Adenosine and its role in cardioplegia : experimental evaluation in the isolated rat heart and in an-vivo primate model

This study was designed to investigate the role of adenosine, an endogenous cardioprotectant agent, without high potassium and as cardioplegic additive to high potassium solutions. Adenosine cardioplegia and potassium cardioplegia supplemented by adenosine (K + ADO) were investigated in terms of hemodynamic, metabolic and ultrastructural recovery in the isolated rat heart and in the in-vivo baboon model during periods of global myocardial ischemia, simulating the clinical situation during open heart surgery. The results obtained in both models show that adenosine improved postischemic hemodynamic function when used without high potassium cardioplegia. The combination of adenosine and high potassium was less effective in both models in terms of hemodynamic recovery; however, improved rhythm stability and coronary vasodilatation were still present. In addition adenosine alone was able to induce fast electromechanical arrest in the isolated rat heart. However, failure of even high concentrations of adenosine to limit ventricular fibrillation in the baboon exclude its use as cardioplegic agent on its own without additional interventions. It appears likely that adenosine without high potassium is cardioprotective via activation of A₁ receptors and opening of ATP-sensitive potassium channels, a mechanism which is probably non-functional in a high potassium environment. In view of the limited cardioprotection achieved with the combination of adenosine and high potassium further studies should aim for additional interventions to induce cardioplegia with adenosine and normokalemic solutions

Foundations of Empirical Software Engineering: The Legacy of Victor R. Basili

This book captures the main scientific contributions of Victor R. Basili, who has significantly shaped the field of empirical software engineering from its very start. He was the first to claim that software engineering needed to follow the model of other physical sciences and develop an experimental paradigm. By working on this postulate, he developed concepts that today are well known and widely used, including the Goal-Question-Metric method, the Quality-Improvement paradigm, and the Experience Factory. He is one of the few software pioneers who can aver that their research results are not just scientifically acclaimed but are also used as industry standards. On the occasion of his 65th birthday, celebrated with a symposium in his honor at the International Conference on Software Engineering in St. Louis, MO, USA in May 2005, Barry Boehm, Hans Dieter Rombach, and Marvin V. Zelkowitz, each a long-time collaborator of Victor R. Basili, selected the 20 most important research papers of their friend, and arranged these according to subject field. They then invited renowned researchers to write topical introductions. The result is this commented collection of timeless cornerstones of software engineering, hitherto available only in scattered publications

Impact of the Level of Homogenization in 3D Thermal Simulation on the Internal Temperature Distribution of Li-Ion Battery Cells

Temperature is an important factor for an optimal battery performance. To gain knowledge about the internal temperature distribution in a battery, many thermal simulation studies are performed. Among other factors, they differ in the level of homogenization (LoH) of the geometry, which directly influences the computing time. However, the effects of different LoH, in particular of the cell layers, on the modeling and prediction quality of the temperature field are scarcely investigated. This work discusses the effect of different LoH of the cell stack on a numerical 3D thermal battery model for different thermal management strategies. A new approach of reducing the number of cell layers of the pouch cell geometry while keeping their volumetric proportions constant is proposed. It is clearly shown that the LoH has a large impact on the thermal transport paths, especially through the current collectors and tabs, and therefore on the predicted internal temperature distribution. In addition, the effect of the LoH differs for different thermal management strategies, because they affect the heat transport paths as well

Fibroblast Growth Factor 21 Response in a Preclinical Alcohol Model of Acute-on-Chronic Liver Injury

