Influenza viruses need to use sialic acid receptors to invade host cells, and the α-2,3 and α-2,6 sialic acids glycosidic bonds linking the terminal sialic acids are generally considered to be the ...most important factors influencing the cross-species transmission of the influenza viruses. The development of methods to detect the binding of influenza virus HA proteins to sialic acid receptors, as well as the development of glycobiological techniques, has led to a richer understanding of the structure of the sialylated glycan in influenza virus hosts. It was found that, in addition to the sialic acid glycosidic bond, sialic acid variants, length of the sialylated glycan, Gal-GlcNAc-linked glycosidic bond within the sialylated glycan, and sulfation/fucosylation of the GlcNAc within the sialylated glycan all affect the binding properties of influenza viruses to the sialic acid receptors, thus indirectly affecting the host specificity of influenza viruses. This paper will review the sialic acid variants, internal structural differences of sialylated glycan molecules that affect the host specificity of influenza viruses, and distribution characteristics of sialic acid receptors in influenza virus hosts, in order to provide a more reliable theoretical basis for the in-depth investigation of cross-species transmission of influenza viruses and the development of new antiviral drugs.
Avian influenza virus (AIV) can evolve multiple strategies to combat host antiviral defenses and establish efficient infectivity in mammals, including humans. H9N2 AIV and its reassortants (such as ...H5N6 and H7N9 viruses) pose an increasing threat to human health; however, the mechanisms involved in their increased virulence remain poorly understood. We previously reported that the M1 mutation T37A has become predominant among chicken H9N2 isolates in China. Here, we report that, since 2010, this mutation has also been found in the majority of human isolates of H9N2 AIV and its emerging reassortants. The T37A mutation of M1 protein enhances the replication of H9N2 AIVs in mice and in human cells. Interestingly, having A37 instead of T37 increases the M1 protein stability and resistance to proteasomal degradation. Moreover, T37 of the H9N2 M1 protein is phosphorylated by protein kinase G (PKG), and this phosphorylation induces the rapid degradation of M1 and reduces viral replication. Similar effects are also observed in the novel H5N6 virus. Additionally, ubiquitination at K187 contributes to M1-37T degradation and decreased replication of the virus harboring T37 in the M1 protein. The prevailing AIVs thereby evolve a phospho-resistant mutation in the M1 protein to avoid viral protein degradation by host factors, which is advantageous in terms of replication in mammalian hosts.
Pancreatic adenocarcinoma (PCa) is a highly aggressive malignancy with high risk of early death (survival time ≤3 months). The present study aimed to identify associated risk factors and develop a ...simple-to-use nomogram to predict early death in metastatic PCa patients.
Patients diagnosed with metastatic PCa between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were collected for model construction and internal validation. An independent data set was obtained from China for external validation. Independent risk variables contributed to early death were identified by logistic regression models, which were then used to construct a nomogram. Internal and external validation was performed to evaluate the nomogram using calibration curves and the receiver operating characteristic curves.
A total of 19,464 patients in the SEER cohort and 67 patients in the Chinese cohort were included. Patients from the SEER database were randomly divided into the training cohort (n = 13,040) and internal validation cohort (n = 6,424). Patients in the Chinese cohort were selected for the external validation cohort. Overall, 10,484 patients experienced early death in the SEER cohort and 35 in the Chinese cohort. A reliable nomogram was constructed on the basis of 11 significant risk factors. Internal validation and external validation of the nomogram showed high accuracy in predicting early death. Decision curve analysis demonstrated that this predictive nomogram had excellent and potential clinical applicability.
The nomogram provided a simple-to-use tool to distinguish early death in patients with metastatic PCa, assisting clinicians in implementing individualized treatment regimens.
