal route followed by an annealing process at the expense of the same PF@Y(OH)CO3 precursor. The whole synthesis procedure is performed in aqueous solution without any surfactant or catalyst. Moreover, YVO4 quasi-octahedral microcrystals with spherical holes are obtained. The formation mechanisms of the yttrium compounds with different morphologies have been discussed. By incorporating proper rare earth activator ions into the Y2O3, YBO3, and YVO4 hosts, the as-synthesized luminescent materials can exhibit eminent performances with both down-conversion and up-conversion luminescence. Furthermore, the as-fabricated light-emitting diode (LED) devices can emit dazzling characteristic emission light, which reveals that the phosphors have application potential in lighting and displays. This simple synthesis strategy may provide a new idea for the fabrication of inorganic compounds with perfect hollow structures and excellent properties.

Microbial hydrogen "manufactory" for enhanced gas therapy and self-activated immunotherapy via reduced immune escape.

BACKGROUND: As an antioxidant, hydrogen (H2) can selectively react with the highly toxic hydroxyl radical (·OH) in tumor cells to break the balance of reactive oxygen species (ROS) and cause oxidative stress. However, due to the high diffusibility and storage difficulty of hydrogen, it is impossible to achieve long-term release at the tumor site, which highly limited their therapeutic effect. RESULTS: Photosynthetic bacteria (PSB) release a large amount of hydrogen to break the balance of oxidative stress. In addition, as a nontoxic bacterium, PSB could stimulate the immune response and increase the infiltration of CD4+ and CD8+ T cells. More interestingly, we found that hydrogen therapy induced by our live PSB did not lead to the up-regulation of PD-L1 after stimulating the immune response, which could avoid the tumor immune escape. CONCLUSION: Hydrogen-immunotherapy significantly kills tumor cells. We believe that our live microbial hydrogen production system provides a new strategy for cancer hydrogen treatment combining with enhanced immunotherapy without up-regulating PD-L1.

Incomplete occlusion and visual symptoms of peri-ophthalmic aneurysm after treatment with a pipeline embolization device: a multi-center cohort study.

OBJECTIVE: Peri-ophthalmic aneurysm is a special type of aneurysm. We assessed the relationship between ophthalmic artery (OA) origin and aneurysm and examined the effect of a pipeline embolization device (PED, Covidien/Medtronic) with or without coils on aneurysm occlusion rate and visual outcomes. METHODS: We retrospectively analyzed 194 peri-ophthalmic aneurysms in 189 patients among 1171 patients treated with a PED in a Chinese post-market multi-center registry study from November 2014 to October 2019. Peri-ophthalmic aneurysms were defined as carotid-ophthalmic segment aneurysms arising from the internal carotid artery dorsal wall at, or distal to, the OA origin, with a superior or superomedial projection. The relationship between OA origin and the aneurysm was classified as follows: type A, OA originating separate from the aneurysm; type B, OA originating from the aneurysm neck or dome. Patients with aneurysm were divided into the PED-only group and the PED + coils group according to treatment. RESULTS: The median follow-up time was 6.8 months (range, 5.3-20.2 months). There were 163 occluded aneurysms (84%) and 31 aneurysms with incomplete occlusion (16%). A multivariate analysis showed that type B aneurysm was a risk factor for incomplete occlusion in the PED-only group (odds ratio [OR] 4.854, 95% confidence interval [CI] 1.878-12.548, P = 0.001). Visual symptoms at final follow-up correlated with preoperative visual symptoms (OR 22.777, 95% CI 3.115-166.555, P = 0.002). CONCLUSIONS: Type B aneurysm is associated with a lower occlusion rate after PED-only treatment. Patients with preoperative visual symptoms should be treated promptly to avoid permanent visual symptoms.

Effect of Adjusted Antiplatelet Therapy on Preventing Ischemic Events After Stenting for Intracranial Aneurysms.

