Gap junctions and connexin hemichannels in the regulation of haemostasis and thrombosis

Platelets are involved in the maintenance of haemostasis but their inappropriate activation leads to thrombosis, a principal trigger for heart attack and ischemic stroke. Although platelets circulate in isolation, upon activation they accumulate or aggregate together to form a thrombus, where they function in a coordinated manner to prevent loss of blood and control wound repair. Recent reports indicate that the stability and functions of a thrombus are maintained through sustained, contact dependent signalling between platelets. Given the role of gap junctions in the coordination of tissue responses, it was hypothesized that gap junctions may be present within a thrombus and mediate intercellular communication between platelets. Therefore studies were performed to explore the presence and functions of connexins in platelets. In this brief review, the roles of hemichannels and gap junctions in the control of thrombosis and haemostasis and the future directions for this research will be discussed.

Dyspnea-related cues engage the prefrontal cortex - evidence from functional brain imaging in COPD

Dyspnea is the major source of disability in chronic obstructive pulmonary disease (COPD). In COPD, environmental cues (e.g. the prospect of having to climb stairs) become associated with dyspnea, and may trigger dyspnea even before physical activity commences. We hypothesised that brain activation relating to such cues would be different between COPD patients and healthy controls, reflecting greater engagement of emotional mechanisms in patients. Methods: Using FMRI, we investigated brain responses to dyspnea-related word cues in 41 COPD patients and 40 healthy age-matched controls. We combined these findings with scores of self-report questionnaires thus linking the FMRI task with clinically relevant measures. This approach was adapted from studies in pain that enables identification of brain networks responsible for pain processing despite absence of a physical challenge. Results: COPD patients demonstrate activation in the medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC) which correlated with the visual analogue scale (VAS) response to word cues. This activity independently correlated with patient-reported questionnaires of depression, fatigue and dyspnea vigilance. Activation in the anterior insula, lateral prefrontal cortex (lPFC) and precuneus correlated with the VAS dyspnea scale but not the questionnaires. Conclusions: Our findings suggest that engagement of the brain's emotional circuitry is important for interpretation of dyspnea-related cues in COPD, and is influenced by depression, fatigue, and vigilance. A heightened response to salient cues is associated with increased symptom perception in chronic pain and asthma, and our findings suggest such mechanisms may be relevant in COPD.

Interacting controls on innate sources of CO2 efflux from a calcareous arid zone soil under experimental acidification and wetting

More than half of global soil carbon is stored as carbonates, primarily in arid and semi-arid zones. Climate change models predict more frequent and severe rainfall events in some parts of the globe, many of which are dominated by calcareous soils. Such events trigger substantial increases in soil CO2 efflux. We hypothesised that the primary source of CO2 emissions from calcareous, arid zone soil during a single wetting event is abiotic and that soil acidification and wetting have a positive, potentially interacting, effect. We manipulated soil pH, soil moisture, and controlled soil respiration by gamma irradiating half of an 11 day incubation experiment. All manipulated experimental treatments had a rapid and enormous effect on CO2 emission. Respiration contributed ca. 5% of total CO2 efflux; the major source (carbonate buffering) varied depending on the extent of acidification and wetting. Maximum CO2 efflux occurred when pH was lowest and at intermediate matric potential. CO2 efflux was lowest at native pH when soil was air dry. Our data suggest that there may be an underestimate of soil-atmosphere carbon fluxes in arid ecosystems with calcareous soils. There is also a clear potential that these soils may become net carbon sources depending on changes in rainfall patterns, rainfall acidity, and future land management. Our findings have major implications for carbon cycling in arid zone soil and further study of carbon dynamics in these terrestrial systems at a landscape level will be required if we are to improve global climate and carbon cycling models.

