Molecular analysis of Coxsackievirus A24 variant isolates from three outbreaks of acute hemorrhagic conjunctivitis in 1988,1994 and 2007 in Beijing,China

Coxsackievirus A24 variant(CVA24v)is a major pathogen that causes continued outbreaks and pandemics of acute hemorrhagic conjunctivitis(AHC).In China,the first confirmed outbreak of CVA24v-related AHC occurred in Beijing in 1988,followed by another two significant outbreaks respectively in 1994 and 2007,which coincides with the three-stage dynamic distribution of AHC in the world after 1970s.To illustrate the genetic characteristics of CVA24v in different periods,a total of 23 strains were isolated from those three outbreaks and the whole genome of those isolations were sequenced and analyzed.Compared with the prototype strain,the 23 strains shared four nucleotide deletions in the 5'UTR except the 0744 strain isolated in 2007.And at the 98th site,one nucleotide insertion was found in all the strains collected from 2007.From 1994 to 2007,amino acid polarity in the VP1 region at the 25th and the 32nd site were changed.Both the 3C and VP1 phylogenetic tree indicated that isolates from 1988 and 1994 belonged to Genotype III(GIII),and 2007 strains to Genotype IV(GIV).According to the Bayesian analysis based on complete genome sequence,the most recent common ancestors for the isolates in1988,1994 and 2007 were respectively estimated around October 1987,February 1993 and December 2004.The evolutionary rate of the CVA24v was estimated to be 7.45×10^(-3) substitutions/site/year.Our study indicated that the early epidemic of CVA24v in Chinese mainland was the GIII.Point mutations and amino acid changes in different genotypes of CVA24v may generate intensity differences of the AHC outbreak.CVA24v has been evolving constantly with a relatively rapid rate.

基于纳米药物调控肿瘤成纤维样细胞用于肿瘤治疗的研究进展

肿瘤成纤维样细胞是肿瘤间质内数量最多的细胞组分.不同类型实体肿瘤的成纤维样细胞来源有所不同,但均对肿瘤微环境的塑造起到至关重要的作用.其可以大量分泌细胞外基质,促进肿瘤血管新生,阻碍药物输运,阻止免疫细胞的肿瘤浸润,增强肿瘤的化疗及免疫治疗耐受等.因此,针对肿瘤成纤维样细胞促进肿瘤发展的功能进行调控,可重塑肿瘤微环境,提高肿瘤的治疗效果.本文简要介绍了肿瘤成纤维样细胞在肿瘤微环境中的重要作用,并重点介绍基于纳米药物精准调控肿瘤成纤维样细胞的研究进展,为继续开发基于调控肿瘤成纤维样细胞的肿瘤治疗策略提供思路.

Construction of meloxicam and bupivacaine co-delivery nanosystem based on the pathophysiological environment of surgical injuries for enhanced postoperative analgesia

Besides peripheral nerve injury,the acute inflammation is one of the pathological features of tissues after surgery,which exacerbates the postoperative pain,especially in the first 48 h after the surgery.Multimodal analgesia(MMA),such as the combination of non-steroidal anti-inflammatory drugs(NSAIDs)with local anesthetics,has shown enhanced potency compared with the usage of local anesthetics alone.However,rare formulations can provide long-term analgesia at a single dose.Herein,bupivacaine(BUP,a local anesthetic)loading poly(lactic-co-glycolic acid)(PLGA)nanoparticles(NPB)were coated with meloxicam(MLX,an NSAID)loading lipid bilayer(LPM),forming a core–shell nanosystem(NPB@LPM)to provide enhanced and long-term analgesia to treat postoperative pain.MLX was encapsulated in the lipid shell,which enabled high dose MLX to be released in the first 48 h after surgery to reduce the acute inflammation induced pain.BUP was encapsulated in the PLGA core to provide a long-term release for the nerve block.This nanosystem provided a 7-day(whole recovery cycle)effective analgesia in the Brennan’s plantar incision rat model.The tissue reactions of NPB@LPM are benign.This work will provide feasible strategies on designing drug delivery systems for postoperative pain management.

Self-assembly of CXCR4 antagonist peptide-docetaxel conjugates for breast tumor multi-organ metastasis inhibition

As a representative chemotherapeutic drug,docetaxel(DTX)has been used for breast cancer treatment for decades.However,the poor solubility of DTX limits its efficacy,and the DTX based therapy increases the metastasis risk due to the upregulation of C-X-C chemokine receptor type 4(CXCR4)expression during the treatment.Herein,we conjugated CXCR4 antagonist peptide(CTCE)with DTX(termed CTCE-DTX)as an anti-metastasis agent to treat breast cancer.CTCE-DTX could selfassemble to nanoparticles,targeting CXCR4-upregulated metastatic tumor cells and enhancing the DTX efficacy.Thus,the CTCE-DTX NPs achieved promising efficacy on inhibiting both bonespecific metastasis and lung metastasis of triple-negative breast cancer.Our work provided a rational strategy on designing peptide-drug conjugates with synergistic anti-tumor efficacy.

