The natural plant product Rottlerin activates Kv7.1/KCNE1 channels

$\textit {Background/Aims:}$ Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 $K^{+}$ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases. $\textit {Methods:}$ Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in $\textit {Xenopus laevisoocytes}$ and on iPSC cardiomyocytes overexpressing Kv7.1 channels. $\textit {Results:}$ We show that currents carried by Kv7.1 ($EC_{50}$ = 1.48 $\mu$M), Kv7.1/KCNE1 ($EC_{50}$ = 4.9 $\mu$M), and Kv7.4 ($EC_{50}$ = 0.148 $\mu$M) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1. $\textit {Conclusion:}$ Rottlerin or an optimized derivative holds a potential as QT interval correcting drug

Reduction of cerebellar grey matter in Crus I and II in schizophrenia

Structural deficiencies within the cerebellum have been associated with schizophrenia. Whereas several region-of-interest-based studies have shown deviations in cerebellar volume, meta-analyses on conventional whole-brain voxel-based morphometry (VBM) studies do not implicate abnormalities in the cerebellum. Since this discrepancy could be due to methodological problems of VBM, we used a cerebellum-optimized VBM procedure. We acquired high-resolution MRI scans from 29 schizophrenia patients and 45 healthy controls and used a VBM approach utilizing the Spatially Unbiased Infratentorial toolbox (Diedrichsen in Neuroimage 33:127-138, 2006). Relative to healthy controls, schizophrenia patients showed reductions of grey matter volume in the left cerebellum Crus I/II that were correlated with thought disorder (p < 0.05; one-sided) and performance in the Trail-making test B (p < 0.01). No cerebellar group differences were detected employing conventional whole-brain VBM. The results derived from the cerebellum analysis provide evidence for distinct grey matter deficits in schizophrenia located in Crus I/II. The association of this area with thought disorder and Trail-making performance supports the previously suggested role of the cerebellum in coordination of mental processes including disordered thought in schizophrenia. The failure of conventional VBM to detect such effects suggests that previous studies might have underestimated the importance of cerebellar structural deficits in schizophrenia

The genus Laminaria sensu lato: recent insights and developments

AbstractThis review about the genus Laminaria sensu lato summarizes the extensive literature that has been published since the overview of the genus given by Kain in 1979. The recent proposal to divide the genus into the two genera Laminaria and Saccharina is acknowledged, but the published data are discussed under a sensu lato concept, introduced here. This includesall species which have been considered to be Laminaria before the division of the genus. In detail, after an introduction the review covers recent insights into phylogeny and taxonomy, and discusses morphotypes, ecotypes, population genetics and demography. It describes growth and photosynthetic performance of sporophytes with special paragraphs on the regulationof sporogenesis, regulation by endogenous rhythms, nutrient metabolism, storage products, and salinity tolerance. The biology of microstages is discussed separately. The ecology of these kelps is described with a focus on stress defence against abiotic and biotic factors and the role of Laminaria as habitat, its trophic interactions and its competition is discussed. Finally, recent developments in aquaculture are summarized. In conclusion to each section, as a perspective and guide to future research, we draw attention to the remaining gaps in the knowledge about the genus and kelps in general

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes