PAR1- and PAR2-induced innate immune markers are negatively regulated by PI3K/Akt signaling pathway in oral keratinocytes

<p>Abstract</p> <p>Background</p> <p>Protease-Activated Receptors (PARs), members of G-protein-coupled receptors, are activated by proteolytic activity of various proteases. Activation of PAR1 and PAR2 triggers innate immune responses in human oral keratinocytes (HOKs), but the signaling pathways downstream of PAR activation in HOKs have not been clearly defined. In this study, we aimed to determine if PAR1- and PAR2-mediated signaling differs in the induction of innate immune markers CXCL3, CXCL5 and CCL20 via ERK, p38 and PI3K/Akt.</p> <p>Results</p> <p>Our data show the induction of innate immunity by PAR1 requires both p38 and ERK MAP kinases, while PAR2 prominently signals via p38. However, inhibition of PI3K enhances expression of innate immune markers predominantly via suppressing p38 phosphorylation signaled by PAR activation.</p> <p>Conclusion</p> <p>Our data indicate that proteases mediating PAR1 and PAR2 activation differentially signal via MAP kinase cascades. In addition, the production of chemokines induced by PAR1 and PAR2 is suppressed by PI3K/Akt, thus keeping the innate immune responses of HOK in balance. The results of our study provide a novel insight into signaling pathways involved in PAR activation.</p

Late-stage diagnosis of HIV infection in Brazilian children: evidence from two national cohort studies

This study analyzed data from two consecutive retrospective cohort samples (1983 to 1998 and 1999 to 2002) of Brazilian children with AIDS (N = 1,758) through mother-to-child-transmission. Late-stage diagnosis (CDC category C) was investigated in relation to the following variables: year of birth, year of HIV diagnosis, and time periods related to changes in government treatment guidelines. Late-stage diagnosis occurred in 731 (41.6%) of cases and was more prevalent in infants under 12 months of age. The rate of late-stage diagnosis decreased from 48% to 36% between the two periods studied. We also observed a reduction in the proportion of late-stage diagnoses and the time lapse between HIV diagnosis and ART initiation. A significant association was found between timely diagnosis and having been born in recent years (OR = 0.62; p = 0.009) and year of HIV diagnosis (OR = 0.72; p = 0.002/OR = 0.62; p < 0.001). Infants under the age of 12 months were more likely to be diagnosed at a late stage than older children (OR = 1.70; p = 0.004). Despite advances, there is a need to improve the effectiveness of policies and programs focused on improving early diagnosis and management of HIV/AIDS

Physical Stress, Not Biotic Interactions, Preclude an Invasive Grass from Establishing in Forb-Dominated Salt Marshes

Biological invasions have become the focus of considerable concern and ecological research, yet the relative importance of abiotic and biotic factors in controlling the invasibility of habitats to exotic species is not well understood. Spartina species are highly invasive plants in coastal wetlands; however, studies on the factors that control the success or failure of Spartina invasions across multiple habitat types are rare and inconclusive.We examined the roles of physical stress and plant interactions in mediating the establishment of the smooth cordgrass, Spartina alterniflora, in a variety of coastal habitats in northern China. Field transplant experiments showed that cordgrass can invade mudflats and low estuarine marshes with low salinity and frequent flooding, but cannot survive in salt marshes and high estuarine marshes with hypersaline soils and infrequent flooding. The dominant native plant Suaeda salsa had neither competitive nor facilitative effects on cordgrass. A common garden experiment revealed that cordgrass performed significantly better when flooded every other day than when flooded weekly. These results suggest that physical stress rather than plant interactions limits cordgrass invasions in northern China.We conclude that Spartina invasions are likely to be constrained to tidal flats and low estuarine marshes in the Yellow River Delta. Due to harsh physical conditions, salt marshes and high estuarine marshes are unlikely to be invaded. These findings have implications for understanding Spartina invasions in northern China and on other coasts with similar biotic and abiotic environments

Design of the PROCON trial: a prospective, randomized multi – center study comparing cervical anterior discectomy without fusion, with fusion or with arthroplasty

BACKGROUND: PROCON was designed to assess the clinical outcome, development of adjacent disc disease and costs of cervical anterior discectomy without fusion, with fusion using a stand alone cage and implantation of a Bryan's disc prosthesis. Description of rationale and design of PROCON trial and discussion of its strengths and limitations. METHODS/DESIGN: Since proof justifying the use of implants or arthroplasty after cervical anterior discectomy is lacking, PROCON was designed. PROCON is a multicenter, randomized controlled trial comparing cervical anterior discectomy without fusion, with fusion with a stand alone cage or with implantation of a disc. The study population will be enrolled from patients with a single level cervical disc disease without myelopathic signs. Each treatment arm will need 90 patients. The patients will be followed for a minimum of five years, with visits scheduled at 6 weeks, 3 months, 12 months, and then yearly. At one year postoperatively, clinical outcome and self reported outcomes will be evaluated. At five years, the development of adjacent disc disease will be investigated. DISCUSSION: The results of this study will contribute to the discussion whether additional fusion or arthroplasty is needed and cost effective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN4168184

