An Endosomal NAADP-Sensitive Two-Pore Ca(2+) Channel Regulates ER-Endosome Membrane Contact Sites to Control Growth Factor Signaling.

Membrane contact sites are regions of close apposition between organelles that facilitate information transfer. Here, we reveal an essential role for Ca(2+) derived from the endo-lysosomal system in maintaining contact between endosomes and the endoplasmic reticulum (ER). Antagonizing action of the Ca(2+)-mobilizing messenger NAADP, inhibiting its target endo-lysosomal ion channel, TPC1, and buffering local Ca(2+) fluxes all clustered and enlarged late endosomes/lysosomes. We show that TPC1 localizes to ER-endosome contact sites and is required for their formation. Reducing NAADP-dependent contacts delayed EGF receptor de-phosphorylation consistent with close apposition of endocytosed receptors with the ER-localized phosphatase PTP1B. In accord, downstream MAP kinase activation and mobilization of ER Ca(2+) stores by EGF were exaggerated upon NAADP blockade. Membrane contact sites between endosomes and the ER thus emerge as Ca(2+)-dependent hubs for signaling

Efficacy and safety of triple versus dual combination blood pressure-lowering drug therapy: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVES:Most patients with hypertension need at least two drugs to achieve goal blood pressure. This systematic review assessed efficacy and safety of triple versus dual combination therapy for the management of hypertension. METHODS:Publication databases, clinical trial registries and regulatory agency websites were searched until April 2018 for double-blind randomized controlled trials (RCTs) comparing triple with dual therapy of BP-lowering drugs, for at least 3 weeks, among patients with hypertension. Meta-analyses for efficacy and safety outcomes were performed using random-effects model. Regimen efficacy was predicted using the Therapeutic Intensity Score (TIS) and the Law et al. method (which predict dose doubling increases efficacy by 100% and around 20%, respectively), and compared with observed efficacy. RESULTS:Fourteen RCTs (11 457 participants) were included. Overall, triple compared with dual therapy reduced BP by 5.4/3.2 mmHg (P < 0.001), and improved BP control by 58 versus 45% [relative risk (RR) 1.33 (95% CI 1.25-1.41)], whereas incidence of withdrawals because of adverse events were 3.3 versus 3.4% [RR 1.24 (95% CI 1.00-1.54), P = 0.05]. Law et al.'s method was superior to TIS in predicting differences in efficacy between triple and dual therapies. For patients uncontrolled on submaximal dose dual therapy, adding a third drug achieved on average approximately four times more BP reduction than doubling the dose of dual therapy component drugs (6.0/3.6 versus 1.5/0.8 mmHg, respectively). CONCLUSION:Addition of a third drug is likely to be more efficacious without increasing adverse events, compared with increasing dose of existing dual therapy. Early use of triple therapy can significantly improve hypertension control

Elevation gradients of lemur abundance emphasise the importance of Madagascar’s lowland rainforest for the conservation of endemic taxa

1. Elevation gradients correlate with changes in several environmental conditions and are known to be related to animal abundance. Animals in regions with a naturally limited extent of lowland rainforest are expected to have evolved adaptations to intermediate elevations that provided a stable environment during their evolution. 2. Since the lowland rainforest of Madagascar has a limited extent and suffers from increasing anthropogenic pressure, it is essential to understand how well species tolerate intermediate and high elevations. In this study, we aim to quantify the relationship between lemur abundance and elevation in the eastern rainforest of Madagascar. 3. We correlated abundance data on 26 lemur species (10 genera), including 492 records from 26 studies, with elevation. We analysed the consistency of correlations across species with a meta‐analytical approach. We controlled for species’ body mass, elevational range and median elevation. We then ran generalised linear mixed models to determine whether lemur abundance was related to elevation, body mass, plant productivity and anthropogenic disturbance. 4. Overall, the abundance of lemur species in Malagasy rainforests was negatively correlated with elevation, and species occupying broader elevational ranges showed stronger correlations. Body mass was not related to species’ tolerance of high elevations. Even though several lemur species are able to occupy the entire elevation gradient, the few remaining patches of lowland rainforests host lemur species at greater abundances than other sites. Abundance across species was negatively related to body mass, elevation and seasonality in plant productivity and positively related to plant productivity. 5. Despite the ecological flexibility of many lemur species, the remnant patches of lowland rainforests host the highest levels of lemur abundance and are key to lemur conservation. It is crucial to preserve this priority habitat both for biodiversity conservation and for our understanding of lemur adaptations

