Search

Innate immunity plays critical antiviral roles. The highly virulent avian influenza viruses (AIVs) H5N1, H7N9, and H5N6 can better escape host innate immune responses than the less virulent seasonal H1N1 virus. Here, we report a mechanism by which transcriptional readthrough (TRT)-mediated suppression of innate immunity occurs post AIV infection. By using cell lines, mouse lungs, and patient PBMCs, we showed that genes on the complementary strand (“trans” genes) influenced by TRT were involved in the disruption of host antiviral responses during AIV infection. The trans-TRT enhanced viral lethality, and TRT abolishment increased cell viability and STAT1/2 expression. The viral NS1 protein directly bound to SSU72, and degradation of SSU72 induced TRT. SSU72 overexpression reduced TRT and alleviated mouse lung injury. Our results suggest that AIVs infection induce TRT by reducing SSU72 expression, thereby impairing host immune responses, a molecular mechanism acting through the NS1-SSU72-trans-TRT-STAT1/2 axis. Thus, restoration of SSU72 expression might be a potential strategy for preventing AIV pandemics.

ProteinS-acylation (also called palmitoylation) is a common post-translational modification whose deregulation plays a key role in the pathogenesis of many diseases. Acyl-biotinyl exchange (ABE), a widely used method for the enrichment ofS-acylated proteins, has the potential of capturing the entireS-acylproteome in any types of biological samples. Here, we showed that current ABE methods suffer from high background arising from the co-isolation of non-S-acylated proteins. The background can be substantially reduced by an additional blockage of residual free cysteine residues with 2,2’-dithiodipyridine prior to biotin-HPDP reaction. Coupling the low-background ABE (LB-ABE) method with label-free quantitative proteomics, 2,895 high-confidence candidateS-acylated proteins (including 1,591 knownS-acylated proteins) were identified from human prostate cancer LNCaP cells, representing so-far the largestS-acylproteome dataset identified in a single study. Immunoblotting analysis confirmed theS-acylation of five known and five novel prostate cancer-relatedS-acylated proteins in LNCaP cells and suggested that theirS-acylation levels were about 0.6-1.8%. In summary, the LB-ABE method largely eliminates the co-isolation of non-S-acylated proteins and enables deepS-acylproteomic analysis. It is expected to facilitate much more comprehensive and accurate quantification ofS-acylproteomes than previous ABE methods.

Despite advances in diagnosis and treatment, metastatic prostate cancer remains incurable and is associated with high mortality rates. Thus, novel actionable drug targets are urgently needed for therapeutic interventions in advanced prostate cancer. Here we report receptor-interacting protein kinase 2 (RIPK2) as an actionable drug target for suppressing prostate cancer metastasis. RIPK2 is frequently amplified in lethal prostate cancers and its overexpression is associated with disease progression and aggressiveness. Genetic and pharmacological inhibition of RIPK2 significantly suppressed prostate cancer progression in vitro and metastasis in vivo. Multi-level proteomic analysis revealed that RIPK2 strongly regulates c-Myc protein stability and activity, largely by activating the MKK7/JNK/c-Myc phosphorylation pathway—a novel, non-canonical RIPK2 signaling pathway. Targeting RIPK2 inhibits this phosphorylation pathway, and thus promotes the degradation of c-Myc—a potent oncoprotein for which no drugs have been approved for clinical use yet. These results support targeting RIPK2 for personalized therapy in prostate cancer patients towards improving survival.

Objective: To detect the changes of coagulation function in patients with early hemorrhagic shock by thromboelastography (TEG). Methods: TEG was performed in 50 patients with early hemorrhagic shock and surgical indications. The TEG parameters were compared with 50 healthy people. The coagulation and fibrinolysis in patients with early hemorrhagic shock were observed. Results: In terms of coagulation parameters, the R value decreased, the α angle increased, and the K value and MA value did not change significantly in patients with early hemorrhagic shock. Fibrinolytic aspects: EPL, LY30 observations have no significant changes compared to normal values. Conclusion: The plasma coagulation factor activity is increased in patients with early hemorrhagic shock; the fibrin level is increased; the blood is in a hypercoagulable state; and the fibrinolysis function is not changed. The timely detection of TEG can be used for coagulation function monitoring and blood transfusion therapy in patients with surgical hemorrhagic shock. It provides an important basis for preventing the formation of deep vein thrombosis.

