Critical time window for NO-cGMP-dependent long-term memory formation after one-trial appetitive conditioning

The nitric oxide (NO)-cGMP signaling pathway is implicated in an increasing number of experimental models of plasticity. Here, in a behavioral analysis using one-trial appetitive associative conditioning, we show that there is an obligatory requirement for this pathway in the formation of long-term memory (LTM). Moreover, we demonstrate that this requirement lasts for a critical period of ~5 hr after training. Specifically, we trained intact specimens of the snail Lymnaea stagnalis in a single conditioning trial using a conditioned stimulus, amyl-acetate, paired with a salient unconditioned stimulus, sucrose, for feeding. Long-term associative memory induced by a single associative trial was demonstrated at 24 hr and shown to last at least 14 d after training. Tests for LTM and its dependence on NO were performed routinely 24 hr after training. The critical period when NO was needed for memory formation was established by transiently depleting it from the animals at a series of time points after training by the injection of the NO-scavenger 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl 3-oxide (PTIO).By blocking the activity of NO synthase and soluble guanylyl cyclase enzymes after training, we provided further evidence that LTM formation depends on an intact NO-cGMP pathway. An electrophysiological correlate of LTM was also blocked by PTIO, showing that the dependence of LTM on NO is amenable to analysis at the cellular level in vitro. This represents the first demonstration that associative memory formation after single-trial appetitive classical conditioning is dependent on an intact NO-cGMP signaling pathway

Numerical simulation of transom-stern waves

The flow field generated by a transom-stern hullform is a complex, broad-banded, three-dimensional phenomenon marked by a large breaking wave. This unsteady multiphase turbulent flow feature is difficult to study experimentally and simulate numerically. The results of a set of numerical simulations, which use the Numerical Flow Analysis (NFA) code, of the flow around the Model 5673 transom stern at speeds covering both wet- and dry-transom operating conditions are shown in the accompanying fluid dynamics video. The numerical predictions for wet-transom and dry-transom conditions are presented to demonstrate the current state of the art in the simulation of ship generated breaking waves. The interested reader is referred to Drazen et al. (2010) for a detailed and comprehensive comparison with experiments conducted at the Naval Surface Warfare Center Carderock Division (NSWCCD).Comment: Fluid Dynamics Video for 2010 APS Division of Fluid Dynamics Gallery of Fluid Motion include

Arrhythmogenesis in Fabry Disease

Purpose of Review: Fabry Disease (FD) is a rare lysosomal storage disorder characterised by multiorgan accumulation of glycosphingolipid due to deficiency in the enzyme α-galactosidase A. Cardiac sphingolipid accumulation triggers various types of arrhythmias, predominantly ventricular arrhythmia, bradyarrhythmia, and atrial fibrillation. Arrhythmia is likely the primary contributor to FD mortality with sudden cardiac death, the most frequent cardiac mode of death. Traditionally FD was seen as a storage cardiomyopathy triggering left ventricular hypertrophy, diastolic dysfunction, and ultimately, systolic dysfunction in advanced disease. The purpose of this review is to outline the current evidence exploring novel mechanisms underlying the arrhythmia substrate. Recent Findings: There is growing evidence that FD cardiomyopathy is a primary arrhythmic disease with each stage of cardiomyopathy (accumulation, hypertrophy, inflammation, and fibrosis) contributing to the arrhythmia substrate via various intracellular, extracellular, and environmental mechanisms. It is therefore important to understand how these mechanisms contribute to an individual’s risk of arrhythmia in FD. Summary: In this review, we outline the epidemiology of arrhythmia, pathophysiology of arrhythmogenesis, risk stratification, and cardiac therapy in FD. We explore how advances in conventional cardiac investigations performed in FD patients including 12-lead electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging have enabled early detection of pro-arrhythmic substrate. This has allowed for appropriate risk stratification of FD patients. This paves the way for future work exploring the development of therapeutic initiatives and risk prediction models to reduce the burden of arrhythmia.<br/