A review of clustering techniques and developments

© 2017 Elsevier B.V. This paper presents a comprehensive study on clustering: exiting methods and developments made at various times. Clustering is defined as an unsupervised learning where the objects are grouped on the basis of some similarity inherent among them. There are different methods for clustering the objects such as hierarchical, partitional, grid, density based and model based. The approaches used in these methods are discussed with their respective states of art and applicability. The measures of similarity as well as the evaluation criteria, which are the central components of clustering, are also presented in the paper. The applications of clustering in some fields like image segmentation, object and character recognition and data mining are highlighted

Transcriptomic Profiling in Childhood H1N1/09 Influenza Reveals Reduced Expression of Protein Synthesis Genes

We compared the blood RNA transcriptome of children hospitalized with influenza A H1N1/09, respiratory syncytial virus (RSV) or bacterial infection, and healthy controls. Compared to controls, H1N1/09 patients showed increased expression of inflammatory pathway genes and reduced expression of adaptive immune pathway genes. This was validated on an independent cohort. The most significant function distinguishing H1N1/09 patients from controls was protein synthesis, with reduced gene expression. Reduced expression of protein synthesis genes also characterized the H1N1/09 expression profile compared to children with RSV and bacterial infection, suggesting that this is a key component of the pathophysiological response in children hospitalized with H1N1/09 infection

Examining the importance of local and global patterns for familiarity detection in soccer action sequences.

Pattern recognition is a defining characteristic of expertise across multiple domains. Given the dynamic interactions at local and global levels, team sports can provide a vehicle for investigating skilled pattern recognition. The aims of this study were to investigate whether global patterns could be recognised on the basis of localised relational information and if relations between certain display features were more important than others for successful pattern recognition. Elite (n = 20), skilled (n = 34) and less-skilled (n = 37) soccer players completed three recognition paradigms of stimuli presented in point-light format across three counterbalanced conditions: 'whole-part'; 'part-whole'; and 'whole-whole'. 'Whole' clips represented a 11 vs. 11 soccer match and 'part' clips presented the same passages of play with only two central attacking players or two peripheral players shown. Elite players recognised significantly more accurately than the skilled and less-skilled groups. Participants were significantly more accurate in the 'whole-whole' condition compared to others, and recognised stimuli featuring the two central attacking players significantly more accurately than those featuring peripheral players. Findings provide evidence that elite players can encode localised relations and then extrapolate this information to recognise more global macro patterns

Ultra-low-dose quadruple combination blood pressure lowering therapy in patients with hypertension: The QUARTET randomized controlled trial protocol.

