Validation of an adaptive transfer function method to estimate the aortic pressure waveform

Aortic pulse wave reflects cardiovascular status, but, unlike the peripheral pulse wave, is difficult to be measured reliably using noninvasive techniques. Thus, the estimation of aortic pulse wave from peripheral ones is of great significance. This study proposed an adaptive transfer function (ATF) method to estimate the aortic pulse wave from the brachial pulse wave. Aortic and brachial pulse waves were derived from 26 patients who underwent cardiac catheterization. Generalized transfer functions (GTF) were derived based on the autoregressive exogenous model. Then, the GTF was adapted by its peak resonance frequency. And the optional peak resonance frequency for an individual was determined by regression formulas using brachial systolic blood pressure. The method was validated using the leave-one-out cross validation method. Compared with previous studies, the ATF method showed better performance in estimating the aortic pulse wave and predicting the feature parameters. The prediction error of the aortic systolic blood pressure and pulse pressure were 0.2 ± 3.1 and -0.9 ± 3.1 mmHg, respectively. The percentage errors of augmentation index, percentage notch amplitude, and ejection duration were -2.1 ± 32.7%, 12.4 ± 9.2%, and -2.4 ± 3.3%, respectively

Integrative Analyses of Transcriptome Sequencing Identify Functional miRNAs in the Chicken Embryo Fibroblasts Cells Infected With Reticuloendotheliosis Virus

In this study, we found a much higher proportion of reticuloendotheliosis virus (REV) infected chicken embryo fibroblasts (CEF) were in active cell division phase than that of control cells which indicated that REV can affect the fate of CEF. So, we performed high-throughput sequencing and transcriptomic analysis to identify functional miRNAs, in order to figure out the possible mechanism in the interaction of REV with CEF. In total, 50 differentially expressed miRNAs (DEmiRNAs) were identified. Then target genes of DEmiRNAs were predicted and identified by transcriptome profile results. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted to analyze the identified target genes of miRNAs which showed that metabolism, cell cycle, and apoptosis were the most related pathways involved in infection of REV. We analyzed the genes related to cell cycle which indicated that CyclinD1-CDK6 complex played an important role in regulating the transition of the cell cycle from G1 phase to S phase during REV infection. Fluorescence microscope identification showed that REV inhibited the apoptosis of CEF which was in accordance with transcriptome results. A novel miRNA, named novel-72 was found, KEGG analysis was conducted to predict the biological function of its target genes which showed that those target genes were significantly enriched in mTOR signaling pathway and functioned to promote cell cycle and cell growth during the REV infection. In conclusion, REV could induce the up-regulation of cell metabolism, cell cycle and mTOR signaling pathway while inhibit apoptosis of the cell

Alterations in the gut microbiota and serum metabolomics of spontaneous cholestasis caused by loss of FXR signal in mice

Background: Farnesoid X receptor (FXR) is a key metabolic target of bile acids (BAs) and is also a target for drugs against several liver diseases. However, the contribution of FXR in the pathogenesis of cholestasis is still not fully understood. The purpose of this study is to provide a comprehensive insight into the metabolic properties of FXR-involved cholestasis in mice.Materials and methods: In this study, an alpha-naphthylisothiocyanate (ANIT)-induced cholestasis mouse model and FXR−/− mice were established to investigate the effect of FXR on cholestasis. The effect of FXR on liver and ileal pathology was evaluated. Simultaneously, Untargeted metabolomics combined with 16s rRNA gene sequencing analysis was applied to reveal the involvement of FXR in the pathogenesis of cholestasis.Results: The results showed that ANIT (75 mg/kg) induced marked cholestasis in WT and FXR −/− mice. It is noteworthy that FXR−/− mice developed spontaneous cholestasis. Compared with WT mice, significant liver and ileal tissue damage were found. In addition, 16s rRNA gene sequencing analysis revealed gut microbiota dysbiosis in FXR−/− mice and ANIT-induced cholestasis mice. Differential biomarkers associated with the pathogenesis of cholestasis caused by FXR knockout were screened using untargeted metabolomics. Notably, Lactobacillus_ johnsonii_FI9785 has a high correlation with the differential biomarkers associated with the pathogenesis and progression of cholestasis caused by FXR knockout.Conclusion: Our results implied that the disorder of the intestinal flora caused by FXR knockout can also interfere with the metabolism. This study provides novel insights into the FXR-related mechanisms of cholestasis

