Atherosclerosis-associated endothelial dysfunction is promoted by miR-199a-5p/SIRT1 axis regulated by circHIF1ɑ.

BACKGROUND AND AIMS: Atherosclerosis (AS) is a chronic inflammatory disease that damages the arterial wall as a result of hyperlipidemia and causes endothelial cell dysfunction, which increases the risk of atherothrombotic events. Multiple pathological conditions have shown ectopic miR-199a-5p levels to cause endothelial injury, but its role in the AS competitive endogenous RNA (CeRNA) network is still unknown. METHODS AND RESULTS: The high-fat diet (HFD) apoE-/- mouse model was constructed in vivo, and ECs were cultured under ox-LDL treatment to induce EC injury in vitro. Immunohistochemistry and immunofluorescence staining were used to assess the effect of miR-199a-5p on the macrophage, SMC, collagen content, and endothelial coverage in the artery wall of mouse model. miR-199a-5p level was validated to be overexpression in the aorta tissue of HFD apoE-/- mice and in the ox-LDL-treated ECs, and even in the plasma EVs of the patients with cerebral AS. Silencing of miR-199a-5p significantly attenuated atherosclerotic progress in HFD apoE-/- mice, and the gain/loss-of-function assay indicated that miR-199a-5p overexpression aggravated ox-LDL-induced disabilities of endothelial proliferation, motility, and neovascularization based on cell counting kit-8 assay, transwell assay and matrigel assay. Mechanistically, miR-199a-5p prevented EC activation by activating the FOXO signaling pathway by targeting SIRT1. Additionally, circular RNA (circRNA) circHIF1ɑ was identified as having a low expression in the ox-LDL-treated EC and mediated SIRT1 expression via sponging miR-199a-5p to rescue ox-LDL-induced EC injury. CONCLUSIONS: Our study demonstrated the vital role of miR-199a-5p/SIRT1 axis regulated by circHIF1ɑ in AS pathogenesis and provided novel effective targets for AS treatment.

Cytokines/chemokines and immune checkpoint molecules in anti-leucine-rich glioma-inactivated 1 encephalitis.

OBJECTIVE: We aimed to investigate levels of cytokines/chemokines and immune checkpoint molecules in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis. METHODS: The study recruited 12 patients with anti-LGI1 encephalitis and six non-inflammatory controls from the Qilu Hospital of Shandong University treated between January 2019 and December 2020. Serum levels of 30 cytokines/chemokines and 10 checkpoint molecules were measured in participants of both the groups. RESULTS: In contrast to those in the control group, 24 cytokines/chemokines and 5 immune checkpoint molecules were differentially expressed in patients with anti-LGI1 encephalitis, with 14 cytokines being upregulated and 10 being downregulated. There were 1033 enriched biological processes and 61 enriched Kyoto Encyclopedia of Genes and Genomes signaling pathways. CONCLUSION: A wide range of cytokines/chemokines and immune checkpoint molecules are implicated in immune regulation in anti-LGI1 encephalitis, indicating that they may serve as important targets in the development and treatment of the disease.

Quantum Interference between Nonidentical Single Particles.

Quantum interference between identical single particles reveals the intrinsic quantum statistic nature of particles, which could not be interpreted through classical physics. Here, we demonstrate quantum interference between nonidentical bosons using a generalized beam splitter based on a quantum memory. The Hong-Ou-Mandel type interference between single photons and single magnons with high visibility is demonstrated, and the crossover from the bosonic to fermionic quantum statistics is observed by tuning the beam splitter to be non-Hermitian. Moreover, multiparticle interference that simulates the behavior of three fermions by three input photons is realized. Our work extends the understanding of the quantum interference effects and demonstrates a versatile experimental platform for studying and engineering quantum statistics of particles.

Synthetic Topological Vacua of Yang-Mills Fields in Bose-Einstein Condensates.

Topological vacua are a family of degenerate ground states of Yang-Mills fields with zero field strength but nontrivial topological structures. They play a fundamental role in particle physics and quantum field theory, but have not yet been experimentally observed. Here we report the first theoretical proposal and experimental realization of synthetic topological vacua with a cloud of atomic Bose-Einstein condensates. Our setup provides a promising platform to demonstrate the fundamental concept that a vacuum, rather than being empty, has rich spatial structures. The Hamiltonian for the vacuum of topological number n=1 is synthesized and the related Hopf index is measured. The vacuum of topological number n=2 is also realized, and we find that vacua with different topological numbers have distinctive spin textures and Hopf links. Our Letter opens up opportunities for exploring topological vacua and related long-sought-after instantons in tabletop experiments.