Prostate cancer (PC) is a major health and economic problem in industrialized countries, yet our understanding of the molecular mechanisms of PC progression and drug response remains limited. Accumulating evidence showed that certain E3 ubiquitin ligases such as SIAH2, RNF7, and SPOP play important roles in PC development and progression. However, the roles and mechanisms of other E3s in PC progression remain largely unexplored. Through an integration analysis of clinical genomic and transcriptomic profiles of PC tumors, this study identified UBR5 as a top PC-relevant E3 ubiquitin ligase whose expression levels are strongly associated with PC progression and aggressiveness. BoxCar and shotgun proteomic analyses of control and UBR5-knockdown PC3 cells complementarily identified 75 UBR5-regulated proteins. Bioinformatic analysis suggested that the 75 proteins form four molecular networks centered around FANCD2, PAF1, YY1, and LAMB3 via direct protein-protein interactions. Experimental analyses demonstrated that UBR5 associates with and downregulates two key DNA damage repair proteins (XRCC3 and FANCD2) and confers PC cell sensitivity to olaparib, a PARP inhibitor in clinical use for cancer therapy. This study represents the first application of BoxCar in PC research, provides new insights into the molecular functions of UBR5 in PC, and suggests that PC patients with UBR5-high tumors may potentially benefit from PARP inhibitor treatment.

Prostate cancer (PC) is a leading cause of morbidity and mortality among men worldwide. Molecular biomarkers work in conjunction with existing clinicopathologic tools to help physicians decide who to biopsy, re-biopsy, treat, or re-treat. The past decade has witnessed the commercialization of multiple PC protein biomarkers with improved performance, remarkable progress in proteomic technologies for global discovery and targeted validation of novel protein biomarkers from clinical specimens, and the emergence of novel, promising PC protein biomarkers. In this review, we summarize these advances and discuss the challenges and potential solutions for identifying and validating clinically useful protein biomarkers in PC diagnosis and prognosis. The identification of multi-protein biomarkers with high sensitivity and specificity, as well as their integration with clinicopathologic parameters, imaging, and other molecular biomarkers, bodes well for optimal personalized management of PC patients.

Background & Aims We investigated the transcriptome of esophageal squamous cell carcinoma (ESCC) cells, activity of gene regulatory (enhancer and promoter regions), and the effects of blocking epigenetic regulatory proteins. Methods We performed chromatin immunoprecipitation sequencing with antibodies against H3K4me1, H3K4me3, and H3K27ac and an assay for transposase-accessible chromatin to map the enhancer regions and accessible chromatin in 8 ESCC cell lines. We used the CRC_Mapper algorithm to identify core regulatory circuitry transcription factors in ESCC cell lines, and determined genome occupancy profiles for 3 of these factors. In ESCC cell lines, expression of transcription factors was knocked down with small hairpin RNAs, promoter and enhancer regions were disrupted by CRISPR/Cas9 genome editing, or bromodomains and extraterminal (BET) family proteins and histone deacetylases (HDACs) were inhibited with ARV-771 and romidepsin, respectively. ESCC cell lines were then analyzed by whole-transcriptome sequencing, immunoprecipitation, immunoblots, immunohistochemistry, and viability assays. Interactions between distal enhancers and promoters were identified and verified with circular chromosome conformation capture sequencing. NOD-SCID mice were given injections of modified ESCC cells, some mice where given injections of HDAC or BET inhibitors, and growth of xenograft tumors was measured. Results We identified super-enhancer-regulated circuits and transcription factors TP63, SOX2, and KLF5 as core regulatory factors in ESCC cells. Super-enhancer regulation of ALDH3A1 mediated by core regulatory factors was required for ESCC viability. We observed direct interactions between the promoter region of TP63 and functional enhancers, mediated by the core regulatory circuitry transcription factors. Deletion of enhancer regions from ESCC cells decreased expression of the core regulatory circuitry transcription factors and reduced cell viability; these same results were observed with knockdown of each core regulatory circuitry transcription factor. Incubation of ESCC cells with BET and HDAC disrupted the core regulatory circuitry program and the epigenetic modifications observed in these cells; mice given injections of HDAC or BET inhibitors developed smaller xenograft tumors from the ESCC cell lines. Xenograft tumors grew more slowly in mice given the combination of ARV-771 and romidepsin than mice given either agent alone. Conclusions In epigenetic and transcriptional analyses of ESCC cell lines, we found the transcription factors TP63, SOX2, and KLF5 to be part of a core regulatory network that determines chromatin accessibility, epigenetic modifications, and gene expression patterns in these cells. A combination of epigenetic inhibitors slowed growth of xenograft tumors derived from ESCC cells in mice.

