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1.  Upward electrical discharges observed above Tropical Depression Dorian 
Nature Communications  2015;6:5995.
Observation of upward electrical discharges from thunderstorms has been sporadically reported in the scientific literature. According to their terminal altitudes, they are classified as starters (20–30 km), jets (40–50 km) and gigantic jets (70–90 km). They not only have a significant impact on the occupied atmospheric volumes but also electrically couple different atmospheric regions. However, as they are rare and unpredictable, our knowledge of them has been built on observations that typically record only one type of such discharges. Here we report a close-distance observation of seven upward discharges including one starter, two jets and four gigantic jets above Tropical Depression Dorian. Our optical and electromagnetic data indicate that all events are of negative polarity, suggesting they are initiated in the same thundercloud charge region. The data also indicate that the lightning-like discharge channel can extend above thunderclouds by about 30 km, but the discharge does not emit low-frequency electromagnetic radiation as normal lightning.
Upward electrical discharges from thunderstorms were discovered recently, and only a very limited set of observations exist because they are rare and unpredictable. Here, the authors present recordings of different types of the discharge above a storm, which contradict current theories of their origins.
PMCID: PMC4354034  PMID: 25607345
2.  FHOD1 is needed for directed Forces and Adhesion Maturation during Cell Spreading and Migration 
Developmental cell  2013;27(5):545-559.
Matrix adhesions provide critical signals for cell growth or differentiation. They form through a number of distinct steps that follow integrin binding to matrix ligands. In an early step, integrins form clusters that support actin polymerization by an unknown mechanism. This raises the question of how actin polymerization occurs at the integrin clusters. We report here that a major formin in mouse fibroblasts, FHOD1 is recruited to integrin clusters, resulting in actin assembly. Using cell-spreading assays on lipid bilayers, solid substrates and high-resolution force sensing pillar arrays, we find that knockdown of FHOD1 impairs spreading, coordinated application of adhesive force and adhesion maturation. Finally we show that targeting of FHOD1 to the integrin sites depends on the direct interaction with Src family kinases, and is upstream of the activation by Rho Kinase. Thus our findings provide insights into the mechanisms of cell migration with implications for development and disease.
PMCID: PMC3890431  PMID: 24331927
3.  Thrombin based gelatin matrix and fibrin sealant mediated clot formation in the presence of clopidogrel 
Thrombosis Journal  2014;12:10.
Platelet inhibitors are commonly used to reduce the risk of atherothrombotic events. The aim of this study was to determine the impact of platelet inhibitors, specifically clopidogrel and aspirin, on clot kinetics, strength, and/or structure during the use of thrombin based gelatin matrices and fibrin sealants.
Blood was collected and heparinized from donors on clopidogrel (and aspirin) and age matched control donors. Blood component analysis, whole blood platelet aggregometry, and activated clotting time (ACT) were used to monitor compliance to therapy and identify any differences between donor groups. Clot kinetics and strength were analyzed using thrombelastography (TEG). Field Emission Scanning Electron Microscopy (FESEM) was used to analyze clot structure.
Blood component profiles were similar for both donor groups. Aggregometry indicated that aggregation response to adenosine diphosphate (ADP) for clopidogrel donors was 12% of that for the controls (p = 0.0021), an expected result of clopidogrel induced platelet inhibition. However, blood from both donor groups had an elevated thrombin induced aggregation response. Heparinization of donor blood resulted in similarly elevated ACTs for both donor groups. TEG results indicated similar clot kinetics and strength between clopidogrel and control donor groups for blood alone and when clotting was induced using thrombin based gelatin matrices and fibrin sealants. FESEM images supported TEG findings in that similar morphologies were observed in ex vivo formed clots from both donor groups when thrombin based gelatin matrices and fibrin sealants were used.
These results suggest that platelet inhibitors do not negatively impact clot kinetics, strength, and structure when clotting is initiated with thrombin based gelatin matrices and fibrin sealants.