BACKGROUND AND PURPOSE: This study tests whether patients with unruptured intracranial aneurysm who underwent stent placement benefitted from platelet function monitoring-guided adjustment of antiplatelet therapy. METHODS: We conducted a randomized, open-label, parallel group, assessor-blinded trial. Patients with unruptured intracranial aneurysm who underwent stent placement were assigned in a 1:1 ratio to receive either drug adjustment (patients who had high on-treatment platelet reactivity to antiplatelet therapy on the basis of platelet function monitoring [monitoring group]) or conventional therapy (without monitoring and drug adjustment [conventional group]). The second monitoring was performed 14 days after randomization in patients with drug adjustment. The primary outcome was the composite frequency of ischemic stroke, transient ischemic attack, stent thrombosis, urgent revascularization, and cerebrovascular death within 7 days after stent implantation. The safety outcome was the composite frequency of major, minor, or minimal bleeding within 1 month after stent implantation. RESULTS: In total, 314 patients were included (n=157 per group). The primary combined outcome occurred in 19 patients (12.1%) in the conventional group and 8 patients (5.1%) in the monitoring group (hazard ratio, 0.39 [95% CI, 0.17-0.92]; P=0.03). Ischemic stroke occurred at a lower frequency in the monitoring group compared with that in the conventional group (4.5% versus 12.1%; hazard ratio, 0.34 [95% CI, 0.14-0.83]; P=0.01), which drove the overall primary combined outcome. The safety outcome occurred in the monitoring group (7.0%) and in the conventional group (1.9%; hazard ratio, 3.87 [95% CI, 1.06-14.14]; P=0.03). A significant difference was observed in the frequency of minor or minimal bleeding events between the two groups (monitoring group versus conventional group, 6.4% versus 1.3%; P=0.02) but not in the frequency of major bleeding events between the two groups. CONCLUSIONS: Platelet function monitoring-guided antiplatelet therapy reduces thromboembolic events in patients with unruptured intracranial aneurysm after stent placement, significantly enhancing minor or minimal bleeding events but not major bleeding events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03989557.

Discrimination of intracranial aneurysm rupture status: patient-specific inflow boundary may not be a must-have condition in hemodynamic simulations.

BACKGROUND: Computational fluid dynamics (CFD) are important in evaluating the hemodynamics of intracranial aneurysm rupture, and the setting of inflow boundary conditions is critical. We evaluated intracranial aneurysm hemodynamics based on generalized versus patient-specific inflow boundary conditions to examine the effect of different hemodynamic results on the discrimination of intracranial aneurysm rupture status. METHODS: We enrolled 148 patients with 156 intracranial aneurysms. For each included aneurysm, we performed CFD simulation once based on patient-specific and once based on generalized inflow boundary conditions. First, we compared the hemodynamics of intracranial aneurysms based on different inflow boundary conditions. Then, we divided the included aneurysms into a ruptured and unruptured group and compared the hemodynamics between the two groups under patient-specific and generalized inflow boundary conditions. RESULTS: For the hemodynamic parameters using specific inflow boundary conditions, more complex flow (p = 0.002), larger minimum WSS (p = 0.024), lower maximum low WSS area (LSA) (p = 0.038), and oscillatory shear index (p = 0.002) were found. Furthermore, we compared the hemodynamics between ruptured and unruptured groups based on different inflow boundary conditions. We found that the significant hemodynamic parameters associated with rupture status were the same, including the proportion of aneurysms with flow complex and unstable flow and the minimum and maximum of LSA (p = 0.011, p = 0.003, p = 0.001 and p = 0.004, respectively). CONCLUSION: Patient-specific and generalized inflow boundary conditions of aneurysmal hemodynamics resulted in significant differences. However, the significant parameters associated with rupture status were the same in both conditions, indicating that patient-specific inflow boundary conditions may not be necessary for predicting rupture risk.

[Change laws of water absorption in Chinese herbal pieces and prediction model of relative density for Chinese medicine decoction].

