Abrogation of IL-6-mediated JAK signalling by the cyclopentenone prostaglandin 15d-PGJ2 in oral squamous carcinoma cells

Cyclopentenone 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) exerts antineoplastic effects on various types of human cancer. We recently showed that treatment with 15d-PGJ2 induces apoptosis accompanied by downregulation of the oncogenic signal transducer and activator of transcription 3 (Stat3) signalling in human oral squamous cell carcinoma (SCC) cells. The current study examines the effects of 15d-PGJ2 on the epidermal growth factor receptor (EGFR) and Janus Kinase (JAK)-mediated signalling pathways. Inhibition of Stat3 by 15d-PGJ2 was abolished by exogenous stimulation with transforming growth factor alpha (TGF-α), but not interleukin 6 (IL-6), supporting a selective effect of 15d-PGJ2 on IL-6-mediated signalling. Importantly, 15d-PGJ2 selectively abrogated constitutive and IL-6-mediated JAK phosphorylation without affecting EGFR-activated levels. Moreover, the inhibitory effect of 15d-PGJ2 on JAK signalling required the reactive α,β-unsaturated carbon within the cyclopentenone ring. Targeting of JAK signalling using a specific JAK inhibitor also abolished Stat3 phosphorylation and resulted in apoptosis in oral SCC cells. Our findings provide the first evidence for 15d-PGJ2–mediated downregulation of constitutive and IL-6-induced JAK signalling in cancer and support that JAK inhibition and suppression of EGFR-independent Stat3 activation by 15d-PGJ2 represent a promising approach for induction of apoptosis in oral SCC cells

A super-Earth transiting a nearby low-mass star

A decade ago, the detection of the first transiting extrasolar planet provided a direct constraint on its composition and opened the door to spectroscopic investigations of extrasolar planetary atmospheres. As such characterization studies are feasible only for transiting systems that are both nearby and for which the planet-to-star radius ratio is relatively large, nearby small stars have been surveyed intensively. Doppler studies and microlensing have uncovered a population of planets with minimum masses of 1.9-10 times the Earth's mass (M_Earth), called super-Earths. The first constraint on the bulk composition of this novel class of planets was afforded by CoRoT-7b, but the distance and size of its star preclude atmospheric studies in the foreseeable future. Here we report observations of the transiting planet GJ 1214b, which has a mass of 6.55 M_Earth and a radius 2.68 times Earth's radius (R_Earth), indicating that it is intermediate in stature between Earth and the ice giants of the Solar System. We find that the planetary mass and radius are consistent with a composition of primarily water enshrouded by a hydrogen-helium envelope that is only 0.05% of the mass of the planet. The atmosphere is probably escaping hydrodynamically, indicating that it has undergone significant evolution during its history. As the star is small and only 13 parsecs away, the planetary atmosphere is amenable to study with current observatories.Comment: 13 pages, 3 figures, published in Natur

Bio-psychosocial determinants of time lost from work following non life threatening acute orthopaedic trauma

<p>Abstract</p> <p>Background</p> <p>To determine factors predicting the duration of time away from work following acute orthopaedic non life threatening trauma</p> <p>Methods</p> <p>Prospective cohort study conducted at four hospitals in Victoria, Australia. The cohort comprised 168 patients aged 18-64 years who were working prior to the injury and sustained a range of acute unintentional orthopaedic injuries resulting in hospitalization. Baseline data was obtained by survey and medical record review. Multivariate Cox proportional hazards regression analysis was used to examine the association between potential predictors and the duration of time away from work during the six month study. The study achieved 89% follow-up.</p> <p>Results</p> <p>Of the 168 participants recruited to the study, 68% returned to work during the six month study. Multivariate Cox proportional hazards regression analysis identified that blue collar work, negative pain attitudes with respect to work, high initial pain intensity, injury severity, older age, initial need for surgery, the presence of co-morbid health conditions at study entry and an orthopaedic injury to more than one region were associated with extended duration away from work following the injury. Participants in receipt of compensation who reported high social functioning at two weeks were 2.58 times more likely to have returned to work than similar participants reporting low social functioning. When only those who had returned to work were considered, the participant reported reason for return to work " to fill the day" was a significant predictor of earlier RTW [RR 2.41 (95% C.I 1.35-4.30)] whereas "financial security" and "because they felt able to" did not achieve significance.</p> <p>Conclusions</p> <p>Many injury-related and psycho social factors affect the duration of time away from work following orthopaedic injury. Some of these are potentially modifiable and may be amenable to intervention. Further consideration of the reasons provided by participants for returning to work may provide important opportunities for social marketing approaches designed to alleviate the financial and social burden associated with work disability.</p