Molecular Epidemiology of Echovirus 18 Circulating in China's Mainland from 2015 to 2016

Echovirus 18(E18), a serotype of Enterovirus B(EV-B) species, is an important pathogen in aseptic meningitis. E18 had rarely been detected in China's Mainland, but became the predominant pathogen associated with viral encephalitis(VE) and meningitis in Hebei province for the first time in 2015. To investigate the molecular epidemiology and genetic characteristics of E18 in China's Mainland, sixteen E18 strains from patient throat swabs with hand, foot, and mouth disease(HFMD) in six provinces in China collected between 2015 and 2016, and four E18 strains isolated from 18 patient cerebrospinal fluid specimens with VE in Hebei Province in 2015 were obtained and sequenced. Combined with the sequences from the GenBank database, we performed an extensive genetic analysis. Phylogenetic analysis of VP1 gene sequences revealed that all E18 strains from China's Mainland after 2015 belonged to subgenotype C2. There were no obvious specific differences in phylogenetic and variation analyses of E18 genome sequences between HFMD and VE/meningitis strains. Potential multiple recombination may have occurred in the 50-untranslated region and in the P2 and P3 nonstructural protein-encoding regions of E18 strains from China. The current E18 strains were potential multiplerecombinant viruses. Overall, these findings supported that E18 caused HFMD, VE, and meningitis, although there were no significant associations between clinical features and viral genomic characteristics.

Co-delivery of doxorubicin and quercetin via mPEG-PLGA copolymer assembly for synergistic anti-tumor efficacy and reducing cardio-toxicity

橡黄素(Que ) 是自然多功能的 bioflavonoid，并且为减少不利副作用并且提高化学疗法的药的反肿瘤功效显示出大潜力。然而，它的临床的申请在生理的系统由于很低的溶解度和结构的不稳定性被限制。此处，我们共同交付由开发 amphiphilic 聚合物包括的 biocompatible nanocarrier 的恐水病的橡黄素和吸水的 doxorubicin (纪录影片) ， methoxy poly (乙烯乙二醇) 并且 poly (D， L-lactide-co-glycolide ) 分别地。反肿瘤和这个系统的预防功效被评估在细胞并且动物模型。我们说明的调查结果 Dox-Que nanoparticulate 明确的表达保护了正常脉管的 endothelial 房间免受免费的任何一个或 nanoparticulate 的伤害导致 doxorubicin 的 cytotoxicity 和增加的癌症房间死亡。与免费 doxorubicin 和它的 nanoformulation 相比，用我们的 nanosystem 的橡黄素和 doxorubicin 的合作交货 synergistically 禁止了肿瘤生长，当在浆液维持心脏的功能指示物的正常层次并且在心织物恢复组织病理学说的损坏时。这研究为提高反癌症药功效并且减少 nanoparticulate 表明有希望的策略正常纸巾上的导致化疗的毒性。

Trends in the biological functions and medical applications of extracellular vesicles and analogues

Natural extracellular vesicles(EVs)play important roles in many life processes such as in the intermolecular transfer of substances and genetic information exchanges.Investigating the origins and working mechanisms of natural EVs may provide an understanding of life activities,especially regarding the occurrence and development of diseases.Additionally,due to their vesicular structure,EVs(in small molecules,nucleic acids,proteins,etc.)could act as efficient drug-delivery carriers.Herein,we describe the sources and biological functions of various EVs,summarize the roles of EVs in disease diagnosis and treatment,and review the application of EVs as drug-delivery carriers.We also assess the challenges and perspectives of EVs in biomedical applications.

Genomic surveillance of coxsackievirus A10 reveals genetic features and recent appearance of genogroup D in Shanghai,China,2016–2020

