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Chronic human heart failure is characterized by abnormalities in [Beta]-adrenergic receptor ([Beta]AR) signaling, including increased levels of [Beta]AR kinase I ([Beta]ARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition of [Beta]ARK1 is sufficient to rescue a model of severe heart failure, we mated transgenic mice overexpressing a peptide inhibitor of [Beta]ARK1 ([Beta]ARKct) with transgenic mice overexpressing the sarcoplasmic reticulum [Ca.sup.2+]-binding protein, calsequestrin (CSQ). CSQ mice have a severe cardiomyopathy and markedly shortened survival (9 [+ or -] 1 weeks). In contrast, CSQ/[Beta]ARKct mice exhibited a significant increase in mean survival age (15 [+ or -] 1 weeks; P [is less than] 0.0001) and showed less cardiac dilation, and cardiac function was significantly improved (CSQ vs. CSQ/[Beta]ARKct, left ventricular end diastolic dimension 5.60 [+ or -] 0.17 mm vs. 4.19 [+ or -] 0.09 mm, P [is less than] 0.005; % fractional shortening, 15 [+ or -] 2 vs. 36 [+ or -] 2, P [is less than] 0.005). The enhancement of the survival rate in CSQ/[Beta]ARKct mice was substantially potentiated by chronic treatment with the [Beta]AR antagonist metoprolol (CSQ/[Beta]ARKct non-treated vs. CSQ/[Beta]ARKct metoprolol treated, 15 [+ or -] 1 weeks vs. 25 [+ or -] 2 weeks, P [is less than] 0.0001). Thus, overexpression of the [Beta]ARKct resulted in a marked prolongation in survival and improved cardiac function in a mouse model of severe cardiomyopathy that can be potentiated with [Beta]-blocker therapy. These data demonstrate a significant synergy between an established heart-failure treatment and the strategy of [Beta]ARK1 inhibition.

Background: The growth arrest-specific transcript 5 gene (GAS5) encodes a long noncoding RNA (lncRNA) and hosts a number of small nucleolar RNAs (snoRNAs) that have recently been implicated in multiple cellular processes and cancer. Here, we investigate the relationship between DNA damage, p53, and the GAS5 snoRNAs to gain further insight into the potential role of this locus in cell survival and oncogenesis both in vivo and in vitro. Methods: We used quantitative techniques to analyse the effect of DNA damage on GAS5 snoRNA expression and to assess the relationship between p53 and the GAS5 snoRNAs in cancer cell lines and in normal, pre-malignant, and malignant human colorectal tissue and used biological techniques to suggest potential roles for these snoRNAs in the DNA damage response. Results: GAS5-derived snoRNA expression was induced by DNA damage in a p53-dependent manner in colorectal cancer cell lines and their levels were not affected by DICER. Furthermore, p53 levels strongly correlated with GAS5-derived snoRNA expression in colorectal tissue. Conclusions: In aggregate, these data suggest that the GAS5-derived snoRNAs are under control of p53 and that they have an important role in mediating the p53 response to DNA damage, which may not relate to their function in the ribosome. We suggest that these snoRNAs are not processed by DICER to form smaller snoRNA-derived RNAs with microRNA (miRNA)-like functions, but their precise role requires further evaluation. Furthermore, since GAS5 host snoRNAs are often used as endogenous controls in qPCR quantifications we show that their use as housekeeping genes in DNA damage experiments can lead to inaccurate results. [ABSTRACT FROM AUTHOR]

Proteins destined for translocation across the prokaryotic cytoplasmic membrane are synthesized as precursors carrying transient N-terminal extensions known as signal sequences. They facilitate initial engagement of precursor proteins with the sec-dependent translocase to initiate active threading of the polypeptide across the membrane. The translocated precursor is then processed by a transcytoplasmic signal peptidase anchored to the inner membrane. The temporal nature of cleavage of the signal sequence during pre-protein translocation has remained elusive. Using an engineered mammalian cytochrome b5 precursor we demonstrate that the signal peptide processing in Escherichia coli is an event that can occur after almost complete exocytoplasmic translocation of the preprotein is accomplished. We discuss implications of the findings in light of the known working model of sec-dependent pre-protein translocon. [ABSTRACT FROM AUTHOR]

Reports that Beta-adrenergic receptor kinase 1 (BetaARK1) inhibition enhances survival and Beta blocker therapy in a mouse model of severe heart failure. Delay in progression of cardiac dysfunction by the BetaARKct peptide.

Objective: To review the indications, efficacy and follow-up for gestational trophoblastic tumor (GTT) patients treated for uterine arteriovenous vascular malformations (AVMs) and bleeding vaginal metastases with modern polyvinyl alcohol particle (PVA)-based radiological embolization., Study Design: GTT patients undergoing embolization were identified from the Charing Cross Hospital database. The patients' records were assessed for indication, technique used, primary and overall success in controlling bleeding, complications and subsequent pregnancy outcome., Results: During the period 2000-2009, 19 patients were treated for persistent or life-threatening bleeding by PVA-based uterine artery embolization performed via the femoral artery approach. Embolization resulted in control of hemorrhage in 18 of the 19 patients; 15 achieved control after the first procedure, with only 4 patients requiring a second procedure. In 1 case surgical intervention was required to control bleeding. The most frequent morbidity from the procedure was pelvic pain, requiring opiate administration; there were no other regular complications. The fertility outcome for these 19 patients indicates that 9 women have gone on to deliver a total of 12 healthy infants postembolization., Conclusion: For GTT patients with heavy bleeding from AVMs, uterine artery embolization is a safe and effective treatment with low short-term toxicity and no obvious detrimental effect on future fertility.