Oviductal Glycoprotein 1 Promotes Hypertension by Inducing Vascular Remodeling Through an Interaction With MYH9.

BACKGROUND: Hypertension is a common cardiovascular disease that is related to genetic and environmental factors, but its mechanisms remain unclear. DNA methylation, a classic epigenetic modification, not only regulates gene expression but is also susceptible to environmental factors, linking environmental factors to genetic modification. Therefore, globally screening differential genomic DNA methylation in patients with hypertension is important for investigating hypertension mechanisms. METHODS: Differential genomic DNA methylation in patients with hypertension, individuals with prehypertension, and healthy control individuals was screened using Illumina 450K BeadChip and verified by pyrosequencing. Plasma OVGP1 (oviduct glycoprotein 1) levels were determined using an enzyme-linked immunosorbent assay. Ovgp1 transgenic and knockout mice were generated to analyze the function of OVGP1. The blood pressure levels of the mouse models were measured using the tail-cuff system and radiotelemetry methods. The role of OVGP1 in vascular remodeling was determined by vascular relaxation studies. Protein-protein interactions were investigated using a pull-down/mass spectrometry assay and verified with coimmunoprecipitation and pull-down assays. RESULTS: We found a hypomethylated site at cg20823859 in the promoter region of OVGP1 and plasma OVGP1 levels were significantly increased in patients with hypertension. This finding indicates that OVGP1 is associated with hypertension. In Ovgp1 transgenic mice, OVGP1 overexpression caused an increase in blood pressure, dysfunctional vasoconstriction and vasodilation, remodeling of arterial walls, and increased vascular superoxide stress and inflammation, and these phenomena were exacerbated by angiotensin II infusion. In contrast, OVGP1 deficiency attenuated angiotensin II-induced vascular oxidase stress, inflammation, and collagen deposition. These findings indicate that OVGP1 is a prohypertensive factor that directly promotes vascular remodeling. Pull-down and coimmunoprecipitation assays showed that MYH9 (nonmuscle myosin heavy chain IIA) interacted with OVGP1, whereas inhibition of MYH9 attenuated OVGP1-induced hypertension and vascular remodeling. CONCLUSIONS: Hypomethylation at cg20823859 in the promoter region of OVGP1 is associated with hypertension and induces upregulation of OVGP1. The interaction between OVGP1 and MYH9 contributes to vascular remodeling and dysfunction. Therefore, OVGP1 is a prohypertensive factor that promotes vascular remodeling by binding with MYH9.

Coordinated Optimal Control of AFS and DYC for Four-Wheel Independent Drive Electric Vehicles Based on MAS Model.

The problem that it is difficult to balance vehicle stability and economy at the same time under the starting steering condition of a four-wheel independent drive electric vehicle (4WIDEV) is addressed. In this paper, we propose a coordinated optimal control method of AFS and DYC for a four-wheel independent drive electric vehicle based on the MAS model. Firstly, the angular velocity of the transverse pendulum at the center of mass and the lateral deflection angle of the center of mass are decoupled by vector transformation, and the two-degree-of-freedom eight-input model of the vehicle is transformed into four two-degree-of-freedom two-input models, and the reduced-dimensional system is regarded as four agents. Based on the hardware connection structure and communication topology of the four-wheel independent drive electric vehicle, the reduced-dimensional model of 4WIDEV AFS and DYC coordinated optimal control is established based on graph theory. Secondly, the deviation of the vehicle transverse swing angular velocity and mass lateral deflection angle from their ideal values is oriented by combining sliding mode variable structure control (SMC) with distributed model predictive control (DMPC). A discrete dynamic sliding mode surface function is proposed for the ith agent to improve the robustness of the system in response to parameter variations and disturbances. Considering the stability and economy of the ith agent, an active front wheel steering and drive torque optimization control method based on SMC and DMPC is proposed for engineering applications. Finally, a hardware-in-the-loop (HIL) test bench is built for experimental verification, and the results show that the steering angle is in the range of 0-5°, and the proposed method effectively weighs the system dynamic performance, computational efficiency, and the economy of the whole vehicle. Compared with the conventional centralized control method, the torque-solving speed is improved by 32.33 times, and the electrical consumption of the wheel motor is reduced by 16.6%.

ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology.

Blood-brain barrier (BBB) defects and cerebrovascular dysfunction contribute to amyloid-ß (Aß) brain accumulation and drive Alzheimer disease (AD) pathology. By regulating vascular functions and inflammation in the microvasculature, a disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) plays a significant protective effect in atherosclerosis and stroke. However, whether ADAMTS13 influences AD pathogenesis remains unclear. Using in vivo multiphoton microscopy, histological, behavioral, and biological methods, we determined BBB integrity, cerebrovascular dysfunction, amyloid accumulation, and cognitive impairment in APPPS1 mice lacking ADAMTS13. We also tested the impact of viral-mediated expression of ADAMTS13 on cerebrovascular function and AD-like pathology in APPPS1 mice. We show that ADAMTS13 deficiency led to an early and progressive BBB breakdown as well as reductions in vessel density, capillary perfusion, and cerebral blood flow in APPPS1 mice. We found that deficiency of ADAMTS13 increased brain plaque load and Aß levels and accelerated cerebral amyloid angiopathy (CAA) by impeding BBB-mediated clearance of brain Aß, resulting in worse cognitive decline in APPPS1 mice. Virus-mediated expression of ADAMTS13 attenuated BBB disruption and increased microvessels, capillary perfusion, and cerebral blood flow in APPPS1 mice already showing BBB damage and plaque deposition. These beneficial vascular effects were reflected by increase in clearance of cerebral Aß, reductions in Aß brain accumulation, and improvements in cognitive performance. Our results show that ADAMTS13 deficiency contributes to AD cerebrovascular dysfunction and the resulting pathogenesis and cognitive deficits and suggest that ADAMTS13 may offer novel therapeutic opportunities for AD.

Response to netarsudil in goniotomy-treated eyes and goniotomy-naïve eyes: a pilot study.

PURPOSE: To compare the intraocular pressure (IOP)-lowering effects of netarsudil on goniotomy-treated eyes versus goniotomy-naïve control eyes. METHODS: Retrospective cohort study of 70 eyes from 49 adult glaucoma patients treated with netarsudil. Thirty-five eyes received sectoral goniotomy using Kahook Dual Blade (KDB) combined with cataract surgery with minimum of 3 months prior to netarsudil treatment. Thirty-five eyes in the control cohort received only cataract surgery prior to netarsudil. Primary outcome was treatment success, defined as ≥ 20% decrease in IOP at minimum 1 month follow-up. Secondary outcome measures included percent of IOP reduction, adverse effects of medication, medication discontinuation rate, and relationship between KDB goniotomy response and netarsudil response. RESULTS: Eighty-three percent of KDB-treated eyes achieved netarsudil treatment success compared to 54% of control eyes (P = .012). IOP reduction was 30.3 ± 16.2% (IQR 21-38%) in KDB-treated eyes and 19.4 ± 12.4% (IQR 9.2-30.8) in control eyes (P = .007). History of prior KDB increased the likelihood of success to netarsudil treatment compared to eyes without prior KDB, regardless of surgical response to KDB (odds ratio 4.51, 95% CI 1.34-15.14, P = .015). The overall rate of adverse effects of netarsudil was 42%, most commonly reported as conjunctival hyperemia, allergy, and blurred vision. CONCLUSIONS: Netarsudil had a greater IOP-lowering effect in eyes treated with prior goniotomy and may serve as a promising adjunctive ocular hypotensive agent to further reduce IOP in eyes with prior goniotomy.

ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery.