Microbial Recognition Via Toll-Like Receptor-Dependent and -Independent Pathways Determines the Cytokine Response of Murine Dendritic Cell Subsets to CD40 Triggering

Dendritic cells (DC) can produce Th-polarizing cytokines and direct the class of the adaptive immune response. Microbial stimuli, cytokines, chemokines, and T cell-derived signals all have been shown to trigger cytokine synthesis by DC, but it remains unclear whether these signals are functionally equivalent and whether they determine the nature of the cytokine produced or simply initiate a preprogrammed pattern of cytokine production, which may be DC subtype specific. Here, we demonstrate that microbial and T cell-derived stimuli can synergize to induce production of high levels of IL-12 p70 or IL-10 by individual murine DC subsets but that the choice of cytokine is dictated by the microbial pattern recognition receptor engaged. We show that bacterial components such as CpG-containing DNA or extracts from Mycobacterium tuberculosis predispose CD8alpha(+) and CD8alpha(-)CD4(-) DC to make IL-12 p70. In contrast, exposure of CD8alpha(+), CD4(+) and CD8alpha(-)CD4(-) DC to heat-killed yeasts leads to production of IL-10. In both cases, secretion of high levels of cytokine requires a second signal from T cells, which can be replaced by CD40 ligand. Consistent with their differential effects on cytokine production, extracts from M. tuberculosis promote IL-12 production primarily via Toll-like receptor 2 and an MyD88-dependent pathway, whereas heat-killed yeasts activate DC via a Toll-like receptor 2-, MyD88-, and Toll/IL-1R domain containing protein-independent pathway. These results show that T cell feedback amplifies innate signals for cytokine production by DC and suggest that pattern recognition rather than ontogeny determines the production of cytokines by individual DC subsets.

Change escalation processes and complex adaptive systems: from incremental reconfigurations to discontinuous restructuring

This study examines when “incremental” change is likely to trigger “discontinuous” change, using the lens of complex adaptive systems theory. Going beyond the simulations and case studies through which complex adaptive systems have been approached so far, we study the relationship between incremental organizational reconfigurations and discontinuous organizational restructurings using a large-scale database of U.S. Fortune 50 industrial corporations. We develop two types of escalation process in organizations: accumulation and perturbation. Under ordinary conditions, it is perturbation rather than the accumulation that is more likely to trigger subsequent discontinuous change. Consistent with complex adaptive systems theory, organizations are more sensitive to both accumulation and perturbation in conditions of heightened disequilibrium. Contrary to expectations, highly interconnected organizations are not more liable to discontinuous change. We conclude with implications for further research, especially the need to attend to the potential role of managerial design and coping when transferring complex adaptive systems theory from natural systems to organizational systems.

Sea-breeze dynamics and convection initiation: the influence of convective parameterization in weather and climate model biases

There are some long-established biases in atmospheric models that originate from the representation of tropical convection. Previously, it has been difficult to separate cause and effect because errors are often the result of a number of interacting biases. Recently, researchers have gained the ability to run multiyear global climate model simulations with grid spacings small enough to switch the convective parameterization off, which permits the convection to develop explicitly. There are clear improvements to the initiation of convective storms and the diurnal cycle of rainfall in the convection-permitting simulations, which enables a new process-study approach to model bias identification. In this study, multiyear global atmosphere-only climate simulations with and without convective parameterization are undertaken with the Met Office Unified Model and are analyzed over the Maritime Continent region, where convergence from sea-breeze circulations is key for convection initiation. The analysis shows that, although the simulation with parameterized convection is able to reproduce the key rain-forming sea-breeze circulation, the parameterization is not able to respond realistically to the circulation. A feedback of errors also occurs: the convective parameterization causes rain to fall in the early morning, which cools and wets the boundary layer, reducing the land–sea temperature contrast and weakening the sea breeze. This is, however, an effect of the convective bias, rather than a cause of it. Improvements to how and when convection schemes trigger convection will improve both the timing and location of tropical rainfall and representation of sea-breeze circulations.

Regulation of early steps of GPVI signal transduction by phosphatases: a systems biology approach

We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation.

Self-immolative base-mediated conjugate release from triazolylmethylcarbamates

A range of carbamate functionalized 1,4-disubstituted triazoles featuring a base sensitive trigger residue, plus a model aromatic amine reporter group, were prepared via copper(I) catalysed azide–alkyne cycloaddition and evaluated for their self-immolative characteristics. This study revealed a clear structure–reactivity relationship, via Hammett analysis, between the structure of the 1,4-disubstituted triazole and the rate of self-immolative release of the amine reporter group, thus demonstrating that under basic conditions this type of triazole derivative has the potential to be employed in a range of chemical release systems.