Post-procedural and long-term functional outcomes of jailed side branches in stented coronary bifurcation lesions assessed with side branch Murray law–based quantitative flow ratio

IntroductionIn coronary bifurcation lesions treated with percutaneous coronary intervention (PCI) using a 1-stent strategy, the occurrence of side branch (SB) compromise may lead to long-term myocardial ischemia in the SB territory. Murray law–based quantitative flow ratio (μQFR) is a novel angiography-based approach estimating fractional flow reserve from a single angiographic view, and thus is more feasible to assess SB compromise in routine practice. However, its association with long-term SB coronary blood flow remains unknown.MethodsA total of 146 patients with 313 non-left main bifurcation lesions receiving 1-stent strategy with drug-eluting stents was included in this retrospective study. These lesions had post-procedural Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 in SBs, and documented angiographic images of index procedure and 6- to 24-month angiographic follow-up. Post-procedural SB μQFR was calculated. Long-term SB coronary blood flow was quantified with the TIMI grading system using angiograms acquired at angiographic follow-up.ResultsAt follow-up, 8 (2.6%), 16 (5.1%), 61 (19.5%), and 228 (72.8%) SBs had a TIMI flow grade of 0, 1, 2, and 3, respectively. The incidences of long-term SB TIMI flow grade ≤1 and ≤2 both tended to decrease across the tertiles of post-procedural SB μQFR. The receiver operating characteristic curve analyses indicated the post-procedural SB μQFR ≤0.77 was the optimal cut-off value to identify long-term SB TIMI flow grade ≤1 (specificity, 37.50%; sensitivity, 87.20%; area under the curve, 0.6673; P = 0.0064), and it was independently associated with 2.57-fold increased risk (adjusted OR, 2.57; 95% CI, 1.02–7.25; P = 0.045) in long-term SB TIMI flow grade ≤1 after adjustment.DiscussionPost-procedural SB μQFR was independently associated with increased risk in impaired SB TIMI flow at long-term follow-up. Further investigations should focus on whether PCI optimization based on μQFR may contribute to improve SB flow in the long term

Atomic structures of enterovirus D68 in complex with two monoclonal antibodies define distinct mechanisms of viral neutralization