This study aims to explore the change laws of water absorption in Chinese herbal pieces and establish the prediction model of relative density for Chinese medicine compound decoction. Firstly, fitted equations of water absorption and decocting time was established by observing the change laws of water absorption in 36 kinds of Chinese herbal pieces in 12 groups(according to the drug-parts) with decocting time. The r value of the mineral group and other type group was 0.691 2 and 0.663 3, respectively. The r value of the remaining 10 groups was 0.802 2-0.925 4. All P values were less than 0.05(n=21). The formula of the amount of water added was optimized by combining the fitted equations with determined water absorption, and the liquid yield could be controlled in a range of 100%±10%. Secondly, it was determined that the liquid density tester could be used for the rapid determination of relative density of Chinese medicine decoction after methodological study and comparison with the pycnometer method. The linear regression equation between the corrected relative density(y) and extraction ratio(%, x) was built by measuring and analyzing the related parameters such as liquid yield, relative density and extraction ratio in 46 kinds of Chinese herbal pieces. The established equation was y=0.041 3x+1.003 7, r=0.930 9(P <0.01, n=46), with linear range of 1.94%-65.75%. Based on this, the prototype model for predicting relative density of Chinese medicine decoction was established, and the relative densities of 8 Chinese medicine decoctions were within the prediction interval of this model in verification. This study lays a foundation for database construction of Chinese medicine decoction, implementation of personalized decocting mode and rapid quality control of Chinese medicine decoction.

[Finite element simulation of stent implantation and its applications in the interventional planning for hemorrhagic cardio-cerebrovascular diseases].

Numerical simulation of stent deployment is very important to the surgical planning and risk assess of the interventional treatment for the cardio-cerebrovascular diseases. Our group developed a framework to deploy the braided stent and the stent graft virtually by finite element simulation. By using the framework, the whole process of the deployment of the flow diverter to treat a cerebral aneurysm was simulated, and the deformation of the parent artery and the distributions of the stress in the parent artery wall were investigated. The results provided some information to improve the intervention of cerebral aneurysm and optimize the design of the flow diverter. Furthermore, the whole process of the deployment of the stent graft to treat an aortic dissection was simulated, and the distributions of the stress in the aortic wall were investigated when the different oversize ratio of the stent graft was selected. The simulation results proved that the maximum stress located at the position where the bare metal ring touched the artery wall. The results also can be applied to improve the intervention of the aortic dissection and the design of the stent graft.

Two-Step Oxidation Synthesis of Sulfur with a Red Aggregation-Induced Emission.

Sulfur is not normally considered a light-emitting material, even though there have been reports of a dim luminescence of this compound in the blue-to-green spectral region. Now, it is shown how to make red-emissive sulfur by a two-step oxidation approach using elemental sulfur and Na2 S as starting materials, with a high photoluminescence quantum yield of 7.2 %. Polysulfide is formed first and is partially transformed into Na2 S2 O3 in the first step, and then turns back to elemental S in the second step. The elevated temperature and relatively oxygen-deficient environment during the second step transforms Na2 S2 O3 into Na2 SO3 incorporated with oxygen vacancies, thus resulting in the formation of a solid-state powder consisting of elemental S embedded in Na2 SO3 . It shows aggregation-induced emission properties, attributed to the influence of oxygen vacancies on the emission dynamics of sulfur by providing additional lower energy states that facilitate the radiative relaxation of excitons.

Hemodynamic impacts of flow diverter devices on the ophthalmic artery.

BACKGROUND: Flow diverter devices are increasingly used for endovascular treatment of internal carotid artery aneurysms. Treatment of ophthalmic segment aneurysms with flow diverter devices also includes coverage of the ophthalmic artery but may result in complications. It is unclear, however, whether these devices mechanically block blood flow in the ophthalmic artery. Also unclear is the relationship between deployment of a flow diverter device and post-treatment occlusion. We studied hemodynamic changes in the ophthalmic artery after deployment of a flow diverter device to determine the relationship between those changes and post-stent occlusion of the artery. METHODS: We analyzed hemodynamic modifications in the ophthalmic artery in 21 patients (19 women, 2 men; mean age 53.43 ± 7.32 years) treated by a single pipeline embolization device. Patient-specific geometries were determined from three-dimensional digital subtraction angiography and the stenting process was simulated. Computational fluid dynamics technology was used to analyze the change in ophthalmic artery hemodynamics. We compared pre-treatment and post-treatment flow velocity of the ophthalmic artery. RESULTS: Among the 21 patients with aneurysms located in the ophthalmic segment, no ophthalmic artery occlusion was found during immediate or follow-up angiography. Post-stent flow velocity in the ophthalmic artery decreased from 0.35 ± 0.19 to 0.33 ± 0.20 m/s, with the difference not being statistically significant (P = 0.106). CONCLUSION: Our results showed no significant change in ophthalmic artery blood flow after pipeline embolization device deployment. Hence, post-stent occlusion of the ophthalmic artery could not be explained by reduced blood flow. Delayed thrombosis and neointimal formation maybe the keys to ophthalmic artery occlusion and need further investigation.