Angiogenic response is essential for ischemic brain repair. The von Willebrand factor (VWF)-cleaving protease disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) is required for endothelial tube formation in vitro, but there is currently no in vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited reduced neovascularization, brain capillary perfusion, pericyte and smooth muscle cell coverage on microvessels, expression of the tight junction and basement membrane proteins, and accelerated blood-brain barrier (BBB) breakdown and extravascular deposits of serum proteins in the peri-infarct cortex at 14 days after stroke. Deficiency of VWF or anti-VWF antibody treatment significantly increased microvessels, perfused capillary length, and reversed pericyte loss and BBB changes in Adamts13-/- mice. Furthermore, we observed that ADAMTS13 deficiency decreased angiopoietin-2 and galectin-3 levels in the isolated brain microvessels, whereas VWF deficiency had the opposite effect. Correlating with this, overexpression of angiopoietin-2 by adenoviruses treatment or administration of recombinant galectin-3 normalized microvascular reductions, pericyte loss, and BBB breakdown in Adamts13-/- mice. The vascular changes induced by angiopoietin-2 overexpression and recombinant galectin-3 treatment in Adamts13-/- mice were abolished by the vascular endothelial growth factor receptor-2 antagonist SU1498. Importantly, treating wild-type mice with recombinant ADAMTS13 at 7 days after stroke markedly increased neovascularization and vascular repair and improved functional recovery at 14 days. Our results suggest that ADAMTS13 controls key steps of ischemic vascular remodeling and that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery.

Recombinant ADAMTS 13 Attenuates Brain Injury After Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Inflammatory responses and blood-brain barrier (BBB) dysfunction play important roles in brain injury after intracerebral hemorrhage (ICH). The metalloprotease ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type I motif, member 13) was shown to limit inflammatory responses through its proteolytic effects on von Willebrand factor. In the present study, we addressed the role of ADAMTS 13 after experimental ICH. METHODS: ICH was induced in mice by intracerebral infusion of autologous blood. The peri-hematomal inflammatory responses, levels of matrix metalloproteinase-9 and intercellular adhesion molecule-1, pericyte coverage on brain capillaries, and BBB permeability were quantified at 24 hours. Functional outcomes, cerebral edema, and hemorrhagic lesion volume were quantified at day 3. RESULTS: Treatment with recombinant ADAMTS 13 (rADAMTS 13) reduced the levels of chemokines and cytokines, myeloperoxidase activity, and microglia activation and neutrophil recruitment after ICH. rADAMTS 13 also decreased interleukin-6 expression in brain endothelial cells stimulated by lipopolysaccharide, whereas recombinant von Willebrand factor reversed this effect. The anti-inflammatory effect of rADAMTS 13 was accompanied by reduced expression of intercellular adhesion molecule-1 and less activation of matrix metalloproteinase, enhanced pericyte coverage of brain microvessels, and attenuated BBB disruption. Furthermore, neutrophil depletion protected against BBB damage, and rADAMTS 13 treatment had no further beneficial effect. Finally, treatment of mice with rADAMTS 13 reduced cerebral edema and hemorrhagic lesion volume and improved neurological functions. CONCLUSIONS: Our findings reveal the importance of rADAMTS 13 in regulating pathological inflammation and BBB function and suggest that rADAMTS 13 may provide a new therapeutic strategy for ICH.

Caspase-3 modulates regenerative response after stroke.