Protein S-acylation (also called palmitoylation) is a common post-translational modification whose deregulation plays a key role in the pathogenesis of many diseases. Acyl-biotinyl exchange (ABE), a widely used method for the enrichment of S-acylated proteins, has the potential of capturing the entire S-acylproteome in any type of biological sample. Here, we showed that current ABE methods suffer from a high background arising from the coisolation of non-S-acylated proteins. The background can be substantially reduced by an additional blockage of residual free cysteine residues with 2,2′-dithiodipyridine prior to the biotin-HPDP reaction. Coupling the low-background ABE (LB-ABE) method with label-free proteomics, 2 895 high-confidence candidate S-acylated proteins (including 1 591 known S-acylated proteins) were identified from human prostate cancer LNCaP cells, representing so-far the largest S-acylproteome data set identified in a single study. Immunoblotting analysis confirmed the S-acylation of five known and five novel prostate cancer-related S-acylated proteins in LNCaP cells and suggested that their S-acylation levels were about 0.6−1.8%. In summary, the LB-ABE method largely eliminates the coisolation of non-S-acylated proteins and enables deep S-acylproteomic analysis. It is expected to facilitate a much more comprehensive and accurate quantification of S-acylproteomes than previous ABE methods.

Polycrystalline Ni50.4Mn27.3Ga22.3 alloy with texture was prepared by conventional casting. The alloy exhibited enhanced magnetocrystalline anisotropy after superelastic training. Decent conventional magnetocaloric effect (MCE) with magnetic-field-induced entropy change ΔS = 9.2 J/kg·K under a magnetic field 30 kOe and inverse MCE with ΔS = 2.5 J/kg·K under 5 kOe were demonstrated when the field was applied parallel and perpendicular to , respectively. As a result, large rotating MCE with ΔS = 4.2 J/kg·K under a low field of 20 kOe was achieved at room temperature. This shows that polycrystalline Ni-Mn-Ga alloys may act as promising magnetic refrigerants.

Additional file 1. Â Supplemental figures S1â S9.

Background Prostate cancer (PCa) is the most frequently diagnosed non-skin cancer and a leading cause of mortality among males in developed countries. However, our understanding of the global changes of protein complexes within PCa tissue specimens remains very limited, although it has been well recognized that protein complexes carry out essentially all major processes in living organisms and that their deregulation drives the pathogenesis and progression of various diseases. Methods By coupling tandem mass tagging-synchronous precursor selection-mass spectrometry/mass spectrometry/mass spectrometry with differential expression and co-regulation analyses, the present study compared the differences between protein complexes in normal prostate, low-grade PCa, and high-grade PCa tissue specimens. Results Globally, a large downregulated putative protein–protein interaction (PPI) network was detected in both low-grade and high-grade PCa, yet a large upregulated putative PPI network was only detected in high-grade but not low-grade PCa, compared with normal controls. To identify specific protein complexes that are deregulated in PCa, quantified proteins were mapped to protein complexes in CORUM (v3.0), a high-quality collection of 4274 experimentally verified mammalian protein complexes. Differential expression and gene ontology (GO) enrichment analyses suggested that 13 integrin complexes involved in cell adhesion were significantly downregulated in both low- and high-grade PCa compared with normal prostate, and that four Prothymosin alpha (ProTα) complexes were significantly upregulated in high-grade PCa compared with normal prostate. Moreover, differential co-regulation and GO enrichment analyses indicated that the assembly levels of six protein complexes involved in RNA splicing were significantly increased in low-grade PCa, and those of four subcomplexes of mitochondrial complex I were significantly increased in high-grade PCa, compared with normal prostate. Conclusions In summary, to the best of our knowledge, the study represents the first large-scale and quantitative, albeit indirect, comparison of individual protein complexes in human PCa tissue specimens. It may serve as a useful resource for better understanding the deregulation of protein complexes in primary PCa. Electronic supplementary material The online version of this article (10.1186/s12014-019-9236-2) contains supplementary material, which is available to authorized users.

