T4SP: A Novel Tool and Database for Type IV Secretion Systems in Bacterial Genomes

Secretion systems, macromolecules to pass which can mediate the across cellular membranes, are essential for virulent and genetic material exchange among bacterial species[1]. Type IV secretion system （T4SS） is one of the secretion systems and it usually consists of 12 genes： VirB1, VirB2 ...VirB11, and VirD4[2]. The structure and molecular mechanisms of these genes have been well analyzed in Gram-negative strains[3] and Gram-positive strains were once believed to be lack of T4SS. However, some recent studies revealed that one or more virB/D genes also exist in some kinds of Gram-positive bacteria and play similar role, and form a T4SS-like system[3]. The VirBl-like, VirB4, VirB6, and VirD4 genes were identified in the chromosome of Gram-positive bacterium Streptococcus suis in our previous studies and their role as important mobile elements for horizontal transfer to recipients in an 89 K pathogenicity island （PAl） was demonstrated[45]. However, their structure and molecular mechanisms in other strains, especially in Gram-positive strains, are remained unclear.

Transcontinental Translational Medicine Collaboration: A Successful SinoCuban Joint B-to-B Program

Translational medicine is a comprehensive discipline that aims to convert laboratory research results into products and technology for clinical application using modern molecular biological techniques, to improve our understanding of the human body and disease and to optimize laboratory design for clinical observation and analysis for basic research. Its ultimate goal is improving holistic medicine and helping patients solve their health problems. Translational medicine includes two processes： bench to bedside and bedside to bench, known as B-to-B processes. The first B-to-B （bench to bedside） refers to the application of results of the laboratory to clinical use as a medical product or a diagnosis and treatment technology. The second B-to-B （bedside to bench） describes the process by which clinical observation and analysis provides ideas and guidance for experiment design for basic medical research. The two processes complement each other and constitute the two-way cycle of translational medicine. Translational medicine can be applied to clinical disease detection in the form of new biomarkers and can accelerate drug discovery. In recent years, with the biotechnology, increasing rapid development of outcomes of research on molecular pathogenesis can be directly applied to clinical theraDv.

Continuous reassortments with local chicken H9N2 virus underlie the human-infecting influenza A （H7N9） virus in the new influenza season, Guangdong, China

亲爱的编辑，

Crystal clear： visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies

Antibody-based PD-IIPD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre- existing T-cell function to modulate antitumor immunity. in this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/ PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-IIPD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural informationwill benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.

Severe human infection with a novel avian-origin influenza A(H7N4) virus

Human infections with influenza H7 subtypes, such as H7N9, have raised concerns worldwide. Here, we report a human infection with a novel influenza A(H7N4) virus. A 68 years-old woman with cardiovascular and cholecystic comorbidities developed rapidly progressed pneumonia with influenza-like-illness as initial symptom, recovered after 23 days-hospitalization including 8 days in ICU. Laboratory indicators for liver and blood coagulation dysfunction were observed. Oseltamivir phosphate, glucocorticoids and antibiotics were jointly implemented, with nasal catheterization of oxygen inhalation for this patient.We obtained the medical records and collected serial respiratory and blood specimens from her. We collected throat, cloacal and/or feces samples of poultry and wild birds from the patient's backyard, neighborhood, local live poultry markets(LPMs) and the nearest lake. All close contacts of the patient were followed up and sampled with throat swabs and sera. Influenza viruses and other respiratory pathogens were tested by real-time RT-PCR, viral culturing and/or sequencing for human respiratory and bird samples. Micro-neutralizing assay was performed for sera. A novel reassortant wild bird-origin H7N4 virus is identified from the patient and her backyard poultry(chickens and ducks) by sequencing, which is distinct from previously-reported avian H7N4 and H7N9 viruses. At least four folds increase of neutralizing antibodies to H7N4 was detected in her convalescent sera. No samples from close contacts, wild birds or other poultry were tested positive for H7N4 by real-time RT-PCR.

The antibiotic resistome： gene flow in environments, animals and human beings

The antibiotic resistance is natural in bacteria and predates the human use of antibiotics. Numerous antibiotic resistance genes （ARGs） have been discovered to confer resistance to a wide range of antibiotics. The ARGs in natural environments are highly integrated and tightly regulated in specific bacterial metabolic networks. However, the antibiotic selection pressure conferred by the use of antibiotics in both human medicine and agriculture practice leads to a significant increase of antibiotic resistance and a steady accumulation of ARGs in bacteria. In this review, we summarized, with an emphasis on an ecological point of view, the important research progress regarding the collective ARGs （antibiotic resistome） in bacterial communities of natural environments, human and animals, i.e., in the one health settings. We propose that the resistance gene flow in nature is ＂from the natural environments＂ and ＂to the natural environments＂; human and animals, as intermediate recipients and disseminators, contribute greatly to such a resistance gene ＂circulation.＂