Stroke is a leading cause of long-lasting disability in humans. However, currently there are still no effective therapies available for promoting stroke recovery. Recent studies have shown that the adult brain has the capacity to regenerate neurons after stroke. Although this neurogenic response may be functionally important for brain repair after injury, the mechanisms underlying stroke-induced neurogenesis are not known. Caspase-3 is a major executioner and has been identified as a key mediator of neuronal death in the acute stage of stroke. Recently, however, accumulating data indicate that caspase-3 also participates in various biological processes that do not cause cell death. Here, we show that cleaved caspase-3 was increased in newborn neuronal precursor cells (NPCs) in the subventricular zone (SVZ) and the dentate gyrus during the period of stroke recovery, with no evidence of apoptosis. We observed that cleaved caspase-3 was expressed by NPCs and limited its self-renewal without triggering apoptosis in cultured NPCs from the SVZ of ischemic mice. Moreover, we revealed that caspase-3 negatively regulated the proliferation of NPCs through reducing the phosphorylation of Akt. Importantly, we demonstrated that peptide inhibition of caspase-3 activity significantly promoted the proliferation and migration of SVZ NPCs and resulted in a significant increase in subsequent neuronal regeneration and functional recovery after stroke. Together, our data identify a previously unknown caspase-3-dependent mechanism that constrains stroke-induced endogenous neurogenesis and should revitalize interest in targeting caspase-3 for treatment of stroke.

Creation and cost-evaluation of a student-run podcast in ophthalmology.

Podcasts are an increasingly popular medical education modality, especially in surgical fields. However, the cost of developing a high-quality medical education podcast presents a barrier to many content creators. The authors developed the podcast series 'The Lenspod,' designed to be a cost-efficient but high-quality education resource in ophthalmology. The REC financial framework has been previously used to estimate the financial costs of technology-based medical education. Using this framework, costs were competitive with other medical education podcasts. It is our hope that similar methodology may be used to create and disseminate future podcasts for medical education.

Les balados sont une modalité d'enseignement médical de plus en plus populaire, en particulier dans les domaines chirurgicaux. Cependant, le coût de création d'un balado éducatif de qualité en médecine constitue un obstacle pour de nombreux créateurs de contenu. Les auteurs sont les créateurs de la série de balados The Lenspod, qui se veut une ressource éducative à la fois rentable et de qualité en ophtalmologie. Appliquant le cadre financier REC, déjà utilisé pour estimer les coûts financiers de modes d'enseignement médical basés sur la technologie, nous avons constaté que les coûts de notre balado sont compétitifs par rapport à d'autres en éducation médicale. Nous espérons qu'une méthode similaire sera utilisée pour créer et diffuser davantage de balados éducatifs en médecine.

Netarsudil as a Predictor of Response for MicroPulse Transscleral Laser Therapy: A Pilot Study.

PURPOSE: To investigate the role of netarsudil as an outcome predictor of MicroPulse transscleral laser therapy (MPTLT). DESIGN: Retrospective comparative study. SUBJECTS: Forty-seven eyes in 33 adult patients with glaucoma with a minimum of 1 month of follow-up after netarsudil treatment and 3 months of follow-up after MPTLT were included. Eyes receiving intraocular pressure (IOP)-lowering procedures in the interim were excluded. INTERVENTION: Ophthalmic eyedrops of netarsudil at 0.02%, followed by MPTLT treatment. MAIN OUTCOME MEASURES: Correlation of success between netarsudil and MPTLT. Netarsudil success was defined as an IOP reduction ≥ 20% from baseline, whereas MPTLT success was defined as an IOP reduction ≥ 20% without additional IOP-lowering medications. Secondary outcomes included success rates, mean IOP reduction, adverse effects after each treatment, and netarsudil discontinuation rate. RESULTS: We found a positive correlation between the netarsudil response and the subsequent MPTLT response (odds ratio, 3.73; 95% confidence interval, 1.05-13.24; P = 0.041). Among netarsudil responders, 73.7% (14/19) of eyes subsequently responded to MPTLT, whereas among netarsudil nonresponders, 42.8% (12/28) of eyes subsequently responded to MPTLT (P = 0.037). From netarsudil, 44.4% of eyes were successful; from MPTLT, 55.3% of eyes were successful. The mean IOP reductions were 2.83 ± 5.74 mmHg from netarsudil and 3.15 ± 6.43 mmHg from MPTLT. Overall, the rate of netarsudil discontinuation was 55.3%. The most common reasons for netarsudil discontinuation were adverse effects (48.9%), followed by high cost (19.1%). The most common adverse effects to netarsudil were conjunctival hyperemia (48.9%) and blurred vision (8.5%). There were no adverse events reported after MPTLT. After MPTLT, 29.8% of eyes required additional IOP-lowering procedures. CONCLUSIONS: The netarsudil response may serve as a predictive marker of the MPTLT response, with over 70% of netarsudil responders subsequently responding favorably to MPTLT in this study.

