Circulating CCRR serves as potential novel biomarker for predicting acute myocardial infarction

Objective:Cold regions exhibit a high prevalence of cardiovascular disease,particularly acute myocardial infarction(AMI),which is one of the leading causes of death associated with cardiovascular conditions.Cardiovascular disease is closely linked to the abnormal expression of long non-coding RNA(lncRNA).This study investigates whether circulating levels of lncRNA cardiac conduction regulatory RNA(CCRR)could serve as a biomarker for AMI.Materials and methods:We measured circulating CCRR from whole blood samples collected from 68 AMI patients and 69 non-AMI subjects.An AMI model was established using C57BL/6 mice.Quantitative reverse transcription PCR(qRT-PCR)was used to assess CCRR expression.Exosomes were isolated from cardiomyocytes,and their characteristics were evaluated using electron microscope and nanoparticle tracking analysis.The exosome inhibitor GW4869 was employed to examine the effect of exosomal CCRR on cardiac function using echocardiography.Protein expression was detected using Western blot and immunofluorescence staining.Results:The circulating level of CCRR was significantly higher in AMI patients(1.93±0.13)than in non-AMI subjects(1.00±0.05,P<0.001).The area under the ROC curve(AUC)of circulating CCRR was 0.821.Similar changes in circulating CCRR levels were consistently observed in an AMI mouse model.Exosomal CCRR derived from hypoxia-induced cardiomyocytes and cardiac tissue after AMI were increased,a change that was reversed by GW4869.Additionally,CCRR-overexpressing exosomes improved cardiac function in AMI.Conclusion:Circulating lncRNA CCRR is a potential predictor of AMI.Exosomal CCRR plays a role in the communication between the heart and other organs through circulation.

Hydroxychloroquine induces long QT syndrome by blocking hERG channel

Objective:In March 2022,more than 600 million cases of Corona Virus Disease 2019(COVID-19)and about 6 million deaths have been reported worldwide.Unfortunately,while effective antiviral therapy has not yet been available,chloroquine(CQ)/hydroxychloroquine(HCQ)has been considered an option for the treatment of COVID-19.While many studies have demonstrated the potential of HCQ to decrease viral load and rescue patients'lives,controversial results have also been reported.One concern associated with HCQ in its clinical application to COVID-19 patients is the potential of causing long QT interval(LQT),an electrophysiological substrate for the induction of lethal ventricular tachyarrhythmias.Yet,the mechanisms for this cardiotoxicity of HCQ remained incompletely understood.Materials and methods:Adult New Zealand white rabbits were used for investigating the effects of HCQ on cardiac electrophysiology and expression of ion channel genes.HEK-293T cells with sustained overexpression of human-ether-a-go-go-related gene(hERG)K+channels were used for whole-cell patch-clamp recordings of hERG K+channel current(IhERG).Quantitative RT-PCR analysis and Western blot analysis were employed to determine the expression of various genes at mRNA and protein levels,respectively.Results:electrocardiogram(ECG)recordings revealed that HCQ prolonged QT and RR intervals and slowed heart rate in rabbits.Whole-cell patch-clamp results showed that HCQ inhibited the tail current of hERG channels and slowed the reactivation process from inactivation state.HCQ suppressed the expression of hERG and hindered the formation of the heat shock protein 90(Hsp90)/hERG complex.Moreover,the expression levels of connexin 43(CX43)and Kir2.1,the critical molecular/ionic determinants of cardiac conduction thereby ventricular arrythmias,were decreased by HCQ,while those of Cav1.2,the main Ca2+handling proteins,remained unchanged and SERCA2a was increased.Conclusion:HCQ could induce LQT but did not induce arrhythmias,and whether it is suitable for the treatment of COVID-19 requires more rigorous investigations and validations in the future.

Internalization of NK cells into tumor cells requires ezrin and leads to programmed cell-in-cell death

Cytotoxic lymphocytes are key players in the orchestration of immune response and elimination of defective cells. We have previously reported that natural killer （NK） cells enter target tumor ceils, leading to either target cell death or self-destruction within tumor cells. However, it has remained elusive as to the fate of NK cells after internalization and whether the heterotypic cell-in-cell process is different from that of the homotypic cell-in-cell event recently named entosis. Here, we show that NK cells undergo a cell-in-cell process with the ultimate fate of apoptosis within tumor cells and reveal that the internalization process requires the actin cytoskeletal regulator, ezrin. To visualize how NK cells enter into tumor cells, we carried out real-time dual color imaging analyses of NK cell internalization into tumor cells. Surprisingly, most NK cells commit to programmed cell death after their entry into tumor cells, which is distinctively different from entosis observed in the homotypic cell-in-cell process. The apoptotic cell death of the internalized NK cells was evident by activation of caspase 3 and DNA fragmentation. Furthermore, NK cell death after internalization is attenuated by the caspase inhibitor, Z-VAD-FMK, confirming apoptosis as the mode of NK cell death within tumor cells. To determine protein factors essential for the entry of NK cells into tumor cells, we car- ried out siRNA-based knockdown analysis and discovered a critical role of ezrin in NK cell internalization. Impor- tantly, PKA-mediated phosphorylation of ezrin promotes the NK cell internalization process. Our findings suggest a novel regulatory mechanism by which ezrin governs NK cell internalization into tumor cells.