The natural course of unruptured intracranial aneurysms in a Chinese cohort: protocol of a multi-center registration study in CIAP.

BACKGROUND: Subarachnoid hemorrhage (SAH) accounts for 4.4% of cerebral vascular disease, which is one of the leading causes of death in China. Rupture of intracranial aneurysms (IAs) is the most common cause of SAH. The natural history of unruptured IAs (UIAs) and the risk factors for rupture are among the key issues regarding the pathogenesis of IA and SAH that remain unclear in the Chinese population. METHODS: The China Intracranial Aneurysm Project (CIAP) is a prospective, observational, multicenter registry study of the natural courses, risk factors for the onset and rupture, treatment methods, comorbidity management and other aspects of intracranial aneurysms. To date, there are five studies in the CIAP. CIAP-1 is a prospective observational cohort study of UIAs. More than 5000 patients who will be followed for at least 1 year are expected to be enrolled in this cohort. These participants come from more than 20 centers that represent different regions in China. Enrollment began on May 1, 2017, and will take approximately 5 years. A nationwide online database of UIAs will be built. Participants' basic, lifestyle, clinical and follow-up information will be collected. The blood samples will be stored in the Central Biological Specimen Bank. Strict standards have been established and will be followed in this study to ensure efficient implementation. DISCUSSION: The natural course of UIAs in the Chinese population will be explored in this registry study. In addition, the risk factors for the rupture of the UIAs and the joint effect of those factors will be analyzed. The present study aims to create a nationwide database of UIAs and investigate the natural course of UIAs in China. Trial registration The Natural Course of Unruptured Intracranial Aneurysms in a Chinese Cohort (ClinicalTrials.gov Identifier: NCT03117803). Registered: July 5, 2017.

Perturbations of BMP/TGF-ß and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM).

BACKGROUND: Brain arteriovenous malformations (BAVM) represent a congenital anomaly of the cerebral vessels with a prevalence of 10-18/100 000. BAVM is the leading aetiology of intracranial haemorrhage in children. Our objective was to identify gene variants potentially contributing to disease and to better define the molecular aetiology underlying non-syndromic sporadic BAVM. METHODS: We performed whole-exome trio sequencing of 100 unrelated families with a clinically uniform BAVM phenotype. Pathogenic variants were then studied in vivo using a transgenic zebrafish model. RESULTS: We identified four pathogenic heterozygous variants in four patients, including one in the established BAVM-related gene, ENG, and three damaging variants in novel candidate genes: PITPNM3, SARS and LEMD3, which we then functionally validated in zebrafish. In addition, eight likely pathogenic heterozygous variants (TIMP3, SCUBE2, MAP4K4, CDH2, IL17RD, PREX2, ZFYVE16 and EGFR) were identified in eight patients, and 16 patients carried one or more variants of uncertain significance. Potential oligogenic inheritance (MAP4K4 with ENG, RASA1 with TIMP3 and SCUBE2 with ENG) was identified in three patients. Regulation of sma- and mad-related proteins (SMADs) (involved in bone morphogenic protein (BMP)/transforming growth factor beta (TGF-ß) signalling) and vascular endothelial growth factor (VEGF)/vascular endotheliual growth factor recepter 2 (VEGFR2) binding and activity (affecting the VEGF signalling pathway) were the most significantly affected biological process involved in the pathogenesis of BAVM. CONCLUSIONS: Our study highlights the specific role of BMP/TGF-ß and VEGF/VEGFR signalling in the aetiology of BAVM and the efficiency of intensive parallel sequencing in the challenging context of genetically heterogeneous paradigm.