Background and Aims: Fibroblast growth factor (FGF) 21 has recently been shown to play a potential role in bile acid metabolism. We aimed to investigate the FGF21 response in an ethanol-induced acute-on-chronic liver injury (ACLI) model in Abcb4−/− mice with deficiency of the hepatobiliary phospholipid transporter. Methods: Total RNA was extracted from wild-type (WT, C57BL/6J) and Abcb4−/ − (KO) mice, which were either fed a control diet (WT-Cont and KO-Cont groups; n = 28/group) or ethanol diet, followed by an acute ethanol binge (WT-EtOH and KOEtOH groups; n = 28/group). A total of 58 human subjects were recruited into the study, including patients with alcohol-associated liver disease (AALD; n = 31) and healthy controls (n = 27). The hepatic and ileal expressions of genes involved in bile acid metabolism, plasma FGF levels, and bile acid and its precursors 7α- and 27-hydroxycholesterol (7α- and 27-OHC) concentrations were determined. Primary mouse hepatocytes were isolated for cell culture experiments. Results: Alcohol feeding significantly induced plasma FGF21 and decreased hepatic Cyp7a1 levels. Hepatic expression levels of Fibroblast growth factor receptor 1 (Fgfr1), Fgfr4, Farnesoid X-activated receptor (Fxr), and Small heterodimer partner (Shp) and plasma FGF15/FGF19 levels did not differ with alcohol challenge. Exogenous FGF21 treatment suppressed Cyp7a1 in a dose-dependent manner in vitro. AALD patients showed markedly higher FGF21 and lower 7α-OHC plasma levels while FGF19 did not differ. Conclusions: The simultaneous upregulation of FGF21 and downregulation of Cyp7a1 expressions upon chronic plus binge alcohol feeding together with the invariant plasma FGF15 and hepatic Shp and Fxr levels suggest the presence of a direct regulatory mechanism of FGF21 on bile acid homeostasis through inhibition of CYP7A1 by an FGF15-independent pathway in this ACLI model. Lay Summary: Alcohol challenge results in the upregulation of FGF21 and repression of Cyp7a1 expressions while circulating FGF15 and hepatic Shp and Fxr levels remain constant both in healthy and pre-injured livers, suggesting the presence of an alternative FGF15-independent regulatory mechanism of FGF21 on bile acid homeostasis through the inhibition of Cyp7a1

The functional genome of CA1 and CA3 neurons under native conditions and in response to ischemia

<p>Abstract</p> <p>Background</p> <p>The different physiological repertoire of CA3 and CA1 neurons in the hippocampus, as well as their differing behaviour after noxious stimuli are ultimately based upon differences in the expressed genome. We have compared CA3 and CA1 gene expression in the uninjured brain, and after cerebral ischemia using laser microdissection (LMD), RNA amplification, and array hybridization.</p> <p>Results</p> <p>Profiling in CA1 vs. CA3 under normoxic conditions detected more than 1000 differentially expressed genes that belong to different, physiologically relevant gene ontology groups in both cell types. The comparison of each region under normoxic and ischemic conditions revealed more than 5000 ischemia-regulated genes for each individual cell type. Surprisingly, there was a high co-regulation in both regions. In the ischemic state, only about 100 genes were found to be differentially expressed in CA3 and CA1. The majority of these genes were also different in the native state. A minority of interesting genes (e.g. inhibinbetaA) displayed divergent expression preference under native and ischemic conditions with partially opposing directions of regulation in both cell types.</p> <p>Conclusion</p> <p>The differences found in two morphologically very similar cell types situated next to each other in the CNS are large providing a rational basis for physiological differences. Unexpectedly, the genomic response to ischemia is highly similar in these two neuron types, leading to a substantial attenuation of functional genomic differences in these two cell types. Also, the majority of changes that exist in the ischemic state are not generated de novo by the ischemic stimulus, but are preexistant from the genomic repertoire in the native situation. This unexpected influence of a strong noxious stimulus on cell-specific gene expression differences can be explained by the activation of a cell-type independent conserved gene-expression program. Our data generate both novel insights into the relation of the quiescent and stimulus-induced transcriptome in different cells, and provide a large dataset to the research community, both for mapping purposes, as well as for physiological and pathophysiological research.</p

Subunit composition, molecular environment, and activation of native TRPC channels encoded by their interactomes.

peer reviewedIn the mammalian brain TRPC channels, a family of Ca2+-permeable cation channels, are involved in a variety of processes from neuronal growth and synapse formation to transmitter release, synaptic transmission and plasticity. The molecular appearance and operation of native TRPC channels, however, remained poorly understood. Here, we used high-resolution proteomics to show that TRPC channels in the rodent brain are macro-molecular complexes of more than 1 MDa in size that result from the co-assembly of the tetrameric channel core with an ensemble of interacting proteins (interactome). The core(s) of TRPC1-, C4-, and C5-containing channels are mostly heteromers with defined stoichiometries for each subtype, whereas TRPC3, C6, and C7 preferentially form homomers. In addition, TRPC1/C4/C5 channels may co-assemble with the metabotropic glutamate receptor mGluR1, thus guaranteeing both specificity and reliability of channel activation via the phospholipase-Ca2+ pathway. Our results unveil the subunit composition of native TRPC channels and resolve the molecular details underlying their activation