Human infection associated with a novel reassortant avian influenza H7N9 virus has recently been identified in China. A total of 132 confirmed cases and 39 deaths have been reported. Most patients presented with severe pneumonia and acute respiratory distress syndrome. Although the first epidemic has subsided, the presence of a natural reservoir and the disease severity highlight the need to evaluate its risk on human public health and to understand the possible pathogenesis mechanism. Here we show that the emerging H7N9 avian influenza virus poses a potentially high risk to humans. We discover that the H7N9 virus can bind to both avian-type (α2,3-linked sialic acid) and human-type (α2,6-linked sialic acid) receptors. It can invade epithelial cells in the human lower respiratory tract and type II pneumonocytes in alveoli, and replicated efficiently in ex vivo lung and trachea explant culture and several mammalian cell lines. In acute serum samples of H7N9-infected patients, increased levels of the chemokines and cytokines IP-10, MIG, MIP-1β, MCP-1, IL-6, IL-8 and IFN-α were detected. We note that the human population is naive to the H7N9 virus, and current seasonal vaccination could not provide protection.
Deep partial thickness burn wounds present big challenges due to the long healing time, large size and irregular shape, pain and reinjury at wound dressing changes, as well as scarring. The clinically effective therapy to alleviate pain at wound dressing changes, and the scar left on the skin after the healing of wound is still unavailable. To combat this, we develop a nanocomposite self-healing hydrogel that can be injected into irregular and deep burn wound beds and subsequently rapidly self-heal to reform into an integrated piece of hydrogel that thoroughly fills the wound area and protects the wound site from external environment, finally being painlessly removed by on-demand dissolving using amino acid solution at wound dressing changes, which accelerates deep partial thickness burn wound healing and prevents scarring. The hydrogel is made out of naturally occurring polymers, namely, water-soluble carboxymethyl chitosan (CMC) and rigid rod-like dialdehyde-modified cellulose nanocrystal (DACNC). They are cross-linked by dynamic Schiff-base linkages between amines from CMC and aldehydes from DACNC. The large aspect ratio and specific surface area of DACNC raise massive active junctions within the hydrogel, which can be readily broken and reformed, allowing hydrogel to rapidly self-heal. Moreover, DACNC serves as nanoreinforcing fillers to improve the hydrogel strength, which also restricts the “soft” CMC chains’ motion when soaked in aqueous system, endowing high fluid uptake capacity (350%) to hydrogel while maintaining integrity. Cytotoxicity assay and three-dimensional cell culture demonstrate excellent biocompatibility of the hydrogel and capacity as extracellular matrix to support cell growth. This work opens a novel pathway to fabricate on-demand dissolvable self-healing hydrogels to speed deep partial thickness burn wound healing and eliminate pain at wound dressing changes and prevent scar formation.
Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) tested 10,641 viruses collected by WHO-recognized National Influenza Centres between May 2013 and May 2014 to determine 50% inhibitory concentration (IC50) data for neuraminidase inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. In addition, neuraminidase (NA) sequence data, available from the WHO CCs and from sequence databases (n=3206), were screened for amino acid substitutions associated with reduced NAI susceptibility. Ninety-five per cent of the viruses tested by the WHO CCs were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 2% (n=172) showed highly reduced inhibition (HRI) against at least one of the four NAIs, commonly oseltamivir, while 0.3% (n=32) showed reduced inhibition (RI). Those showing HRI were A(H1N1)pdm09 with NA H275Y (n=169), A(H3N2) with NA E119V (n=1), B/Victoria-lineage with NA E117G (n=1) and B/Yamagata-lineage with NA H273Y (n=1); amino acid position numbering is A subtype and B type specific. Although approximately 98% of circulating viruses tested during the 2013-2014 period were sensitive to all four NAIs, a large community cluster of A(H1N1)pdm09 viruses with the NA H275Y substitution from patients with no previous exposure to antivirals was detected in Hokkaido, Japan. Significant numbers of A(H1N1)pdm09 NA H275Y viruses were also detected in China and the United States: phylogenetic analyses showed that the Chinese viruses were similar to those from Japan, while the United States viruses clustered separately from those of the Hokkaido outbreak, indicative of multiple resistance-emergence events. Consequently, global surveillance of influenza antiviral susceptibility should be continued from a public health perspective.
