Citations

Rationale: Activity of the large conductance Ca 2+ -activated K + (BK) channels is profoundly modulated by its β 1 subunit (BK-β 1 ). However, BK-β 1 expression is downregulated in diabetic vessels. The ubiquitin–proteasome system (UPS) is a major mechanism of intracellular protein degradation. Whether UPS participates in BK-β 1 downregulation in diabetic vessels is unknown. Objective: We hypothesize that UPS facilitates vascular BK-β 1 degradation in diabetes. Methods and Results: Using patch clamp and molecular biological approaches, we found that BK-β 1 –mediated channel activation and BK-β 1 protein expression were reduced in aortas of streptozotocin-induced diabetic rats and in human coronary arterial smooth muscle cells (CASMCs) cultured in high glucose. This was accompanied by upregulation of F-box only protein (FBXO)-9 and FBXO-32 (atrogin-1), the key components of the Skp1-Cullin-F-box (SCF) type ubiquitin ligase complex. BK-β 1 expression was suppressed by the FBXO activator doxorubicin but enhanced by FBXO-9 small interfering RNA or by the proteasome inhibitor MG-132. Cotransfection of atrogin-1 in HEK293 cells significantly reduced Flag-hSlo-β 1 expression by 2.16-fold, compared with expression of Flag-hSlo-β 1 V146A (a mutant without the PDZ-binding motif). After cotransfection with atrogin-1, the ubiquitination of Flag-hSlo-β 1 was increased by 1.91-fold, compared with that of hSlo-β 1 V146A, whereas cotransfection with atrogin-1ΔF (a nonfunctional mutant without the F-box motif) had no effect. Moreover, inhibition of Akt signaling attenuated the phosphorylation of forkhead box O transcription factor (FOXO)-3a and enhanced atrogin-1 expression, which in turn suppressed BK-β 1 protein levels in human CASMCs. Conclusions: Downregulation of vascular BK-β 1 expression in diabetes and in high-glucose culture conditions was associated with FOXO-3a/FBXO-dependent increase in BK-β 1 degradation.

Purpose In this article, the authors address the hypothesis that the severe and persistent speech disorder reported in persons with galactosemia meets contemporary diagnostic criteria for Childhood Apraxia of Speech (CAS). A positive finding for CAS in this rare metabolic disorder has the potential to impact treatment of persons with galactosemia and inform explanatory perspectives on CAS in neurological, neurodevelopmental, and idiopathic contexts. Method Thirty-three youth with galactosemia and significant prior or persistent speech sound disorder were assessed in their homes in 17 states. Participants completed a protocol yielding information on their cognitive, structural, sensorimotor, language, speech, prosody, and voice status and function. Results Eight of the 33 participants (24%) met contemporary diagnostic criteria for CAS. Two participants, 1 of whom was among the 8 with CAS, met criteria for ataxic or hyperkinetic dysarthria. Groupwise findings for the remaining 24 participants are consistent with a classification category termed Motor Speech Disorder–Not Otherwise Specified (Shriberg, Fourakis et al., 2010a). Conclusion The authors estimate the prevalence of CAS in galactosemia at 18 per hundred—180 times the estimated risk for idiopathic CAS. Findings support the need to study risk factors for the high occurrence of motor speech disorders in galactosemia despite early compliant dietary management.

ABSTRACTTransgenic expression of the RNA-dependent RNA polymerase 3Dpolinhibited infection of Theiler's murine encephalitis virus (TMEV), a picornavirus from which it was derived. Here, we infected 3Dpoltransgenic mice with another picornavirus, as well as an alphaherpesvirus and a rhabdovirus. 3Dpoltransgenic FVB mice had significantly lower viral loads and survived longer after infection with all three types of viruses than nontransgenic FVB mice. Viral inhibition among three different types of virus by transgenic 3Dpolsuggests that the mechanism of action is not the direct interference with picornaviral 3Dpolbut instead may be the changing of host cells to an antiviral state before or after viral infection occurs, as basal interferon levels were higher in 3Dpoltransgenic mice before infection. Further study of this mechanism may open new possibilities for future antiviral therapy.

Arterial elasticity has gained importance in the past decades as it has been shown to be an independent predictor of cardiovascular diseases. Ultrasound radiation force has been used to excite propagating waves in arterial vessels in order to measure the wave speeds and characterize the elastic properties of the vessels. Excised pig carotid arteries were excited with impulsive radiation force using 3-MHz tonebursts of length 200, and the propagating waves were measured along the length of the artery over a distance of 2 cm. A 2-D fast Fourier transform was performed on the spatiotemporal data for identification of several propagating modes in the vessel. Multiple propagating modes could be visualized from the spatiotemporal data that varied with the transmural pressure of the artery under investigation over a range of 10–100 mm Hg. The modes present in the data were fitted with a theoretical model to estimate the elasticity of the arteries. The comparison with the model provides insight into characterizing the elastic properties of the artery. [This work was supported in part by NIH Grant no. EB002640.]

Vibro-acoustography with rectilinear raster scanning using confocal or linear array transducers have been reported before. Endo-cavity imaging requires a different type of scanning due to space limitation. This paper describes 3-D endo-cavity vibro-acoustography by a rotating linear array that scans the volume of interest. In this configuration a linear array is used to steer the beam electronically, which is combined with the rotational motion of the transducer to scan the beam in a cylindrical volume. This particular geometry produces special artifacts in the image. One such artifact is non-uniformity in signal power due to angular variations with respect to the hydrophone. Another artifact is related to the geometrical distortion in the image. In this paper, we will present examples of vibro-acoustography images with linear and rotational scanning and describe image characteristics and methods to reduce the artifacts. [Work supported by NIH Grant P50 CA91956P2.]

Characterization of viscoelastic soft tissues and materials has been a subject of active research for the past two decades. Techniques involving measuring the motion of embedded spheres in viscoelastic media have been employed to measure the viscoelastic material properties of the media surrounding the sphere. The published work using this technique has been restricted to using the Kelvin–Voigt model, which has worked for gelatin-based materials. We report an extension of this method using different viscoelastic rheological models such as the Maxwell, generalized Maxwell, Zener, and Kelvin–Voigt fractional derivative models. We performed experiments using a focused 3-MHz transducer to produce radiation force and a 7.5-MHz pulse-echo transducer to measure the sphere motion. Two phantoms were tested; one made of gelatin and another made of rubber with stainless steel spheres embedded in the materials. The response was fitted with the generalized theoretical model to find the material properties over bandwidths of 25–3000 Hz. The median absolute errors ranged from 0.0036–0.0421 and 0.0365–0.0879 for the gelatin and rubber phantoms, respectively. This generalized method offers added flexibility to characterize different types of viscoelastic materials using the most appropriate rheological model. [Work supported in part by NIH Grant nos. EB002167 and DK082408.]