Coxsackievirus A10(CVA10)is one of the major causative agents of hand,foot and mouth disease(HFMD).To investigate the epidemiological characteristics as well as genetic features of CVA10 currently circulating in Shanghai,China,we collected a total of 9,952 sporadic HFMD cases from January 2016 to December 2020.In the past five years,CVA10 was the fourth prevalent causatives associated with HFMD in Shanghai and the overall positive rate was 2.78%.The annual distribution experienced significant fluctuations over the past five years.In addition to entire VP1 sequencing,complete genome sequencing and recombination analysis of CVA10 isolates in Shanghai were further performed.A total of 64 near complete genomes and 11 entire VP1 sequences in this study combined with reference sequences publicly available were integrated into phylogenetic analysis.The CVA10sequences in this study mainly belonged to genogroup C and presented 91%-100%nucleotide identity with other Chinese isolates based on VP1 region.For the first time,our study reported the appearance of CVA10 genogroup D in Chinese mainland,which had led to large-scale outbreaks in Europe previously.The recombination analysis showed the recombination break point located between 5,100 nt and 6,700 nt,which suggesting intertypic recombination with CVA16 genogroup D.To conclusion,CVA10 genogroup C was the predominant genogroup in Shanghai during 2016-2020.CVA10 recombinant genogroup D was firstly reported in circulating in Chinese mainland.Continuous surveillance is needed to better understand the evolution relationships and transmission pathways of CVA10 to help to guide disease control and prevention.

Surveillance, epidemiology, and pathogen spectrum of hand, foot, and mouth disease in mainland of China from 2008 to 2017

Hand,foot and mouth disease(HFMD)was reported in May 2,2008 to be the 38th legally notifiable disease in China's National Notifiable Disease Reporting and Surveillance System.In order to solve the infection,an extensive three-level HFMD surveillance laboratory network was established.In this study,the framework of that network is assessed and the incidence of HFMD in China from 2008 to 2017 is reported using a descriptive epidemiologic method.During these 10 years,a series of techniques have been widely applied in all the network laboratories.Using information and material obtained from the network,a virus bank and database containing 18,238 viruses were established.Nationally,18,184,834 HFMD cases,including 152,436 severe cases and 3633 fatal cases,were reported in mainland of China.The average annual incidence in the population was 133.99/100,000 people,with a maximum incidence of 205.06/100,000 people in 2014.The incidence and mortality rates of HFMD were the highest in children aged 1–2 years.The numbers of reported cases fluctuated,with a high incidence observed every 2 years.An overall increase in the number of reported cases was also observed throughout the study period.Despite this,the incidence of severe cases and the mortality rate have been decreasing.High-risk regions are located in southern,eastern,and central China.Two peaks of HFMD infection cases were observed annually except for Northeast China.Different proportions of enterovirus serotypes were observed during the studied years.The predominant enterovirus varies from year to year,but the disease severity is always closely related to the specific serotype.EV-A71 is the dominant serotype associated with severe and fatal cases,with constituent ratios of 70.03%and 92.23%,respectively.The studied highly sensitive and efficient surveillance network provides information that is critical for prevention and control of the disease.It is extremely necessary and important to continuously conduct extensive virological surveillance for HFMD.

生物可降解镁植入物——骨肿瘤患者的潜在支架

骨癌患者切除术后可能发生复发和转移.传统的金属支架可以对骨缺损部位提供力学支撑,但无法有效清除复发的肿瘤细胞.本文中,我们介绍了一种可以抑制骨肉瘤生长的生物可降解镁丝植入物.简而言之,镁丝释放镁离子激活锌指蛋白Snail1从胞浆到细胞核的转运,通过下游的miRNA-181d-5p/TIMP3和miRNA-181c-5p/NLK两条平行的抗肿瘤信号通路诱导骨肉瘤细胞凋亡,抑制骨肉瘤细胞增殖.同时,镁丝释放出的氢气消除了细胞内过多的活性氧,从而抑制了骨肿瘤细胞的生长.裸鼠骨肉瘤细胞皮下荷瘤实验进一步证实镁丝能有效抑制肿瘤生长,延长荷瘤小鼠生存期.此外,镁丝对正常细胞和组织无毒性,揭示了镁植入物是骨肉瘤患者潜在的抗肿瘤支架材料.

COVID-19 Outbreak Caused by Contaminated Packaging of Imported Cold-Chain Products—Liaoning Province,China,July 2020

Summary What is known about this topic?Few major outbreaks of coronavirus disease 2019(COVID-19)have occurred in China after major nonpharmaceutical interventions and vaccines have been deployed and implemented.However,sporadic outbreaks that had high possibility to be linked to cold chain products were reported in several cities of China..What is added by this report?In July 2020,a COVID-19 outbreak occurred in Dalian,China.The investigations of this outbreak strongly suggested that the infection source was from COVID-19 virus-contaminated packaging of frozen seafood during inbound unloading personnel contact.What are the implications for public health practice?Virus contaminated paper surfaces could maintain infectivity for at least 17–24 days at-25℃.Exposure to COVID-19 virus-contaminated surfaces is a potential route for introducing the virus to a susceptible population.Countries with no domestic transmission of COVID-19 should consider introducing prevention strategies for both inbound travellers and imported goods.Several measures to prevent the introduction of the virus via cold-chain goods can be implemented.