Measurement of Spin Chern Numbers in Quantum Simulated Topological Insulators.

The topology of quantum systems has become a topic of great interest since the discovery of topological insulators. However, as a hallmark of the topological insulators, the spin Chern number has not yet been experimentally detected. The challenge to directly measure this topological invariant lies in the fact that this spin Chern number is defined based on artificially constructed wave functions. Here we experimentally mimic the celebrated Bernevig-Hughes-Zhang model with cold atoms, and then measure the spin Chern number with the linear response theory. We observe that, although the Chern number for each spin component is ill defined, the spin Chern number measured by their difference is still well defined when both energy and spin gaps are nonvanished.

Einstein-Podolsky-Rosen Energy-Time Entanglement of Narrow-Band Biphotons.

We report the direct characterization of energy-time entanglement of narrow-band biphotons produced from spontaneous four-wave mixing in cold atoms. The Stokes and anti-Stokes two-photon temporal correlation is measured by single-photon counters with nanosecond temporal resolution, and their joint spectrum is determined by using a narrow linewidth optical cavity. The energy-time entanglement is verified by the joint frequency-time uncertainty product of 0.063±0.0044, which does not only violate the separability criterion but also satisfies the continuous variable Einstein-Podolsky-Rosen steering inequality.

Circular RNA circ_0003204 inhibits proliferation, migration and tube formation of endothelial cell in atherosclerosis via miR-370-3p/TGFßR2/phosph-SMAD3 axis.

BACKGROUND: Circular RNAs (circRNAs) represent a class of non-coding RNAs (ncRNAs) which are widely expressed in mammals and tissue-specific, of which some could act as critical regulators in the atherogenesis of cerebrovascular disease. However, the underlying mechanisms by which circRNA regulates the ectopic phenotype of endothelial cells (ECs) in atherosclerosis remain largely elusive. METHODS: CCK-8, transwell, wound healing and Matrigel assays were used to assess cell viability, migration and tube formation. QRT-qPCR and Immunoblotting were used to examine targeted gene expression in different groups. The binding sites of miR-370-3p (miR-370) with TGFßR2 or hsa_circ_0003204 (circ_0003204) were predicted using a series of bioinformatic tools, and validated using dual luciferase assay and RNA immunoprecipitation (RIP) assay. The localization of circ_0003204 and miR-370 in ECs were investigated by fluorescence in situ hybridization (FISH). Gene function and pathways were enriched through Metascape and gene set enrichment analysis (GSEA). The association of circ_0003204 and miR-370 in extracellular vesicles (EVs) with clinical characteristics of patients were investigated using multiple statistical analysis. RESULTS: Circ_0003204, mainly located in the cytoplasm of human aorta endothelial cells (HAECs), was upregulated in the ox-LDL-induced HAECs. Functionally, the ectopic expression of circ_0003204 inhibited proliferation, migration and tube formation of HAECs exposed to ox-LDL. Mechanically, circ_0003204 could promote protein expression of TGFßR2 and its downstream phosph-SMAD3 through sponging miR-370, and miR-370 targeted the 3' untranslated region (UTR) of TGFßR2. Furthermore, the expression of circ_0003204 in plasma EVs was upregulated in the patients with cerebral atherosclerosis, and represented a potential biomarker for diangnosis and prognosis of cerebrovascular atherogenesis. CONCLUSIONS: Circ_0003204 could act as a novel stimulator for ectopic endothelial inactivation in atherosclerosis and a potential biomarker for cerebral atherosclerosis.

δ-Quench Measurement of a Pure Quantum-State Wave Function.

The measurement of a quantum state wave function not only acts as a fundamental part in quantum physics but also plays an important role in developing practical quantum technologies. Conventional quantum state tomography has been widely used to estimate quantum wave functions, which usually requires complicated measurement techniques. The recent weak-value-based quantum measurement circumvents this resource issue but relies on an extra pointer space. Here, we theoretically propose and then experimentally demonstrate a direct and efficient measurement strategy based on a δ-quench probe: by quenching its complex probability amplitude one by one (δ quench) in the given basis, we can directly obtain the quantum wave function of a pure ensemble by projecting the quenched state onto a postselection state. We confirm its power by experimentally measuring photonic complex temporal wave functions. This new method is versatile and can find applications in quantum information science and engineering.

Low free triiodothyronineis predicts worsen neurological outcome of patients with acute ischemic stroke: a retrospective study with bioinformatics analysis.