Benzaldehyde-terminated telechelic four-armed polyethylene glycol (PEG-BA) is synthesized and cross-linked with carboxymethyl chitosan (CMC) to form dynamic hydrogels with strong mechanical performance. The gelation temperature and time, mechanical performance, and self-healing behaviors are systematically investigated. The hydrogels have good storage modulus up to 3162.06 ± 21.06 Pa, comparable to conventional bulk hydrogels. The separated alternate hydrogel lines connect together to become an integrated hydrogel film after 5 min at room temperature without any external intervention. This is due to the dynamic equilibrium between the Schiff base linkages and the aldehyde groups of PEG-BA and amine groups on CMC backbone. The hydrogel shows excellent cytocompatibility and the cell viability is as high as 90.7 ± 6.8% after 2 d 3D encapsulation in the hydrogel. In vivo tests indicate that the hydrogels can effectively stop bleeding when the hydrogel is directly injected into a rabbit liver incision. The total blood loss is reduced from 0.65 ± 0.10 g to 0.29 ± 0.11 g, and the hemostasis time is decreased from 167 ± 21 s to 120 ± 10 s, when compared to a gauze treatment with physical compression. These self-healing hydrogels have potential to be used as a novel hemostatic material.
The novel low-pathogenic avian influenza A H7N9 viruses (LPAI H7N9 viruses) have been a threat to public health since their emergence in 2013 because of the high rates of mortality and morbidity that they cause. Recently, highly pathogenic variants of these avian influenza A H7N9 viruses (HPAI H7N9 viruses) have emerged and caused human infections and outbreaks among poultry in mainland China. However, it is still unclear how the HPAI H7N9 virus was generated and how it evolved and spread in China. Here, we show that the ancestor virus of the HPAI H7N9 viruses originated in the Yangtze River Delta region and spread southward to the Pearl River Delta region, possibly through live poultry trade. After introduction into the Pearl River Delta region, the origin LPAI H7N9 virus acquired four amino acid insertions in the hemagglutinin (HA) protein cleavage site and mutated into the HPAI H7N9 virus in late May 2016. Afterward, the HPAI H7N9 viruses further reassorted with LPAI H7N9 or H9N2 viruses locally and generated multiple different genotypes. As of 14 July 2017, the HPAI H7N9 viruses had spread from Guangdong Province to at least 12 other provinces. The rapid geographical expansion and genetic evolution of the HPAI H7N9 viruses pose a great challenge not only to public health but also to poultry production. Effective control measures, including enhanced surveillance, are therefore urgently needed. The LPAI H7N9 virus has caused five outbreak waves in humans and was recently reported to have mutated into highly pathogenic variants. It is unknown how the HPAI H7N9 virus originated, evolved, and disseminated in China. In this study, we comprehensively analyzed the sequences of HPAI H7N9 viruses from 28 human and 21 environmental samples covering eight provinces in China that were taken from November 2016 to June 2017. The results show that the ancestor virus of the HPAI H7N9 viruses originated in the Yangtze River Delta region. However, the insertion of four amino acids into the HA protein cleavage site of an LPAI H7N9 virus occurred in late May 2016 in the Pearl River Delta region. The mutated HPAI H7N9 virus further reassorted with LPAI H7N9 or H9N2 viruses that were cocirculating in poultry. Considering the rapid geographical expansion of the HPAI H7N9 viruses, effective control measures are urgently needed.
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.
With no or low virulence in poultry, avian influenza A(H7N9) virus has caused severe infections in humans. In the current fifth epidemic wave, a highly pathogenic avian influenza (HPAI) H7N9 virus emerged. The insertion of four amino acids (KRTA) at the haemagglutinin (HA) cleavage site enabled trypsin-independent infectivity of this virus. Although maintaining dual receptor-binding preference, its HA antigenicity was distinct from low-pathogenic avian influenza A(H7N9). The neuraminidase substitution R292K conferred a multidrug resistance phenotype.
Due to enzootic infections in poultry and persistent human infections in China, influenza A (H7N9) virus has remained a public health threat. The Yangtze River Delta region, which is located in eastern China, is well recognized as the original source for H7N9 outbreaks. Based on the evolutionary analysis of H7N9 viruses from all three outbreak waves since 2013, we identified the Pearl River Delta region as an additional H7N9 outbreak source. H7N9 viruses are repeatedly introduced from these two sources to the other areas, and the persistent circulation of H7N9 viruses occurs in poultry, causing continuous outbreak waves. Poultry movements may contribute to the geographic expansion of the virus. In addition, the AnH1 genotype, which was predominant during wave 1, was replaced by JS537, JS18828, and AnH1887 genotypes during waves 2 and 3. The establishment of a new source and the continuous evolution of the virus hamper the elimination of H7N9 viruses, thus posing a long-term threat of H7N9 infection in humans. Therefore, both surveillance of H7N9 viruses in humans and poultry and supervision of poultry movements should be strengthened. IMPORTANCESince its occurrence in humans in eastern China in spring 2013, the avian H7N9 viruses have been demonstrating the continuing pandemic threat posed by the current influenza ecosystem in China. As the viruses are silently circulated in poultry, with potentially severe outcomes in humans, H7N9 virus activity in humans in China is very important to understand. In this study, we identified a newly emerged H7N9 outbreak source in the Pearl River Delta region. Both sources in the Yangtze River Delta region and the Pearl River Delta region have been established and found to be responsible for the H7N9 outbreaks in mainland China.
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