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Michael CW Chan Renee WY Chan Wendy CL Yu Carol CC Ho WH Chui CK Lo Kit M Yuen Yi Guan John M Nicholls JS Malik Peiris 《Respiratory research》2009,10(1):102
Background
Highly pathogenic avian influenza (HPAI) H5N1 virus is entrenched in poultry in Asia and Africa and continues to infect humans zoonotically causing acute respiratory disease syndrome and death. There is evidence that the virus may sometimes spread beyond respiratory tract to cause disseminated infection. The primary target cell for HPAI H5N1 virus in human lung is the alveolar epithelial cell. Alveolar epithelium and its adjacent lung microvascular endothelium form host barriers to the initiation of infection and dissemination of influenza H5N1 infection in humans. These are polarized cells and the polarity of influenza virus entry and egress as well as the secretion of cytokines and chemokines from the virus infected cells are likely to be central to the pathogenesis of human H5N1 disease.Aim
To study influenza A (H5N1) virus replication and host innate immune responses in polarized primary human alveolar epithelial cells and lung microvascular endothelial cells and its relevance to the pathogenesis of human H5N1 disease.Methods
We use an in vitro model of polarized primary human alveolar epithelial cells and lung microvascular endothelial cells grown in transwell culture inserts to compare infection with influenza A subtype H1N1 and H5N1 viruses via the apical or basolateral surfaces.Results
We demonstrate that both influenza H1N1 and H5N1 viruses efficiently infect alveolar epithelial cells from both apical and basolateral surface of the epithelium but release of newly formed virus is mainly from the apical side of the epithelium. In contrast, influenza H5N1 virus, but not H1N1 virus, efficiently infected polarized microvascular endothelial cells from both apical and basolateral aspects. This provides a mechanistic explanation for how H5N1 virus may infect the lung from systemic circulation. Epidemiological evidence has implicated ingestion of virus-contaminated foods as the source of infection in some instances and our data suggests that viremia, secondary to, for example, gastro-intestinal infection, can potentially lead to infection of the lung. HPAI H5N1 virus was a more potent inducer of cytokines (e.g. IP-10, RANTES, IL-6) in comparison to H1N1 virus in alveolar epithelial cells, and these virus-induced chemokines were secreted onto both the apical and basolateral aspects of the polarized alveolar epithelium.Conclusion
The predilection of viruses for different routes of entry and egress from the infected cell is important in understanding the pathogenesis of influenza H5N1 infection and may help unravel the pathogenesis of human H5N1 disease. 相似文献33.
Tainá CC Monte Rosana Gentile Juberlan Garcia Ester Mota Jeannie N Santos Arnaldo Maldonado Júnior 《Memórias do Instituto Oswaldo Cruz》2014,109(8):1057-1063
Angiostrongylus cantonensis is the etiologic agent of eosinophilic
meningoencephalitis in humans. Cases have been recorded in many parts of the world,
including Brazil. The aim of this study was to compare the differences in the biology
and morphology of two different Brazilian haplotypes of A. : ac8 and
ac9. A significantly larger number of L1 larvae eliminated in the faeces of rodents
at the beginning of the patent period was observed for ac9 haplotype and compared to
the total of L1 larvae eliminated, there was a significant difference between the two
haplotypes. The ac9 haplotype showed a significant difference in the proportion of
female and male specimens (0.6:1), but the same was not observed for ac8 (1.2:1). The
morphometric analysis showed that male and female specimens isolated from ac8
haplotype were significantly larger with respect to body length, oesophagus length,
spicule length (male) and distance from the anus to the rear end (female) compared to
specimens from ac9. The morphological analysis by light microscopy showed little
variation in the level of bifurcations at the lateral rays in the right lobe of the
copulatory bursa between the two haplotypes. The biological, morphological and
morphometric variations observed between the two haplotypes agree with the observed
variation at the molecular level using the cytochrome oxidase subunit I marker and
reinforce the possible influence of geographical isolation on the development of
these haplotypes. 相似文献
34.
Summary Much of the statistical methodology underlying the experimental design of phase 1 trials in oncology is intended for studies involving a single cytotoxic agent. The goal of these studies is to estimate the maximally tolerated dose, the highest dose that can be administered with an acceptable level of toxicity. A fundamental assumption of these methods is monotonicity of the dose–toxicity curve. This is a reasonable assumption for single‐agent trials in which the administration of greater doses of the agent can be expected to produce dose‐limiting toxicities in increasing proportions of patients. When studying multiple agents, the assumption may not hold because the ordering of the toxicity probabilities could possibly be unknown for several of the available drug combinations. At the same time, some of the orderings are known and so we describe the whole situation as that of a partial ordering. In this article, we propose a new two‐dimensional dose‐finding method for multiple‐agent trials that simplifies to the continual reassessment method (CRM), introduced by O'Quigley, Pepe, and Fisher (1990, Biometrics 46 , 33–48), when the ordering is fully known. This design enables us to relax the assumption of a monotonic dose–toxicity curve. We compare our approach and some simulation results to a CRM design in which the ordering is known as well as to other suggestions for partial orders. 相似文献
35.
36.
Claudia T Guimaraes Christiano C Simoes Maria Marta Pastina Lyza G Maron Jurandir V Magalhaes Renato CC Vasconcellos Lauro JM Guimaraes Ubiraci GP Lana Carlos FS Tinoco Roberto W Noda Silvia N Jardim-Belicuas Leon V Kochian Vera MC Alves Sidney N Parentoni 《BMC genomics》2014,15(1)
Background
Aluminum (Al) toxicity is an important limitation to food security in tropical and subtropical regions. High Al saturation on acid soils limits root development, reducing water and nutrient uptake. In addition to naturally occurring acid soils, agricultural practices may decrease soil pH, leading to yield losses due to Al toxicity. Elucidating the genetic and molecular mechanisms underlying maize Al tolerance is expected to accelerate the development of Al-tolerant cultivars.Results
Five genomic regions were significantly associated with Al tolerance, using 54,455 SNP markers in a recombinant inbred line population derived from Cateto Al237. Candidate genes co-localized with Al tolerance QTLs were further investigated. Near-isogenic lines (NILs) developed for ZmMATE2 were as Al-sensitive as the recurrent line, indicating that this candidate gene was not responsible for the Al tolerance QTL on chromosome 5, qALT5. However, ZmNrat1, a maize homolog to OsNrat1, which encodes an Al3+ specific transporter previously implicated in rice Al tolerance, was mapped at ~40 Mbp from qALT5. We demonstrate for the first time that ZmNrat1 is preferentially expressed in maize root tips and is up-regulated by Al, similarly to OsNrat1 in rice, suggesting a role of this gene in maize Al tolerance. The strongest-effect QTL was mapped on chromosome 6 (qALT6), within a 0.5 Mbp region where three copies of the Al tolerance gene, ZmMATE1, were found in tandem configuration. qALT6 was shown to increase Al tolerance in maize; the qALT6-NILs carrying three copies of ZmMATE1 exhibited a two-fold increase in Al tolerance, and higher expression of ZmMATE1 compared to the Al sensitive recurrent parent. Interestingly, a new source of Al tolerance via ZmMATE1 was identified in a Brazilian elite line that showed high expression of ZmMATE1 but carries a single copy of ZmMATE1.Conclusions
High ZmMATE1 expression, controlled either by three copies of the target gene or by an unknown molecular mechanism, is responsible for Al tolerance mediated by qALT6. As Al tolerant alleles at qALT6 are rare in maize, marker-assisted introgression of this QTL is an important strategy to improve maize adaptation to acid soils worldwide.Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-153) contains supplementary material, which is available to authorized users. 相似文献37.
Lu Chen Soon-Keat Ooi Ronald C. Conaway Joan W. Conaway 《Journal of visualized experiments : JoVE》2014,(92)
INO80 chromatin remodeling complexes regulate nucleosome dynamics and DNA accessibility by catalyzing ATP-dependent nucleosome remodeling. Human INO80 complexes consist of 14 protein subunits including Ino80, a SNF2-like ATPase, which serves both as the catalytic subunit and the scaffold for assembly of the complexes. Functions of the other subunits and the mechanisms by which they contribute to the INO80 complex''s chromatin remodeling activity remain poorly understood, in part due to the challenge of generating INO80 subassemblies in human cells or heterologous expression systems. This JOVE protocol describes a procedure that allows purification of human INO80 chromatin remodeling subcomplexes that are lacking a subunit or a subset of subunits. N-terminally FLAG epitope tagged Ino80 cDNA are stably introduced into human embryonic kidney (HEK) 293 cell lines using Flp-mediated recombination. In the event that a subset of subunits of the INO80 complex is to be deleted, one expresses instead mutant Ino80 proteins that lack the platform needed for assembly of those subunits. In the event an individual subunit is to be depleted, one transfects siRNAs targeting this subunit into an HEK 293 cell line stably expressing FLAG tagged Ino80 ATPase. Nuclear extracts are prepared, and FLAG immunoprecipitation is performed to enrich protein fractions containing Ino80 derivatives. The compositions of purified INO80 subcomplexes can then be analyzed using methods such as immunoblotting, silver staining, and mass spectrometry. The INO80 and INO80 subcomplexes generated according to this protocol can be further analyzed using various biochemical assays, which are described in the accompanying JOVE protocol. The methods described here can be adapted for studies of the structural and functional properties of any mammalian multi-subunit chromatin remodeling and modifying complexes. 相似文献
38.
Further characterization of the binding of human recombinant interleukin 2 to heparin and identification of putative binding sites 总被引:1,自引:1,他引:1
We have previously provided compelling evidence that human recombinant
interleukin 2 (IL-2) binds to the sulfated polysaccharides heparin, highly
sulfated heparan sulfate and fucoidan. Here we show that IL-2 binding is
dependent on heparin chain length, but with fragments as small as 15-mers
retaining binding activity. The addition of exogenous heparin has no effect
on the in vitro biological activity of IL-2. In addition soluble IL-2
receptor alpha and beta polypeptides do not compete with heparin for the
binding of IL-2. IL-2 bound by heparin is still recognized by two IL-2
specific monoclonal antibodies, 3H9 and H2- 8, whose epitopes lie in the
amino terminal region. Murine IL-2 unlike its human counterpart fails to
bind to heparin. Human IL-2 analogs with single amino acid substitutions at
positions Lys43, Thr51, and Gln126 analogs no longer bind to heparin. By
contrast the Arg38Ala analog retains heparin full heparin binding activity.
These experimental findings together with molecular modeling studies
suggest two putative heparin binding sites on human IL-2, one involving
four basic residues, Lys48, Lys49, Lys54, and His55, and the other being a
discontinuous site comprising Lys43, Lys64, Arg81, and Arg83. Neither of
these two clusters is completely conserved in murine IL-2. Overall our data
suggest that the binding of human IL-2 to heparin and heparan sulfate does
not interfere with IL-2/IL-2 receptor interactions. Therefore, binding to
glycosaminoglycan may be a mechanism for retaining the cytokine in an
active form close to its site of secretion in the tissue, thus favoring a
paracrine role for IL-2.
相似文献
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