As a recycling center, lysosomes are filled with numerous acid hydrolase enzymes that break down waste materials and invading pathogens. Recently, lysosomal cell death has been defined as “lysosomal membrane permeabilization and the consequent leakage of lysosome contents into cytosol.” Here, we show that the neuraminidase (NA) of H5N1 influenza A virus markedly deglycosylates and degrades lysosome-associated membrane proteins (LAMPs; the most abundant membrane proteins of lysosome), which induces lysosomal rupture, and finally leads to cell death of alveolar epithelial carcinoma A549 cells and human tracheal epithelial cells. The NA inhibitors peramivir and zanamivir could effectively block the deglycosylation of LAMPs, inhibit the virus cell entry, and prevent cell death induced by the H5N1 influenza virus. The NA of seasonal H1N1 virus, however, does not share these characteristics. Our findings not only reveal a novel role of NA in the early stage of the H5N1 influenza virus life cycle but also elucidate the molecular mechanism of lysosomal rupture crucial for influenza virus induced cell death. IMPORTANCE The integrity of lysosomes is vital for maintaining cell homeostasis, cellular defense and clearance of invading pathogens. This study shows that the H5N1 influenza virus could induce lysosomal rupture through deglycosylating lysosome-associated membrane proteins (LAMPs) mediated by the neuraminidase activity of NA protein. NA inhibitors such as peramivir and zanamivir could inhibit the deglycosylation of LAMPs and protect lysosomes, which also further interferes with the H5N1 influenza virus infection at early stage of life cycle. This work is significant because it presents new concepts for NA's function, as well as for influenza inhibitors' mechanism of action, and could partially explain the high mortality and high viral load after H5N1 virus infection in human beings and why NA inhibitors have more potent therapeutic effects for lethal avian influenza virus infections at early stage.

Background: Prostate Cancer (PCa) is the most common non-skin cancer among American man. Currently, major challenges in the clinical management of PCa include 1) a lack of biomarkers that can reliably distinguish aggressive from indolent PCa and 2) a shortage of therapeutic strategies that can prevent or suppress the progression of PCa into aggressive PCa. Methods: Label-free quantitative proteomics was performed on three widely used PCa cell lines with different levels of aggressiveness (i.e., LNCaP, DU145 and PC3). Upstream regulator analysis and network modeling were conducted to identify candidate key promoters of PCa aggressiveness. The levels of gene amplification, mRNA expression, and protein expression of a key candidate promoter, receptor-interacting protein kinase 2 (RIPK2), were compared by analyzing publicly accessible PCa genomic and transcriptomic datasets and by immunohistochemistry (IHC) staining of PCa tissue microarrays (TMA). Cell proliferation and invasion assays were performed to compare PC3 cells with or without CRISPR/Cas9 knock-out of RIPK2. Quantitative proteomics and bioinformatics analysis were conducted to identify the underlying mechanisms, followed by validation via western blotting, quantitative real-time PCR (qRT-PCR) and in vitro functional assays. Results: Quantitative proteomics analysis of the three PCa cell lines identified over 6,500 proteins, among which 341 are significantly (adjusted p-value < 0.01) differentially expressed. Bioinformatic analysis and network modeling revealed RIPK2 as a novel candidate key promoter of aggressive PCa. Consistently, the levels of RIPK2 DNA amplification, mRNA expression, and protein expression are significantly higher in more aggressive PCa than in less aggressive PCa. Moreover, cell functional assays showed a significant inhibition of cell proliferation and invasion after the CRISPR/Cas9 depletion of RIPK2 in PC3 cells. Mechanistically, quantitative proteomics identified MAX (Myc-associated factor X) as one of the most prominent candidate downstream effectors of RIPK2. Consistently, upstream regulator analysis suggested that Myc activity was significantly downregulated in RIPK2 deleted PC3 cells, compared with control cells. These findings were further validated by RT-PCR, western blotting, and MYC luciferase reporter assay. In addition, pathway enrichment analysis identified the EIF2 signaling pathway, a key pathway regulated by MAX:MYC, as the most significantly downregulated pathway after RIPK2 knock-out. Conclusion: Taken together, our data elucidate that RIPK2's amplification and overexpression in PCa cells may activate the MAX:MYC-EIF2 signaling axis and thus in turn promote PCa cell proliferation and invasion. The aberrant activation of the RIPK2-MAX:MYC-EIF2 pathway may serve as a valuable biomarker and novel drug target of PCa progression. Citation Format: Yiwu Yan, Bo Zhou, Xiaopu Yuan, Michael E. Doche, Zhaoxuan Ma, Colm Morrissey, Arkadiusz Gertych, Sungyong You, Beatrice Knudsen, Michael R. Freeman, Wei Yang. Receptor-interacting protein kinase 2 promotes prostate cancer progression by activating the MAX:MYC pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2694.

