Impact of total cerebral small vessel disease score on ophthalmic artery morphologies and hemodynamics.

BACKGROUND: Cerebral small vessel disease (CSVD) is a systemic disease, affecting not only the brain, but also eyes and other organs. The total CSVD score is a tool for comprehensive evaluation of brain lesions in patients with CSVD. The ophthalmic artery (OA) is a direct response to ocular blood flow. However, little is known about the correlation between CSVD and characteristics of OA. We investigated the OA morphologies and hemodynamics in patients with CSVD and the correlation between these changes and the total CSVD score. METHODS: This cross-sectional observational study included 34 eyes from 22 patients with CSVD and 10 eyes from 5 healthy controls. The total CSVD score was rated according to the CSVD signs on magnetic resonance imaging. OA morphological characteristics were measured on the basis of 3D OA model reconstruction. OA hemodynamic information was calculated using computational fluid dynamics simulations. RESULTS: The total CSVD score negatively correlated with the OA diameter, blood flow velocity, and mass flow ratio (all P < 0.05). After adjusting for potential confounding factors, the total CSVD score was still independently correlated with the OA blood velocity (ß = - 0.202, P = 0.005). The total CSVD score was not correlated with OA angle (P > 0.05). The presence of cerebral microbleeds and enlarged perivascular spaces was correlated with the OA diameter (both P < 0.01), while the lacunar infarcts and white matter hyperintensities were correlated with the OA blood velocity (both P < 0.001). CONCLUSIONS: The decrease of the blood velocity in the OA was associated with the increase in the total CSVD score. The changes of the OA diameter and velocity were associated with the presence of various CSVD signs. The findings suggest that more studies are needed in the future to evaluate CSVD by observing the morphologies and hemodynamics of OA.

[Mechanism of Marsdenia tenacissima against ovarian cancer based on network pharmacology and experimental verification].

The present study aimed to explore the main active components and underlying mechanisms of Marsdenia tenacissima in the treatment of ovarian cancer(OC) through network pharmacology, molecular docking, and in vitro cell experiments. The active components of M. tenacissima were obtained from the literature search, and their potential targets were obtained from SwissTargetPrediction. The OC-related targets were retrieved from Therapeutic Target Database(TTD), Online Mendelian Inheritance in Man(OMIM), GeneCards, and PharmGKB. The common targets of the drug and the disease were screened out by Venn diagram. Cytoscape was used to construct an "active component-target-disease" network, and the core components were screened out according to the node degree. The protein-protein interaction(PPI) network of the common targets was constructed by STRING and Cytoscape, and the core targets were screened out according to the node degree. GO and KEGG enrichment analyses of potential therapeutic targets were carried out with DAVID database. Molecular docking was used to determine the binding activity of some active components to key targets by AutoDock. Finally, the anti-OC activity of M. tenacissima extract was verified based on SKOV3 cells in vitro. The PI3K/AKT signaling pathway was selected for in vitro experimental verification according to the results of GO function and KEGG pathway analyses. Network pharmacology results showed that 39 active components, such as kaempferol, 11α-O-benzoyl-12ß-O-acetyltenacigenin B, and drevogenin Q, were screened out, involving 25 core targets such as AKT1, VEGFA, and EGFR, and the PI3K-AKT signaling pathway was the main pathway of target protein enrichment. The results of molecular docking also showed that the top ten core components showed good binding affinity to the top ten core targets. The results of in vitro experiments showed that M. tenacissima extract could significantly inhibit the proliferation of OC cells, induce apoptosis of OC cells through the mitochondrial pathway, and down-regulate the expression of proteins related to the PI3K/AKT signaling pathway. This study shows that M. tenacissima has the characteristics of multi-component, multi-target, and multi-pathway synergistic effect in the treatment of OC, which provides a theoretical basis for in-depth research on the material basis, mechanism, and clinical application.

Intensified wintertime secondary inorganic aerosol formation during heavy haze pollution episodes (HPEs) in Beijing, China.