Sibling influence on the human capital of the left-behind

While a growing literature has analyzed the effects of parental migration on the educational outcomes of children left behind, this study is the first to highlight the importance of sibling interactions in such a context. Using panel data from the RUMiC Survey, we find that sibling influence on school performance is stronger among left- behind children. Hence, parental migration seems to trigger changes in familial roles and sibling effects among children. However, it is primarily older sisters who exhibit a positive influence on their younger siblings. We corroborate our results by performing a series of tests to mitigate endogeneity issues. The results from the analysis suggest that sibling effects in migrant households might be a mechanism shaping children’s outcomes and success and that adjustments within the family left behind have the potential to generate benefits – or reduce hardships – in response to parental migration.

Natural disasters, economic growth and sustainable development in China: an empirical study using provincial panel data

Using a newly developed integrated indicator system with entropy weighting, we analyzed the panel data of 577 recorded disasters in 30 provinces of China from 1985–2011 to identify their links with the subsequent economic growth. Meteorological disasters promote economic growth through human capital instead of physical capital. Geological disasters did not trigger local economic growth from 1999–2011. Generally, natural disasters overall had no significant impact on economic growth from 1985–1998. Thus, human capital reinvestment should be the aim in managing recoveries, and it should be used to regenerate the local economy based on long-term sustainable development.

Advancements in decadal climate predictability: the role of nonoceanic drivers

We review recent progress in understanding the role of sea ice, land surface, stratosphere, and aerosols in decadal-scale predictability and discuss the perspectives for improving the predictive capabilities of current Earth system models (ESMs). These constituents have received relatively little attention because their contribution to the slow climatic manifold is controversial in comparison to that of the large heat capacity of the oceans. Furthermore, their initialization as well as their representation in state-of-the-art climate models remains a challenge. Numerous extraoceanic processes that could be active over the decadal range are proposed. Potential predictability associated with the aforementioned, poorly represented, and scarcely observed constituents of the climate system has been primarily inspected through numerical simulations performed under idealized experimental settings. The impact, however, on practical decadal predictions, conducted with realistically initialized full-fledged climate models, is still largely unexploited. Enhancing initial-value predictability through an improved model initialization appears to be a viable option for land surface, sea ice, and, marginally, the stratosphere. Similarly, capturing future aerosol emission storylines might lead to an improved representation of both global and regional short-term climatic changes. In addition to these factors, a key role on the overall predictive ability of ESMs is expected to be played by an accurate representation of processes associated with specific components of the climate system. These act as “signal carriers,” transferring across the climatic phase space the information associated with the initial state and boundary forcings, and dynamically bridging different (otherwise unconnected) subsystems. Through this mechanism, Earth system components trigger low-frequency variability modes, thus extending the predictability beyond the seasonal scale.

El Niño 2015/2016 impact analysis, monthly outlook November 2015

During the summer and autumn 2015, El Niño conditions in the east and central Pacific have strengthened, disrupting weather patterns throughout the tropics and into the mid-latitudes. For example, rainfall during this summer’s Indian monsoon was approximately 15% below normal. The continued strong El Niño conditions have the potential to trigger damaging impacts (e.g., droughts, famines, floods), particularly in less-developed tropical countries, which would require a swift and effective humanitarian response to mitigate damage to life and property (e.g., health, migration, infrastructure). This analysis uses key climatic variables (temperature, soil moisture and precipitation) as measures to monitor the ongoing risk of these potentially damaging impacts. The previous 2015-2016 El Niño Impact Analysis was based on observations over the past 35 years and produced Impact Tables showing the likelihood and severity of the impacts on temperature and rainfall by season. The current report is an extension of this work providing information from seasonal forecast models to give a more detailed monthly outlook of the potential near-term impacts of the current El Niño conditions by region. This information has been added to the Impact Tables in the form of a monthly outlook column. This monthly outlook is an indication of the average likely conditions for that month and region and is not a definite prediction of weather impacts.

