The First Reported Case of Co-Infection with Neisseria Meningitidis and Bordetella Pertussis in the Cerebrospinal Fluid Specimen of a Normal Four-Year-Old Child

Pertussis is an acute and highly contagious respiratory disease caused by Bordetella pertussis(B.pertussis),which occurs in people of all ages and is most dangerous for young children,especially infants.The introduction of whole-cell pertussis vaccines(wPVs)in the 1950s dramatically reduced the incidence of pertussis worldwide[1].However,over the past two decades,many studies have reported the resurgence of pertussis in different countries[2].Epidemiological surveillance in Hubei Province over the last 3 years revealed a clear increasing trend in the incidence of pertussis during the coronavirus disease 2019(COVID-19)epidemic.

A novel mouse model of calcific aortic valve stenosis

Background:Calcific aortic valve stenosis(CAVS)is one of the most challenging heart diseases in clinical with rapidly increasing prevalence.However,study of the mecha-nism and treatment of CAVS is hampered by the lack of suitable,robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposi-tion.Here,we aim to establish a mouse model to mimic the development and features of CAVS.Methods:The model was established via aortic valve wire injury(AVWI)combined with vitamin D subcutaneous injected in wild type C57/BL6 mice.Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradi-ent.Histopathological specimens were collected and examined in respect of valve thickening,calcium deposition,collagen accumulation,osteogenic differentiation and inflammation.Results:Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time depend-ent manner and tended to be stable at 28 days.Compared with the sham group,sim-ple AVWI or the vitamin D group,the hybrid model group showed typical pathological features of CAVS,including hemodynamic alterations,increased aortic valve thicken-ing,calcium deposition,collagen accumulation at 28 days.In addition,osteogenic dif-ferentiation,fibrosis and inflammation,which play critical roles in the development of CAVS,were observed in the hybrid model.Conclusions:We established a novel mouse model of CAVS that could be induced efficiently,robustly and economically,and without genetic intervention.It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effec-tive pharmacological targets.

U-Net-based deep learning for tracking and quantitative analysis of intracellular vesicles in time-lapse microscopy images

Fluorescence microscopy has become an essential tool for biologists,to visualize the dynamics of intracellular structures with specific labeling.Quantitatively measuring the dynamics of moving objects inside the cell is pivotal for understanding of the underlying regulatory mechanism.Protein-containing vesicles are involved in various biological processes such as material transportation,organelle interaction,and hormonal regulation,whose dynamic characteristics are signi¯cant to disease diagnosis and drug screening.Although some algorithms have been developed for vesicle tracking,most of them have limited performance when dealing with images with low resolution,poor signal-to-noise ratio(SNR)and complicated motion.Here,we proposed a novel deep learning-based method for intracellular vesicle tracking.We trained the U-Net for vesicle localization and motion classification,with demonstrates great performance in both simulated datasets and real biological samples.By combination with fan-shaped tracker(FsT)we have previously developed,this hybrid new algorithm significantly improved the performance of particle tracking with the function of subsequently automated vesicle motion classification.Furthermore,its performance was further demonstrated in analyzing with vesicle dynamics in different temperature,which achieved reasonable outcomes.Thus,we anticipate that this novel method would have vast applications in analyzing the vesicle dynamics in living cells.

CSCO guidelines for metastatic colorectal cancer:personalized medicine in clinical practice

Colorectal cancer(CRC)is the second most common cancer in China,the morbidity and mortality rates of which are rapidly increasing1,2.Among newly-diagnosed CRC patients,20%have metastatic disease at the time of presentation and an additional 25%present with localized disease and will subsequently develop metastases3.The treatment of metastatic colorectal cancer(mCRC)is gradually moving towards the era of precision therapy,which involves guided treatment based on individual genetic characteristics4.Since the first edition of the Chinese Society of Clinical Oncology(CSCO)guidelines was published in 2017,the guidelines have been updated annually according to the latest clinical trial findings5-9.Herein we summarize how the CSCO guidelines enable tailor-made treatments of mCRC with different molecular characteristics(Figure 1).

