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51.

Background

Human nasopharynx is often colonized by potentially pathogenic bacteria. Gene polymorphisms in mannose-binding lectin (MBL), toll-like receptor (TLR) 2 and TLR4 have been reported. The present study aimed to investigate possible association between nasopharyngeal bacterial colonization and gene polymorphisms of MBL, TLR2 and TLR4 in healthy infants.

Methodology/Principal Findings

From August 2008 to June 2010, 489 nasopharyngeal swabs and 412 blood samples were taken from 3-month-old healthy Finnish infants. Semi-quantitative culture was performed and pyrosequencing was used for detection of polymorphisms in MBL structural gene at codons 52, 54, and 57, TLR2 Arg753Gln and TLR4 Asp299Gly. Fifty-nine percent of subjects were culture positive for at least one of the four species: 11% for Streptococcus pneumoniae, 23% for Moraxella catarrhalis, 1% for Haemophilus influenzae and 25% for Staphylococcus aureus. Thirty-two percent of subjects had variant types in MBL, 5% had polymorphism of TLR2, and 18% had polymorphism of TLR4. Colonization rates of S. pneumoniae and S. aureus were significantly higher in infants with variant types of MBL than those with wild type (p = .011 and p = .024). Colonization rates of S. aureus and M. catarrhalis were significantly higher in infants with polymorphisms of TLR2 and of TLR4 than those without (p = .027 and p = .002).