Air pollution in China is complex, and the formation mechanism of chemical components in particulate matter is still unclear. This study selected three consecutive heavy haze pollution episodes (HPEs) during winter in Beijing for continuous field observation, including an episode with heavy air pollution under red alert. Clean days during the observation period were selected for comparison. The HPE characteristics of Beijing in winter were: under the influence of adverse meteorological conditions such as high relative humidity, temperature inversion and low wind speed; and strengthening of secondary transformation reactions, which further intensified the accumulation of secondary aerosols and other pollutants, promoting the explosive growth of PM2.5. PM2.5/CO values, as indicators of the contribution of secondary transformation in PM2.5, were approximately 2 times higher in the HPEs than the average PM2.5/CO during the clean period. The secondary inorganic aerosols (sulfate nitrate and ammonium salt) were significantly enhanced during the HPEs, and the conversion coefficients were remarkably improved. In addition, it is interesting to observe that the production of sulfate tended to exceed that of nitrate in the late stage of all three HPEs. The existence of aqueous phase reactions led to the explosive growth sulfur oxidation ratio (SOR) and rapid generation of sulfate under high relative humidity (RH>70%).

The lncRNA TUG1/miR-145-5p/FGF10 regulates proliferation and migration in VSMCs of hypertension.

Vascular remodeling is a characteristic pathological feature of hypertension, it can cause of increasing vascular resistance and decrease of compliance. Vascular smooth muscle cell (VSMCs) dysfunction is the important foundation of vascular remodeling. Increasing evidences have revealed that lncRNA is an important regulatory factor of VSMC function. In this paper, we explored the function of lncRNA TUG1 in vascular remodeling of hypertension. Here, we found that lncRNA TUG1 was highly expressed in aorta of spontaneously hypertensive rats (SHR) rats and promoted the proliferation and migration of VSMCs (SHR-VSMCs). Bioinformatics analyze showed that lncRNA TUG1 sequence had miR-145-5p binding sites. Luciferase reporter test, RNA pulldown and qRT-PCR showed that lncRNA TUG1 could bind miR-145-5p. Similarly, bioinformatics analyze found that FGF10 3 'UTR contained miR-145-5p binding sites. Luciferase reporter test, qRT-PCR and Western blot were shown that miR-145-5p inhibited FGF10 expression by binding to its 3 'UTR. MTT showed that miR-145-5p inhibited and FGF10 promoted SHR-VMSCs proliferation and migration. Overexpression of miR-145-5p or knocking down of FGF10 after overexpresion of lncRNA TUG1 could rescue the proliferation and migration promoted by lncRNA TUG1. LncRNA TUG1 and FGF10 promoted and miR-145-5p suppressed the expression of ß-catenin, TCF and LEF in SHR-VSMCs. Therefore, lncRNA TUG1/miR-145-5p/FGF10 promotes the proliferation and migration of VSMCs in hypertensive state by activating the Wnt/ß-catenin pathway.

Macular evaluation of the retinal and choroidal vasculature changes in anterior ischemic optic neuropathy-a case control study.

