The murine natural cytotoxic receptor NKp46/NCR1 controls TRAIL protein expression in NK cells and ILC1

TRAIL is an apoptosis-inducing ligand constitutively expressed on liver resident type 1 innate lymphoid cells (ILC1) and a subset of Natural Killer (NK) cells where it contributes to NK cell anti-tumor, anti-viral and immunoregulatory functions. Yet the intrinsic pathways involved in TRAIL expression in ILC remain unidentified. Here we demonstrate that the murine natural cytotoxic receptor mNKp46/NCR1, expressed on ILC1 and NK cells, controls TRAIL protein expression. Using NKp46-deficient mice, we show that liver ILC1 lack constitutive expression of TRAIL protein and that NK cells activated in vitro and in vivo fail to upregulate cell-surface TRAIL in the absence of NKp46. We show that NKp46 regulates TRAIL expression in a dose-dependent manner and that the reintroduction of NKp46 in mature NK cells deficient for NKp46 is sufficient to restore TRAIL surface expression. These studies uncover a link between NKp46 and TRAIL expression in ILC with potential implications in pathologies involving NKp46-expressing cells

The relationship between the error catastrophe, survival of the flattest, and natural selection

<p>Abstract</p> <p>Background</p> <p>The quasispecies model is a general model of evolution that is generally applicable to replication up to high mutation rates. It predicts that at a sufficiently high mutation rate, quasispecies with higher mutational robustness can displace quasispecies with higher replicative capacity, a phenomenon called "survival of the flattest". In some fitness landscapes it also predicts the existence of a maximum mutation rate, called the error threshold, beyond which the quasispecies enters into error catastrophe, losing its genetic information. The aim of this paper is to study the relationship between survival of the flattest and the transition to error catastrophe, as well as the connection between these concepts and natural selection.</p> <p>Results</p> <p>By means of a very simplified model, we show that the transition to an error catastrophe corresponds to a value of zero for the selective coefficient of the mutant phenotype with respect to the master phenotype, indicating that transition to the error catastrophe is in this case similar to the selection of a more robust species. This correspondence has been confirmed by considering a single-peak landscape in which sequences are grouped with respect to their Hamming distant from the master sequence. When the robustness of a classe is changed by modification of its quality factor, the distribution of the population changes in accordance with the new value of the robustness, although an error catastrophe can be detected at the same values as in the general case. When two quasispecies of different robustness competes with one another, the entry of one of them into error catastrophe causes displacement of the other, because of the greater robustness of the former. Previous works are explicitly reinterpreted in the light of the results obtained in this paper.</p> <p>Conclusions</p> <p>The main conclusion of this paper is that the entry into error catastrophe is a specific case of survival of the flattest acting on phenotypes that differ in the trade-off between replicative ability and mutational robustness. In fact, entry into error catastrophe occurs when the mutant phenotype acquires a selective advantage over the master phenotype. As both entry into error catastrophe and survival of the flattest are caused by natural selection when mutation rate is increased, we propose differentiating between them by the level of selection at which natural selection acts. So we propose to consider the transition to error catastrophe as a phenomenon of intra-quasispecies selection, and survival of the flattest as a phenomenon of inter-quasispecies selection.</p

Glucanocellulosic ethanol: The undiscovered biofuel potential in energy crops and marine biomass

Converting biomass to biofuels is a key strategy in substituting fossil fuels to mitigate climate change. Conventional strategies to convert lignocellulosic biomass to ethanol address the fermentation of cellulose-derived glucose. Here we used super-resolution fluorescence microscopy to uncover the nanoscale structure of cell walls in the energy crops maize and Miscanthus where the typical polymer cellulose forms an unconventional layered architecture with the atypical (1, 3)-β-glucan polymer callose. This raised the question about an unused potential of (1, 3)-β-glucan in the fermentation of lignocellulosic biomass. Engineering biomass conversion for optimized (1, 3)-β-glucan utilization, we increased the ethanol yield from both energy crops. The generation of transgenic Miscanthus lines with an elevated (1, 3)-β-glucan content further increased ethanol yield providing a new strategy in energy crop breeding. Applying the (1, 3)-β-glucan-optimized conversion method on marine biomass from brown macroalgae with a naturally high (1, 3)-β-glucan content, we not only substantially increased ethanol yield but also demonstrated an effective co-fermentation of plant and marine biomass. This opens new perspectives in combining different kinds of feedstock for sustainable and efficient biofuel production, especially in coastal regions