Reemergent Cases of COVID-19--Dalian City,Liaoning Province,China,July 22,2020

From July 22-23,3 local COVID-19 cases were reported in Dalian City,Liaoning Province,China.All 3 patients reported that they did not leave Dalian 14 days before the onset of disease and had no COVID-19 case contact history and no foreign personnel contact history.Epidemiological investigation,medical isolation,and nucleic acid detection was immediately carried out in Dalian,and 12 asymptomatic infections were detected in close contacts of Patient 1.Because asymptomatic infections made up a large proportion of total infections,the outbreak was likely observed in the beginning stages.

Ferritin nanocages for early theranostics of tumors via inflammation-enhanced active targeting

Engineered nanocarriers have been widely developed for tumor theranostics.However,the delivery of imaging probes or therapeutic drugs to the tumor pre-formation site for early and accurate detection and therapy remains a major challenge.Here,by using tailor-functionalized human H-ferritin(HFn),we developed a triple-modality nanoprobe IRdye800-M-HFn and achieved the early imaging of tumor cells before the formation of solid tumor tissues.Then,we developed an HFn-doxorubicin(Dox)drug delivery system by loading Dox into the HFn protein cage and achieved early-stage tumor therapy.The intravenous injection of HFn nanoprobes enabled the imaging of tumor cells as early as two days after tumor implantation,and the triple-modality imaging techniques,namely,near-infrared fluorescence molecular imaging(NIR-FMI),magnetic resonance imaging(MRI),and photoacoustic imaging(PAI),ensured the accuracy of detection.Further exploration indicated that HFn could specifically penetrate into pre-solid tumor sites by tumor-associated inflammation-mediated blood vessel leakage,followed by effective accumulation in tumor cells by the specific targeting property of HFn to transferrin receptor 1.Thus,the HFn-Dox drug delivery system delivered Dox into the tumor pre-formation site and effectively killed tumor cells at early stage.IRDye800-M-HFn nanoprobes and HFn-Dox provide promising strategies for early-stage tumor diagnosis and constructive implications for early-stage tumor treatment.

Nanotechnological strategies for prostate cancer imaging and diagnosis

The high incidence rates and complicated subtypes of prostate cancer(PCa)call for the demand of the precise diagnostic and therapeutic strategies.Current clinical imaging techniques,such as MRI,CT,and ultrasonography are difficult to accurately detect the early-stage tumor lesions,and biochemical assays or biopsies are invasive and cannot provide sufficient information for the PCa staging and classification.Nanotechnology has the potential to improve the accuracy of current diagnosis strategies by targeting specific PCa biomarkers and/or integrating multiple imaging modes.In this review,we briefly introduce current clinical PCa imaging strategies and their major limitations,and highlight representative works on nanoparticle-mediated multimode imaging strategies.We also discuss the challenges of nanotechnology-based PCa diagnosis,and come up with suggestions and perspectives.

Structural and functional analysis of a potent human neutralizing antibody against enterovirus A71

Enterovirus A71(EV-A71) causes major outbreaks of hand,foot,and mouth disease(HFMD) in many countries,most frequently affecting children,and a small proportion of cases may lead to death.Currently,no vaccine is available in most endemic regions,and no licenced treatments for EV-A71 infection are available.Here,we characterize a human monoclonal antibody(Hu MAb),E1,by screening a Fab antibody phage library derived from patients who recovered from EV-A71 infection.E1 exhibits strong neutralizing activity against EV-A71 virus in cells.The cryo-electron microscopy(cryo-EM) structures of the EV-A71 virion in complex with E1 Fab fragments demonstrated that E1 recognized an epitope formed by residues in the BC and HI loops of VP1.In a mouse model,E1 effectively protected against lethal EV-A71 challenge in both prophylactic and therapeutic treatment.In particular,E1 significantly reduces virus titers and muscle damage.E1 might represent a potential adjunct to EV-A71 treatment.

New Simian Enterovirus 19(EV-A122) Strains in China Reveal Large-Scale Inter-Serotype Recombination between Simian EV-As

Dear Editor,The genus Enterovirus(EV),belonging to the family Picornaviridae,order Picornavirales,comprises 15 species:Enterovirus A–L and rhinovirus A–C(Zell et al.2017).Enterovirus A(EV-A)has 25 serotypes,including several pathogens,such as EV-A71,coxsackievirus A16(CV-A16),and CV-A6 that infect humans,as well as four serotypes(EV-A122,123,124,and 125)isolated from simians(Zell et al.2017).EV genomes share a similar structure with a length of 7.5 kb,and two open reading frames(ORFs)flanked by 5′-and 3′-untranslated regions(UTRs)in some EVs(Oberste et al.2013b;Zell et al.2017;Guo et al.2019;Lulla et al.2019).