Fucosyltransferase 8 regulates adult neurogenesis and cognition of mice by modulating the Itga6-PI3K/Akt signaling pathway

Fucosyltransferase 8(Fut8)and core fucosylation play critical roles in regulating various biological processes,including immune response,signal transduction,proteasomal degradation,and energy metabolism.However,the function and underlying mechanism of Fut8 and core fucosylation in regulating adult neurogenesis remains unknown.We have shown that Fut8 and core fucosylation display dynamic features during the differentiation of adult neural stem/progenitor cells(aNSPCs)and postnatal brain development.Fut8 depletion reduces the proliferation of a NSPCs and inhibits neuronal differentiation of aNSPCs in vitro and in vivo,respectively.Additionally,Fut8 deficiency impairs learning and memory in mice.Mechanistically,Fut8 directly interacts with integrinα6(Itga6),an upstream regulator of the PI3kAkt signaling pathway,and catalyzes core fucosylation of Itga6.Deletion of Fut8 enhances the ubiquitination of Itga6 by promoting the binding of ubiquitin ligase Trim21 to Itga6.Low levels of Itga6 inhibit the activity of the PI3K/Akt signaling pathway.Moreover,the Akt agonist SC79 can rescue neurogenic and behavioral deficits caused by Fut8 deficiency.In summary,our study uncovers an essential function of Fut8 and core fucosylation in regulating adult neurogenesis and sheds light on the underlying mechanisms.

The Functional Redundancy of Neddylation E2s and E3s in Modulating the Fitness of Regulatory T Cells

Neddylation is necessary for activation of Cullin-RING ligases(CRLs),which degrade various immune regulatory proteins.Our recent study showed that while depletion of neddylation E2-E3 pair Ube2f-Sag in regulatory T(T_(reg))cells had no obvious phenotype,the same depletion of either Ube2m or Rbx1 caused inflammation disorders with different severity.Whether these E2s or E3s compensate each other in functional regulations of T_(reg)cells is,however,previously unknown.In this report,we generated Foxp3^(Cre);Ube2m^(fl/fl);Ube2f^(fl/fl)or Foxp3^(Cre);Rbx1^(fl/fl);Sag^(fl/fl)double-null mice by simultaneous deletion of both neddylation E2s or E3s in T_(reg)cells,respectively.Remarkably,Ube2m&Ube2f double-null mice developed much severe autoimmune phenotypes than did Ube2m-null mice,indicating that Ube2m markedly compensates Ube2f in T_(reg)cells.The minor worsened autoimmune phenotypes seen at the very early stage in Rbx1&Sag double-null than Rbx1-null mice is likely due to already severe phenotypes of the later,indicating a minor compensation of Rbx1 for Sag.The RNA profiling-based analyses revealed that up-and down-regulations of few signaling pathways in T_(reg)cells are associated with the severity of autoimmune phenotypes.Finally,severer inflammation phenotypes seen in mice with double E3-null than with double E2-null T_(reg)cells indicate a neddylation-independent mechanism of 2 E3s,also known to serve as the RING component of CRLs in regulation of T_(reg)cell fitness.

Neddylation Regulation of Immune Responses

Neddylation plays a vital role in post-translational modification, intricately shaping the regulation of diverse biological processes, including those related to cellular immune responses. In fact, neddylation exerts control over both innate and adaptive immune systems via various mechanisms. Specifically, neddylation influences the function and survival of innate immune cells, activation of pattern recognition receptors and GMP-AMP synthase–stimulator of interferon genes pathways, as well as the release of various cytokines in innate immune reactions. Moreover, neddylation also governs the function and survival of antigen-presenting cells, which are crucial for initiating adaptive immune reactions. In addition, neddylation regulates T cell activation, proliferation, differentiation, survival, and their effector functions, thereby ensuring an appropriate adaptive immune response. In this review, we summarize the most recent findings in these aspects and delve into the connection between dysregulated neddylation events and immunological disorders, especially inflammatory diseases. Lastly, we propose future directions and potential treatments for these diseases by targeting neddylation.

Development of an onsite calibration device for robot manipulators

A novel in-contact three-dimensional(3D)measuring device,called MultiCal,is proposed as a convenient,low-cost(less than US$5000),and robust facility for onsite kinematic calibration and online measurement of robot manipulator accuracy.The device hasμm-level accuracy and can be easily embedded in robot cells.During the calibration procedure,the robot manipulator first moves automatically to multiple end-effector orientations with its tool center point(TCP)constrained on a fixed point by a 3D displacement measuring device(single point constraint),and the corresponding joint angles are recorded.Then,the measuring device is precisely mounted at different positions using a well-designed fixture,and the above measurement process is repeated to implement a multi-point constraint.The relative mounting positions are accurately measured and used as prior information to improve calibration accuracy and robustness.The results of theoretical analysis indicate that MultiCal reduces calibration accuracy by 10%to 20%in contrast to traditional non-contact 3D or six-dimensional(6D)measuring devices(such as laser trackers)when subject to the same level of artificial measurement noise.The results of a calibration experiment conducted on a Staubli TX90 robot show that MultiCal has only 7%to 14%lower calibration accuracy compared to a measuring arm with a laser scanner,and 21%to 30%lower time efficiency compared to a 6D binocular vision measuring system,yielding maximum and mean absolute position errors of 0.831 mm and 0.339 mm,respectively.