PMCID: PMC4041347  PMID: 24891841
Floseal; Tisseel; Clopidogrel; Thrombelastography; Thrombin; Hemostasis
4.  Two distinct phosphorylation events govern the function of muscle FHOD3 
Posttranslational modifications such as phosphorylation are universally acknowledged regulators of protein function. Recently we characterised a striated muscle-specific isoform of the formin FHOD3 that displays distinct subcellular targeting and protein half-life compared to its non-muscle counterpart, which is dependent on phosphorylation by CK2 (formerly casein kinase 2). We now show that the two isoforms of FHOD3 are already expressed in the vertebrate embryonic heart. Analysis of CK2alpha knockout mice showed that phosphorylation by CK2 is required for proper targeting of muscle FHOD3 to the myofibrils also in embryonic cardiomyocytes in situ. The localisation of muscle FHOD3 in the sarcomere varies depending on the maturation state, being either broader or restricted to the Z-disc proper in adult heart. Following myofibril disassembly such as in dedifferentiating adult rat cardiomyocytes in culture, the expression of non-muscle FHOD3 is up-regulated, which is reversed once the myofibrils are reassembled. The shift in expression levels of different isoforms is accompanied by an increased co-localisation with p62, which is involved in autophagy, and affects the half-life of FHOD3.
Phosphorylation of three amino acids in the C-terminus of FHOD3 by ROCK1 is sufficient for activation, which results in increased actin filament synthesis in cardiomyocytes and also a broader localisation pattern of FHOD3 in the myofibrils. ROCK1 can directly phosphorylate FHOD3 and FHOD3 seems to be the downstream mediator of the exaggerated actin filament formation phenotype that is induced in cardiomyocytes upon the overexpression of constitutively active ROCK1. We conclude that the expression of the muscle FHOD3 isoform is characteristic for the healthy mature heart and that two distinct phosphorylation events are crucial to regulate its activity in thin filament assembly and maintenance.
PMCID: PMC3696992  PMID: 23052206
myofibril; formin; cardiac cytoarchitecture; heart development
5.  Effects of perhexiline-induced fuel switch on the cardiac proteome and metabolome 
Perhexiline is a potent anti-anginal drug used for treatment of refractory angina and other forms of heart disease. It provides an oxygen sparing effect in the myocardium by creating a switch from fatty acid to glucose metabolism through partial inhibition of carnitine palmitoyltransferase 1 and 2. However, the precise molecular mechanisms underlying the cardioprotective effects elicited by perhexiline are not fully understood. The present study employed a combined proteomics, metabolomics and computational approach to characterise changes in murine hearts upon treatment with perhexiline. According to results based on difference in-gel electrophoresis, the most profound change in the cardiac proteome related to the activation of the pyruvate dehydrogenase complex. Metabolomic analysis by high-resolution nuclear magnetic resonance spectroscopy showed lower levels of total creatine and taurine in hearts of perhexiline-treated mice. Creatine and taurine levels were also significantly correlated in a cross-correlation analysis of all metabolites. Computational modelling suggested that far from inducing a simple shift from fatty acid to glucose oxidation, perhexiline may cause complex rebalancing of carbon and nucleotide phosphate fluxes, fuelled by increased lactate and amino acid uptake, to increase metabolic flexibility and to maintain cardiac output. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".
Graphical abstract
► Mice were fed perhexiline to achieve steady state concentrations. ► Hearts were analysed using a combined proteomic and metabolomic approach. ► Computer modelling was used to cross-validate the findings. ► Perhexiline has more wide-ranging and complex metabolic effects than previously thought.
PMCID: PMC3573230  PMID: 23277191
CPT, carnitine palmitoyltransferase; DIGE, difference in-gel electrophoresis; FCS, foetal calf serum; FDR, false discovery rate; GO, Gene ontology; 1H NMR, proton nuclear magnetic resonance spectroscopy; LC-MS/MS, liquid chromatography tandem mass spectrometry; TCA, tricarboxylic acid; Metabolomics; Proteomics; Cardioprotection; Metabolism; Heart failure
6.  Proteomics: from single molecules to biological pathways 
Cardiovascular Research  2012;97(4):612-622.
The conventional reductionist approach to cardiovascular research investigates individual candidate factors or linear signalling pathways but ignores more complex interactions in biological systems. The advent of molecular profiling technologies that focus on a global characterization of whole complements allows an exploration of the interconnectivity of pathways during pathophysiologically relevant processes, but has brought about the issue of statistical analysis and data integration. Proteins identified by differential expression as well as those in protein–protein interaction networks identified through experiments and through computational modelling techniques can be used as an initial starting point for functional analyses. In combination with other ‘-omics’ technologies, such as transcriptomics and metabolomics, proteomics explores different aspects of disease, and the different pillars of observations facilitate the data integration in disease-specific networks. Ultimately, a systems biology approach may advance our understanding of cardiovascular disease processes at a ‘biological pathway’ instead of a ‘single molecule’ level and accelerate progress towards disease-modifying interventions.