MiR-181b suppresses proliferation of and reduces chemoresistance to temozolomide in U87 glioma stem cells

MicroRNAs regulate self renewal and differentiation of cancer stem cells.There,we sought to identify the expression of miR-181b in glioma stem cells and investigate the biological effect of miR-181b on glioma stem cells in this study.MiR-181b expression was measured by real-time PCR in glioma stem cells isolated from U87 cells by FACS sorting.After miR-181b was overexpressed in U87 glioma stem cells by miR-181b lentiviral expression vector and/or treatment of temozolomide,secondary neurosphere assay,soft agar colony assay and MTT assay were performed.Compared with U87 cells,the expression of miR-181b was significantly decreased in U87 glioma stem cells.Overexpression of miR-181b decreased neurosphere formation by U87 glioma stem cells in vitro and suppressed colony formation in soft agar,and the cell growth inhibition rates increased in a time-dependent manner in U87 glioma stem cells infected with miR-181b lentivirus.Furthermore,miR-181b had a synergistic effect on temozolomide-induced inhibition of secondary neurosphere and soft agar colony,and on cell growth inhibition rates.MiR-181b functions as a tumor suppressor that suppresses proliferation and reduces chemoresistance to temozolomide in glioma stem cells.

Molecular and morphological data confirmed the presence of the rare species Mattirolomyces terfezioides in China

Although the species Mattiwlomyces terfezioides(≡ Terfezia terfezioides) has been recorded from China several times but it is really rare taxon with important ecological and economic value,the conspecihcity with European material has never been tested by molecular data.We re-examined three specimens labelled as T.terfezioides,one as T.leonis and one as Terfezia sp.in the herbarium HMAS and obtained five ITS and three LSU sequences.Our morphological observation and DNA sequences show that one specimen(HMAS 83766) labelled as M.terfezioides turns out to be Choiromyces sp.and the other four are M.terfezioides.The ITS and(or) LSU sequences of the Chinese samples are identical with or with 99%similarity to those from the European samples,which fully confirms the presence of M.terfezioides in China.The species is currently known from northern China(Hebei Province,Beijing and Shanxi Province).This study shows that M terfezioides has a Euroasia distribution other than European endemism and such distribution might be explained by the co-occurrence with the potential host tree Robinia pseudoacacia.

Duchesnea Phenolic Fraction Inhibits Tumor Growth through Restoring the Th1/Th2 Balance in U14 Cervical Cancer Bearing Mice

Duchesnea indica (Andr.) Focke has been traditionally used to treat cancer in Asian countries for centuries. In the present study, transplanted U14 cervical cancer mouse model was used to evaluate the antitumor and immunomodulatory activity of Duchesnea phenolic fraction (DPF). ELISA and RIA assay were employed to measured the serum concentration of Th1/Th2 cytokines (IL-2, IL-4, IFN-γ and TNF-α). Administration with 0.25 g/kg, 0.5 g/kg and 1 g/kg DPF significantly reduced the tumor weight by 34.37%, 43.89% and 56.28%, respectively, as compared to the tumor control group. Furthermore, the serum level of IL-2, IFN-γ and TNF-α increased and IL-4 level decreased in a dose-dependent manner during DPF treatment, indicating that the antitumor activity of DPF may be associated with the decrease of TNF-α level and restoration of the balance of Th1/Th2 cell responses. These data suggested that DPF, a mixture of plant polyphenols, had potent anticancer activity which was in part accomplished by its immunomodulatory ability.

Realization of High-Fidelity Controlled-Phase Gates in Extensible Superconducting Qubits Design with a Tunable Coupler

High-fidelity two-qubit gates are essential for the realization of large-scale quantum computation and simulation.Tunable coupler design is used to reduce the problem of parasitic coupling and frequency crowding in manyqubit systems and thus thought to be advantageous. Here we design an extensible 5-qubit system in which center transmon qubit can couple to every four near-neighboring qubits via a capacitive tunable coupler and experimentally demonstrate high-fidelity controlled-phase(CZ) gate by manipulating central qubit and one nearneighboring qubit. Speckle purity benchmarking and cross entropy benchmarking are used to assess the purity fidelity and the fidelity of the CZ gate. The average purity fidelity of the CZ gate is 99.69±0.04% and the average fidelity of the CZ gate is 99.65±0.04%, which means that the control error is about 0.04%. Our work is helpful for resolving many challenges in implementation of large-scale quantum systems.