RNA sequencing-based optimization of biological lipid droplets for sonodynamic therapy to reverse tumor hypoxia and elicit robust immune response

Mitochondria-targeted sonodynamic therapy(SDT)is a promising strategy to inhibit tumor growth and activate the anti-tumor immune responses.Identifying the mechanisms underlying mitochondria-targeted SDT,further optimizing its efficacy,developing novel sonosensitizer carriers with good biocompatibility pose major challenges to the clinical practice of SDT.In this study,we investigated the mechanisms of mitochondria-targeted SDT and demonstrated that it suppressed the mitochondrial electron transport chain(ETC)in pancreatic cancer cells through RNA-sequencing analysis.Based on these findings,we constructed the functional lipid droplets(LDs)(CPI-613/IR780@LDs),which combined mitochondria-targeted SDT with the tricarboxylic acid(TCA)cycle inhibitor CPI-613.CPI-613/IR780@LDs synergistically inhibited the TCA cycle and the ETC of mitochondrial aerobic respiration to reduce oxygen consumption and increase reactive oxygen species(ROS)generation at the tumor site,thus enhancing the efficacy of SDT in hypoxic pancreatic cancer.Moreover,the combination of mitochondria-targeted SDT and anti-PD-1 antibody exhibited excellent tumor inhibition and activated anti-tumor immune responses by increasing tumorinfiltrating CD8+T cells and reducing regulatory T cells,synergistically arresting the growth of both primary and metastatic pancreatic tumors.Meanwhile,lipid droplets are cell-derived biological carriers with natural mitochondrial targeting ability and can achieve efficient hydrophobic drug loading through active phagocytosis.Therefore,the functional lipid droplet-based SDT combined with anti-PD-1 antibody holds great potential in the clinical treatment of hypoxic pancreatic cancer.

Evaluating the efficacy and cardiotoxicity of EGFR-TKI AC0010 with a novel multifunctional biosensor

Non-small cell lung cancer(NSCLC)is a leading cause of cancer mortality worldwide.Although epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)have dramatically improved the life expectancy of patients with NSCLC,concerns about TKI-induced cardiotoxicities have increased.AC0010,a novel third-generation TKI,was developed to overcome drug resistance induced by EGFR-T790M mutation.However,the cardiotoxicity of AC0010 remains unclear.To evaluate the efficacy and cardiotoxicity of AC0010,we designed a novel multifunctional biosensor by integrating microelectrodes(MEs)and interdigital electrodes(IDEs)to comprehensively evaluate cell viability,electrophysiological activity,and morphological changes(beating of cardiomyocytes).The multifunctional biosensor can monitor AC0010-induced NSCLC inhibition and cardiotoxicity in a quantitative,label-free,noninvasive,and real-time manner.AC0010 was found to significantly inhibit NCI-H1975(EGFR-L858R/T790M mutation),while weak inhibition was found for A549(wild-type EGFR).Negligible inhibition was found in the viabilities of HFF-1(normal fibroblasts)and cardiomyocytes.With the multifunctional biosensor,we found that 10μM AC0010 significantly affected the extracellular field potential(EFP)and mechanical beating of cardiomyocytes.The amplitude of EFP continuously decreased after AC0010 treatment,while the interval decreased first and then increased.We analyzed the change in the systole time(ST)and diastole time(DT)within a beating interval and found that the DT and DT/beating interval rate decreased within 1 h after AC0010 treatment.This result probably indicated that the relaxation of cardiomyocytes was insufficient,which may further aggravate the dysfunction.Here,we found that AC0010 significantly inhibited EGFR-mutant NSCLC cells and impaired cardiomyocyte function at low concentrations(10μM).This is the first study in which the risk of AC0010-induced cardiotoxicity was evaluated.In addition,novel multifunctional biosensors can comprehensively evaluate the antitumor efficacy and cardiotoxicity of drugs and candidate compounds.

