Taijiao Jiang

Sequential Reassortments Underlie Diverse Influenza H7N9 Genotypes in China

Initial genetic characterizations have suggested that the influenza A (H7N9) viruses responsible for the current outbreak in China are novel reassortants. However, little is known about the pathways of their evolution and, in particular, the generation of diverse viral genotypes. Here we report an in-depth evolutionary analysis of whole-genome sequence data of 45 H7N9 and 42 H9N2 viruses isolated from humans, poultry, and wild birds during recent influenza surveillance efforts in China. Our analysis shows that the H7N9 viruses were generated by at least two steps of sequential reassortments involving distinct H9N2 donor viruses in different hosts. The first reassortment likely occurred in wild birds and the second in domestic birds in east China in early 2012. Our study identifies the pathways for the generation of diverse H7N9 genotypes in China and highlights the importance of monitoring multiple sources for effective surveillance of potential influenza outbreaks.

A magnetic protein biocompass

The notion that animals can detect the Earths magnetic field was once ridiculed, but is now well established. Yet the biological nature of such magnetosensing phenomenon remains unknown. Here, we report a putative magnetic receptor (Drosophila CG8198, here named MagR) and a multimeric magnetosensing rod-like protein complex, identified by theoretical postulation and genome-wide screening, and validated with cellular, biochemical, structural and biophysical methods. The magnetosensing complex consists of the identified putative magnetoreceptor and known magnetoreception-related photoreceptor cryptochromes (Cry), has the attributes of both Cry- and iron-based systems, and exhibits spontaneous alignment in magnetic fields, including that of the Earth. Such a protein complex may form the basis of magnetoreception in animals, and may lead to applications across multiple fields.

Genetic tuning of the novel avian influenza A(H7N9) virus during interspecies transmission, China, 2013

A novel avian influenza A(H7N9) virus causing human infection emerged in February 2013 in China. To elucidate the mechanism of interspecies transmission, we compared the signature amino acids of avian influenza A(H7N9) viruses from human and non-human hosts and analysed the reassortants of 146 influenza A(H7N9) viruses with full genome sequences. We propose a genetic tuning procedure with continuous amino acid substitutions and reassorting that mediates host adaptation and interspecies transmission. When the early influenza A(H7N9) virus, containing ancestor haemagglutinin (HA) and neuraminidase (NA) genes similar to A/Shanghai/05 virus, circulated in waterfowl and transmitted to terrestrial poultry, it acquired an NA stalk deletion at amino acid positions 69 to 73. Then, receptor binding preference was tuned to increase the affinity to human-like receptors through HA G186V and Q226L mutations in terrestrial poultry. Additional mammalian adaptations such as PB2 E627K were selected in humans. The continual reassortation between H7N9 and H9N2 viruses resulted in multiple genotypes for further host adaptation. When we analysed a potential association of mutations and reassortants with clinical outcome, only the PB2 E627K mutation slightly increased the case fatality rate. Genetic tuning may create opportunities for further adaptation of influenza A(H7N9) and its potential to cause a pandemic.

mapping of H3n2 influenza antigenic evolution in China reveals a strategy for vaccine strain recommendation

One of the primary efforts in influenza vaccine strain recommendation is to monitor through gene sequencing the viral surface protein haemagglutinin (HA) variants that lead to viral antigenic changes. Here we have developed a computational method, denoted as PREDAC, to predict antigenic clusters of influenza A (H3N2) viruses with high accuracy from viral HA sequences. Application of PREDAC to large-scale HA sequence data of H3N2 viruses isolated from diverse regions of Mainland China identified 17 antigenic clusters that have dominated for at least one season between 1968 and 2010. By tracking the dynamics of the dominant antigenic clusters, we not only find that dominant antigenic clusters change more frequently in China than in the United States/Europe, but also characterize the antigenic patterns of seasonal H3N2 viruses within China. Furthermore, we demonstrate that the coupling of large-scale HA sequencing with PREDAC can significantly improve vaccine strain recommendation for China.

Coiled-coil networking shapes cell molecular machinery

Coiled coil is a principal oligomerization motif. A comprehensive map of coiled-coil interactions (CCIs) in yeast is reported. Computational analysis reveals that CCIs are extensively involved in cell machinery organization. Disrupting the CCIs in the kinetochore leads to defects in kinetochore assembly and cell division.