Lysyl hydroxylase 1 (LH1) deficiency promotes angiotensin II (Ang II)-induced dissecting abdominal aortic aneurysm.

Rationale: The progressive disruption of extracellular matrix (ECM) proteins, particularly early elastin fragmentation followed by abnormalities in collagen fibril organization, are key pathological processes that contribute to dissecting abdominal aortic aneurysm (AAA) pathogenesis. Lysyl hydroxylase 1 (LH1) is essential for type I/III collagen intermolecular crosslinking and stabilization. However, its function in dissecting AAA has not been explored. Here, we investigated whether LH1 is significantly implicated in dissecting AAA progression and therapeutic intervention. Methods and Results: Sixteen-week-old male LH1-deficient and wild-type (WT) mice on the C57Bl/6NCrl background were infused with angiotensin II (Ang II, 1000 ng/kg per minute) via subcutaneously implanted osmotic pumps for 4 weeks. Ang II increased LH1 levels in the abdominal aortas of WT mice, whereas mice lacking LH1 developed dissecting AAA. To evaluate the related mechanism, we performed whole-transcriptomic analysis, which demonstrated that LH1 deficiency aggravated gene transcription alterations; in particular, the expression of thrombospondin-1 was markedly upregulated in the aortas of LH1-deficient mice. Furthermore, targeting thrombospondin-1 with TAX2 strongly inhibited the proinflammatory process, matrix metalloproteinase (MMP) activity and vascular smooth muscle cells (VSMCs) apoptosis, ultimately decreasing the incidence of dissecting AAA. Restoration of LH1 protein expression in LH1-deficient mice by intraperitoneal injection of an adeno-associated virus normalized thrombospondin-1 levels, subsequently alleviating dissecting AAA formation and preserving aortic structure and function. Consistently, in human AAA specimens, decreased LH1 expression was associated with increased thrombospondin-1 levels. Conclusions: LH1 deficiency contributes to dissecting AAA pathogenesis, at least in part, by upregulating thrombospondin-1 expression, which subsequently enables proinflammatory processes, MMP activation and VSMCs apoptosis. Our study provides evidence that LH1 is a potential critical therapeutic target for AAA.

Metabolomic Characterization of Fatty Acids in Patients With Coronary Artery Ectasias.

Background: We used a targeted metabolomics approach to identify fatty acid (FA) metabolites that distinguished patients with coronary artery ectasia (CAE) from healthy Controls and patients with coronary artery disease (CAD). Materials and methods: Two hundred fifty-two human subjects were enrolled in our study, such as patients with CAE, patients with CAD, and Controls. All the subjects were diagnosed by coronary angiography. Plasma metabolomic profiles of FAs were determined by an ultra-high-performance liquid chromatography coupled to triple quadrupole mass spectrometric (UPLC-QqQ-MS/MS). Results: Ninety-nine plasma metabolites were profiled in the discovery sets (n = 72), such as 35 metabolites of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), 10 FAs, and 54 phospholipids. Among these metabolites, 36 metabolites of AA, EPA, and DHA showed the largest difference between CAE and Controls or CAD. 12-hydroxyeicosatetraenoic acid (12-HETE), 17(S)-hydroxydocosahexaenoic acid (17-HDoHE), EPA, AA, and 5-HETE were defined as a biomarker panel in peripheral blood to distinguish CAE from CAD and Controls in a discovery set (n = 72) and a validation set (n = 180). This biomarker panel had a better diagnostic performance than metabolite alone in differentiating CAE from Controls and CAD. The areas under the ROC curve of the biomarker panel were 0.991 and 0.836 for CAE versus Controls and 1.00 and 0.904 for CAE versus CAD in the discovery and validation sets, respectively. Conclusions: Our findings revealed that the metabolic profiles of FAs in the plasma from patients with CAE can be distinguished from those of Controls and CAD. Differences in FAs metabolites may help to interpret pathological mechanisms of CAE.