The microplastic deformation behavior of 20 vol.% SiCp / Al composites with various SiC particle sizes were investigated. The SiC particles are in four nominal sizes of 1, 5, 20 and 56 µm. The experimental results showed that the micro-yield strength is very sensitive to composite microstructure features. As the particle size increases, the micro-yield strength of composites decrease firstly, and then increase. The observed results were attributed to thermal residual stress and dislocation density due to the large difference in coefficient of thermal expansion between the matrix and reinforcement.

Ultra-thin tetrahedral amorphous carbon (ta-C) films have been prepared by filtered catholic vacuum arc system for recording slider applications. In order to study the corrosion behavior of the slider coatings deposited at different substrate bias, the micro-structure and surface properties of the ta-C films were respectively investigated in terms of Raman spectroscopy, atomic force microscopy, water contact angle and corrosion measurements. Results showed that a very smooth ta-C film with lowest surface energy and highest sp 3 bonding content was obtained at the medium bias voltage of 100 V. However, as to the protection against corrosion, the optimum bias was found to be greater than that giving the maximum diamond-like properties.

The coefficients of thermal expansion (CTEs) of 20 vol% SiCp/Al composites fabricated by powder metallurgy process were measured and examined from room temperature to 450 °C. The SiC particles are in three nominal sizes 5, 20 and 56μm. The CTEs of the SiCp/Al composites were shown to be apparently dependent on the particle size. That the larger particle size, the higher CTEs of the composites, is thought to be due to the difference in original thermal residual stresses and matrix plasticity during thermal loading. At low temperature, the experimental CTEs show substantial deviation from the prediction of the elastic analysis derived by Kerner and rule of mixture (ROM), while the Kerner’s model agrees relatively well at high temperatures for the composite with the larger particle size.

A multi-inclusion cell model is used to investigate the effect of deformation temperature and whisker rotation on the hot compressive behavior of metal matrix composites with misaligned whiskers. Numerical results show that deformation temperature influences the work-hardening behavior of the matrix and the rotation behavior of the whiskers. With increasing temperature, the work hardening rate of the matrix decreases, but the whisker rotation angle increases. Both whisker rotation and the increase of deformation temperature can induce reductions in the load supported by whisker and the load transferred from matrix to whisker. Additionally, it is found that during large strain deformation at higher temperatures, the enhancing of deformation temperature can reduce the effect of whisker rotation. Meanwhile, the stress-strain behavior of the composite is rather sensitive to deformation temperature. At a relatively lower temperature (150° C), the composite exhibits work hardening due to the matrix work hardening, but at relatively higher temperatures (300° C and above), the composite shows strain softening due to whisker rotation. It is also found that during hot compression at higher temperatures, the softening rate of the composite decreases with increasing temperature. The predicted stress-strain behavior of the composite is approximately in agreement with the experimental results.

Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model

The potential for avian influenza H5N1 outbreaks has increased in recent years. Thus, it is paramount to develop novel strategies to alleviate death rates. Here we show that avian influenza A H5N1-infected patients exhibit markedly increased serum levels of angiotensin II. High serum levels of angiotensin II appear to be linked to the severity and lethality of infection, at least in some patients. In experimental mouse models, infection with highly pathogenic avian influenza A H5N1 virus results in downregulation of angiotensin-converting enzyme 2 (ACE2) expression in the lung and increased serum angiotensin II levels. Genetic inactivation of ACE2 causes severe lung injury in H5N1-challenged mice, confirming a role of ACE2 in H5N1-induced lung pathologies. Administration of recombinant human ACE2 ameliorates avian influenza H5N1 virus-induced lung injury in mice. Our data link H5N1 virus-induced acute lung failure to ACE2 and provide a potential treatment strategy to address future flu pandemics. Supplementary information The online version of this article (doi:10.1038/ncomms4594) contains supplementary material, which is available to authorized users., H5N1 avian influenza viruses can be highly pathogenic. Here, the authors show that H5N1 infection leads to increased serum levels of angiotensin II in patients and mice, and that administration of angiotensin-converting enzyme 2 ameliorates lung injury in infected mice. Supplementary information The online version of this article (doi:10.1038/ncomms4594) contains supplementary material, which is available to authorized users.

The threat of a new influenza pandemic has existed since 1997, when the highly pathogenic H5N1 strain of avian influenza A virus infected humans in Hong Kong and spread across Asia, where it continued to infect poultry and people. The human mortality rate of H5N1 infection is about 60%, whereas that of seasonal H1N1 infection is less than 0.1%. The high mortality rate associated with H5N1 infection is predominantly a result of respiratory failure caused by acute lung injury; however, how viral infection contributes to this disease pathology is unclear. Here, we used electron microscopy to show the accumulation of autophagosomes in H5N1-infected lungs from a human cadaver and mice, as well as in infected A549 human epithelial lung cells. We also showed that H5N1, but not seasonal H1N1, induced autophagic cell death in alveolar epithelial cells through a pathway involving the kinase Akt, the tumor suppressor protein TSC2, and the mammalian target of rapamycin. Additionally, we suggest that the hemagglutinin protein of H5N1 may be responsible for stimulating autophagy. When applied prophylactically, reagents that blocked virus-induced autophagic signaling substantially increased the survival rate of mice and substantially ameliorated the acute lung injury and mortality caused by H5N1 infection. We conclude that the autophagic cell death of alveolar epithelial cells likely plays a crucial role in the high mortality rate of H5N1 infection, and we suggest that autophagy-blocking agents might be useful as prophylactics and therapeutics against infection of humans by the H5N1 virus.

BACKGROUND: A novel 2009 swine-origin influenza A H1N1 virus (S-OIV H1N1) has been transmitted among humans worldwide. However, the pathogenesis of this virus in human airway epithelial cells and mammals is not well understood. METHODOLOGY/PRINCIPAL FINDING: In this study, we showed that a 2009 A (H1N1) influenza virus strain, A/Beijing/501/2009, isolated from a human patient, caused typical influenza-like symptoms including weight loss, fluctuations in body temperature, and pulmonary pathological changes in ferrets. We demonstrated that the human lung adenocarcinoma epithelial cell line A549 was susceptible to infection and that the infected cells underwent apoptosis at 24 h post-infection. In contrast to the seasonal H1N1 influenza virus, the 2009 A (H1N1) influenza virus strain A/Beijing/501/2009 induced more cell death involving caspase-3-dependent apoptosis in A549 cells. Additionally, ferrets infected with the A/Beijing/501/2009 H1N1 virus strain exhibited increased body temperature, greater weight loss, and higher viral titers in the lungs. Therefore, the A/Beijing/501/2009 H1N1 isolate successfully infected the lungs of ferrets and caused more pathological lesions than the seasonal influenza virus. Our findings demonstrate that the difference in virulence of the 2009 pandemic H1N1 influenza virus and the seasonal H1N1 influenza virus in vitro and in vivo may have been mediated by different mechanisms. CONCLUSION/SIGNIFICANCE: Our understanding of the pathogenesis of the 2009 A (H1N1) influenza virus infection in both humans and animals is broadened by our findings that apoptotic cell death is involved in the cytopathic effect observed in vitro and that the pathological alterations in the lungs of S-OIV H1N1-infected ferrets are much more severe.

