DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal.

The molecular controls that govern the differentiation of embryonic stem (ES) cells remain poorly understood. DGCR8 is an RNA-binding protein that assists the RNase III enzyme Drosha in the processing of microRNAs (miRNAs), a subclass of small RNAs. Here we study the role of miRNAs in ES cell differentiation by generating a Dgcr8 knockout model. Analysis of mouse knockout ES cells shows that DGCR8 is essential for biogenesis of miRNAs. On the induction of differentiation, DGCR8-deficient ES cells do not fully downregulate pluripotency markers and retain the ability to produce ES cell colonies; however, they do express some markers of differentiation. This phenotype differs from that reported for Dicer1 knockout cells, suggesting that Dicer has miRNA-independent roles in ES cell function. Our findings indicate that miRNAs function in the silencing of ES cell self-renewal that normally occurs with the induction of differentiation.

Loss of cardiac microRNA-mediated regulation leads to dilated cardiomyopathy and heart failure.

RATIONALE: Heart failure is a deadly and devastating disease that places immense costs on an aging society. To develop therapies aimed at rescuing the failing heart, it is important to understand the molecular mechanisms underlying cardiomyocyte structure and function. OBJECTIVE: microRNAs are important regulators of gene expression, and we sought to define the global contributions made by microRNAs toward maintaining cardiomyocyte integrity. METHODS AND RESULTS: First, we performed deep sequencing analysis to catalog the miRNA population in the adult heart. Second, we genetically deleted, in cardiac myocytes, an essential component of the machinery that is required to generate miRNAs. Deep sequencing of miRNAs from the heart revealed the enrichment of a small number of microRNAs with one, miR-1, accounting for 40% of all microRNAs. Cardiomyocyte-specific deletion of dgcr8, a gene required for microRNA biogenesis, revealed a fully penetrant phenotype that begins with left ventricular malfunction progressing to a dilated cardiomyopathy and premature lethality. CONCLUSIONS: These observations reveal a critical role for microRNAs in maintaining cardiac function in mature cardiomyocytes and raise the possibility that only a handful of microRNAs may ultimately be responsible for the dramatic cardiac phenotype seen in the absence of dgcr8.

Preliminary Experience on Laser Interstitial Thermal Ablation Therapy in the Treatment of Extra-axial Masses: Indications, Imaging Characterization and Outcomes.

Laser thermal ablation is a novel minimally invasive neurosurgical technique that has proven to be beneficial in the treatment of a select group of neurosurgical conditions such as primary brain neoplasms, brain metastases, radiation necrosis, and epileptogenic lesions such as cortical dysplasia and mesial temporal sclerosis. The applicability of laser thermal ablation and its utility in the treatment of extra-axial (EA) brain neoplasms, mainly meningioma, is another novel use of this technique. Our article discusses the use and benefits of this technique in this particular clinical scenario. We describe our experience in a group of symptomatic patients from our institution with EA masses, mainly recurrent meningiomas, that failed previous more conventional treatment therapies such as surgery and radiotherapy. Our paper emphasizes patient selection, indications for the procedure, and post-treatment imaging characteristics of the ablated lesions.