Vascular endothelial growth factor (VEGF) plays a pivotal role in angiogenesis. Previous studies focused on transcriptional regulation modulated by proximal upstream cis-regulatory elements (CREs) of the human vegfa promoter. However, we hypothesized that distal upstream CREs may also be involved in controlling vegfa transcription. In this study, we found that the catalytic domain of Seryl-tRNA synthetase (SerRS) interacted with transcription factor Yin Yang 1 (YY1) to form a SerRS/YY1 complex that negatively controls vegfa promoter activity through binding distal CREs at −4654 to −4623 of vegfa. Particularly, we demonstrated that the −4654 to −4623 segment, which predominantly controls vegfa promoter activity, is involved in competitive binding between SerRS/YY1 complex and NFKB1. We further showed that VEGFA protein and blood vessel development were reduced by overexpression of either SerRS or YY1, but enhanced by the knockdown of either SerRS or yy1. In contrast, these same parameters were enhanced by overexpression of NFKB1, but reduced by knockdown of nfkb1. Therefore, we suggested that SerRS does not bind DNA directly but form a SerRS/YY1 complex, which functions as a negative effector to regulate vegfa transcription through binding at the distal CREs; while NFKB1 serves as a positive effector through competing with SerRS/YY1 binding at the overlapping CREs.
Transdermal drug delivery through microneedles is a minimally invasive procedure causing little or no pain, and is a potentially attractive alternative to intramuscular and subdermal drug delivery methods. This paper demonstrates the fabrication of a hollow microneedle array using a polymer-based process combining UV photolithography and replica molding techniques. The key characteristic of the proposed fabrication process is to define a hollow lumen for microfluidic access via photopatterning, allowing a batch process as well as high throughput. A hollow SU-8 microneedle array, consisting of 825mum tall and 400 mum wide microneedles with 15-25 mum tip diameters and 120 mum diameter hollow lumens was designed, fabricated and characterized.
In this paper, a speaker adaptation method to adapt an existing speaking rate-dependent hierarchical prosodic model (SR-HPM) of an SR-controlled Mandarin TTS system to new speaker's data for realizing a new voice is proposed. Two main problems are addressed: data sparseness for few adaptation utterances existing only in a small range of normal speaking rate and no adaptation data in both ranges of fast and slow speaking rates. The proposed method follows the idea of SR-HPM training to firstly normalize the prosodic-acoustic features of the new speaker's speech data, to then train an HPM by the prosody labeling and modeling algorithm, and to lastly refine the HPM to an SR-dependent model. The MAP adaptation method with model parameter extrapolation is applied to cope with the above two problems. Experimental results on a male speaker's adaptation data confirmed that the resulting adaptive SR-HPM has reasonable parameters covering a wide range of speaking rates and hence can be used in the TTS system to generate prosodic-acoustic features for synthesizing the new speaker's voice of any given SR.
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