Zr-Ti alloy powders were added into the weld groove to join D36 steel by using flux aided backing submerged arc welding (FAB-SAW). The inclusions, microstructure and mechanical properties of Zr-Ti ...miroalloyed weld metals were investigated. The results showed that the core of inclusions was composed of Zr, Al, Ti, Si, Mn oxides, while the surface layer of inclusions was composed of TiO (or Ti2O3), ZrO2 and MnS. The first precipitated ZrO2 can act as nucleation sites for Al, Ti, Si, Mn oxides and increases the fraction of inclusions with size of smaller than 1.0 μm. Due to the refined size and increased density of inclusions, the proportion of acicular ferrite (AF) was significantly increased while the proportion of grain boundary ferrite (GBF) and ferrite side-plate (FSP) were remarkably decreased in the microstructure. The tensile properties and impact toughness at −20 °C of weld metal were obviously promoted. The nucleation of AF was ascribed to the low lattice misfit between TiO (and ZrO2) and α-Fe as well as a high inert interfacial energy of MnS. When the content of Zr was 0.09 wt %, the percentage of AF in FAB-SAW weld metal was reached to 82%, resulting in the weld metal with elongation of 25%, ultimate strength of 615 MPa and impact energy at −20 °C of 145 J.
•Adding Zr-Ti powder into FAB-SAW promotes the inclusions and AF.•Ti-oxides, MnS and ZrO2 induce the nucleation of AF.•AF proportion increases with the number of inclusions with size less than 2.0 μm.•FAB weld metal with higher AF proportion presents better mechanical properties.
In China, H9N2 avian influenza virus (AIV) has become widely prevalent in poultry, causing huge economic losses after secondary infection with other pathogens. Importantly, H9N2 AIV continuously ...infects humans, and its six internal genes frequently reassort with other influenza viruses to generate novel influenza viruses that infect humans, threatening public health. Inactivated whole-virus vaccines have been used to control H9N2 AIV in China for more than 20 years, and they can alleviate clinical symptoms after immunization, greatly reducing economic losses. However, H9N2 AIVs can still be isolated from immunized chickens and have recently become the main epidemic subtype. A more effective vaccine prevention strategy might be able to address the current situation. Herein, we analyze the current status and vaccination strategy against H9N2 AIV and summarize the progress in vaccine development to provide insight for better H9N2 prevention and control.
Two new diketopiperazines (1, 2), one new polyprenol (3), together with 19 known compounds (4-22) were obtained from the EtOAc extract of Bionectria sp. Y1085, an endophytic fungus isolated from the ...plant Huperzia serrata. Their structures were elucidated by extensive NMR and MS analysis. Bionectin D (1) is a rare diketopiperazine with a single methylthio substitution at the α-carbon of cyclized amino acid residue. The antibacterial activity of compounds was assayed against Escherichia coli, Staphylococcus aureus, and Salmonella typhimurium ATCC 6539, and some metabolites (1, 2, 10, 11, and 14) exhibited evident antibacterial activity.
Adaptation of the viral polymerase complex comprising PB1, PB2, and PA is necessary for efficient influenza A virus replication in new host species. We found that PA mutation K356R (PA-K356R) has ...become predominant since 2014 in avian H9N2 viruses in China as with seasonal human H1N1 viruses. The same mutation is also found in most human isolates of emergent avian H7N9 and H10N8 viruses whose six internal gene segments are derived from the H9N2 virus. We further demonstrated the mammalian adaptive functionality of the PA-K356R mutation. Avian H9N2 virus with the PA-K356R mutation in human A549 cells showed increased nuclear accumulation of PA and increased viral polymerase activity that resulted in elevated levels of viral transcription and virus output. The same mutant virus in mice also enhanced virus replication and caused lethal infection. In addition, combined mutation of PA-K356R and PB2-E627K, a well-known mammalian adaptive marker, in the H9N2 virus showed further cooperative increases in virus production and severity of infection in vitro and in vivo In summary, PA-K356R behaves as a novel mammalian tropism mutation, which, along with other mutations such as PB2-E627K, might render avian H9N2 viruses adapted for human infection.