El Niño 2015/2016 impact analysis, monthly outlook December 2015

During the summer and autumn 2015, El Niño conditions in the east and central Pacific have strengthened, disrupting weather patterns throughout the tropics and into the mid-latitudes. For example, rainfall during this summer’s Indian monsoon was approximately 15% below normal. The continued strong El Niño conditions have the potential to trigger damaging impacts (e.g. droughts, famines, floods), particularly in less-developed tropical countries, which would require a swift and effective humanitarian response to mitigate damage to life and property (e.g. health, migration, infrastructure). This analysis uses key climatic variables (temperature, soil moisture and precipitation) as measures to monitor the ongoing risk of these potentially damaging impacts. The previous 2015-2016 El Niño Impact Analysis was based on observations over the past 35 years and produced Impact Tables showing the likelihood and severity of the impacts on temperature and rainfall by season. The current report is an extension of this work providing information from observations and seasonal forecast models to give a more detailed outlook of the potential near-term impacts of the current El Niño conditions by region. This information has been added to the Impact Tables in the form of an ‘Observations and Outlook’ row. This consists of observational information for the past seasons of JJA 2015 and SON 2015, a detailed monthly outlook from 5 modeling centres for Dec 2015 and then longer-term seasonal forecast information from 2 modeling centres for the future seasons of JF 2016 and MAM 2016. The seasonal outlook information is an indication of the average likely conditions for that coming month (or season) and region and is not a definite prediction of weather impacts.

El Niño 2015/2016 impact analysis, monthly outlook January 2016

During the summer and autumn of 2015, El Niño conditions in the east and central Pacific have strengthened, disrupting weather patterns throughout the tropics and into the mid-latitudes. For example, rainfall during this summer’s Indian monsoon was approximately 15% below normal. The continued strong El Niño conditions have the potential to trigger damaging impacts (e.g., droughts, famines, floods), particularly in less-developed tropical countries, which would require a swift and effective humanitarian response to mitigate damage to life and property (e.g., health, migration, infrastructure). This analysis uses key climatic variables (temperature, soil moisture and precipitation) as measures to monitor the ongoing risk of these potentially damaging impacts. The previous 2015-2016 El Niño Impact Analysis was based on observations over the past 35 years and produced Impact Tables showing the likelihood and severity of the impacts on temperature and rainfall by season. The current report is an extension of this work providing information from observations and seasonal forecast models to give a more detailed outlook of the potential near-term impacts of the current El Niño conditions by region. This information has been added to the Impact Tables in the form of an ‘Observations and Outlook’ row. This consists of observational information for the past seasons of JJA 2015, SON 2015 and Dec 2015, a detailed monthly outlook from 4 modeling centres for Jan 2016 and then longer-term seasonal forecast information from 2 modeling centres for the future seasons of Feb 2016, MAM 2016 and Jun 2016. The seasonal outlook information is an indication of the average likely conditions for that coming month (or season) and region and is not a definite prediction of weather impacts.

El Niño 2015/2016 impact analysis, monthly outlook February 2016

During the summer and autumn of 2015, El Niño conditions in the east and central Pacific strengthened, disrupting weather patterns throughout the tropics and into the mid-latitudes. For example, rainfall during the summer’s Indian monsoon was approximately 15% below normal. The continued strong El Niño conditions have the potential to trigger damaging impacts (e.g., droughts, famines, floods), particularly in less-developed tropical countries, which would require a swift and effective humanitarian response to mitigate damage to life and property (e.g., health, migration, infrastructure). This analysis uses key climatic variables (temperature, soil moisture and precipitation) as measures to monitor the ongoing risk of these potentially damaging impacts. The previous 2015-2016 El Niño Impact Analysis was based on observations over the past 35 years and produced Impact Tables showing the likelihood and severity of the impacts on temperature and rainfall by season. The current report is an extension of this work, providing information from observations and seasonal forecast models to give a more detailed outlook of the potential near-term impacts of the current El Niño conditions by region. This information has been added to the Impact Tables in the form of an ‘Observations and Outlook’ row. This consists of observational information for the past seasons of JJA 2015, SON 2015 and DJ 2015/2016, a detailed monthly outlook from 5 modeling centres for Feb 2016 and then longer-term seasonal forecast information from 2 modeling centres for the future seasons of MAM 2016 and JJ 2016. The seasonal outlook information is an indication of the average likely conditions for that coming month (or season) and region and is not a definite prediction of weather impacts. This report has been produced by University of Reading for Evidence on Demand with the assistance of the UK Department for International Development (DFID) contracted through the Climate, Environment, Infrastructure and Livelihoods Professional Evidence and Applied Knowledge Services (CEIL PEAKS) programme, jointly managed by DAI (which incorporates HTSPE Limited) and IMC Worldwide Limited.