Identification of circular RNA expression profiles and potential biomarkers for intracerebral hemorrhage.

Aim: To investigate the expression profiles of circRNAs after intracerebral hemorrhage (ICH). Materials & methods: RNA sequencing and qRT-PCR were used to investigate and validate circRNA expression levels. Bioinformatics analysis was performed to explore potential functions of the circRNAs. Results: Expression levels of 15 circRNAs were consistently altered in patients with ICH compared with their expression levels in hypertension. Three circRNAs, hsa_circ_0001240, hsa_circ_0001947 and hsa_circ_0001386, individually or combined, were confirmed as promising biomarkers for predicting and diagnosing ICH. The circRNAs were involved mainly in lysine degradation and the immune system. Conclusion: This is the first study to report expression profiles of circRNAs after ICH and to propose that three circRNAs are potential biomarkers for ICH.

A latent topic model with Markov transition for process data.

We propose a latent topic model with a Markov transition for process data, which consists of time-stamped events recorded in a log file. Such data are becoming more widely available in computer-based educational assessment with complex problem-solving items. The proposed model can be viewed as an extension of the hierarchical Bayesian topic model with a hidden Markov structure to accommodate the underlying evolution of an examinee's latent state. Using topic transition probabilities along with response times enables us to capture examinees' learning trajectories, making clustering/classification more efficient. A forward-backward variational expectation-maximization (FB-VEM) algorithm is developed to tackle the challenging computational problem. Useful theoretical properties are established under certain asymptotic regimes. The proposed method is applied to a complex problem-solving item in the 2012 version of the Programme for International Student Assessment (PISA).

Neutrophil extracellular traps released by neutrophils impair revascularization and vascular remodeling after stroke.

Neovascularization and vascular remodeling are functionally important for brain repair after stroke. We show that neutrophils accumulate in the peri-infarct cortex during all stages of ischemic stroke. Neutrophils producing intravascular and intraparenchymal neutrophil extracellular traps (NETs) peak at 3-5 days. Neutrophil depletion reduces blood-brain barrier (BBB) breakdown and enhances neovascularization at 14 days. Peptidylarginine deiminase 4 (PAD4), an enzyme essential for NET formation, is upregulated in peri-ischemic brains. Overexpression of PAD4 induces an increase in NET formation that is accompanied by reduced neovascularization and increased BBB damage. Disruption of NETs by DNase 1 and inhibition of NET formation by genetic ablation or pharmacologic inhibition of PAD increases neovascularization and vascular repair and improves functional recovery. Furthermore, PAD inhibition reduces stroke-induced STING-mediated production of IFN-ß, and STING knockdown and IFN receptor-neutralizing antibody treatment reduces BBB breakdown and increases vascular plasticity. Collectively, our results indicate that NET release impairs vascular remodeling during stroke recovery.

Oleic Acid Attenuates Ang II (Angiotensin II)-Induced Cardiac Remodeling by Inhibiting FGF23 (Fibroblast Growth Factor 23) Expression in Mice.