Mutations of the polymerase complex (PB1, PB2, and PA) of influenza A virus are necessary for viral adaptation to new hosts. This study reports a novel and predominant mammalian adaptive mutation, PA-K356R, in avian H9N2 viruses and human isolates of emergent H7N9 and H10N8 viruses. We found that PA-356R in H9N2 viruses causes significant increases in virus replication and severity of infection in human cells and mice and that PA-K356R cooperates with the PB2-E627K mutation, a well-characterized human adaptive marker, to exacerbate mammalian infection in vitro and in vivo Therefore, the PA-K356R mutation is a significant adaptation in H9N2 viruses and related H7N9 and H10N8 reassortants toward human infectivity.
Influenza A virus (IAV) is an important zoonotic pathogen that can cause disease in animals such as poultry and pigs, and it can cause infection and even death in humans, posing a serious threat to ...public health. IAV is an enveloped virus that relies on host cell metabolic systems, especially lipid metabolism systems, to complete its life cycle in host cells. On the other side, host cells regulate their metabolic processes to prevent IAV replication and maintain their normal physiological functions. This review summarizes the roles of fatty acid, cholesterol, phospholipid and glycolipid metabolism in IAV infection, proposes future research challenges, and looks forward to the prospective application of lipid metabolism modification to limit IAV infection, which will provide new directions for the development of anti-influenza drugs.
An ultra-sensitive method is described here for the determination of HIF-1α (an early biomarker for myocardial infarction) in circulating exosomes in serum. Gold nanospheres were functionalized with ...a HIF-1α-binding aptamer via sulfydryl chemistry. The apt-AuNP-coated gold seeds were grown by seed-mediated growth, and this significantly increased the peroxidase-mimicking property the nanoparticles. A chromogenic system composed of 3,3′5,5′-tetramethylbenzidine and hydrogen peroxide was used. Absorbance at 652 nm increases linearly in the 0.3 to 200 ng L
−1
HIF-1α concentration range, and the limit of detection is 0.2 ng L
−1
. The method was tested by analyzing rat serum from isoproterenol (ISO)-induced myocardial infarction. It allows HIF-1α to be directly determined in a 25 μL sample without preconcentration. The assay is not interfered by the polydispersity of exosomes released under either health and disease conditions.
Graphical abstract
Gold nanospheres were functionalized with a HIF-1α-binding aptamer via sulfydryl chemistry. Nanosized gold seed particles were then modified with the functionalized gold nanospheres, and this strongly increases the peroxidase-mimicking activity of the nanomaterial. By using the tetramethylbenzidine/H
2
O
2
chromogenic system, the absorbance at 652 nm increases linearly in the 0.3 to 200 ng L
-1
HIF-1α concentration range.
Since May 2014, highly pathogenic avian influenza H5N6 virus has been reported to cause six severe human infections three of which were fatal. The biological properties of this subtype, in particular ...its relative pathogenicity and transmissibility in mammals, are not known. We characterized the virus receptor-binding affinity, pathogenicity, and transmissibility in mice and ferrets of four H5N6 isolates derived from waterfowl in China from 2013-2014. All four H5N6 viruses have acquired a binding affinity for human-like SAα2,6Gal-linked receptor to be able to attach to human tracheal epithelial and alveolar cells. The emergent H5N6 viruses, which share high sequence similarity with the human isolate A/Guangzhou/39715/2014 (H5N6), were fully infective and highly transmissible by direct contact in ferrets but showed less-severe pathogenicity than the parental H5N1 virus. The present results highlight the threat of emergent H5N6 viruses to poultry and human health and the need to closely track their continual adaptation in humans.
Extended epizootics and panzootics of H5N1 viruses have led to the emergence of the novel 2.3.4.4 clade of H5 virus subtypes, including H5N2, H5N6, and H5N8 reassortants. Avian H5N6 viruses from this clade have caused three fatalities out of six severe human infections in China since the first case in 2014. However, the biological properties of this subtype, especially the pathogenicity and transmission in mammals, are not known. Here, we found that natural avian H5N6 viruses have acquired a high affinity for human-type virus receptor. Compared to the parental clade 2.3.4 H5N1 virus, emergent H5N6 isolates showed less severe pathogenicity in mice and ferrets but acquired efficient in-contact transmission in ferrets. These findings suggest that the threat of avian H5N6 viruses to humans should not be ignored.
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