Realization of Fast All-Microwave Controlled-Z Gates with a Tunable Coupler

The development of high-fidelity two-qubit quantum gates is essential for digital quantum computing.Here,we propose and realize an all-microwave parametric controlled-Z(CZ)gates by coupling strength modulation in a superconducting Transmon qubit system with tunable couplers.After optimizing the design of the tunable coupler together with the control pulse numerically,we experimentally realized a 100 ns CZ gate with high fidelity of 99.38%±0.34%and the control error being 0.1%.We note that our CZ gates are not affected by pulse distortion and do not need pulse correction,providing a solution for the real-time pulse generation in a dynamic quantum feedback circuit.With the expectation of utilizing our all-microwave control scheme to reduce the number of control lines through frequency multiplexing in the future,our scheme draws a blueprint for the high-integrable quantum hardware design.

Analysis and control of multidrug-resistant bacteria in hospital

Objective:To investigate the status of multidrug-resistant bacteria and the prevention and control measures of nosocomial in-fection in our hospital.Methods:The annual monitoring of multidrug-resistant bacteria infection was measured to summarize the bacteria species,statistical distribution and antibiotic resistance.Identification of multidrug-resistant bacteria infection in patients infected or hospital acquired infections was taken to analyze the reasons of multidrug-resistant bacteria strain and put forward the relevant measures.Results:The top five of multidrug-resistant strains infections were:Gram-positive bacteria including methicillin-resistant Staphylococcus aureus,Staphylococcus aureus;Gram-negative bacteria including Escherichia coli,Acinetobacter bauman-nii,Klebsiella pneumoniae.Conclusions:The occurrence of multidrug-resistant hospital infections could be prevented by rational use of antibiotics,hand hygiene and disinfection management,and reinforced monitoring of multidrug-resistant bacteria.

人工智能在胎儿超声心动图中的应用与进展

先天性心脏病(congenital heart disease,CHD)在所有新生儿中占1%,是最常见的出生缺陷,也是新生儿先天性出生缺陷死亡的主要原因[1],准确的产前诊断可显著提高CHD的围手术期治疗效果和手术成功率,降低新生儿死亡率。胎儿超声心动图由于具有无创、无辐射、实时、动态等优势,已成为胎儿CHD主要的筛查和诊断工具[2]。在过去的20年中,在产前诊断CHD的准确性方面取得了重要的研究进展,既往多项研究报道了胎儿超声心动图可以准确检出CHD,准确率高达85%[3,4]。

LncRNA CCRR maintains Ca^(2+)homeostasis against myocardial infarction through the FTO-SERCA2a pathway

Cardiac conduction regulatory RNA(CCRR)has been documented as an antiarrhythmic lncRNA in our earlier investigation.This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca^(2+)homeostasis in myocardial infarction(MI).Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca^(2+)homeostasis and reduced the heightened methylation level of SERCA2a following MI.These effects were also observed in CCRR overexpressing transgenic mice.A conserved sequence domain of CCRR mimicked the protective function observed with the full length.Furthermore,silencing CCRR in healthy mice led to intracellular Ca^(2+)overloading of cardiomyocytes.CCRR increased SERCA2a protein stability by upregulating FTO expression.The direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation(RIP)analysis and RNA pulldown experiments.Activation of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in MI.This study demonstrates that CCRR is a protective lncRNA that acts by maintaining the function of FTO,thereby reducing the m^(6)A RNA methylation level of SERCA2a,ultimately preserving calcium homeostasis for myocardial contractile function in MI.Therefore,CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.

MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages

Primary immune thrombocytopenia(ITP)is an autoimmune hemorrhagic disorder in which macrophages play a critical role.Mammalian sterile-20-like kinase 4(MST4),a member of the germinal-center kinase STE20 family,has been demonstrated to be a regulator of inflammation.Whether MST4 participates in the macrophage-dependent inflammation of ITP remains elusive.The expression and function of MST4 in macrophages of ITP patients and THP-1 cells,and of a macrophage-specific Mst4−/−(Mst4ΔM/ΔM)ITP mouse model were determined.Macrophage phagocytic assays,RNA sequencing(RNA-seq)analysis,immunofluorescence analysis,coimmunoprecipitation(co-IP),mass spectrometry(MS),bioinformatics analysis,and phosphoproteomics analysis were performed to reveal the underlying mechanisms.The expression levels of the MST4 gene were elevated in the expanded M1-like macrophages of ITP patients,and this elevated expression of MST4 was restored to basal levels in patients with remission after high-dose dexamethasone treatment.The expression of the MST4 gene was significantly elevated in THP-1-derived M1 macrophages.Silencing of MST4 decreased the expression of M1 macrophage markers and cytokines,and impaired phagocytosis,which could be increased by overexpression of MST4.In a passive ITP mouse model,macrophage-specific depletion of Mst4 reduced the numbers of M1 macrophages in the spleen and peritoneal lavage fluid,attenuated the expression of M1 cytokines,and promoted the predominance of FcγRIIb in splenic macrophages,which resulted in amelioration of thrombocytopenia.Downregulation of MST4 directly inhibited STAT1 phosphorylation,which is essential for M1 polarization of macrophages.Our study elucidates a critical role for MST4 kinase in the pathology of ITP and identifies MST4 kinase as a potential therapeutic target for refractory ITP.