BACKGROUND: This study aimes to characterize the fundus structural changes in patients with nonarteritic anterior ischemic optic neuropathy (NAION) and the correlation between macular vessel density, retinal nerve fibre layer (RNFL) parameters and visual field sensitivity (VFS) in NAION patients. METHODS: A retrospective case control study was performed using 37 eyes with NAION, 30 uninvolved contralateral eyes, and 27 eyes of healthy age-matched subjects. Data on the retinas and choroidal vessel densities and VFS were compared among the three groups. RESULTS: The NAION group exhibited significantly lower RNFL thicknesses, lower ganglion cell complexes (GCC), larger global loss volume (GLV) values and focal loss volume (FLV) values when compared with both uninvolved eyes and healthy eyes (p < 0.01 for all comparisons). The superficial vessel density (SVD) valus (whole, parafovea, superior-hemi and inferior-hemi) were significantly lower in NAION eyes, followed by uninvolved eyes and healthy eyes (p < 0.01; LSD, p < 0.05 for all comparisons). The deep vessel density (DVD) values (parafovea, superior-hemi and inferior-hemi) were the lowest by a significant value in NAION eyes, followed by uninvolved eyes and healthy eyes (p < 0.01; LSD, p < 0.05 for all comparisons). However, DVD value measurements (whole and fovea) of healthy and uninvolved eyes were not significantly different. The average threshold deviation (TD) was - 11.02 ± 3.75 dB for the overall field region, - 6.01 ± 2.21 dB for the affected superior field region and - 9.98 ± 3.34 dB for the affected inferior field region in NAION eyes. A statistically significant correlation was found between the RNFL thickness and visual field(VF) loss (r = - 0.788, p < 0.001). CONCLUSION: In addition to peripapillary vascular changes occurring in NAION eyes, macular vessel density is also involved. Furthermore, NAION-uninvolved eyes exhibited abnormalities compared with healthy eyes. This indicates that vascular changes may occur before changes in retinal thickness at the early stages of NAION.

[Analysis of Similarities and Differences between Guidance of Magnetic Resonance Diagnostic Devices Clinical Evaluation and Guidance of Medical Device Clinical Evaluation].

Clinical evaluation of medical devices plays an important role in the life cycle of medical devices. This paper introduces guidance of magnetic resonance diagnostic devices clinical evaluation and guidance of medical device clinical evaluation issued by CFDA. Their similarities and differences of the framework and content are analyzed, especially the definition, clinical evaluation methods and support data. By comparison, the clinical evaluation work of registration applicants can be more scientific and reasonable. At the same time, it can also be used for reference by the food and drug administration departments in evaluating the clinical evaluation of other products.

[Expression of Bcl-2 and Bax on retinal with a rat model for ocular ischemic syndrome].

OBJECTIVE: To tell the difference of Bcl-2 and Bax expression on the retina between the ocular ischemic syndrome group and the sham group. METHODS: Experimental study. To establish the ocular ischemic syndrome model by bilateral common carotid arteries obliteration (BCCAO) in BN rats. Twenty BN rats were divided into two groups randomly: 12 in the model group and 8 in the sham group. In model group, midline incised in the neck and bilateral common carotid artery obliterated. While in the sham group, midline incised in the neck with no obliteration. Pupillary reflex were detected in both groups. After 1 month, rats underwent fundus fluorescein angiography (FFA) examination. Optical coherence tomography (OCT) was used to measure and tell the retina thickness difference in both groups. Expression of Bcl-2 and Bax on rat retina and change of the Bcl-2/Bax ratio were detected by immunohistochemical staining. Chisquare test was used for classification variable, two independent samples T test was used for quantitative data. RESULTS: Compared to the sham group, only 1 eye of BCCAO group maintained its direct pupillary reflex, other eyes of the group appeared either lost or weakened their direct pupillary reflex. However, all rats in the sham group maintained their pupillary reflex. FFA showed that in the BCCAO group, retinal circulation time was significantly longer than it was in the sham group (aterial phase:t=6.19,P<0.01; arteriovenous phase:t=8.24,P<0.01; venous phase:t=2.73,P<0.05). And in the model group, the background choroidal patchy hypofluorescence and typical arterial forward phenomenon in the early phase of arterial time were observed. OCT showed that in the model group, an obvious decrease of the thickness of neuroepithelial layer of retina was observed, which was (195.67±8.84) µm in the model group and (219.31± 6.92) µm in the sham group. It had statistically significant difference (P<0.05). Immunohistochemical staining results showed imbalance of Bcl-2, Bax expression on rat retina. Compared with the sham group, expression level of bax which was (5.67±0.84) µm in the model group was significantly increased (P<0.05) , while it was (2.34 ± 0.57) µm in the sham group. There was no significant difference (P>0.05) in Bcl-2 expression in both groups, which was (5.61±0.98) µm in the model group and which was (5.63±0.88) µm in the sham group. And Bcl-2/Bax ratio was observed statistically significant decreased (P<0.05) in the BCCAO group compared with that in the sham group, which was (1.01 ± 0.23) in the model group, and which was (2.47±0.47) in the sham group. CONCLUSIONS: BCCAO of rats lead to the injury of retina function, diminish of retinal thickness, imbalance of Bax and Bcl-2 expression.