Novel function of biguanides in inhibition of phospholipase D1 expression via a translational mechanism in cancer cells

Phospholipase D(PLD)and its product phosphatidic acid(PA)function as pleiotropic factors in the regulation of cancer progression,which includes the promotion of cell growth,survival,cell migration,and angiogenesis.1 Chemical inhibition of the enzymatic activity of PLD1 and PLD2,or genetic down-regulation of their expression both induce tumor suppression,1 while the compounds for PLD expression inhibition are barely reported.Here,we astonishingly found that the anti-hyperglycemic agents biguanides decreased PLD1 protein expression in cancer cells and further investigated its underlying regulatory mechanism.

Exogeneous metal ions as therapeutic agents in cardiovascular disease and their delivery strategies

Metal ions participate in many metabolic processes in the human body,and their homeostasis is crucial for life.In cardiovascular diseases(CVDs),the equilibriums of metal ions are frequently interrupted,which are related to a variety of disturbances of physiological processes leading to abnormal cardiac functions.Exogenous supplement of metal ions has the potential to work as therapeutic strategies for the treatment of CVDs.Compared with other therapeutic drugs,metal ions possess broad availability,good stability and safety and diverse drug delivery strategies.The delivery strategies of metal ions are important to exert their ther-apeutic effects and reduce the potential toxic side effects for cardiovascular applications,which are also receiving increasing attention.Controllable local delivery strategies for metal ions based on various biomaterials are constantly being designed.In this review,we comprehensively summarized the positive roles of metal ions in the treatment of cVDs from three aspects:protecting cells from oxidative stress,inducing angiogenesis,and adjusting the functions of ion channels.In addition,we introduced the transferability of metal ions in vascular reconstruction and cardiac tissue repair,as well as the currently available engineered strategies for the precise delivery of metal ions,such as integrated with nanoparticles,hydrogels and scaffolds.

Towards understanding bogus traffic service in online social networks

Critical functionality and huge infuence of the hot trend/topic page(HTP)in microblogging sites have driven the creation of a new kind of underground service called the bogus traffic service(BTS).BTS provides a kind of illegal service which hijacks the HTP by pushing the controlled topics into it for malicious customers with the goal of guiding public opinions.To hijack HTP,the agents of BTS maintain an army of black-market accounts called bogus trafic accounts(BTAs)and control BTAs to generate a burst of fake trafic by massively retweeting the tweets containing the customer desired topic(hashtag).Although this service has been extensively exploited by malicious customers,little has been done to understand it.In this paper,we conduct a systematic measurement study of the BTS.We first investigate and collect 125 BTS agents from a variety of sources and set up a honey pot account to capture BTAs from these agents.We then build a BTA detector that detects 162218 BTAs from Weibo,the largest Chinese microblogging site,with a precision of 94.5%.We further use them as a bridge to uncover 296916 topics that might be involved in bogus trafic.Finally,we uncover the operating mechanism from the perspectives of the attack cycle and the attack entity.The highlights of our findings include the temporal attack patterns and intelligent evasion tactics of the BTAs.These findings bring BTS into the spotlight.Our work will help in understanding and ultimately eliminating this threat.

Protein neddylation and its role in health and diseases

NEDD8(Neural precursor cell expressed developmentally downregulated protein 8)is an ubiquitin-like protein that is covalently attached to a lysine residue of a protein substrate through a process known as neddylation,catalyzed by the enzyme cascade,namely NEDD8 activating enzyme(E1),NEDD8 conjugating enzyme(E2),and NEDD8 ligase(E3).The substrates of neddylation are categorized into cullins and non-cullin proteins.Neddylation of cullins activates CRLs(cullin RING ligases),the largest family of E3 ligases,whereas neddylation of non-cullin substrates alters their stability and activity,as well as subcellular localization.Significantly,the neddylation pathway and/or many neddylation substrates are abnormally activated or over-expressed in various human diseases,such as metabolic disorders,liver dysfunction,neurodegenerative disorders,and cancers,among others.Thus,targeting neddylation becomes an attractive strategy for the treatment of these diseases.In this review,we first provide a general introduction on the neddylation cascade,its biochemical process and regulation,and the crystal structures of neddylation enzymes in complex with cullin substrates;then discuss how neddylation governs various key biological processes via the modification of cullins and non-cullin substrates.We further review the literature data on dysregulated neddylation in several human diseases,particularly cancer,followed by an outline of current efforts in the discovery of small molecule inhibitors of neddylation as a promising therapeutic approach.Finally,few perspectives were proposed for extensive future investigations.