BACKGROUD: Patients with acute ischemic stroke (AIS) often experience low serum free triiodothyronine (FT3), but the association of low FT3 with stroke severity, subtype and prognosis has not yet been thoroughly studied, and the molecular events underlying these clinical observation were also unclear. METHODS: We retrospectively collected 221 cases of AIS and 182 non-AIS cases with detailed clinical data from our department. FT3 concentrations were measured on admission to predict functional outcome within 3 months using multivariable models adjusted for other risk factors. Receiver operating characteristic (ROC) curves were calculated to define the best cutoff value of FT3 of stroke severity, subtypes and neurological outcome. Gene set enrichment, pathway mapping and network analyses of deferentially expressed genes (DEGs) were performed. RESULTS: FT3 was significantly decreased in AIS patients with National Institutes of Health Stroke Scale (NIHSS) > 3 and 3-months modified Rankin Scale (mRS) > 2. The cut-off value of FT3 for NIHSS on admission was 4.30 pmol/L. Also, FT3 level was significantly lower in large artery atherosclerosis (LAA) group and cardioembolism (CE) group than that in small vessel occlusion (SVO). FT3 value served as an independent predictor for neurological outcomes for which the cut-off value of FT3 was 4.38 pmol/l. Gene ontology (GO) analysis showed that the biological function of DEGs was mainly enriched in multicellur organism, neuron differentiation and cellular response to hypoxia. The cellular components were involved in extracelluar region, exosome and matrix, and the molecular functions were transcriptional activator activity, DNA binding and nuclear hormone receptor binding. Signal pathways analysis was indicative of neuroactive ligand-receptor interaction, thyroid hormone signaling pathway, and protein digestion and absorption these DEGs were involved in. Six related gene were identified as hubs from the protein-protein interaction (PPI) networks. Three modules were selected from PPI, of which MMP4, ADRA2C and EIF3E were recognized as the seed genes. CONCLUSIONS: Low FT3 value on admission was associated with stroke severity, subtype and prognosis. In addition, DEGs identified from bioinformatics analysis are likely to be candidates for elucidating clinical outcomes with low FT3, and provide us with therapeutic targets for improving stroke prognosis.

miR-138 promotes migration and tube formation of human cytomegalovirus-infected endothelial cells through the SIRT1/p-STAT3 pathway.

Human cytomegalovirus (HCMV) has been reported to be linked to vascular disease through the induction of neovessel formation. We have previously reported that microRNA (miR)-217 and miR-199a-5p enhance endothelial angiogenesis via inhibition of sirtuin 1 (SIRT1) in HCMV-infected human umbilical vein endothelial cells (HUVECs). Here, we found that miR-138 also suppressed the expression of the SIRT1 protein and stimulated phosphorylation of signal transducer and activator of transcription 3 (p-STAT3). Moreover, the regulation of p-STAT3 expression mediated by SIRT1 was found to promote HCMV-induced angiogenesis. These findings revealed that miR-138 might promote angiogenesis of HCMV-infected HUVECs by activating the SIRT1-mediated p-STAT3 pathway, and this could provide novel insights into HCMV-induced angiogenesis.

Efficiently loading a single photon into a single-sided Fabry-Perot cavity.

We demonstrate that a single photon with an optimal temporal waveform can be efficiently loaded into a cavity. Using heralded narrow-band single photons with exponential growth wave packet shaped by an electro-optical amplitude modulator, whose time constant matches the photon lifetime in the cavity, we demonstrate a loading efficiency of (87±2)% from free space to a single-sided Fabry-Perot cavity. We further demonstrate directly loading heralded single Stokes photons into the cavity with an efficiency of (60±5)% without the electro-optical amplitude modulator and verify the time reversal between the frequency-entangled paired photons. Our result and approach may enable promising applications in realizing large-scale quantum networks based on cavity quantum electrodynamics.

B-FMEA-TRIZ model for scheme decision in conceptual product design: A study on upper-limb hemiplegia rehabilitation exoskeleton.

Upper-limb rehabilitation devices are essential in restoring and improving the motor function of hemiplegic patients. However, developing a product design that meets the needs of users is challenging. Current design tools and methods suffer from limitations such as a single model, poor synergy between integrated models, and subjective bias in analysing user needs and translating them into product attributes. To address these issues, this study proposes a new structural design decision-making model based on Behaviour Analysis (B), Failure Mode Effect Analysis (FMEA), and Teoriya Resheniya Izobreatatelskikh Zadatch (TRIZ theory). The model was developed and applied to design an upper-limb rehabilitation exoskeleton for hemiplegia. In this paper, an empirical investigation was conducted in several rehabilitation hospitals in Xuzhou City and used user journey mapping to identify potential failure points in the behaviour process. Then, the fault models were ranked according to the Fuzzy Risk Priority Number (FRPN) calculated by FMEA and used TRIZ theory to determine principles for resolving contradictions and generating creative design solutions for the product. By integrating B, FMEA, and TRIZ theory, it eliminated subjective bias in product design, improved the design decision-making process, and provided new methods and ideas for designing assistive rehabilitation devices and similar products. The framework of the proposed approach can be used in other contexts to develop effective and precise product designs that meet the needs of users.