PMCID: PMC3583257  PMID: 23180722
Proteins; Metabolites; Mass spectrometry; Systems biology; Bioinformatics
7.  Formin follows function: a muscle-specific isoform of FHOD3 is regulated by CK2 phosphorylation and promotes myofibril maintenance 
The Journal of Cell Biology  2010;191(6):1159-1172.
Phosphorylation of the muscle-specific formin splice variant FHOD3 by CK2 regulates its stability, myofibril targeting, and myofibril integrity.
Members of the formin family are important for actin filament nucleation and elongation. We have identified a novel striated muscle–specific splice variant of the formin FHOD3 that introduces a casein kinase 2 (CK2) phosphorylation site. The specific targeting of muscle FHOD3 to the myofibrils in cardiomyocytes is abolished in phosphomutants or by the inhibition of CK2. Phosphorylation of muscle FHOD3 also prevents its interaction with p62/sequestosome 1 and its recruitment to autophagosomes. Furthermore, we show that muscle FHOD3 efficiently promotes the polymerization of actin filaments in cardiomyocytes and that the down-regulation of its expression severely affects myofibril integrity. In murine and human cardiomyopathy, we observe reduced FHOD3 expression with a concomitant isoform switch and change of subcellular targeting. Collectively, our data suggest that a muscle-specific isoform of FHOD3 is required for the maintenance of the contractile structures in heart muscle and that its function is regulated by posttranslational modification.
PMCID: PMC3002041  PMID: 21149568
8.  Comparison of Two Gelatin and Thrombin Combination Hemostats in a Porcine Liver Abrasion Model 
Journal of Investigative Surgery  2013;26(3):141-148.
Surgical hemostasis is achieved using adjunctive hemostats when conventional methods fail.
This study compares the effectiveness of two adjunctive gelatin-thrombin hemostats.
To determine effectiveness, hemostats were compared in vivo, in vitro, and using scanning electron microscopy (SEM).
In vivo, a heparinized porcine liver abrasion model was used to compare hemostatic success, degree of bleeding, and blood loss at 2, 5, and 10 minutes post-treatment. In vitro, thrombin in the supernatant of each hemostat and Red Blood Cells (RBC'S) in the supernatant of clots formed by each was compared.
Ultrastructure of one gelatin was smooth and the other stellate. In vivo, smooth gelatin provided superior hemostatic success at 5 (85% vs. 60%; OR: 5.3; 95% CI: 1.66 to 17.9) and 10 mins (72.5% vs. 47.5%; OR: 5.0; 95% CI: 1.55 to 16.1). Smooth gelatin had a statistically different degree of bleeding at 5 (0.58 ± 0.87 [Mean ± SD] vs. 1.03 ± 1.12; OR: 3.36; 95% CI: 1.34 to 8.41) and 10 mins (1.13 ± 1.14 vs. 1.65 ± 1.05; OR: 3.87; 95% CI: 1.62 to 9.21). Mean blood loss was less with smooth gelatin at 2 (0.07 ± 0.19 vs. 0.13 ± 0.63 ml/min), 5 (0.04 ± 0.13 vs. 0.23 ± 0.45 ml/min), and 10 mins (0.09 ± 0.24 vs. 0.21 ± 0.32 ml/min). In vitro, supernatant of smooth gelatin had significantly less thrombin (6.81 vs. 10.9 IU/ml, p = .001), and significantly less RBC's than stellate gelatin (0.07 vs. 0.09 × 106/ul, p = .0085).
Smooth gelatin has an increased ability to retain thrombin and RBC's in vitro which may explain why it provides superior hemostatic effectiveness, superior control of bleeding, and greater reduced blood loss in vivo.
PMCID: PMC3667676  PMID: 23514063
gelatin; thrombin; hemostat; adjunctive hemostats; hemostatic efficacy; bleeding model; floseal; surgiflo

Results 1-9 (9)