A small molecule inhibitor of the UBE2F-CRL5 axis induces apoptosis and radiosensitization in lung cancer

Protein neddylation is catalyzed by a neddylation activating enzyme(NAE,E1),an E2 conjugating enzyme,and an E3 ligase.In various types of human cancers,the neddylation pathway is abnormally activated.Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer.Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent,there are no small molecules available that selectively target UBE2F.Here,we report,for the first time,the discovery,via structure-based virtual screen and chemical optimization,of such a small molecule,designated as HA-9104.HA-9104 binds to UBE2F,reduces its protein levels,and consequently inhibits cullin-5 neddylation.Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5(CRL5)activity,leading to accumulation of the CRL5 substrate,NOXA,to induce apoptosis.Moreover,HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest.Biologically,HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models.In summary,we discovered a small molecule,designated HA-9104,that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation.

Covalently grafting first-generation PAMAM dendrimers onto MXenes with self-adsorbed AuNPs for use as a functional nanoplatform for highly sensitive electrochemical biosensing of cTnT

2D MXene-Ti3C2Tx has demonstrated promising application prospects in various fields;however,it fails to function properly in biosensor setups due to restacking and anodic oxidation problems.To expand beyond these existing limitations,an effective strategy to for modifying the MXene by covalently grafting first-generation poly(amidoamine)dendrimers onto an MXene in situ(MXene@PAMAM)was reported herein.When used as a conjugated template,the MXene not only preserved the high conductivity but also conferred a specific 2D architecture and large specific surface areas for anchoring PAMAM.The PAMAM,an efficient spacer and stabilizer,simultaneously suppressed the substantial restacking and oxidation of the MXene,which endowed this hybrid with improved electrochemical performance compared to that of the bare MXene in terms of favorable conductivity and stability under anodic potential.Moreover,the massive amino terminals of PAMAM offer abundant active sites for adsorbing Au nanoparticles(AuNPs).The resulting 3D hierarchical nanoarchitecture,AuNPs/MXene@PAMAM,had advanced structural merits that led to its superior electrochemical performance in biosensing.As a proof of concept,this MXene@PAMAM-based nanobiosensing platform was applied to develop an immunosensor for detecting human cardiac troponin T(cTnT).A fast,sensitive,and highly selective response toward the target in the presence of a[Fe(CN)6]^(3-/4-)redox marker was realized,ensuring a wide detection of 0.1-1000 ng/mL with an LOD of 0.069 ng/mL.The sensor's signal only decreased by 4.38%after 3 weeks,demonstrating that it exhibited satisfactory stability and better results than previously reported MXene-based biosensors.This work has potential applicability in the bioanalysis of cTnT and other biomarkers and paves a new path for fabricating high-performance MXenes for biomedical applications and electrochemical engineering.

A deep learning-based method for pediatric congenital heart disease detection with seven standard views in echocardiography

Background With the aggregation of clinical data and the evolution of computational resources,artificial intelligence-based methods have become possible to facilitate clinical diagnosis.For congenital heart disease(CHD)detection,recent deep learning-based methods tend to achieve classification with few views or even a single view.Due to the complexity of CHD,the input images for the deep learning model should cover as many anatomical structures of the heart as possible to enhance the accuracy and robustness of the algorithm.In this paper,we first propose a deep learning method based on seven views for CHD classification and then validate it with clinical data,the results of which show the competitiveness of our approach.Methods A total of 1411 children admitted to the Children’s Hospital of Zhejiang University School of Medicine were selected,and their echocardiographic videos were obtained.Then,seven standard views were selected from each video,which were used as the input to the deep learning model to obtain the final result after training,validation and testing.Results In the test set,when a reasonable type of image was input,the area under the curve(AUC)value could reach 0.91,and the accuracy could reach 92.3%.During the experiment,shear transformation was used as interference to test the infection resistance of our method.As long as appropriate data were input,the above experimental results would not fluctuate obviously even if artificial interference was applied.Conclusions These results indicate that the deep learning model based on the seven standard echocardiographic views can effectively detect CHD in children,and this approach has considerable value in practical application.

Multigenerational birth cohort study in China:importance,necessity and beyond

A birth cohort study is an epidemiological study that enrolls a group of people who were born during a specifc period of time and follows up with them from the prenatal period to adulthood and even old age.The establishment of a birth cohort study enables the exploration of the etiology of diseases and enriches the understanding and awareness of health status among the reproductive population.Additionally,it provides evidence-based support for the launch of public health policies and programs and thus practically promotes the health care of women and children,facilitating the early prevention of disease in childhood and adulthood[1].