Conclusions

Our study suggests that there is an association between nasopharyngeal bacterial colonization and genetic variation of MBL, TLR2 and TLR4 in young infants. This finding supports a role for these genetic variations in susceptibility of children to respiratory infections.  相似文献   
52.
Defending from DDoS attacks have become more difficult because they have evolved in many ways. Absence of a specific predetermined pattern, increase of number of attack devices, and distributed execution of the DDoS attack makes hard the recognition of the attack sources and thus application of countermeasures. When the DDoS attack is being executed, most of the cases, the target cannot provide its services normally; this is not a significant problem for non-critical application, but, for availability critical services such as stock financial, stock market, or governmental, the effect of the attack may involve huge damage. In this paper, we propose a DDoS avoidance strategy to provide service availability to those preregistered important users. In the proposed strategy, we divide the attack scenario in different time points and provide alternative access channels to already authenticated and other valid users.  相似文献   
53.
Monosodium urate (MSU) is an endogenous danger signal that is crystallized from uric acid released from injured cells. MSU is known to activate inflammatory response in macrophages but the molecular mechanisms involved have remained uncharacterized. Activated macrophages start to secrete proteins to activate immune response and to recruit other immune cells to the site of infection and/or tissue damage. Secretome characterization after activation of innate immune system is essential to unravel the details of early phases of defense responses. Here, we have analyzed the secretome of human primary macrophages stimulated with MSU using quantitative two-dimensional gel electrophoresis based proteomics as well as high-throughput qualitative GeLC-MS/MS approach combining protein separation by SDS-PAGE and protein identification by liquid chromatography-MS/MS. Both methods showed that MSU stimulation induced robust protein secretion from lipopolysaccharide-primed human macrophages. Bioinformatic analysis of the secretome data showed that MSU stimulation strongly activates unconventional, vesicle mediated protein secretion. The unconventionally secreted proteins included pro-inflammatory cytokines like IL-1β and IL-18, interferon-induced proteins, and danger signal proteins. Also active forms of lysosomal proteases cathepsins were secreted on MSU stimulation, and cathepsin activity was essential for MSU-induced unconventional protein secretion. Additionally, proteins associated to phosphorylation events including Src family tyrosine kinases were increased in the secretome of MSU-stimulated cells. Our functional studies demonstrated that Src, Pyk2, and PI3 kinases act upstream of cathepsins to activate the overall protein secretion from macrophages. In conclusion, we provide the first comprehensive characterization of protein secretion pathways activated by MSU in human macrophages, and reveal a novel role for cathepsins and Src, Pyk2, PI3 kinases in the activation of unconventional protein secretion.The innate immune system is activated in response to microbial infection and tissue damage. Macrophages are the central players of the innate immunity and detect the presence of pathogen-associated molecular patterns (PAMPs)1 and damage-associated molecular patterns (DAMPs) with their pattern recognition receptors. This recognition results in the activation of antimicrobial defense, inflammatory response, tissue regeneration, and recruitment of other inflammatory cells to the site of infection and/or tissue damage (1). Proper innate immune response is essential for the activation of the adaptive immune system. At present it is thought that the activation of innate immunity is most effective when both signals of microbial origin and damage are perceived at the same time (2, 3).Monosodium urate (MSU) is an endogenous DAMP that is crystallized from uric acid released by injured cells (4). Uric acid is a byproduct of purine degradation, and abnormally high levels of uric acid in serum, or hyperuricemia, is a hallmark of metabolic disorders where balance between intake of purines via food and excretion of uric acid is distorted. A well-known disease associated to hyperuricemia is gouty arthritis, in which deposits of MSU can be found in synovial fluid of peripheral joints, and MSU-induced inflammation is the initial trigger of symptoms (5). Hyperuricemia is also linked to other inflammatory diseases, like metabolic syndrome (6, 7), type 2 diabetes (8), and cardiovascular disease (9). MSU-induced inflammation is driven by the innate immune system. MSU engages antigen-presenting cells, macrophages, and dendritic cells. It is a potent adjuvant, initiating a robust adaptive immune response (4). Recently it has been shown that the adjuvant properties of alum are dependent on release of uric acid in vivo (10).It is unclear how cells detect the presence of MSU. It has been suggested that MSU activates intracellular signaling pathways in dendritic cells by directly engaging cellular membranes, particularly the cholesterol-rich components of the plasma membrane (11). Recently Uratsuji and coworkers showed that MSU activates inflammatory response in keratinocytes and monocytic THP-1 cells through membrane-associated P2Y6 (12). It is also well-documented that MSU activates the NLRP3 inflammasome in macrophages (13). The NLRP3 inflammasome is a multiprotein complex comprising of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), Apoptosis-associated speck-like protein containing a CARD (ASC) and cysteine protease Caspase-1. Activation of NLRP3 inflammasome results in the autocleavage of Caspase-1. The activated Caspase-1 then in turn cleaves pro-inflammatory cytokines IL-1β and IL-18 into their biologically active forms, which are then readily secreted (1417). However, the signaling pathways that are involved in MSU-induced NLRP3 inflammasome activation have remained only partially characterized.Macrophages respond to activating stimuli by producing inflammatory mediators that are delivered to neighboring cells through multiple protein secretion pathways including both conventional and unconventional protein secretion (18). Conventionally secreted proteins contain an N-terminal signal peptide, which directs their transport to the plasma membrane through the well-characterized endoplasmic reticulum (ER)-Golgi pathway. In contrast, mediators and regulators of unconventional protein secretion pathways are less well understood. At present, different proteomic techniques allow for in-depth analysis of the secretome, the global pattern of secreted proteins. Secretome analysis is important in revealing complex cellular processes that require communication and signaling between the cells, and it has recently been applied to analyze the signaling pathways related to cell differentiation (19, 20), cancer (21, 22), and immune responses (2325). In the present work we have characterized the secretome of human primary macrophages that have been activated simultaneously by microbial signal lipopolysaccharide (LPS) and endogenous danger signal MSU to get a global view of macrophage response to combined PAMP and DAMP stimulation.  相似文献   
54.
Native fauna in species poor communities, such as those of the Baltic Sea, may be particularly vulnerable to the effects of species invasions. However, the interspecific interactions that result in the negative impacts on native species tend to be poorly understood. One contributing factor to this knowledge gap may be that the vulnerability of native species can vary between different life-history stages. For example, the parental care phase is often risky both for the developing offspring and care-giving parents. Accordingly, we investigated the interactions between invasive mud crabs, Rhithropanopeus harrissii, and native nest-building littoral fish, with a special focus on the sand goby, Pomatoschistus minutus. Firstly, our field survey demonstrated that while the recently established mud crab and native nest-building fish have different habitat and depth optima, their distributions also have a considerable overlap, with a high potential for interactions between them. Secondly, our laboratory experiments indicate that the crabs are likely to impact the fish negatively, especially by taking over occupied nests, as well as pre-occupying nesting resources that are of very limited supply in the studied population. We did not find evidence for successful predation on eggs guarded by male sand gobies naive to the mud crabs. Collectively, the results suggest that the invasive crabs have high potential to negatively impact native fish. Furthermore, the results support the scenario that the parental phase can be a particularly vulnerable life-history stage in face of novel selection pressures, such as species invasions.  相似文献   
55.
The isotopomer distributions of metabolites are invaluable pieces of information in the computation of the flux distribution in a metabolic network. We describe the use of tandem mass spectrometry with the daughter ion scanning technique in the discovery of positional isotopomer distributions (PID). This technique increases the possibilities of mass spectrometry since given the same fragment ions, it uncovers more information than the full scanning mode. The mathematics of the new technique is slightly more complicated than the techniques needed by full scanning mode methods. Our experiments, however, show that in practice the inadequacy of the fragmentation of amino acids in the tandem mass spectrometer does not allow uncovering the PID exactly even if the daughter ion scanning is used. The computational techniques have been implemented in a MATLAB application called PIDC (Positional Isotopomer Distribution Calculator).  相似文献   
56.