IGF-1R inhibition sensitizes breast cancer cells to ATM-Related Kinase (ATR) inhibitor and cisplatin

The complexity of the IGF-1 signalling axis is clearly a roadblock in targeting this receptor in cancer therapy. Here, we sought to identify mediators of resistance, and potential co-targets for IGF-1R inhibition. By using an siRNA functional screen with the IGF-1R tyrosine kinase inhibitor (TKI) BMS-754807 in MCF-7 cells we identified several genes encoding components of the DNA damage response (DDR) pathways as mediators of resistance to IGF-1R kinase inhibition. These included ATM and Ataxia Telangiectasia and RAD3-related kinase (ATR). We also observed a clear induction of DDR in cells that were exposed to IGF-1R TKIs (BMS-754807 and OSI-906) as indicated by accumulation of γ-H2AX, and phosphorylated Chk1. Combination of the IGF-1R/IR TKIs with an ATR kinase inhibitor VE-821 resulted in additive to synergistic cytotoxicity compared to either drug alone. In MCF-7 cells with stably acquired resistance to the IGF-1R TKI (MCF-7-R), DNA damage was also observed, and again, dual inhibition of the ATR kinase and IGF-1R/IR kinase resulted in synergistic cytotoxicity. Interestingly, dual inhibition of ATR and IGF-1R was more effective in MCF-7-R cells than parental cells. IGF-1R TKIs also potentiated the effects of cisplatin in a panel of breast cancer cell lines. Overall, our findings identify induction of DDR by IGF-1R kinase inhibition as a rationale for co-targeting the IGF-1R with ATR kinase inhibitors or cisplatin, particularly in cells with acquired resistance to TKIs

Assessment of continuous fermentative hydrogen and methane co-production using macro- and micro-algae with increasing organic loading rate

A two-stage continuous fermentative hydrogen and methane co-production using macro-algae (Laminaria digitata) and micro-algae (Arthrospira platensis) at a C/N ratio of 20 was established. The hydraulic retention time (HRT) of first-stage H2 reactor was 4 days. The highest specific hydrogen yield of 55.3 mL/g volatile solids (VS) was obtained at an organic loading rate (OLR) of 6.0 gVS/L/d. In the second-stage CH4 reactor at a short HRT of 12 days, a specific methane yield of 245.0 mL/gVS was achieved at a corresponding OLR of 2.0 gVS/L/d. At these loading rates, the two-stage continuous system offered process stability and effected an energy yield of 9.4 kJ/gVS, equivalent to 77.7% of that in an idealised batch system. However, further increases in OLR led to reduced hydrogen and methane yields in both reactors. The process was compared to a one-stage anaerobic co-digestion of algal mixtures at an HRT of 16 days. A remarkably high salinity level of 13.3 g/kg was recorded and volatile fatty acid accumulations were encountered in the one-stage CH4 reactor. The two-stage system offered better performances in both energy return and process stability. The gross energy potential of the advanced gaseous biofuels from this algal mixture may reach 213 GJ/ha/yr

Systems biology coupled with label-free high-throughput detection as a novel approach for diagnosis of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a treatable and preventable disease state, characterised by progressive airflow limitation that is not fully reversible. Although COPD is primarily a disease of the lungs there is now an appreciation that many of the manifestations of disease are outside the lung, leading to the notion that COPD is a systemic disease. Currently, diagnosis of COPD relies on largely descriptive measures to enable classification, such as symptoms and lung function. Here the limitations of existing diagnostic strategies of COPD are discussed and systems biology approaches to diagnosis that build upon current molecular knowledge of the disease are described. These approaches rely on new 'label-free' sensing technologies, such as high-throughput surface plasmon resonance (SPR), that we also describe

A Test of Kangaroo Care on Preterm Infant Breastfeeding

To test the effects of kangaroo care (KC) on breastfeeding outcomes in preterm infants compared to two control groups and to explore whether maternal-infant characteristics and the mother’s choice to use KC were related to breastfeeding measures