11月5日，《自然》子刊《自然•微生物学》（Nature Microbiology）在线刊出了我校夏宁邵教授团队发表的题为“Atomic Structures of Enterovirus D68 in Complex with Two Monoclonal Antibodies Define Distinct Mechanisms of Viral Neutralization”的研究论文。这是夏宁邵教授团队在《自然•通讯》（Nature Communications，2017）、《科学•进展》（Science Advances，2018）上发表手足口病重要病原体CVA6、CVA10研究论文之后的又一项关于肠道病毒的重要研究成果。该研究通过解析肠道病毒D组68型（EV-D68）不同类型病毒颗粒及其免疫复合物的高分辨率结构，系统阐明了EV-D68病毒的生活周期及各时期的病毒中和机制，进一步完善了小RNA病毒的吸附入胞及感染机制理论，为EV-D68新型疫苗、抗病毒治疗药物的研发提供重要的理论指导。该研究依托电镜技术平台，解析了EV-D68病毒生活周期中的三种代表性颗粒成熟颗粒、脱衣壳中间态和前体病毒衣壳的近原子分辨率结构，阐明了三种病毒颗粒间的结构差异，以及成熟颗粒转变为脱衣壳中间态的分子机制。夏宁邵教授、李少伟教授、程通副教授和美国国立卫生研究院（NIH）高级研究员Barney Graham博士为该论文的共同通讯作者。郑清炳工程师、博士生朱瑞、博士后徐龙发、博士生何茂洲和美国加州大学圣地亚哥分校颜晓东博士为该论文共同第一作者。【Abstract】Enterovirus D68 (EV-D68) undergoes structural transformation between mature, cell-entry intermediate (A-particle) and empty forms throughout its life cycle. Structural information for the various forms and antibody-bound capsids will facilitate the development of effective vaccines and therapeutics against EV-D68 infection, which causes childhood respiratory and paralytic diseases worldwide. Here, we report the structures of three EV-D68 capsid states representing the virus at major phases. We further describe two original monoclonal antibodies (15C5 and 11G1) with distinct structurally defined mechanisms for virus neutralization. 15C5 and 11G1 engage the capsid loci at icosahedral three-fold and five-fold axes, respectively. To block viral attachment, 15C5 binds three forms of capsids, and triggers mature virions to transform into A-particles, mimicking engagement by the functional receptor ICAM-5, whereas 11G1 exclusively recognizes the A-particle. Our data provide a structural and molecular explanation for the transition of picornavirus capsid conformations and demonstrate distinct mechanisms for antibody-mediated neutralization.This work was supported by a grant from the National Science and Technology Major Projects for Major New Drugs Innovation and Development (no. 2018ZX09711003-005-003), the National Science and Technology Major Project of Infectious Diseases (no. 2017ZX10304402-002-003), the National Natural Science Foundation of China (no. 81401669 and 81801646) and the Natural Science Foundation of Fujian Province (no. 2015J05073). This work was supported in part by funding by the National Institutes of Health (grants R37-GM33050, GM071940, DE025567 and AI094386). We acknowledge the use of instruments at the Electron Imaging Center for Nanomachines supported by UCLA and by instrumentation grants from the NIH (1S10RR23057 and 1U24GM116792) and NSF (DBI-1338135 and DMR-1548924). 该研究获得了国家自然科学基金、新药创制国家科技重大专项、传染病防治国家科技重大专项和美国国立卫生研究院基金的资助

Identification of antibodies with non-overlapping neutralization sites that target coxsackievirus A16

手足口病（Hand, Foot and Mouth Disease，HFMD）是一种由人肠道病毒引起的全球性传染病，主要发生于5岁以下的婴幼儿。2月5日，我校夏宁邵教授团队在《细胞》子刊《细胞•宿主与微生物》（Cell Host & Microbe）上在线发表题为“Identification of antibodies with non-overlapping neutralization sites that target coxsackievirus A16”的研究论文。该研究首次揭示了手足口病主要病原体柯萨奇病毒A组16型（CVA16）三种衣壳颗粒形式与三种不同类型的治疗性中和抗体的全面相互作用细节和非重叠的中和表位结构信息，阐明了CVA16成熟颗粒是疫苗候选主要保护性免疫原的理论基础，建立了可指导疫苗研制的免疫原特异检测方法，为CVA16疫苗及抗病毒药物研究提供关键基础。我校夏宁邵教授、李少伟教授、程通副教授和美国加州大学洛杉矶分校纳米系统研究所Z. Hong Zhou（周正洪）教授为该论文的共同通讯作者。我校博士生何茂洲、徐龙发博士后、郑清炳高级工程师、博士生朱瑞和尹志超为该论文共同第一作者。【Abstract】Hand, foot, and mouth disease is a common childhood illness primarily caused by coxsackievirus A16 (CVA16), for which there are no current vaccines or treatments. We identify three CVA16-specific neutralizing monoclonal antibodies (nAbs) with therapeutic potential: 18A7, 14B10, and NA9D7. We present atomic structures of these nAbs bound to all three viral particle forms—the mature virion, A-particle, and empty particle—and show that each Fab can simultaneously occupy the mature virion. Additionally, 14B10 or NA9D7 provide 100% protection against lethal CVA16 infection in a neonatal mouse model. 18A7 binds to a non-conserved epitope present in all three particles, whereas 14B10 and NA9D7 recognize broad protective epitopes but only bind the mature virion. NA9D7 targets an immunodominant site, which may overlap the receptor-binding site. These findings indicate that CVA16 vaccines should be based on mature virions and that these antibodies could be used to discriminate optimal virion-based immunogens.This work was supported by grants from the Major Program of National Natural Science Foundation of China ( 81991490 ), the National Science and Technology Major Projects for Major New Drugs Innovation and Development ( 2018ZX09711003-005-003 ), the National Science and Technology Major Project of Infectious Diseases ( 2017ZX10304402-002-003 ), the National Natural Science Foundation of China ( 31670933 and 81801646 ), the China Postdoctoral Science Foundation ( 2018M640599 and 2019T120557 ), the Principal Foundation of Xiamen University ( 20720190117 ), and the National Institutes of Health ( R37-GM33050 , GM071940 , DE025567 , and AI094386 ). 该研究获得了国家自然科学基金、新药创制国家科技重大专项、传染病防治国家科技重大专项和美国国立卫生研究院基金的资助