Ciliary muscles contraction leads to axial length extension--The possible initiating factor for myopia.

PURPOSE: This study aimed to investigate the underlying factors driving the onset of myopia, specifically the role of the ciliary muscle's contraction in the elongation of the axial length of the eye. METHODS: The retrospective study was conducted utilizing data from three ophthalmic centers in Shanghai and Beijing. Both Chinese and Caucasian children were involved. The axial length of the subjects' eyes was measured in both relaxed and contracted state of the ciliary muscle. A comprehensive mechanical model was also developed to observe the influence of ciliary muscle contraction on the axial length. RESULTS: This study included a sample of 198 right eyes of 198 myopic children. Of these, 97 were male and 101 were female, 126 were of Chinese ethnicity and 72 were Caucasian. The age of onset for myopia ranged from 5.9 to 16.9 years old. The axial length of the eye decreased 0.028 ± 0.007mm following dilation, indicating relaxation of the ciliary muscle (t paired student = 15.16, p = 6.72 x 10-35). In contrast, ciliary muscle contraction resulted in an increase in axial length. Considering proportionality, a significant 90.4% (179 eyes) exhibited a reduced axial length, while a minor 9.6% (19 eyes) demonstrated an increase post-mydriasis. Finite element modeling demonstrated that muscle contraction caused a tension force that transmits towards the posterior pole of the eye, causing it to extend posteriorly. CONCLUSION: The contraction of the ciliary muscle leads to an extension of the axial length. This could potentially be the initiating factor for myopia.

Effect of PCI on ophthalmic artery hemodynamics in patients with acute coronary syndrome.

Purpose: We aimed to explore the effects of percutaneous coronary intervention (PCI) on the ophthalmic artery (OA) hemodynamics in patients with acute coronary syndrome (ACS). Methods: A total of 73 participants (Group0: healthy controls, Group1: Patients with ACS underwent PCI < 3 months, Group2: Patients with ACS underwent PCI ≥ 3 months) were enrolled. Computed tomographic angiography images were used to construct three-dimensional models of participants' OAs. Numerical simulations based on computational fluid dynamics were used to acquire hemodynamic parameters. Results: The angle between the OA and internal carotid artery in Group2 was significantly larger compared with Group0 and Group1 (P = 0.003 and P = 0.044). Hemodynamic simulation showed a significantly slower OA blood velocity in Group1 than in the control (P < 0.001) and Group2 (P = 0.033). Lower wall shear stress was found in Group1 than that in control (P = 0.040). Patients after PCI had a higher wall pressure than healthy controls (P = 0.012 and P = 0.004). Mass flow ratios were decreased in Group1 and Group2 (P = 0.021 and P = 0.002). The hemodynamic parameters of OA were correlated with several clinical indicators. Conclusions: The OA blood flow velocity of patients with ACS after PCI initially slowed down, which increased the risk of plaque formation, and then showed an increasing trend. There was a correlation between OA hemodynamic parameters and clinical indexes related to cardiac stress. Ischemia-reperfusion injury and changes in blood flow status after PCI may affect OA morphology and hemodynamics, leading to ocular lesions. Trial registration: ChiCTR2100050428.

Potency switch between CHK1 and MK2: discovery of imidazo[1,2-a]pyrazine- and imidazo[1,2-c]pyrimidine-based kinase inhibitors.

Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2.

The application of unmanned aerial vehicle oblique photography technology in online tourism design.