The Hurst exponent as an indicator of the behaviour of a model monopile in an ocean wave testing basin

With the importance of renewable energy well-established worldwide, and targets of such energy quantified in many cases, there exists a considerable interest in the assessment of wind and wave devices. While the individual components of these devices are often relatively well understood and the aspects of energy generation well researched, there seems to be a gap in the understanding of these devices as a whole and especially in the field of their dynamic responses under operational conditions. The mathematical modelling and estimation of their dynamic responses are more evolved but research directed towards testing of these devices still requires significant attention. Model-free indicators of the dynamic responses of these devices are important since it reflects the as-deployed behaviour of the devices when the exposure conditions are scaled reasonably correctly, along with the structural dimensions. This paper demonstrates how the Hurst exponent of the dynamic responses of a monopile exposed to different exposure conditions in an ocean wave basin can be used as a model-free indicator of various responses. The scaled model is exposed to Froude scaled waves and tested under different exposure conditions. The analysis and interpretation is carried out in a model-free and output-only environment, with only some preliminary ideas regarding the input of the system. The analysis indicates how the Hurst exponent can be an interesting descriptor to compare and contrast various scenarios of dynamic response conditions

Arrhythmogenesis in Fabry Disease

Purpose of Review Fabry Disease (FD) is a rare lysosomal storage disorder characterised by multiorgan accumulation of glycosphingolipid due to deficiency in the enzyme α-galactosidase A. Cardiac sphingolipid accumulation triggers various types of arrhythmias, predominantly ventricular arrhythmia, bradyarrhythmia, and atrial fibrillation. Arrhythmia is likely the primary contributor to FD mortality with sudden cardiac death, the most frequent cardiac mode of death. Traditionally FD was seen as a storage cardiomyopathy triggering left ventricular hypertrophy, diastolic dysfunction, and ultimately, systolic dysfunction in advanced disease. The purpose of this review is to outline the current evidence exploring novel mechanisms underlying the arrhythmia substrate. Recent Findings There is growing evidence that FD cardiomyopathy is a primary arrhythmic disease with each stage of cardiomyopathy (accumulation, hypertrophy, inflammation, and fibrosis) contributing to the arrhythmia substrate via various intracellular, extracellular, and environmental mechanisms. It is therefore important to understand how these mechanisms contribute to an individual’s risk of arrhythmia in FD. Summary In this review, we outline the epidemiology of arrhythmia, pathophysiology of arrhythmogenesis, risk stratification, and cardiac therapy in FD. We explore how advances in conventional cardiac investigations performed in FD patients including 12-lead electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging have enabled early detection of pro-arrhythmic substrate. This has allowed for appropriate risk stratification of FD patients. This paves the way for future work exploring the development of therapeutic initiatives and risk prediction models to reduce the burden of arrhythmia

The potential of power to gas to provide green gas utilising existing CO2 sources from industries, distilleries and wastewater treatment facilities

The suitability of existing sources of CO2 in a region (Ireland) for use in power to gas systems was determined using multi criteria decision analysis. The main sources of CO2 were from the combustion of fossil fuels, cement production, alcohol production, and wastewater treatment plants. The criteria used to assess the suitability of CO2 sources were: annual quantity of CO2 emitted; concentration of CO2 in the gas; CO2 source; distance to the electricity network; and distance to the gas network. The most suitable sources of CO2 were found to be distilleries, and wastewater treatment plants with anaerobic digesters. The most suitable source of CO2, a large distillery, could be used to convert 461 GWh/a of electricity into 258 GWh/a of methane. The total electricity requirement of this system is larger than the 348 GWh of renewable electricity dispatched down in Ireland in 2015. This could allow for the conversion of electricity that would be curtailed into a valuable energy vector. The resulting methane could fuel 729 compressed natural gas fuelled buses per annum. Synergies in integrating power to gas at a wastewater treatment plant include use of oxygen in the wastewater treatment process