Diagnosing Cervical Fusion: A Comprehensive Literature Review

STUDY DESIGN: Comprehensive literature review. PURPOSE: To document the criteria for fusion utilized in these studies to determine if a consensus on the definition of a solid fusion exists. OVERVIEW OF LITERATURE: Numerous studies have reported on fusion rates following anterior cervical arthrodesis. There is a wide discrepancy in the fusion rates in these studies. While factors such as graft type, Instrumentation, and technique play a factor in fusion rate, another reason for the difference may be a result of differences in the definition of fusion following anterior cervical spine surgery. METHODS: A comprehensive English Medline literature review from 1966 to 2004 using the key words anterior, cervical, and fusion was performed. We divided these into two groups: newer studies done between 2000 and 2004, and earlier studies done between 1966 and 2000. These articles were then analyzed for the number of patients, follow-up period, graft type, and levels fused. Moreover, all of the articles were examined for their definition of fusion along with their fusion rate. RESULTS: In the earlier studies from 1966 to 2000, there was no consensus for what constituted a solid fusion. Only fifteen percent of these studies employed the most stringent definition of a solid fusion which was the presence of bridging bone and the absence of motion on flexion and extension radiographs. On the other hand, the later studies (2000 to 2004) used such a definition a majority (63%) of the time, suggesting that a consensus opinion for the definition of fusion is beginning to form. CONCLUSIONS: Our study suggests that over the past several years, a consensus definition of fusion is beginning to form. However, a large percentage of studies are still being published without using stringent fusion criteria. To that end, we recommend that all studies reporting on fusion rates use the most stringent criteria for solid fusion following anterior cervical spine surgery: the absence of motion on flexion/extension views and presence of bridging trabeculae on lateral x-rays. We believe that a universal adoption of such uniform criteria will help to standardize such studies and make it more possible to compare one study with another

Long-term outcome after anterior cervical discectomy without fusion

To retrospectively study the long-term outcome of patients after anterior cervical discectomy without fusion (ACD) compared to results published on the long-term outcome after ACD with fusion (ACDF). We reviewed the charts of all patients receiving ACD surgery between 1985 and 2000 to analyze the direct post-operative results as well as complications of the surgery. Moreover, 102 patients, randomly selected, were interviewed with the neck disability index to study possible persisting complaints up to 18 years after ACD surgery. A total of 551 Patients were identified. Two months post-operative follow up at the outpatient clinic revealed that 90.1% of patients were satisfied with the result of ACD surgery. At the time of the survey, this percentage had dropped to 67.6%. In addition, 20.6% and 11.8% had obtained moderate to severe complaints, respectively, in daily-life activities. Complaints were mainly localized in the neck region and occasionally provoked radiating pain in the arm. On the short term, ACD leads to a satisfied outcome. Over the longer term, patients report increasing complaints. The increase in complaints at the time of the survey may be the result of ongoing degenerative effects. Compared to published data on ACDF, there is no superiority of any fusion technique compared to ACD alone

The Receptor Tyrosine Kinase FGFR4 Negatively Regulates NF-kappaB Signaling

NFκB signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NFκB activation has not been previously described, although FGFs have been known to antagonize TNFα-induced apoptosis. assays. FGF19 stimulation of endogenous FGFR4 in TNFα-treated DU145 prostate cancer cells also leads to a decrease in IKKβ activity, concomitant reduction in NFκB nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNFα treatment of DU145 cells, in comparison with TNFα alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NFκB signaling.These results identify a compelling link between FGFR4 signaling and the NFκB pathway, and reveal that FGFR4 activation leads to a negative effect on NFκB signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NFκB signaling will not be limited to FGFR4 alone

Microsporidia::Why Make Nucleotides if You Can Steal Them?

Microsporidia are strict obligate intracellular parasites that infect a wide range of eukaryotes including humans and economically important fish and insects. Surviving and flourishing inside another eukaryotic cell is a very specialised lifestyle that requires evolutionary innovation. Genome sequence analyses show that microsporidia have lost most of the genes needed for making primary metabolites, such as amino acids and nucleotides, and also that they have only a limited capacity for making adenosine triphosphate (ATP). Since microsporidia cannot grow and replicate without the enormous amounts of energy and nucleotide building blocks needed for protein, DNA, and RNA biosynthesis, they must have evolved ways of stealing these substrates from the infected host cell. Providing they can do this, genome analyses suggest that microsporidia have the enzyme repertoire needed to use and regenerate the imported nucleotides efficiently. Recent functional studies suggest that a critical innovation for adapting to intracellular life was the acquisition by lateral gene transfer of nucleotide transport (NTT) proteins that are now present in multiple copies in all microsporidian genomes. These proteins are expressed on the parasite surface and allow microsporidia to steal ATP and other purine nucleotides for energy and biosynthesis from their host. However, it remains unclear how other essential metabolites, such as pyrimidine nucleotides, are acquired. Transcriptomic and experimental studies suggest that microsporidia might manipulate host cell metabolism and cell biological processes to promote nucleotide synthesis and to maximise the potential for ATP and nucleotide import. In this review, we summarise recent genomic and functional data relating to how microsporidia exploit their hosts for energy and building blocks needed for growth and nucleic acid metabolism and we identify some remaining outstanding questions

Photonic transistor and router using a single quantum-dotconfined spin in a single-sided optical microcavity

The future Internet is very likely the mixture of all-optical Internet with low power consumption and quantum Internet with absolute security guaranteed by the laws of quantum mechanics. Photons would be used for processing, routing and com-munication of data, and photonic transistor using a weak light to control a strong light is the core component as an optical analogue to the electronic transistor that forms the basis of modern electronics. In sharp contrast to previous all-optical tran-sistors which are all based on optical nonlinearities, here I introduce a novel design for a high-gain and high-speed (up to terahertz) photonic transistor and its counterpart in the quantum limit, i.e., single-photon transistor based on a linear optical effect: giant Faraday rotation induced by a single electronic spin in a single-sided optical microcavity. A single-photon or classical optical pulse as the gate sets the spin state via projective measurement and controls the polarization of a strong light to open/block the photonic channel. Due to the duality as quantum gate for quantum information processing and transistor for optical information processing, this versatile spin-cavity quantum transistor provides a solid-state platform ideal for all-optical networks and quantum networks