FIRE (facilitating implementation of research evidence) : a study protocol

Research evidence underpins best practice, but is not always used in healthcare. The Promoting Action on Research Implementation in Health Services (PARIHS) framework suggests that the nature of evidence, the context in which it is used, and whether those trying to use evidence are helped (or facilitated) affect the use of evidence. Urinary incontinence has a major effect on quality of life of older people, has a high prevalence, and is a key priority within European health and social care policy. Improving continence care has the potential to improve the quality of life for older people and reduce the costs associated with providing incontinence aids

Cytokine Plasma Levels: Reliable Predictors for Radiation Pneumonitis?

BACKGROUND: Radiotherapy (RT) is the primary treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but even with highly conformal treatment planning, radiation pneumonitis (RP) remains the most serious, dose-limiting complication. Previous clinical reports proposed that cytokine plasma levels measured during RT allow to estimate the individual risk of patients to develop RP. The identification of such cytokine risk profiles would facilitate tailoring radiotherapy to maximize treatment efficacy and to minimize radiation toxicity. However, cytokines are produced not only in normal lung tissue after irradiation, but are also over-expressed in tumour cells of NSCLC specimens. This tumour-derived cytokine production may influence circulating plasma levels in NSCLC patients. The aim of the present study was to investigate the prognostic value of TNF-alpha, IL-1beta, IL-6 and TGF-beta1 plasma levels to predict radiation pneumonitis and to evaluate the impact of tumour-derived cytokine production on circulating plasma levels in patients irradiated for NSCLC. METHODOLOGY/PRINCIPAL FINDINGS: In 52 NSCLC patients (stage I-III) cytokine plasma levels were investigated by ELISA before and weekly during RT, during follow-up (1/3/6/9 months after RT), and at the onset of RP. Tumour biopsies were immunohistochemically stained for IL-6 and TGF-beta1, and immunoreactivity was quantified (grade 1-4). RP was evaluated according to LENT-SOMA scale. Tumour response was assessed according to RECIST criteria by chest-CT during follow-up. In our clinical study 21 out of 52 patients developed RP (grade I/II/III/IV: 11/3/6/1 patients). Unexpectedly, cytokine plasma levels measured before and during RT did not correlate with RP incidence. In most patients IL-6 and TGF-beta1 plasma levels were already elevated before RT and correlated significantly with the IL-6 and TGF-beta1 production in corresponding tumour biopsies. Moreover, IL-6 and TGF-beta1 plasma levels measured during follow-up were significantly associated with the individual tumour responses of these patients. CONCLUSIONS/SIGNIFICANCE: The results of this study did not confirm that cytokine plasma levels, neither their absolute nor any relative values, may identify patients at risk for RP. In contrast, the clear correlations of IL-6 and TGF-beta1 plasma levels with the cytokine production in corresponding tumour biopsies and with the individual tumour responses suggest that the tumour is the major source of circulating cytokines in patients receiving RT for advanced NSCLC

Predicting ICU survival: A meta-level approach

<p>Abstract</p> <p>Background</p> <p>The performance of separate Intensive Care Unit (ICU) status scoring systems vis-à-vis prediction of outcome is not satisfactory. Computer-based predictive modeling techniques may yield good results but their performance has seldom been extensively compared to that of other mature or emerging predictive models. The objective of the present study was twofold: to propose a prototype meta-level predicting approach concerning Intensive Care Unit (ICU) survival and to evaluate the effectiveness of typical mining models in this context.</p> <p>Methods</p> <p>Data on 158 men and 46 women, were used retrospectively (75% of the patients survived). We used Glasgow Coma Scale (GCS), Acute Physiology And Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) and Injury Severity Score (ISS) values to structure a decision tree (DTM), a neural network (NNM) and a logistic regression (LRM) model and we evaluated the assessment indicators implementing Receiver Operating Characteristics (ROC) plot analysis.</p> <p>Results</p> <p>Our findings indicate that regarding the assessment of indicators' capacity there are specific discrete limits that should be taken into account. The Az score ± SE was 0.8773± 0.0376 for the DTM, 0.8061± 0.0427 for the NNM and 0.8204± 0.0376 for the LRM, suggesting that the proposed DTM achieved a near optimal Az score.</p> <p>Conclusion</p> <p>The predicting processes of ICU survival may go "one step forward", by using classic composite assessment indicators as variables.</p