Metal oxide nanoparticles (NPs) are among the most highly produced nanomaterials, and have many diverse functions in catalysis, environmental remediation, as sensors, and in the production of personal care products. In this study, the toxicity of several widely used metal oxide NPs such as copper oxide, silica, titanium oxide and ferric oxide NPs, were evaluated In vitro. We exposed A549, H1650 and CNE-2Z cell lines to metal oxide NPs, and found CuO NPs to be the most toxic, SiO2 mild toxic, while the other metal oxide NPs had little effect on cell viability. Furthermore, the autophagic biomarker LC3-II significantly increased in A549 cells treated with CuO NPs, and the use of the autophagy inhibitors wortmannin and 3-methyladenin significantly improved cell survival. These results indicate that the cytoxicity of CuO NPs may involve the autophagic pathway in A549 cells.

BACKGROUND: The 2009 influenza pandemic affected people in almost all countries in the world, especially in younger age groups. During this time, the debate over whether to use corticosteroid treatment in severe influenza H1N1 infections patients resurfaced and was disputed by clinicians. There is an urgent need for a susceptible animal model of 2009 H1N1 infection that can be used to evaluate the pathogenesis and the therapeutic effect of corticosteroid treatment during infection. METHODOLOGY/PRINCIPAL FINDINGS: We intranasally inoculated two groups of C57BL/6 and BALB/c mice (using 4- or 6-to 8-week-old mice) to compare the pathogenesis of several different H1N1 strains in mice of different ages. Based on the results, a very susceptible 4-week-old C57BL/6 mouse model of Beijing 501 strain of 2009 H1N1 virus infection was established, showing significantly elevated lung edema and cytokine levels compared to controls. Using our established animal model, the cytokine production profile and lung histology were assessed at different times post-infection, revealing increased lung lesions in a time-dependent manner. In additional,the mice were also treated with dexamethasone, which significantly improved survival rate and lung lesions in infected mice compared to those in control mice. Our data showed that corticosteroid treatment ameliorated acute lung injury induced by the 2009 A/H1N1 virus in mice and suggested that corticosteroids are valid drugs for treating 2009 A/H1N1 infection. CONCLUSIONS/SIGNIFICANCE: Using the established, very susceptible 2009 Pandemic Influenza A (H1N1) mouse model, our studies indicate that corticosteroids are a potential therapeutic remedy that may address the increasing concerns over future 2009 A/H1N1 pandemics.

The 2009 flu pandemic involved the emergence of a new strain of a swine-origin H1N1 influenza virus (S-OIV H1N1) that infected almost every country in the world. Most infections resulted in respiratory illness and some severe cases resulted in acute lung injury. In this report, we are the first to describe a mouse model of S-OIV virus infection with acute lung injury and immune responses that reflect human clinical disease. The clinical efficacy of the antiviral oseltamivir (Tamiflu) administered in the early stages of S-OIV H1N1 infection was confirmed in the mouse model. Moreover, elevated levels of IL-17, Th-17 mediators and IL-17-responsive cytokines were found in serum samples of S-OIV-infected patients in Beijing. IL-17 deficiency or treatment with monoclonal antibodies against IL-17-ameliorated acute lung injury induced by the S-OIV H1N1 virus in mice. These results suggest that IL-17 plays an important role in S-OIV-induced acute lung injury and that monoclonal antibodies against IL-17 could be useful as a potential therapeutic remedy for future S-OIV H1N1 pandemics.

In this paper, electroless Ni-PTFE-P and Ni-Al2O3-P coating were successfully deposited on the surface of medium carbon steel shaft. Scanning electron microscopy (SEM) and EDX measurement were used to characterize the morphology and chemical composition of the coatings. The results showed that lubricating PTFE particles and hared alumina particles have been uniformly incorporated into the Ni-PTFE-P coating and Ni-Al2O3-P coating, respectively. Friction behavior and wear resistance of the surface modification shafts in rolling contact with bushing were mainly studied. The results showed that shaft with Ni-Al2O3-P coating shows the best wear resistance in rolling contact with the bushing owing to the high wear resistance of alumina particle, whereas produces severe grain abrasion on its friction partner (bushing). Ni-PTFE-P coating deposited on the shaft plays an excellent role in reducing the wear of the bushing.