在61比特可编程超导量子处理器上对量子多体态进行量子神经元感知

对具有不同性质和物相的多体量子态进行分类是量子多体物理学中最基本的任务之一.然而,由于巨大数量的相互作用的粒子所产生的指数级的复杂性,大规模量子态的分类对于经典的方法来说极具挑战性.本文提出了一种新的方法,称为量子神经元感知.利用一个61比特的超导量子处理器作为演示,作者表明该方案可以有效地对两种不同类型的多体现象,即遍历相和局域相,进行分类.量子神经元感知过程使他们能够通过只测量一个量子比特来区分这些多体物相,并提供比传统方法(如测量不平衡度)更好的分辨率.本研究证明了量子神经元感知在近期量子处理器应用的可行性和扩展性,并为探索更大规模系统中的量子多体现象开辟了新的途径.

Author Correction:MST4 kinase regulates immune thrombocytopenia by phosphorylating STAT1-mediated M1 polarization of macrophages

In this article,the details for Affiliation 1 were incorrectly given as‘Department of Hematology,Fudan University,Shanghai 200032,China’but should have been‘Department of Hematology,Zhongshan Hospital,Fudan University,Shanghai 200032,China’;the details for Affiliation 3 were incorrectly given as‘Department of Transfusion Medicine,Fudan University,Shanghai 200032,China’but should have been‘Department of Transfusion Medicine,Zhongshan Hospital,Fudan University,Shanghai 200032,China’;the details for Affiliation 4 were incorrectly given as‘Department of Laboratory Medicine,Fudan University,Shanghai 200032,China’but should have been‘Department of Laboratory Medicine,Zhongshan Hospital,Fudan University,Shanghai 200032,China’.The original article has been corrected.

Biallelic mutations in CDC20 cause female infertility characterized by abnormalities in oocyte maturation and early embryonic development

Dear Editor,Previously,the Mendelian phe no types in huma n oocyte maturation arrest,fertilization failure and early embryonic arrest,are largely underestimated.In recent years,"missing"Men delian phe no types and genes in these processes are beginning to be uncovered by us and others(Huang et al.,2014;Alazami et al..2015;Feng et al.,2016;Xu et al.,2016;Chen et al.,2017;Sang et al.,2019).However,the genetic basis for majority of patients resulting from abnormalities in these phe no types remains to be elucidated.

Quantum computational advantage via 60-qubit 24-cycle random circuit sampling

To ensure a long-term quantum computational advantage,the quantum hardware should be upgraded to withstand the competition of continuously improved classical algorithms and hardwares.Here,we demonstrate a superconducting quantum computing systems Zuchongzhi 2.1,which has 66 qubits in a two-dimensional array in a tunable coupler architecture.The readout fidelity of Zuchongzhi 2.1 is considerably improved to an average of 97.74%.The more powerful quantum processor enables us to achieve larger-scale random quantum circuit sampling,with a system scale of up to 60 qubits and 24 cycles,and fidelity of FXEB=(3·66±0·345)×10^(-4).The achieved sampling task is about 6 orders of magnitude more difficult than that of Sycamore[Nature 574,505(2019)]in the classic simulation,and 3 orders of magnitude more difficult than the sampling task on Zuchongzhi 2.0[arXiv:2106.14734(2021)].The time consumption of classically simulating random circuit sampling experiment using state-of-the-art classical algorithm and supercomputer is extended to tens of thousands of years(about 4·8×104years),while Zuchongzhi 2.1 only takes about 4.2 h,thereby significantly enhancing the quantum computational advantage.

LncRNA MIAT impairs cardiac contractile function by acting on mitochondrial translocator protein TSPO in a mouse model of myocardial infarction

Dear Editor,Long non-coding RNA MIAT(IncR-MIAT)has recently been identified as a risk factor for myocardial infarction(Ml).1 However,how IncR-MIAT controls Ml remained yet to be determined.To shed light on this issue,we firstly detected the expression of IncR-MIAT using qRT-PCR and found a robust elevation(>5-fold)of IncR-MIAT level in heart of Ml mice relative to sham-operated control counterparts(Supplementary Fig.S1a). MIAT in NMVCs(Supplementary Fig.Sic).