Radial dyssynchrony assessed by cardiovascular magnetic resonance in relation to left ventricular function, myocardial scarring and QRS duration in patients with heart failure

Radial dyssynchrony is almost universal in patients with heart failure. This vies against the notion that a lack of response to CRT is related to a lack of dyssynchrony

Studying kinetochore kinases

Mitotic kinetochores are signaling network hubs that regulate chromosome movements, attachment error-correction, and the spindle assembly checkpoint. Key switches in these networks are kinases and phosphatases that enable rapid responses to changing conditions. Describing the mechanisms and dynamics of their localized activation and deactivation is therefore instrumental for understanding the spatiotemporal control of chromosome segregation

Spatial heterogeneity and peptide availability determine CTL killing efficiency in vivo

The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. However the spleen is a heterogeneous environment and splenocytes comprise multiple cell types. Are some cell types intrinsically more susceptible to lysis than others? Quantitatively, what impacts are made by the spatial distribution of targets and effectors, and the level of peptide-MHC on the target cell surface? To address these questions we revisited the splenocyte killing assay, using CTL specific for an epitope of influenza virus. We found that at the cell population level T cell targets were killed more rapidly than B cells. Using modeling, quantitative imaging and in vitro killing assays we conclude that this difference in vivo likely reflects different migratory patterns of targets within the spleen and a heterogeneous distribution of CTL, with no detectable difference in the intrinsic susceptibilities of the two populations to lysis. Modeling of the stages involved in the detection and killing of peptide-pulsed targets in vitro revealed that peptide dose influenced the ability of CTL to form conjugates with targets but had no detectable effect on the probability that conjugation resulted in lysis, and that T cell targets took longer to lyse than B cells. We also infer that incomplete killing in vivo of cells pulsed with low doses of peptide may be due to a combination of heterogeneity in peptide uptake and the dissociation, but not internalisation, of peptide-MHC complexes. Our analyses demonstrate how population-averaged parameters in models of immune responses can be dissected to account for both spatial and cellular heterogeneity

Environmental Factors in the Relapse and Recurrence of Inflammatory Bowel Disease:A Review of the Literature

The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability

Prolonged mitotic arrest induces a caspase-dependent DNA damage response at telomeres that determines cell survival

A delay in the completion of metaphase induces a stress response that inhibits further cell proliferation or induces apoptosis. This response is thought to protect against genomic instability and is important for the effects of anti-mitotic cancer drugs. Here, we show that mitotic arrest induces a caspase-dependent DNA damage response (DDR) at telomeres in non-apoptotic cells. This pathway is under the control of Mcl-1 and other Bcl-2 family proteins and requires caspase-9, caspase-3/7 and the endonuclease CAD/DFF40. The gradual caspase-dependent loss of the shelterin complex protein TRF2 from telomeres promotes a DDR that involves DNA-dependent protein kinase (DNA-PK). Suppression of mitotic telomere damage by enhanced expression of TRF2, or the inhibition of either caspase-3/7 or DNA-PK during mitotic arrest, promotes subsequent cell survival. Thus, we demonstrate that mitotic stress is characterised by the sub-apoptotic activation of a classical caspase pathway, which promotes telomere deprotection, activates DNA damage signalling, and determines cell fate in response to a prolonged delay in mitosis

Growing evidence that SNe Iax are not a one-parameter family The case of PS1-12bwh

In this study, we present observations of a type Iax supernova, PS1-12bwh, discovered during the Pan-STARRS1 3 pi-survey. Our analysis was driven by previously unseen pre-maximum, spectroscopic heterogeneity. While the light curve and post-maximum spectra of PS1-12bwh are virtually identical to those of the well-studied type Iax supernova, SN 2005hk, the -2 day spectrum of PS1-12bwh does not resemble SN 2005hk at a comparable epoch; instead, we found it to match a spectrum of SN 2005hk taken over a week earlier (12 day). We are able to rule out the cause as being incorrect phasing, and argue that it is not consistent with orientation effects predicted by existing explosion simulations. To investigate the potential source of this difference, we performed radiative transfer modelling of both supernovae. We found that the pre-maximum spectrum of PS1-12bwh is well matched by a synthetic spectrum generated from a model with a lower density in the high velocity (greater than or similar to 6000 km s(-1)) ejecta than SN 2005hk. The observed differences between SN 2005hk and PS1-12bwh may therefore be attributed primarily to differences in the high velocity ejecta alone, while comparable densities for the lower velocity ejecta would explain the nearly identical post-maximum spectra. These two supernovae further highlight the diversity within the SNe Iax class, as well as the challenges in spectroscopically identifying and phasing these objects, especially at early epochs

Impacts of large-scale climatic disturbances on the terrestrial carbon cycle

BACKGROUND: The amount of carbon dioxide in the atmosphere steadily increases as a consequence of anthropogenic emissions but with large interannual variability caused by the terrestrial biosphere. These variations in the CO(2 )growth rate are caused by large-scale climate anomalies but the relative contributions of vegetation growth and soil decomposition is uncertain. We use a biogeochemical model of the terrestrial biosphere to differentiate the effects of temperature and precipitation on net primary production (NPP) and heterotrophic respiration (Rh) during the two largest anomalies in atmospheric CO(2 )increase during the last 25 years. One of these, the smallest atmospheric year-to-year increase (largest land carbon uptake) in that period, was caused by global cooling in 1992/93 after the Pinatubo volcanic eruption. The other, the largest atmospheric increase on record (largest land carbon release), was caused by the strong El Niño event of 1997/98. RESULTS: We find that the LPJ model correctly simulates the magnitude of terrestrial modulation of atmospheric carbon anomalies for these two extreme disturbances. The response of soil respiration to changes in temperature and precipitation explains most of the modelled anomalous CO(2 )flux. CONCLUSION: Observed and modelled NEE anomalies are in good agreement, therefore we suggest that the temporal variability of heterotrophic respiration produced by our model is reasonably realistic. We therefore conclude that during the last 25 years the two largest disturbances of the global carbon cycle were strongly controlled by soil processes rather then the response of vegetation to these large-scale climatic events

The environmental impact of fertilizer embodied in a wheat-to-bread supply chain

Food production and consumption cause approximately one-third of total greenhouse gas emissions, and therefore delivering food security challenges not only the capacity of our agricultural system, but also its environmental sustainability. Knowing where and at what level environmental impacts occur within particular food supply chains is necessary if farmers, agri-food industries and consumers are to share responsibility to mitigate these impacts. Here we present an analysis of a complete supply chain for a staple of the global diet, a loaf of bread. We obtained primary data for all the processes involved in the farming, production and transport systems that lead to the manufacture of a particular brand of 800 g loaf. The data were analysed using an advanced life cycle assessment (LCA) tool, yielding metrics of environmental impact, including greenhouse gas emissions. We show that more than half of the environmental impact of producing the loaf of bread arises directly from wheat cultivation, with the use of ammonium nitrate fertilizer alone accounting for around 40%. These findings reveal the dependency of bread production on the unsustainable use of fertilizer and illustrate the detail needed if the actors in the supply chain are to assume shared responsibility for achieving sustainable food production