One step closer to understanding the role of bacteria in diabetic foot ulcers: characterising the microbiome of ulcers

Background: The aim of this study was to characterise the microbiome of new and recurrent diabetic foot ulcers using 16S amplicon sequencing (16S AS), allowing the identification of a wider range of bacterial species that may be important in the development of chronicity in these debilitating wounds. Twenty patients not receiving antibiotics for the past three months were selected, with swabs taken from each individual for culture and 16S AS. DNA was isolated using a combination of bead beating and kit extraction. Samples were sequenced on the Illumina Hiseq 2500 platform. Results: Conventional laboratory culture showed positive growth from only 55 % of the patients, whereas 16S AS was positive for 75 % of the patients (41 unique genera, representing 82 different operational taxonomic units (OTU’s). S. aureus was isolated in 72 % of culture-positive samples, whereas the most commonly detected bacteria in all ulcers were Peptoniphilusspp., Anaerococcus spp. and Corynebacterium spp., with the addition of Staphylococcus spp. in new ulcers. The majority of OTU’s residing in both new and recurrent ulcers (over 67 %) were identified as facultative or strict anaerobic Gram-positive organisms. Principal component analysis (PCA) showed no difference in clustering between the two groups (new and recurrent ulcers). Conclusions: The abundance of anaerobic bacteria has important implications for treatment as it suggests that the microbiome of each ulcer “starts afresh” and that, although diverse, are not distinctly different from one another with respect to new or recurrent ulcers. Therefore, when considering antibiotic therapy the duration of current ulceration may be a more important consideration than a history of healed ulcer

Fungal Endophyte Diversity in Sarracenia

Fungal endophytes were isolated from 4 species of the carnivorous pitcher plant genus Sarracenia: S. minor, S. oreophila, S. purpurea, and S. psittacina. Twelve taxa of fungi, 8 within the Ascomycota and 4 within the Basidiomycota, were identified based on PCR amplification and sequencing of the internal transcribed spacer sequences of nuclear ribosomal DNA (ITS rDNA) with taxonomic identity assigned using the NCBI nucleotide megablast search tool. Endophytes are known to produce a large number of metabolites, some of which may contribute to the protection and survival of the host. We speculate that endophyte-infected Sarracenia may benefit from their fungal associates by their influence on nutrient availability from within pitchers and, possibly, by directly influencing the biota within pitchers

Mycobacteria counteract a TLR-mediated nitrosative defense mechanism in a zebrafish infection model.

Pulmonary tuberculosis (TB), caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb), is a major world health problem. The production of reactive nitrogen species (RNS) is a potent cytostatic and cytotoxic defense mechanism against intracellular pathogens. Nevertheless, the protective role of RNS during Mtb infection remains controversial. Here we use an anti-nitrotyrosine antibody as a readout to study nitration output by the zebrafish host during early mycobacterial pathogenesis. We found that recognition of Mycobacterium marinum, a close relative of Mtb, was sufficient to induce a nitrosative defense mechanism in a manner dependent on MyD88, the central adaptor protein in Toll like receptor (TLR) mediated pathogen recognition. However, this host response was attenuated by mycobacteria via a virulence mechanism independent of the well-characterized RD1 virulence locus. Our results indicate a mechanism of pathogenic mycobacteria to circumvent host defense in vivo. Shifting the balance of host-pathogen interactions in favor of the host by targeting this virulence mechanism may help to alleviate the problem of infection with Mtb strains that are resistant to multiple drug treatments

Sin Nombre Virus and Rodent Species Diversity: A Test of the Dilution and Amplification Hypotheses