Leucine-induced promotion of post-absorptive EAA utilization and hepatic gluconeogenesis contributes to protein synthesis in skeletal muscle of dairy calves.

The high rate of protein synthesis in skeletal muscle of dairy calves can benefit their first lactation even lifetime milk yield. Since the rate of protein synthesis is relatively low in the post-absorptive state, the aim of this research was to determine whether leucine supplementation could increase the post-absorptive essential amino acid (EAA) utilization and protein synthesis in the skeletal muscle. Ten male neonatal dairy calves (38 ± 3 kg) were randomly assigned to either the control (CON, no leucine supplementation, n = 5) or supplementation with 1.435 g leucine/L milk (LEU, n = 5). Results showed that leucine significantly increased the length and protein concentration in longissimus dorsi (LD) muscle, whereas it decreased creatinine concentration and glutamic-oxalacetic transaminase (GOT) activity. Compared to the control group, leucine supplementation also reduced the glutamic-pyruvic transaminase (GPT) activity. Supplementation of leucine improved the phosphorylation of mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and substrates ribosomal protein S6 kinase 1 (p70S6K). Supplementation of leucine resulted in increased concentrations of glucose, methionine, threonine, histidine and EAAs and decreased concentration of arginine in serum. Liver glucose concentration was higher and pyranic acid was lower in LEU compared to CON. In conclusion, leucine supplementation can promote post-absorptive EAA utilization and hepatic gluconeogenesis, which contributes to protein synthesis in skeletal muscle of dairy calves.

China Intracranial Aneurysm Project (CIAP): protocol for a registry study on a multidimensional prediction model for rupture risk of unruptured intracranial aneurysms.

BACKGROUND: Ruptured aneurysms, the commonest cause of nontraumatic subarachnoid hemorrhage, can be catastrophic; the mortality and morbidity of affected patients being very high. Some risk factors, such as smoking, hypertension and female sex have been identified, whereas others, such as hemodynamics, imaging, and genomics, remain unclear. Currently, no accurate model that includes all factors for predicting such rupture is available. We plan to use data from a large cohort of Chinese individuals to set up a multidimensional model for predicting risk of rupture of unruptured intracranial aneurysms (UIAs). METHODS: The China Intracranial Aneurysm Project-2 (CIAP-2) will comprise screening of a cohort of 500 patients with UIA (From CIAP-1) and focus on hemodynamic factors, high resolution magnetic resonance imaging (HRMRI) findings, genetic factors, and biomarkers. Possible risk factors for rupture of UIA, including genetic factors, biomarkers, HRMRI, and hemodynamic factors, will be analyzed. The first project of the China Intracranial Aneurysm Project (CIAP-1; chaired by the Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China) will prospectively collect a cohort of 5000 patients with UIA from 20 centers in China, and collect baseline information for each patient. Multidimensional data will be acquired in follow-up assessments. Statistically significant clinical features in the UIA cohort will also be analyzed and integrated into the model for predicting risk of UIA rupture. After the model has been set up, the resultant evidence-based prediction will provide a preliminary theoretical basis for treating aneurysms at high risk of rupture. DISCUSSION: This study will explore the risk of rupture of aneurysms and develop a scientific multidimensional model for predicting rupture of unruptured intracranial aneurysms. Clinical Trials registration A Study on a Multidimensional Prediction Model for Rupture Risk of Unruptured Intracranial Aneurysms (CIAP-2), NCT03133624. Registered: 16 April 2017. https://clinicaltrials.gov/ct2/show/NCT03133624.

Whole-exome sequencing reveals known and novel variants in a cohort of intracranial vertebral-basilar artery dissection (IVAD).