Tilt photography of unmanned aerial vehicles (UAVs) is widely used in urban management, cadastral mapping, disaster monitoring and other fields, but there are few innovative applications in online tourism. In this study, empirical design and usability testing methods were adopted, advanced positioning technology and Cesium engine were used to build a 3D real online travel application based on tilt photography, and the interactive function was realized through JavaScript language dynamic interactive function script. Meanwhile, combined with the questionnaire survey, the mobile application Rating Scale (MARS) was used to evaluate the function and quality of the application. The results show that engagement, functionality and aesthetics have no significant influence on user perception. Information quality and subjective quality of application have significant positive influence on user perception, and the influence of information quality is more significant. This study extends the application of oblique photography in tourism and provides experience for the development of tourism digitization.

Application of Proteomics Analysis and Animal Models in Optic Nerve Injury Diseases.

Optic nerve damage is a common cause of blindness. Optic nerve injury is often accompanied by fundus vascular disease, retinal ganglion cell apoptosis, and changes in retinal thickness. These changes can cause alterations in protein expression within neurons in the retina. Proteomics analysis offers conclusive evidence to decode a biological system. Furthermore, animal models of optic nerve injury made it possible to gain insight into pathological mechanisms, therapeutic targets, and effective treatment of such injuries. Proteomics takes the proteome as the research object and studies protein changes in cells and tissues. At present, a variety of proteomic analysis methods have been widely used in the research of optic nerve injury diseases. This review summarizes the application of proteomic research in optic nerve injury diseases and animal models of optic nerve injury. Additionally, differentially expressed proteins are summarized and analyzed. Various optic nerve injuries, including those associated with different etiologies, are discussed along with their potential therapeutic targets and future directions.

An anoikis-related lncRNA signature is a useful tool for predicting the prognosis of patients with lung adenocarcinoma.

Background: Anoikis-related long non-coding RNAs (ARLs) play a critical role in tumor metastasis and progression, suggesting that they may serve as risk markers for cancer. This study aimed to investigate the prognostic value of ARLs in patients with lung adenocarcinoma (LUAD). Methods: Clinical data, RNA sequencing (RNA-seq) data, and mutation data from the LUAD project were obtained from The Cancer Genome Atlas (TCGA) database. The Molecular Signatures Database (MSigDB) and the GeneCard database were used to collect an anoikis-related gene (ARG) set. Pearson correlation analysis was performed to identify ARLs. LASSO and Cox regression were then used to establish a prognostic risk signature for ARLs. The median risk score served as the basis for categorizing patients into high and low-risk groups. Kaplan-Meier analysis was utilized to compare the prognosis between these two groups. The study also examined the associations between risk scores and prognosis, clinicopathological characteristics, immune status, tumor mutation burden (TMB), and chemotherapeutic agents. LncRNA expression was assessed using quantitative real-time PCR (qRT-PCR). Results: A total of 480 RNA expression profiles, 501 ARGs, and 2698 ARLs were obtained from the database. A prognostic ARL signature for LUAD was established, consisting of 9 lncRNAs. Patients in the low-risk group exhibited significantly better prognosis compared to those in the high-risk group (P < 0.001). The 9 lncRNAs from the ARL signature were identified as independent prognostic factors (P < 0.001). The signature demonstrated high accuracy in predicting LUAD prognosis, with area under the curve values exceeding 0.7. The risk scores for ARLs showed strong negative correlations with stroma score (P = 5.9E-07, R = -0.23), immune score (P = 9.7E-09, R = -0.26), and microenvironment score (P = 8E-11, R = -0.29). Additionally, the low-risk group exhibited significantly higher TMB compared to the high-risk group (P = 4.6E-05). High-risk status was significantly associated with lower half-maximal inhibitory concentrations for most chemotherapeutic drugs. Conclusion: This newly constructed signature based on nine ARLs is a useful instrument for the risk stratification of LUAD patients. The signature has potential clinical significance for predicting the prognosis of LUAD patients and guiding personalized immunotherapy.