BACKGROUND:Species diversity is proposed to greatly impact the prevalence of pathogens. Two predominant hypotheses, the "Dilution Effect" and the "Amplification Effect", predict divergent outcomes with respect to the impact of species diversity. The Dilution Effect predicts that pathogen prevalence will be negatively correlated with increased species diversity, while the Amplification Effect predicts that pathogen prevalence will be positively correlated with diversity. For many host-pathogen systems, the relationship between diversity and pathogen prevalence has not be empirically examined. METHODOLOGY/PRINCIPAL FINDINGS:We tested the Dilution and Amplification Effect hypotheses by examining the prevalence of Sin Nombre virus (SNV) with respect to diversity of the nocturnal rodent community. SNV is directly transmitted primarily between deer mice (Peromyscus maniculatus). Using mark-recapture sampling in the Spring and Fall of 2003-2005, we measured SNV prevalence in deer mice at 16 landscape level sites (3.1 hectares each) that varied in rodent species diversity. We explored several mechanisms by which species diversity may affect SNV prevalence, including reduced host density, reduced host persistence, the presence of secondary reservoirs and community composition. We found a negative relationship between species diversity and SNV prevalence in deer mice, thereby supporting the Dilution Effect hypothesis. Deer mouse density and persistence were lower at sites with greater species diversity; however, only deer mouse persistence was positively correlated with SNV prevalence. Pinyon mice (P. truei) may serve as dilution agents, having a negative effect on prevalence, while kangaroo rats (Dipodomys ordii), may have a positive effect on the prevalence of SNV, perhaps through effects on deer mouse behavior. CONCLUSIONS/SIGNIFICANCE:While previous studies on host-pathogen systems have found patterns of diversity consistent with either the Dilution or Amplification Effects, the mechanisms by which species diversity influences prevalence have not been investigated. Our study indicates that changes in host persistence, coupled with interspecific interactions, are important mechanisms through which diversity may influence patterns of pathogens. Our results reveal the complexity of rodent community interactions with respect to SNV dynamics

M-CSF Signals through the MAPK/ERK Pathway via Sp1 to Induce VEGF Production and Induces Angiogenesis In Vivo

BACKGROUND: M-CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors. VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel formation. Previously, we reported that in vitro M-CSF induces the expression of biologically-active VEGF from human monocytes. METHODOLOGY AND RESULTS: In this study, we demonstrate the molecular mechanism of M-CSF-induced VEGF production. Using a construct containing the VEGF promoter linked to a luciferase reporter, we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M-CSF stimulation. Further analysis revealed that M-CSF induced VEGF through the MAPK/ERK signaling pathway via the transcription factor, Sp1. Thus, inhibition of either ERK or Sp1 suppressed M-CSF-induced VEGF at the mRNA and protein level. M-CSF also induced the nuclear localization of Sp1, which was blocked by ERK inhibition. Finally, mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M-CSF-treated human monocytes. To evaluate the biological significance of M-CSF induced VEGF production, we used an in vivo angiogenesis model to illustrate the ability of M-CSF to recruit mononuclear phagocytes, increase VEGF levels, and enhance angiogenesis. Importantly, the addition of a neutralizing VEGF antibody abolished M-CSF-induced blood vessel formation. CONCLUSION: These data delineate an ERK- and Sp1-dependent mechanism of M-CSF induced VEGF production and demonstrate for the first time the ability of M-CSF to induce angiogenesis via VEGF in vivo

Estimation of target strength of Sardina pilchardus and Sardinella aurita by theoretical approach

The target strength (TS) patterns of Sardina pilchardus and Sardinella aurita at 38 and 120 kHz were estimated by a prolate-spheroid model, using measurements of swimbladder length and width. The ratio of swimbladder length to total length (TL) was similar in both species, however the ratio of swimbladder width to TL was smaller and more variable for S. aurita. Assuming a normal distribution of fish swimming orientation angle (θfish) with mean ± standard deviation (SD) of 0 ± 10°, the normalized (by TL) average TS (b20) was estimated to be -64.0 dB (38 kHz) and -65.2 dB (120 kHz) for S. pilchardus, and -66.2 dB (38 kHz) and -67.2 dB (120 kHz) for S. aurita. Compared with currently applied b20 values at 38 kHz, our results under four different θfish assumptions (0 ± 10°, 0 ± 15°, -5 ± 10°, and -5 ± 15°) were 6-9 dB higher for S. pilchardus and 5-7 dB higher for S. aurita. This suggests four- to eightfold overestimation risk for S. pilchardus and three- to fivefold overestimation risk for S. aurita when using the currently applied b20 values