High blood pressure is the leading cause of preventable morbidity and mortality globally. Many patients remain on single-drug treatment with poor control although guidelines recognize that most require combination therapy for blood pressure control. Our hypothesis is that a single-pill combination of four blood pressure- lowering agents each at a quarter dose may provide a simple, safe and effective blood pressure lowering solution which may also improve long term-adherence. The QUARTET (Quadruple UltrA-low-dose tReaTment for hypErTension) double-blind, active controlled, randomized clinical trial will examine whether ultra-low-dose quadruple combination therapy is more effective than guideline recommended standard care, in lowering blood pressure. QUARTET will enroll 650 participants with high blood pressure, either on no treatment or on monotherapy. Participants will be randomized 1:1 and allocated to intervention therapy of a single pill (quadpill) containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg and bisoprolol 2.5 mg or to control therapy of a single identical appearing pill containing irbesartan 150 mg. In both arms step up therapy of open-label amlodipine 5mg will be provided if BP is >140/90 at 6weeks. The primary outcome is the difference between groups in the change from baseline in mean unattended automated office systolic blood pressure at 12weeks follow-up. The primary outcome and some secondary outcomes will be assessed at 12weeks, there is an optional 12months extension phase to assess longer term efficacy and tolerability. Our secondary aims are to assess if this approach is safe, has fewer adverse effects and better tolerability compared to standard care control. QUARTET will therefore provide evidence for the effectiveness and safety of a new paradigm in the management of high blood pressure

Variation in the use of chemotherapy in lung cancer

Factors influencing the use of chemotherapy for the initial (6 months) treatment of lung cancer in South East England were investigated. The variables explored as possibly influencing the use of chemotherapy were sex, age, the year of diagnosis, the type of lung cancer, the stage, the index of multiple deprivation and the cancer network of residence. χ2 analysis and multivariate logistic regression models were used to examine the effect of each of the variables on the use of chemotherapy. The results showed a highly significant trend in use of chemotherapy over time; the adjusted proportion of patients receiving chemotherapy increasing from 13.6% in 1994 to 29.3% in 2003. However, age, cancer network and type of lung cancer had the strongest influence on the use of chemotherapy. This finding is important when we consider that the NHS Cancer Plan aims at improving inequalities in cancer care in the UK

Infall of gas as the formation mechanism of stars up to 20 times more massive than the Sun

Theory predicts and observations confirm that low-mass stars (like the Sun) in their early life grow by accreting gas from the surrounding material. But for stars ~ 10 times more massive than the Sun (~10 M_sun), the powerful stellar radiation is expected to inhibit accretion and thus limit the growth of their mass. Clearly, stars with masses >10 M_sun exist, so there must be a way for them to form. The problem may be solved by non-spherical accretion, which allows some of the stellar photons to escape along the symmetry axis where the density is lower. The recent detection of rotating disks and toroids around very young massive stars has lent support to the idea that high-mass (> 8 M_sun) stars could form in this way. Here we report observations of an ammonia line towards a high-mass star forming region. We conclude from the data that the gas is falling inwards towards a very young star of ~20 M_sun, in line with theoretical predictions of non-spherical accretion.Comment: 11 pages, 2 figure

Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer

Conceptual models of carcinogenesis typically consist of an evolutionary sequence of heritable changes in genes controlling proliferation, apoptosis, and senescence. We propose that these steps are necessary but not sufficient to produce invasive breast cancer because intraductal tumour growth is also constrained by hypoxia and acidosis that develop as cells proliferate into the lumen and away from the underlying vessels. This requires evolution of glycolytic and acid-resistant phenotypes that, we hypothesise, is critical for emergence of invasive cancer. Mathematical models demonstrate severe hypoxia and acidosis in regions of intraductal tumours more than 100 m from the basement membrane. Subsequent evolution of glycolytic and acid-resistant phenotypes leads to invasive proliferation. Multicellular spheroids recapitulating ductal carcinoma in situ (DCIS) microenvironmental conditions demonstrate upregulated glucose transporter 1 (GLUT1) as adaptation to hypoxia followed by growth into normoxic regions in qualitative agreement with model predictions. Clinical specimens of DCIS exhibit periluminal distribution of GLUT-1 and Na+/H+ exchanger (NHE) indicating transcriptional activation by hypoxia and clusters of the same phenotype in the peripheral, presumably normoxic regions similar to the pattern predicted by the models and observed in spheroids. Upregulated GLUT-1 and NHE-1 were observed in microinvasive foci and adjacent intraductal cells. Adaptation to hypoxia and acidosis may represent key events in transition from in situ to invasive cancer