Discovery of [11C]MK-8056: A Selective PET Imaging Agent for the Study of mGluR2 Negative Allosteric Modulators.

Modification of potent, selective metabotropic glutamate receptor 2 negative allosteric modulator (mGluR2 NAM) led to a series of analogues with excellent binding affinity, lipophilicity, and suitable physicochemical properties for a PET tracer with convenient chemical handles for incorporation of a 11C or 18F radiolabel. [11C]MK-8056 was synthesized and evaluated in vivo and demonstrated appropriate affinity, selectivity, and physicochemical properties to be used as a positron emission tomography tracer for mGluR2.

Discovery of MK-8768, a Potent and Selective mGluR2 Negative Allosteric Modulator.

Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.

Research on the Structural Relationship of Online Persistent Purchase of Museum Cultural and Creative Products in the Context of Digitalization.

With the development and support of modern technologies such as digital media and online live stream, it has become an effective way to promote the online transaction of museum cultural and creative products. Based on the Technology Acceptance Model combined with the Post-Acceptance Model of Information System Continuance and the theories on customer satisfaction index, this research introduces perceived interest (PI) and media richness (MR) as variables and constructs a model of the influencing factors of online consumers' persistent purchase (PP) of museum products. The research model and related hypotheses were verified through structural equation modeling (SEM). The research found that perceived value (PV) and satisfaction (SAT) are the key variables that have impact on the PP of consumers. Perceived quality, brand trust, MR, PI, and perceived usefulness have significant effects on PV and SAT. Involvement in purchasing decisions positively moderates the impact on SAT of PV. The conclusion can be referred to for operators and product developers.

Bioisosteric approach to the discovery of imidazo[1,2-a]pyrazines as potent Aurora kinase inhibitors.

Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.

Discovery of imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors.

The synthesis and structure-activity relationships (SAR) of novel, potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors are described. The X-ray crystal structure of imidazo[1,2-a]pyrazine Aurora inhibitor 1j is disclosed. Compound 10i was identified as lead compound with a promising overall profile.

Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors.

We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.

Explosive morning growth phenomena of NH3 on the North China Plain: Causes and potential impacts on aerosol formation.

Atmospheric ammonia (NH3) as the most important alkaline gas in the atmosphere has attracted much attention in recent years due to its critical role in haze formation, especially on the North China Plain (NCP). Comprehensive studies are needed for investigating diurnal variations of NH3 and underlying mechanisms in different seasons and their potential impacts on atmospheric chemistry. In this study, continuous long-term observation (Mar. 2016 to May 2017) of NH3 at a rural site in the NCP was used to characterize the diurnal variation of NH3 in different seasons and to unveil its causes and potential impacts on atmospheric chemistry. NH3 concentrations displayed rapid increases during the morning, reaching very prominent peaks mostly between 8:00 to 11:00 LT. Such frequent (55%) morning peaks were mainly caused by the evaporation of dew and guttation water droplets. Average dew and guttation water volume concentrations of 750 mL m-2 was estimated for spring, which resulted in approximate NH3 emissions of 800 ng m-2 s- 1. Such high emission fluxes from dew and guttation water evaporation have never been reported before, suggesting dew and guttation droplets to be significant night-time reservoirs and strong morning sources for NH3. In light of recent studies putting forward that NH3 can promote the heterogeneous formation of HONO and nitrate under high humidity conditions, we investigated the differences in HONO and aerosol chemical composition diurnal variations between days with and without NH3 morning spikes during November. HONO, nitrate and sulfate concentrations were significantly higher for days with NH3 morning spikes, with HONO displaying a morning peak near that of NH3. These results demonstrate that the prevailing NH3 morning spikes on the NCP have significant influences on aerosol formation and atmospheric chemistry. NH3 emission mitigation strategies and regulations are urgently needed.