JunB-CBFbeta signaling is essential to maintain sarcomeric Z-disc structure and when defective leads to heart failure.

In muscle cells, a complex network of Z-disc proteins allows proper reception, transduction and transmission of mechanical and biochemical signals. Mutations in genes encoding different Z-disc proteins such as integrin-linked kinase (ILK) and nexilin have recently been shown to cause heart failure by distinct mechanisms such as disturbed mechanosensing, altered mechanotransduction or mechanical Z-disc destabilization. We identified core-binding factor β (CBFβ) as an essential component for maintaining sarcomeric Z-disc and myofilament organization in heart and skeletal muscle.

Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy.

Z-disks, the mechanical integration sites of heart and skeletal muscle cells, link anchorage of myofilaments to force reception and processing. The key molecules that enable the Z-disk to persistently withstand the extreme mechanical forces during muscle contraction have not yet been identified. Here we isolated nexilin (encoded by NEXN) as a novel Z-disk protein.

In-vivo characterization of human dilated cardiomyopathy genes in zebrafish.

Due to lack of families suitable for linkage analysis and positional cloning most of the genetic causes of human dilated cardiomyopathy (DCM) are still unknown. To facilitate rapid identification and validation of novel DCM disease genes appropriate animal models are needed. To assess here for the first time whether the zebrafish is a suitable model organism to validate DCM candidate genes using antisense knock-down strategies, we inactivated in zebrafish known human DCM disease genes and then evaluated the resulting cardiac phenotypes.

The tight coupling between category and causal learning.

The main goal of the present research was to demonstrate the interaction between category and causal induction in causal model learning. We used a two-phase learning procedure in which learners were presented with learning input referring to two interconnected causal relations forming a causal chain (Experiment 1) or a common-cause model (Experiments 2a, b). One of the three events (i.

The role of learning data in causal reasoning about observations and interventions.

Recent studies have shown that people have the capacity to derive interventional predictions for previously unseen actions from observational knowledge, a finding that challenges associative theories of causal learning and reasoning (e.g., Meder, Hagmayer, & Waldmann, 2008).

A single serine in the carboxyl terminus of cardiac essential myosin light chain-1 controls cardiomyocyte contractility in vivo.

Although it is well known that mutations in the cardiac essential myosin light chain-1 (cmlc-1) gene can cause hypertrophic cardiomyopathy, the precise in vivo structural and functional roles of cMLC-1 in the heart are only poorly understood. We have isolated the zebrafish mutant lazy susan (laz), which displays severely reduced contractility of both heart chambers. By positional cloning, we identified a nonsense mutation within the zebrafish cmlc-1 gene to be responsible for the laz phenotype, leading to expression of a carboxyl-terminally truncated cMLC-1.

HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy.

Human dilated cardiomyopathy (DCM), a disorder of the cardiac muscle, causes considerable morbidity and mortality and is one of the major causes of sudden cardiac death. Genetic factors play a role in the etiology and pathogenesis of DCM. Disease-associated genetic variations identified to date have been identified in single families or single sporadic patients and explain a minority of the etiology of DCM.

Right into the heart of microRNA-133a.

MicroRNAs play an essential role in diverse cellular processes, such as proliferation, differentiation, apoptosis, and stress response. Recent studies demonstrate that miRNAs are important for timing developmental decisions and fine-tuning cellular determination in vertebrate heart development. In an elegant set of experiments reported in this issue of Genes & Development, Liu et al.

Inferring interventional predictions from observational learning data.

Previous research has shown that people are capable of deriving correct predictions for previously unseen actions from passive observations of causal systems (Waldmann & Hagmayer, 2005). However, these studies were limited, since learning data were presented as tabulated data only, which may have turned the task more into a reasoning rather than a learning task. In two experiments, we therefore presented learners with trial-by-trial observational learning input referring to a complex causal model consisting of four events.

Deficient zebrafish ether-à-go-go-related gene channel gating causes short-QT syndrome in zebrafish reggae mutants.

Background: Genetic predisposition is believed to be responsible for most clinically significant arrhythmias; however, suitable genetic animal models to study disease mechanisms and evaluate new treatment strategies are largely lacking.

Methods And Results: In search of suitable arrhythmia models, we isolated the zebrafish mutation reggae (reg), which displays clinical features of the malignant human short-QT syndrome such as accelerated cardiac repolarization accompanied by cardiac fibrillation. By positional cloning, we identified the reg mutation that resides within the voltage sensor of the zebrafish ether-à-go-go-related gene (zERG) potassium channel.

Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice.

It has been suggested that monocytes/macrophages represent the pivotal cell type during early adaptive growth of pre-existent arterial anastomoses toward functional collateral arteries (arteriogenesis) upon arterial occlusion. This hypothesis was supported by previous studies providing evidence that elevation of the peripheral monocyte count, increased monocyte survival (e.g.

Aspirin, but not clopidogrel, reduces collateral conductance in a rabbit model of femoral artery occlusion.

Objectives: The objective of this study was to test the potential of aspirin and clopidogrel to influence collateral artery growth (arteriogenesis).

Background: Aspirin and clopidogrel are antiplatelet agents commonly used in the treatment of ischemic cardiovascular disease. Both inhibit platelet aggregation; however, they differ mechanistically because aspirin acts via cyclooxygenase (COX) inhibition, while clopidogrel noncompetitively antagonizes the P2Y12 adenosine diphosphate receptor.

Divergent effects of GM-CSF and TGFbeta1 on bone marrow-derived macrophage arginase-1 activity, MCP-1 expression, and matrix metalloproteinase-12: a potential role during arteriogenesis.

Granulocyte/macrophage-colony stimulating factor (GM-CSF) and transforming growth factor (TGF)beta1 induce arteriogenesis in a nonischemic model of femoral artery ligation. Moreover, clinical trials demonstrated an improved collateralization after injection of bone marrow cells. In the present study, the expression of arteriogenic factors in bone marrow-derived macrophages (BMDM) was measured to verify the potential of these cells to influence collateral artery growth.

Sultamicillin versus amoxicillin in the treatment of tonsillitis and pharyngitis: a European multicenter study.

In this multicenter open, comparative study, 135 patients were treated with sultamicillin (67 subjects; 500 mg every 12 h) or amoxicillin (68 subjects; 500 mg every 8 h) for 10 d. Of the pathogens isolated pre-treatment, 24 of 29 (including 4 of 6 resistant strains) in the sultamicillin group were eradicated at the end of treatment, as were 17 of 22 in the amoxicillin group. At follow-up, the figures were 17 of 25 and 16 of 19, respectively.

Clinical and laboratory evaluation of the effect of cephradine on patients with ear, nose and throat infections.

27 patients with ear, nose and throat infections have been treated with cephradine orally. Ten patients received 250 mg and 17 patients 500 mg every 6 h during 10 days. 26 patients were cured.