Aim

Toll-like receptors (TLR) play a crucial role in innate immunity, protecting the host from pathogens such as viruses. Genetic variations in TLRs have been associated with the severity of viral bronchiolitis in infancy and with the later occurrence of post-bronchiolitis asthma. The aim of the present study was to evaluate if there are any exploratory associations between TLR gene polymorphisms and lung function at 5 to 7 years of age in former bronchiolitis patients.

Methods

We performed impulse oscillometry (IOS) at the median age of 6.3 years for 103 children who had been hospitalized for bronchiolitis at less than six months of age. The main parameters evaluated were airway resistance and reactance at 5Hz in baseline and post-exercise measurements. Data on single nucleotide polymorphisms (SNP) of TLR1 rs5743618, TLR2 rs5743708, TLR6 rs5743810 and TLR10 rs4129009 (TLR2 subfamily) and TLR3 rs3775291, TLR4 rs4986790, TLR7 rs179008, TLR8 rs2407992 and TLR 9 rs187084 were available for analyses.

Results

The TLR4 rs4986790 wild genotype A/A was associated with a greater Rrs5 response (0.72 vs. -0.42, p = 0.03) to exercise. In TLR6 rs5743810, the minor allele T was associated with greater Rrs5 response (0.80 vs. -0.03, p = 0.04) to exercise. In TLR7 rs179008, the major allele A was associated with baseline decline in dRrs/df (-1.03 vs 0.61, p = 0.01) and increased Fres (2.28 vs. 0.89, p = 0.01) in girls.

Conclusion

Among the nine studied TLRs, only TLR7 rs179008 showed some exploratory associations with post-bronchiolitis lung function deficiency, and polymorphisms of TLR4 rs4986790, and TLR6 rs5743810 in particular, with airway reactivity. These findings call for further confirmatory studies.  相似文献   
57.
Adult tissue maintenance is often dependent on resident stem cells; however, the phenotypic and functional heterogeneity existing within this self-renewing population is poorly understood. Here, we define distinct subsets of undifferentiated spermatogonia (spermatogonial progenitor cells; SPCs) by differential response to hyperactivation of mTORC1, a key growth-promoting pathway. We find that conditional deletion of the mTORC1 inhibitor Tsc2 throughout the SPC pool using Vasa-Cre promotes differentiation at the expense of self-renewal and leads to germline degeneration. Surprisingly, Tsc2 ablation within a subset of SPCs using Stra8-Cre did not compromise SPC function. SPC activity also appeared unaffected by Amh-Cre-mediated Tsc2 deletion within somatic cells of the niche. Importantly, we find that differentiation-prone SPCs have elevated mTORC1 activity when compared to SPCs with high self-renewal potential. Moreover, SPCs insensitive to Tsc2 deletion are preferentially associated with mTORC1-active committed progenitor fractions. We therefore delineate SPC subsets based on differential mTORC1 activity and correlated sensitivity to Tsc2 deletion. We propose that mTORC1 is a key regulator of SPC fate and defines phenotypically distinct SPC subpopulations with varying propensities for self-renewal and differentiation.  相似文献   
58.

Background  

Lately, there has been a great interest in the application of information extraction methods to the biomedical domain, in particular, to the extraction of relationships of genes, proteins, and RNA from scientific publications. The development and evaluation of such methods requires annotated domain corpora.  相似文献   
59.
The gene (vgb) encoding the hemoglobin (VHb) ofVitreoscilla sp. was cloned intoBurkholderia sp. and the effect of VHb on the growth characteristics of genetically engineeredBurkholderia (YV1) were compared with wild typeBurkholderia (R34) using continuous flow reactors (chemostat) at various dilution rates under aerobic conditions. Batch oxygen uptake rate showed that YV1 has much higher oxygen uptake rate than R34 (i.e. 0.63 mg O2/g biomass/min vs. 1.43 mg O2/g biomass/min for R34 and YV1 respectively at a dilution rate of 1.2 day−1). Monod parameters, maximum growth rate (μmax) and half saturation coefficient (Ks) were found to be 7.03 day−1 and 691 mg/L for R34 respectively, compared to 5.49 day−1 and 404 mg/L for YV1 respectively. At low dilution rates (<2.5 day−1), when the substrate is present in low concentrations, the growth yield was much higher in YV1 (0.52) than in R34 (0.37). Although substrate utilization rates were similar between R34 and YV1, the latter showed much higher oxygen uptake rate than did R34 at all dilution rates. When the stability of VHb was tested on agar plates containing 40 μg/L of kanamycin and 100 μg/L of ampicillin,vgb gene containing VHb plasmid in YV1 was stable over 82 days. When survivability under oxygen limited conditions was tested, R34 survived only for 11 days whereas YV1 survived over 25 days in liquid media; in agar plate experiments, R34 did not survive more than 40 days whereas more than 75% of YV1 survived over 110 days.  相似文献   
60.
Atherosclerosis is an inflammatory process of the arterial wall. CD73 (also known as ecto-5′-nucleotidase) is a key regulator of cell signaling in response to inflammation and hypoxia, and may be important in the development of atherosclerosis. Recently, we have shown that high CD73 activity can be detected in the serum of patients with peripheral arterial disease (PAD). Using this same PAD patient cohort of 226 subjects with 38 femoral artery samples obtained during surgical endarcterectomy and control artery samples taken during autopsy, we explored the association of serum CD73 activity with overall atherosclerotic burden and the expression of CD73 in mature and developing plaques. Interestingly, we found that CD73 activity had a tendency to increase along with more severe presentation of PAD (from 249 nmol/mL/h in moderate disease to 332 nmol/mL/h in severe disease; P = 0.013) and that CD73 expression is elevated in the vasa vasorum of developing plaques, but completely lost in mature occlusive plaques removed during endarcterectomy (P < 0.001). The current findings implicate that as a result of shedding and loss of CD73 from the arterial wall, CD73 activity is elevated in the serum of patients with widespread atherosclerosis. These findings highlight the importance of a better understanding of the local role of CD73 in the development and maturation of arterial atherosclerotic plaques in man.  相似文献   
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