Ppm1b negatively regulates necroptosis through dephosphorylating ​Rip3

该研究论文发现蛋白磷酸酶Ppm1b 通过去磷酸化RIP3负调控程序性细胞坏死（necroptosis），阐明了RIP3磷酸化状态的精确调控对于细胞和机体在生理和病理状态下的存活至关重要。The auto-phosphorylation of murine ​receptor-interacting protein 3 (​Rip3) on Thr 231 and Ser 232 in the necrosome is required to trigger necroptosis. However, how ​Rip3 phosphorylation is regulated is still largely unknown. Here we identified ​protein phosphatase 1B (​Ppm1b) as a ​Rip3 phosphatase and found that ​Ppm1b restricts necroptosis in two settings: spontaneous necroptosis caused by ​Rip3 auto-phosphorylation in resting cells, and ​tumour necrosis factor-α (​TNF)-induced necroptosis in cultured cells. We revealed that ​Ppm1b selectively suppresses necroptosis through the dephosphorylation of ​Rip3, which then prevents the recruitment of ​mixed lineage kinase domain-like protein (​Mlkl) to the necrosome. We further showed that ​Ppm1b deficiency (​Ppm1bd/d) in mice enhanced ​TNF-induced death in a ​Rip3-dependent manner, and the role of ​Ppm1b in inhibiting necroptosis was evidenced by elevated ​Rip3 phosphorylation and tissue damage in the caecum of ​TNF-treated ​Ppm1bd/d mice. These data indicate that ​Ppm1b negatively regulates necroptosis through dephosphorylating ​Rip3 in vitro and in vivo

A Search for Light Super Symmetric Baryons

We have searched for the production and decay of light super-symmetric baryons produced in 800 GeV/c proton copper interactions in a charged hyperon beam experiment. We observe no evidence for the decays R+(uud \g^~) -> S(uds \g^~) pi+ and X-(ssd \g^~) -> S(uds \g^~) pi- in the predicted parent mass and lifetime ranges of 1700-2500 Mev/c2 and 50-500 ps. Production upper limits for R+ at xF=0.47, Pt=1.4 GeV/c2 and X- at xF=0.48, Pt=0.65 GeV/c2 of less than 10^-3 of all charged secondary particles produced are obtained for all but the highest masses and shortest lifetimes predicted.Comment: 9 pages, uuencoded postscript 4 figures uuencoded, tar-compressed file (submitted to PRL

Bio-inspired geotechnical engineering: Principles, current work, opportunities and challenges

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