A new unconventional HLA-A2-restricted epitope from HBV core protein elicits antiviral cytotoxic T lymphocytes

Cytotoxic T cells （CTLs） play a key role in the control of Hepatitis B virus （HBV） infection and viral clearance. However, most of identified CTL epitopes are derived from HBV of genotypes A and D, and few have been defined in virus of genotypes B and C which are more prevalent in Asia. As HBV core protein （HBc） is the most conservative and immunogenic component, in this study we used an overlapping 9-mer peptide pool cov- ering HBc to screen and identify specific CTL epitopes. An unconventional HLA-A2-restricted epitope HBc141- 149 was discovered and structurally characterized by crystallization analysis. The immunogenicity and anti- HBV activity were further determined in HBV and HLA- A2 transgenic mice. Finally, we show that mutations in HBc141-149 epitope are associated with viral parame- ters and disease progression in HBV infected patients. Our data therefore provide insights into the structure characteristics of this unconventional epitope binding to MHC-I molecules, as well as epitope specific CTL activity that orchestrate T cell response and immune evasion in HBV infected patients.

Highly pathogenic avian influenza H5N1 Clade 2.3.2.1c virus in migratory birds,2014–2015

A novel Clade 2.3.2.1c H5N1 reassortant virus caused several outbreaks in wild birds in some regions of China from late 2014 to 2015.Based on the genetic and phylogenetic analyses,the viruses possess a stable gene constellation with a Clade 2.3.2.1c HA,a H9N2-derived PB2 gene and the other six genes of Asian H5N1-origin.The Clade 2.3.2.1c H5N1 reassortants displayed a high genetic relationship to a human H5N1 strain(A/Alberta/01/2014).Further analysis showed that similar viruses have been circulating in wild birds in China,Russia,Dubai(Western Asia),Bulgaria and Romania(Europe),as well as domestic poultry in some regions of Africa.The affected areas include the Central Asian,East Asian-Australasian,West Asian-East African,and Black Sea/Mediterranean flyways.These results show that the novel Clade 2.3.2.1c reassortant viruses are circulating worldwide and may have gained a selective advantage in migratory birds,thus posing a serious threat to wild birds and potentially humans.

Serological Investigation of Laboratory-Confirmed and Suspected Ebola Virus Disease Patients During the Late Phase of the Ebola Outbreak in Sierra Leone

This study aimed to investigate the serological characteristics of Ebola virus(EBOV) infection during the late phase of the Ebola outbreak in Sierra Leone. In total, 877 blood samples from 694 suspected Ebola virus disease(EVD) cases assessed from March to December 2015, were analyzed via real-time reverse transcription polymerase chain reaction(RT-PCR) for viral RNA and enzyme-linked immunosorbent assay(ELISA) and Luminex to detect antibodies against EBOV. Viral load and EBOV-specific IgM/IgG titers displayed a declining trend during March to December 2015. Viral RNA load decreased rapidly at earlier stages after disease onset, while EBOV-specific IgM and IgG still persisted in 58.1%(18/31) and 93.5%(29/31) of the confirmed EVD patients and in 3.8%(25/663) and 17.8%(118/663) of the RNA-negative suspected patients in the later phase, respectively. Dynamic analysis of longitudinally collected samples from eight EVD patients revealed typically reversed trends of declining viral load and increasing IgM and/or IgG titers in response to the EBOV infection.The present results indicate that certain populations of Sierra Leone developed immunity to an EBOV infection in the late phase of the outbreak, providing novel insights into the risk assessment of EBOV infections among human populations.

An infectious clone of the highly pathogenic porcine reproductive and respiratory syndrome virus: Topology of glycoprotein 3 (GP3) addressing the intrachain disulfide bonds

The highly pathogenic porcine reproductive and respiratory virus (hpPRRSV) with discontinuous 30 amino acid (aa) deletion as a gene marker has caused great economic loss in pig industry and since 2007 has become the dominant strain prevalent in China and Vietnam since 2007.Reverse genetics method is a powerful tool urgently needed to be used on the hpPRRSV to study the intriguing molecular mechanism of transcription,replication and the virulence determinant factors.In our study,we successfully constructed a fulllength infectious clone,prBJSY07,based on hpPRRSV isolate,BJSY07.The rescued virus,vrBJSY07,showed similar growth characters to those of the parental virus,BJSY07.We also found that a rescued virus vBJSY07 generated from pBJSY07 was viable but displayed decreased and delayed reproductive capacity,which might be caused by two amino acids mutations,S83C and S117C in glycoprotein 3 (GP3),acquired during the preparation of the infectious clone.The topology of the wild type GP3 and the mutant were further analyzed by bioinformatics and revealed that the mutated GP3 possessed slightly altered structure,most likely by forming a new disulfide bond between the two new cysteine residues.As GP3 is a cysteine-rich glycoprotein,common for viral glycoproteins,our results show that GP3 can accommodate even more cysteine mutations.Based on this,a topological model of GP3 is proposed by addressing the intrachain disulfides.