Secluded Dark Matter Coupled to a Hidden CFT

Models of secluded dark matter offer a variant on the standard WIMP picture and can modify our expectations for hidden sector phenomenology and detection. In this work we extend a minimal model of secluded dark matter, comprised of a U(1)'-charged dark matter candidate, to include a confining hidden-sector CFT. This provides a technically natural explanation for the hierarchically small mediator-scale, with hidden-sector confinement generating m_{gamma'}>0. Furthermore, the thermal history of the universe can differ markedly from the WIMP picture due to (i) new annihilation channels, (ii) a (potentially) large number of hidden-sector degrees of freedom, and (iii) a hidden-sector phase transition at temperatures T << M_{dm} after freeze out. The mediator allows both the dark matter and the Standard Model to communicate with the CFT, thus modifying the low-energy phenomenology and cosmic-ray signals from the secluded sector.Comment: ~50p, 8 figs; v2 JHEP versio

The Acid Test of Fluoride: How pH Modulates Toxicity

Background: It is not known why the ameloblasts responsible for dental enamel formation are uniquely sensitive to fluoride ($F^−$). Herein, we present a novel theory with supporting data to show that the low pH environment of maturating stage ameloblasts enhances their sensitivity to a given dose of $F^−$. Enamel formation is initiated in a neutral pH environment (secretory stage); however, the pH can fall to below 6.0 as most of the mineral precipitates (maturation stage). Low pH can facilitate entry of $F^−$ into cells. Here, we asked if $F^−$ was more toxic at low pH, as measured by increased cell stress and decreased cell function. Methodology/Principal Findings: Treatment of ameloblast-derived LS8 cells with $F^−$ at low pH reduced the threshold dose of $F^−$ required to phosphorylate stress-related proteins, PERK, eIF2α, JNK and c-jun. To assess protein secretion, LS8 cells were stably transduced with a secreted reporter, Gaussia luciferase, and secretion was quantified as a function of $F^−$ dose and pH. Luciferase secretion significantly decreased within 2 hr of $F^−$ treatment at low pH versus neutral pH, indicating increased functional toxicity. Rats given 100 ppm $F^−$ in their drinking water exhibited increased stress-mediated phosphorylation of eIF2α in maturation stage ameloblasts (pH<6.0) as compared to secretory stage ameloblasts (pH∼7.2). Intriguingly, $F^−$-treated rats demonstrated a striking decrease in transcripts expressed during the maturation stage of enamel development (Klk4 and Amtn). In contrast, the expression of secretory stage genes, AmelX, Ambn, Enam and Mmp20, was unaffected. Conclusions: The low pH environment of maturation stage ameloblasts facilitates the uptake of $F^−$, causing increased cell stress that compromises ameloblast function, resulting in dental fluorosis

Medicine in the Popular Press: The Influence of the Media on Perceptions of Disease

In an age of increasing globalization and discussion of the possibility of global pandemics, increasing rates of reporting of these events may influence public perception of risk. The present studies investigate the impact of high levels of media reporting on the perceptions of disease. Undergraduate psychology and medical students were asked to rate the severity, future prevalence and disease status of both frequently reported diseases (e.g. avian flu) and infrequently reported diseases (e.g. yellow fever). Participants considered diseases that occur frequently in the media to be more serious, and have higher disease status than those that infrequently occur in the media, even when the low media frequency conditions were considered objectively ‘worse’ by a separate group of participants. Estimates of severity also positively correlated with popular print media frequency in both student populations. However, we also see that the concurrent presentation of objective information about the diseases can mitigate this effect. It is clear from these data that the media can bias our perceptions of disease