CSF Findings in Chinese Patients with NMDAR, LGI1 and GABABR Antibody-Associated Encephalitis.

Purpose: CSF inflammation in subtypes of antibody-defined autoimmune encephalitis (AE) ranges in intensity from moderate to severe. In a retrospective, cross-sectional study, we characterized CSF findings in Chinese patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E), anti-leucine-rich glioma-inactivated 1 encephalitis (LGI1-E), and anti-gamma aminobutyric acid-B receptor encephalitis (GABABR-E). Patients and Methods: The AE cases, including 102 NMDAR-E, 68 LGI1-E and 15 GABABR-E, were included. CSF inflammatory parameters consisted primarily of CSF leukocytes, oligoclonal bands (OCBs), and CSF/serum albumin ratios (QAlb). Ten serum cytokines were evaluated in order to classify AE subtypes. Results: 88% of NMDAR-E, 80% of GABABR-E, and 51% of LGI1-E patients had aberrant CSF features. In NMDAR-E, the CSF leukocyte count, CSF protein concentration, and age-adjusted QAlb were significantly higher than in LGI1-E, but did not differ from GABABR-E. Blood-CSF barrier dysfunction was less common in NMDAR-E patients with >40 years old. On admission, inflammatory CSF response was more prevalent in NMDAR-E patients with a higher CASE score. With age <60 years, CSF inflammatory changes were less frequent in LGI1-E patients, but more common in GABABR-E patients. MCP-1, IL-10, IL-1ß, and IL-4 were potential classifiers for NMDAR-E, LGI1-E, and GABABR-E, and correlated substantially with CSF leukocyte count and QAlb. Conclusion: Subtype-specific patterns are formed by the various inflammatory CSF parameters in NMDAR-E, LGI1-E, and GABABR-E, and their correlation with disease severity, age, and disease duration. CSF inflammatory characteristics associated with MCP-1, IL-10, IL-1ß, and IL-4 may be potential immunopathogeneses targeting markers for these AE subtypes.

Differential-phase-shift quantum key distribution using heralded narrow-band single photons.

We demonstrate the first proof of principle differential phase shift (DPS) quantum key distribution (QKD) using narrow-band heralded single photons with amplitude-phase modulations. In the 3-pulse case, we obtain a quantum bit error rate (QBER) as low as 3.06% which meets the unconditional security requirement. As we increase the pulse number up to 15, the key creation efficiency approaches 93.4%, but with a cost of increasing the QBER. Our result suggests that narrow-band single photons maybe a promising source for the DPS-QKD protocol.

MiR-199a-5p promotes migration and tube formation of human cytomegalovirus-infected endothelial cells through downregulation of SIRT1 and eNOS.

Human cytomegalovirus (HCMV) infection has been shown to contribute to vascular disease through the induction of angiogenesis. However, the role of microRNA in angiogenesis induced by HCMV infection remains unclear. The present study was thus designed to explore the potential effect of miR-199a-5p on angiogenesis and to investigate the underlying mechanism in endothelial cells. We found that HCMV infection of endothelial cells (ECs) enhanced expression of miR-199a-5p and reduced the SIRT1 protein level at 24 h postinfection (hpi). Transfection with miR-199a-5p mimics significantly suppressed SIRT1 protein expression and promoted cellular migration and tube formation induced by HCMV infection, which could be reversed by transfection with an miR-199a-5p inhibitor. Furthermore, pretreatment with resveratrol depressed motility and tube formation of HCMV-infected ECs, which could be reversed by SIRT1 siRNA. Finally, overexpression of miR-199a-5p decreased the level of eNOS modulated by SIRT1, an effect repressed by transfection with an miR-199a-5p inhibitor. In summary, HCMV infection of endothelial cells upregulates miR-199a-5p expression and enhances cell migration and tube formation through downregulation of SIRT1/eNOS by miR-199a-5p.

Abnormal DNA methylation analysis of leucine-rich glioma-inactivated 1 antibody encephalitis reveals novel methylation-driven genes related to prognostic and clinical features.

BACKGROUND: Aberrant DNA methylation occurs commonly during pathogenesis of neuroimmunological diseases and is of clinical value in various encephalitis subtypes. However, knowledge of the impact of DNA methylation changes on pathogenesis of leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis remains limited. METHODS: A total of 44 cytokines and 10 immune checkpoint moleculars (ICMs) in the serum of patients with LGI1 encephalitis and healthy donors (HDs) were measured to evaluate the association of them with clinical parameters. Genome-wide DNA methylation profiles were performed in peripheral blood mononuclear cell (PBMC) from LGI1 encephalitis patients and HDs using reduced representation bisulfite sequencing (RRBS) and validated for the methylation status by pyrosequencing. MicroRNA profiles were acquired in serum exosome by small RNA sequencing. Targeted cytokines expression was assessed at the presence or absence of miR-2467-5p in PBMCs and the culture media, and the binding of miR-2467-5p and its targeted genes was validated by luciferase assay. RESULTS: There existed significant difference in 22 cytokines/chemokines and 6 ICMs between LGI1 encephalitis patients and HDs. Decreased PDCD1 with increased ICAM1 could predict unfavorable prognosis in one-year follow-up for LGI1 encephalitis patients. Fifteen of cytokines/chemokines and ICMs presented DNA-methylated changes in the promoter and gene body using RRBS in which five were verified as methylation status by pyrosequencing, and the methylation level of CSF3, CCL2, and ICAM1 was conversely associated with their expression in PBMCs. By combining RRBS data with exosome-derived microRNA sequencing, we found that hypomethylated-driven hsa-miR-2467-5p presented elevated expression in serum exosomes and PBMCs in LGI1 encephalitis. Mechanically, miR-2467-5p significantly induced reduced expression of CSF3 and PDCD1 by binding with their 3`UTR while enhanced CCL15 expression, but not significantly correlated with peripheral blood CD19 + B cell proportion of LGI1 encephalitis patients. CONCLUSIONS: Our results provided convincing evidence for DNA methylation changes, microRNA profiles in serum exosome for LGI1 encephalitis, and we also identified several novel cytokines related to clinical features in which some represented epigenetic modification of methylated-driven pattern and microRNA modulation. Our study contributed to develop treatment for epigenetic pathogenesis in LGI1 encephalitis.

Transcriptomics Analysis Revealed Key Genes Associated with Macrophage Autophagolysosome in Male ApoE-/- Mice Aortic Atherosclerosis.

Purpose: Atherosclerosis (AS) is the most common cause of cardiovascular and cerebrovascular diseases. However, the mechanisms underlying atherosclerotic plaque progression remain unclear. This study aimed to investigate the genes associated with the development of atherosclerosis in the aorta of ApoE-/- male mice, which could serve as novel biomarkers and therapeutic targets in interventions to halt plaque progression. Methods: Eight-week-old ApoE-/- mice were fed a normal purified laboratory diet or a Western Diet (WD) for 6 or 22 weeks. High-throughput sequencing technology was used to analyze the transcriptomes of the aortas of four groups of mice that were exposed to different dietary conditions. We retrieved and downloaded the human Arteriosclerosis Disease Chip dataset GSE100927 from the Gene Expression Omnibus (GEO) database and selected 29 cases of carotid atherosclerotic lesions and 12 cases of normal carotid tissues as the experimental and control groups, respectively, to further verify our dataset. In addition, we used quantitative reverse transcription polymerase chain reaction (QT-PCR) to verify the expression levels of the core genes in an atherosclerosis mouse model. Results: There were 265 differentially expressed genes (DEGs) between the ApoE-/- Male mice AS22W group and Sham22W group. In addition to the well-known activation of inflammation and immune response, t the autophagy-lysosome system is also an important factor that affects the development of atherosclerosis. We identified five core genes (Atp6ap2, Atp6v0b, Atp6v0d2, Atp6v1a, and Atp6v1d) in the protein-protein interaction (PPI) network that were closely related to autophagosomes. Hub genes were highly expressed in the carotid atherosclerosis group in the GSE100927 dataset (P < 0.001). QT-PCR showed that the RNA level of Atp6v0d2 increased significantly during the development of atherosclerotic plaque in ApoE-/- male mice. Conclusion: Five core genes which affect the development of aortic atherosclerosis through the autophagy-lysosome system, especially Atp6v0d2, were screened and identified using bioinformatic techniques.

Optimal storage and retrieval of single-photon waveforms.

We report an experimental demonstration of optimal storage and retrieval of heralded single-photon wave packets using electromagnetically induced transparency (EIT) in cold atoms at a high optical depth. We obtain an optimal storage efficiency of (49 ± 3)% for single-photon waveforms with a temporal likeness of 96%. Our result brings the EIT quantum light-matter interface closer to practical quantum information applications.