Characterization of human αβTCR repertoire and discovery of D-D fusion in TCRβ chains

The characterization of the human T-cell receptor （TCR） repertoire has made remarkable progress, with most of the work focusing on the TCRβ chains. Here, we ana- lyzed the diversity and complexity of both the TCRa and TCRβ repertoires of three healthy donors. We found that the diversity of the TCRα repertoire is higher than that of the TCRβ repertoire, whereas the usages of the V and J genes tended to be preferential with similar TRAV and TRAJ patterns in all three donors. The V-J pairings, like the V and J gene usages, were slightly preferential. We also found that the TRDV1 gene rearranges with the majority of TRAJ genes, suggesting that TRDV1 is a shared TRAV/DV gene （TRAV42/DV1）. Moreover, we uncovered the presence of tandem TRBD （TRB D gene） usage in -2% of the productive human TCRβ CDR3 sequences.

献血感染丙型肝炎病毒人群的T细胞免疫及与肝损伤的相关性研究

丙型肝炎是由感染丙型肝炎病毒(Hepatitis C virus,HCV)引起的,至今仍是世界公共卫生的严重威胁。为研究HCV感染者的T细胞免疫状态及其对疾病进展的影响,我们招募了62位研究对象,包括20位健康对照、42位HCV感染者。我们通过HCV主要的T细胞免疫原非结构蛋白3(NS3蛋白)多肽库体外刺激外周血淋巴细胞,利用流式细胞方法检测CD8^+T细胞和CD4^+T细胞的γ-干扰素(IFN-γ)、白介素-2(IL-2)和肿瘤坏死因子-α(TNF-α)的分泌水平。同时,我们检测了研究对象血清中白介素-6(IL-6)和白介素-10(IL-10)的水平。结果表明,HCV感染者外周血中仍持续存在针对NS3的特异性CD8^+T细胞和CD4^+T细胞。感染者血清中IL-6、IL-10显著高于对照人群。相关性分析显示,HCV感染者外周血中分泌IFN-γ和TNF-α的HCV特异性CD8^+T细胞水平及血清中IL-10水平与血清中的谷丙转氨酶(ALT)和谷草转氨酶(AST)呈现正相关。本研究表明,HCV感染者体内针对病毒的特异性细胞免疫持续保持一定的水平,并且可能与病人的肝损伤有关,该研究对于了解HCV感染的细胞免疫特征及研发相应的免疫干预策略具有一定的意义。

Can Ebola virus become endemic in the human population？

The 2014-15 Ebola virus reported during March 2014 Guinea. has shown itself to （EBOV） outbreak, originally n the Western African nation of be resistant to traditional con- tainment methods, with over 28,000 infections and 11,000 deaths over 18 months. Recently, news that a Scottish nurse had relapsed to EBOV disease with neurological symptoms at 10 months after recovery have astonished experts. The prolonged nature of the outbreak has led to questions whether EBOV can become endemic in the human popula- tion, an undesirable outcome due to the large amount of resources required to keep this virus under control. In this commentary, we discuss aspects EBOV disease with those caused by pathogens considered endemic in humans, as well as factors which may contribute to sustained EBOV transmission in humans.

Gluconate 5-dehydrogenase （Ga5DH） participates in Streptococcus suis cell division

Bacterial cell division is strictly regulated in the formation of equal daughter cells. This process is governed by a series of spatial and temporal regulators, and several new factors of interest to the field have recently been identified. Here, we report the requirement of gluconate 5-dehydrogenase （Ga5DH） in cell division of the zoonotic pathogen Strepto- coccus suis. GaSDH catalyzes the reversible reduction of 5-ketogluconate to D-gluconate and was localized to the site of cell division. The deletion of Ga5DH in S. suis resulted in a plump morphology with aberrant septa joining the progeny. A significant increase was also observed in cell length. These defects were determined to be the conse- quence of Ga5DH deprivation in S. suis causing FtsZ delo- calization. In addition, the interaction of FtsZ with Ga5DH in vitro was confirmed by protein interaction assays. These results indicate that GaSDH may function to prevent the formation of ectopic Z rings during S. suis cell division.

Atypical group 1 neuraminidase pH1N1-N1 bound to a group 1 inhibitor

Influenza virus is a member of the Orthomyxoviridae family and is the causative agent of seasonal and pandemic flu.