Plasma metabolic profiles were compared between patients with hypertension with and without left ventricular hypertrophy and significantly decreased oleic acid (OA) levels were observed in the peripheral blood of patients with hypertension with left ventricular hypertrophy. We sought to determine the effect and underlying mechanisms of OA on cardiac remodeling. In vitro studies with isolated neonatal mouse cardiomyocytes and cardiac fibroblasts revealed that OA significantly attenuated Ang II (angiotensin II)-induced cardiomyocyte growth and cardiac fibroblast collagen expression. In vivo, cardiac function, hypertrophic growth of cardiomyocytes, and fibrosis were analyzed after an Ang II (1000 ng/kg/minute) pump was implanted for 14 days. We found that OA could significantly prevent Ang II-induced cardiac remodeling in mice. RNA sequencing served as a gene expression roadmap highlighting gene expression changes in the hearts of Ang II-induced mice and OA-treated mice. The results revealed that FGF23 (fibroblast growth factor 23) expression was significantly upregulated in mouse hearts in response to Ang II infusion, which was significantly suppressed in the hearts of OA-treated mice. Furthermore, overexpression of FGF23 in the heart by injection of an AAV-9 vector aggravated Ang II-induced cardiac remodeling and impaired the protective effect of OA on cardiac remodeling. Further study found that OA could suppress Ang II-induced FGF23 expression by inhibiting the translocation of Nurr1 (nuclear receptor-related 1 protein) from the cytoplasm to the nucleus. Our findings suggest a novel role of OA in preventing Ang II-induced cardiac remodeling via suppression of FGF23 expression.

mtDNA Copy Number Contributes to All-Cause Mortality of Lacunar Infarct in a Chinese Prospective Stroke Population.

The study aimed to investigate the relationship between mtDNA copy number and the risk of all-cause mortality in stroke. One thousand four hundred eighty-four stroke patients were documented including 273 deaths (127 thrombosis, 52 lacunar, 94 hemorrhage). Patients in the third quartile had the lowest mortality rates in overall stroke and the three subtypes. The lowest quartile of mtDNA copy number (Q1 < 85.85) indicated an increased risk of all-cause mortality in stroke patients (adjusted HR, 1.52; 95% CI, 1.08-2.14; p = 0.017). In the subtype analysis, the risk of all-cause mortality appeared only in lacunar infarct, and the patients in the Q1 (< 87.76) and Q4 (> 150.61) mtDNA copy number groups showed significantly higher risks of HRs (Q1, adjusted HR, 3.87, 95% CI, 1.52-9.83; Q4, adjusted HR, 3.08, 95% CI, 1.16-8.18). Stroke patients with lacunar infarct in mtDNA copy number < 87.76 or > 150.61 were at a high risk of poor outcomes in all-cause mortality.

Low Serum Uric Acid Levels Promote Hypertensive Intracerebral Hemorrhage by Disrupting the Smooth Muscle Cell-Elastin Contractile Unit and Upregulating the Erk1/2-MMP Axis.

Intracerebral hemorrhage (ICH) is a catastrophic stroke with high mortality, and the mechanism underlying ICH is largely unknown. Previous studies have shown that high serum uric acid (SUA) levels are an independent risk factor for hypertension, cardiovascular disease (CVD), and ischemic stroke. However, our metabolomics data showed that SUA levels were lower in recurrent intracerebral hemorrhage (R-ICH) patients than in ICH patients, indicating that lower SUA might contribute to ICH. In this study, we confirmed the association between low SUA levels and the risk for recurrence of ICH and for cardiac-cerebral vascular mortality in hypertensive patients. To determine the mechanism by which low SUA effects ICH pathogenesis, we developed the first low SUA mouse model and conducted transcriptome profiling of the cerebrovasculature of ICH mice. When combining these assessments with pathological morphology, we found that low SUA levels led to ICH in mice with angiotensin II (Ang II)-induced hypertension and aggravated the pathological progression of ICH. In vitro, our results showed that p-Erk1/2-MMP axis were involved in the low UA-induce degradation of elastin, and that physiological concentrations of UA and p-Erk1/2-specific inhibitor exerted a protective role. This is the first report describing to the disruption of the smooth muscle cell (SMC)-elastin contractile units in ICH. Most importantly, we revealed that the upregulation of the p-Erk1/2-MMP axis, which promotes the degradation of elastin, plays a vital role in mediating low SUA levels to exacerbate cerebrovascular rupture during the ICH process.