RASP: rapid modeling of protein side chain conformations

MOTIVATION Modeling of side chain conformations constitutes an indispensable effort in protein structure modeling, protein-protein docking and protein design. Thanks to an intensive attention to this field, many of the existing programs can achieve reasonably good and comparable prediction accuracy. Moreover, in our previous work on CIS-RR, we argued that the prediction with few atomic clashes can complement the current existing methods for subsequent analysis and refinement of protein structures. However, these recent efforts to enhance the quality of predicted side chains have been accompanied by a significant increase of computational cost. RESULTS In this study, by mainly focusing on improving the speed of side chain conformation prediction, we present a RApid Side-chain Predictor, called RASP. To achieve a much faster speed with a comparable accuracy to the best existing methods, we not only employ the clash elimination strategy of CIS-RR, but also carefully optimize energy terms and integrate different search algorithms. In comprehensive benchmark testings, RASP is over one order of magnitude faster (~ 40 times over CIS-RR) than the recently developed methods, while achieving comparable or even better accuracy.

A comprehensive surveillance of adamantane resistance among human influenza A virus isolated from mainland China between 1956 and 2009

BACKGROUND Adamantane-derived drugs have been used for treatment and prophylaxis of influenza A virus infection for many years worldwide. Rapid surveillance of antiviral drug resistance is important for appropriate clinical guideline development. Here, we retrospectively assessed adamantane resistance among different influenza A subtypes (H1N1, H3N2 and H5N1) over 53 years (1956-2009) in mainland China. METHODS A total of 1,451 viruses, including 773 H3N2 viruses, 647 H1N1 viruses and 31 human H5N1 viruses, were analysed by matrix gene sequencing and assayed for drug resistance. RESULTS Our results show that the prevalence of adamantane-resistant H3N2 viruses was low between 1956 and 2002, but substantially increased in 2003 to the extent that since 2006 all H3N2 viruses have been drug resistant. The percentage of adamantane-resistant H1N1 viruses also increased from 50.0% in 2004 to 98.7% in 2007; however, this decreased to 46.7% in 2009. Only three adamantane-resistant H5N1 viruses have been detected since 2003, when the first case of human H5N1 virus infection was detected in mainland China. Phylogenetic analysis demonstrated that the increase of adamantane-resistant isolates was caused by point mutations or intrasubtype reassortment instead of intersubtype reassortment. CONCLUSIONS Because of the high percentage of adamantane-resistant H3N2 and H1N1 viruses in mainland China, the use of amantadine and rimantadine drugs for prophylaxis and treatment of current seasonal influenza A infection is not recommended.

A peptide derived from the C‐terminus of PB1 inhibits influenza virus replication by interfering with viral polymerase assembly

Efficient assembly of the influenza virus RNA‐dependent RNA polymerase, a heterotrimeric complex formed by three subunits (PA, PB1 and PB2) is critical for virus replication and pathogenicity. Therefore, interfering with the assembly of the RNA‐dependent RNA polymerase complex could offer novel and effective anti‐influenza therapeutics. In the present study, we show that a short peptide derived from amino acids 731–757 of PB1 (PB1731–757) can disrupt the interaction between the C‐terminal part of PB1 (denoted as PB1c corresponding to PB1676–757) and the N‐terminal part of PB2 (denoted as PB2n corresponding to PB21–40). We further show that PB1731–757 is capable of inhibiting viral polymerase activity and viral replication. Interestingly, we find that PB1731–757 interacts with PB1c rather than PB2n. Furthermore, mutational analyses show that the hydrophobic sites of PB1c play an essential role in the PB1c–PB1731–757 interaction. The characterization of the inhibitory effect of PB1731–757 on viral polymerase activity and viral replication could offer a potential target for anti‐influenza drug development.

Improved side-chain modeling by coupling clash-detection guided iterative search with rotamer relaxation

MOTIVATION Side-chain modeling has seen wide applications in computational structure biology. Most of the popular side-chain modeling programs explore the conformation space using discrete rigid rotamers for speed and efficiency. However, in the tightly packed environments of protein interiors, these methods will inherently lead to atomic clashes and hinder the prediction accuracy. RESULTS We present a side-chain modeling method (CIS-RR), which couples a novel clash-detection guided iterative search (CIS) algorithm with continuous torsion space optimization of rotamers (RR). Benchmark testing shows that compared with the existing popular side-chain modeling methods, CIS-RR removes atomic clashes much more effectively and achieves comparable or even better prediction accuracy while having comparable computational cost. We believe that CIS-RR could be a useful method for accurate side-chain modeling. AVAILABILITY CIS-RR is available to non-commercial users at our website: http://jianglab.ibp.ac.cn/lims/cisrr/cisrr.html.

Intracellular CD24 disrupts the ARF–NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation

CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels. These data provide a general mechanism for functional inactivation of ARF and reveal an important cellular context for genetic and viral inactivation of TP53.