MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension.

Loss of the growth-suppressive effects of bone morphogenetic protein (BMP) signaling has been demonstrated to promote pulmonary arterial endothelial cell dysfunction and induce pulmonary arterial smooth muscle cell (PASMC) proliferation, leading to the development of pulmonary arterial hypertension (PAH). MicroRNAs (miRs) mediate higher order regulation of cellular function through coordinated modulation of mRNA targets; however, miR expression is altered by disease development and drug therapy. Here, we examined treatment-naive patients and experimental models of PAH and identified a reduction in the levels of miR-140-5p. Inhibition of miR-140-5p promoted PASMC proliferation and migration in vitro. In rat models of PAH, nebulized delivery of miR-140-5p mimic prevented the development of PAH and attenuated the progression of established PAH. Network and pathway analysis identified SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) as a key miR-140-5p target and regulator of BMP signaling. Evaluation of human tissue revealed that SMURF1 is increased in patients with PAH. miR-140-5p mimic or SMURF1 knockdown in PASMCs altered BMP signaling, further supporting these factors as regulators of BMP signaling. Finally, Smurf1 deletion protected mice from PAH, demonstrating a critical role in disease development. Together, these studies identify both miR-140-5p and SMURF1 as key regulators of disease pathology and as potential therapeutic targets for the treatment of PAH

A Re-Evaluation of the Nature of Speech Errors in Normal and Disordered Speakers

It is well known that speech errors in normal and aphasic speakers share certain key characteristics. Traditionally, many of these errors are regarded as serial misorderings of abstract phonological segments, which maintain the phonetic well-formedness of the utterance. The current paper brings together the results of several articulatory studies undertaken independently for both subject populations. These show that, in an error, instead of one segment substituting for another, two segments are often produced simultaneously even though only one segment may be heard. Such data pose problems for current models of speech production by suggesting that the commonly assumed dichotomous distinction between phonological and phonetic errors may not be tenable in the current form or may even be altogether redundant