Alterations of gut microbiota contribute to the progression of unruptured intracranial aneurysms.

Unruptured intracranial aneurysm (UIA) is a life-threatening cerebrovascular condition. Whether changes in gut microbial composition participate in the development of UIAs remains largely unknown. We perform a case-control metagenome-wide association study in two cohorts of Chinese UIA patients and control individuals and mice that receive fecal transplants from human donors. After fecal transplantation, the UIA microbiota is sufficient to induce UIAs in mice. We identify UIA-associated gut microbial species link to changes in circulating taurine. Specifically, the abundance of Hungatella hathewayi is markedly decreased and positively correlated with the circulating taurine concentration in both humans and mice. Consistently, gavage with H. hathewayi normalizes the taurine levels in serum and protects mice against the formation and rupture of intracranial aneurysms. Taurine supplementation also reverses the progression of intracranial aneurysms. Our findings provide insights into a potential role of H. hathewayi-associated taurine depletion as a key factor in the pathogenesis of UIAs.

Overexpression of LH3 reduces the incidence of hypertensive intracerebral hemorrhage in mice.

Hypertensive intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease with no effective treatment. Lysyl hydroxylase 3 (LH3) is essential for collagen IV intermolecular crosslinking and stabilization. Deficiency in LH3 affects the assembly and secretion of collagen IV and basement membrane (BM) integrity of vessels. Here, we investigated whether LH3 has significant implications for disease progression and therapeutic intervention. Spontaneous hypertensive ICH of mice was induced by angiotensin II and L-NAME treatment. The adeno-associated virus was delivered into brain by stereotactic injection to knockdown or overexpress LH3. We found LH3 levels were reduced in human patients with ICH and gradually decreased in mice before ICH. LH3 knockdown increased the incidence of hypertensive ICH in mice. The incidence, number, and size of ICHs in mice were markedly reduced by LH3 overexpression. RNA-seq revealed that LH3 overexpression significantly reversed the profound alterations in gene transcriptional profiles of cerebral vessels. LH3 overexpression was sufficient to enhance BM integrity, inhibit matrix metalloproteinase activity, attenuate microglial activation and leukocyte infiltration, and reduce VSMC apoptosis before ICH. These results indicate that LH3 overexpression attenuates susceptibility to hypertensive ICH. We emphasize that LH3 modulation may serve as a viable approach for future investigations of ICH prevention.

Wireless Patrol Sign-In System with Mental Fatigue Detection.

Current sign-in methods of patrolling security guards mainly comprise signature, image identification, and fingerprint identification; notably, none of these methods indicate the physical and mental conditions of such guards. In particular, when patrolling security guards perform their duties consecutively for a long period of time, adequate attention should be directed toward their levels of mental fatigue. When a handwriting sign-in system is adopted, security guards may not record their sign-in time accurately, or they may fake signatures during long shifts. In addition, image identification systems cannot comprehensively reflect the physical and mental statuses of on-duty security guards, particularly their levels of fatigue. Monitor fatigue in patrolling security guards is important to avoid burnout and stress in the workplace. Therefore, in this study, a patrolling sign-in system that integrates physiological signals and images was designed. A thermometer, hand dynamometer, and electromyography sensor were combined to measure physiological signals. Results showed that hand grip strength and the median frequency of electromyography signals gradually reduced when muscle fatigue occurred. The system determined whether a security guard had signed in punctually and whether this person should stay on duty. Overall, this system was verified to operate effectively, and it is therefore applicable for monitoring the sign-in of patrolling security guards who work long shifts. This case series study proposed a conceptual prototype of the system; large-scale testing should be performed in subsequent research.