Intracranial vertebral-basilar artery dissection (IVAD) is an arterial disorder leading to life-threatening consequences. Genetic factors are known to be causative to certain syndromic forms of IVAD. However, systematic study of the molecular basis of sporadic and isolated IVAD is lacking. To identify genetic variants contributing to the etiology of IVAD, we enrolled a cohort of 44 unrelated cases with a clinical diagnosis of isolated IVAD and performed whole-exome sequencing (WES) for all the participants; a trio exome sequencing approach was used when samples from both parents were available. Four previously reported disease-causing heterozygous variants (three in COL3A1 and one in FBN1) and seven novel heterozygous variants in IVAD-related genes were identified. In addition, six variants in novel IVAD genes including two de novo heterozygous nonsynonymous variants (each in VPS52 and CDK18), two stop-gain variants (each in MYH9 and LYL1), and two heterozygous biallelic variants in TNXB were considered to be possibly contributing to the phenotype, with unknown significance according to the existing knowledge. A significantly higher mutational rate of IVAD candidate genes was observed in patients versus our in-house controls (P = 0.002) (DISCO study, http://www.discostudy.org/ , n = 2248). Our study provided a mutational landscape for patients with isolated IVAD.

Shear Stress Induces Phenotypic Modulation of Vascular Smooth Muscle Cells via AMPK/mTOR/ULK1-Mediated Autophagy.

Phenotypic modulation of vascular smooth muscle cells (VSMCs) is involved in the pathophysiological processes of the intracranial aneurysms (IAs). Although shear stress has been implicated in the proliferation, migration, and phenotypic conversion of VSMCs, the molecular mechanisms underlying these events are currently unknown. In this study, we investigated whether shear stress(SS)-induced VSMC phenotypic modulation was mediated by autophagy involved in adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) pathway. The results show that shear stress could inhibit the expression of key VSMC contractile genes and induce pro-inflammatory/matrix-remodeling genes levels, contributing to VSMCs phenotypic switching from a contractile to a synthetic phenotype. More importantly, Shear stress also markedly increased the levels of the autophagy marker microtubule-associated protein light chain 3-II (LC3II), Beclin-1, and p62 degradation. The autophagy inhibitor 3-methyladenine (3-MA) significantly blocked shear-induced phenotypic modulation of VSMCs. To further explore the molecular mechanism involved in shear-induced autophagy, we found that shear stress could activate AMPK/mTOR/ULK1 signaling pathway in VSMCs. Compound C, a pharmacological inhibitor of AMPK, significantly reduced the levels of p-AMPK and p-ULK, enhanced p-mTOR level, and finally decreased LC3II and Beclin-1 level, which suggested that activated AMPK/mTOR/ULK1 signaling was related to shear-mediated autophagy. These results indicate that shear stress promotes VSMC phenotypic modulation through the induction of autophagy involved in activating the AMPK/mTOR/ULK1 pathway.

Effect of NF-kB signaling pathway on the expression of MIF, TNF-α, IL-6 in the regulation of intervertebral disc degeneration.

OBJECTIVE: Τo investigate the effect of NF-kB signaling pathway on the expression of MIF, TNF-α, and IL-6 in the regulation of disc degeneration. METHODS: The disc tissue was taken from 56 patients with cervical spondylosis. According to the preoperative MRI and intraoperative disc herniation, the patients were divided into two groups: degeneration group and herniation group. The control group was 34 patients with cervical trauma with no history of cervical spondylosis. According to the preoperative JOA scores of cervical spondylosis, patients were divided into three groups: mild, moderate and severe. ELISA was used to detect the expression of MIF, IL-6, and TNF-α in the cervical intervertebral disc. NF-kB mRNA expression in the intervertebral disc was detected by qRT-PCR. RESULTS: The expression levels of NF-kB mRNA, MIF, IL-6 and TNF-α in the control group were significantly higher than those in the degeneration group and the herniation group (p⟨0.05). There was a positive correlation between the expression of NF-kB mRNA, MIF, IL-6, TNF- and cervical intervertebral disc degeneration. The expression of MIF, IL-6, and TNF-α in the mild, moderate, and severe group was negatively correlated with the JOA score. CONCLUSIONS: The expressions of NF-kB, MIF, IL-6, and TNF-α in intervertebral disc tissue in patients with disc herniation were increased and related to the degree of disc herniation. It may play an important role in the pathophysiological process of disc herniation.