Thyroid Hormone Receptor α Plays an Essential Role in Male Skeletal Muscle Myoblast Proliferation, Differentiation, and Response to Injury.

Thyroid hormone plays an essential role in myogenesis, the process required for skeletal muscle development and repair, although the mechanisms have not been established. Skeletal muscle develops from the fusion of precursor myoblasts into myofibers. We have used the C2C12 skeletal muscle myoblast cell line, primary myoblasts, and mouse models of resistance to thyroid hormone (RTH) α and ß, to determine the role of thyroid hormone in the regulation of myoblast differentiation. T3, which activates thyroid hormone receptor (TR) α and ß, increased myoblast differentiation whereas GC1, a selective TRß agonist, was minimally effective. Genetic approaches confirmed that TRα plays an important role in normal myoblast proliferation and differentiation and acts through the Wnt/ß-catenin signaling pathway. Myoblasts with TRα knockdown, or derived from RTH-TRα PV (a frame-shift mutation) mice, displayed reduced proliferation and myogenic differentiation. Moreover, skeletal muscle from the TRα1PV mutant mouse had impaired in vivo regeneration after injury. RTH-TRß PV mutant mouse model skeletal muscle and derived primary myoblasts did not have altered proliferation, myogenic differentiation, or response to injury when compared with control. In conclusion, TRα plays an essential role in myoblast homeostasis and provides a potential therapeutic target to enhance skeletal muscle regeneration.

Scalable heuristics for design of DNA probe arrays.

Design of DNA arrays for very large-scale immobilized polymer synthesis (VLSIPS) (Fodor et al., 1991) seeks to minimize effects of unintended illumination during mask exposure steps. Hannenhalli et al. (2002) formulate this requirement as the Border Minimization Problem and give an algorithm for placement of probes at array sites under the assumption that the array synthesis is synchronous; i.e., nucleotides are synthesized in a periodic sequence (ACGT)(k) and every probe grows by exactly one nucleotide with every group of four masks. Drawing on the analogy with VLSI placement, in this paper we describe and experimentally validate the engineering of several scalable, high-quality placement heuristics for both synchronous and asynchronous DNA array design. We give empirical results on both randomly generated and industry test cases confirming the scalability and improved solution quality enjoyed by our methods. In general, our techniques improve on state-of-the-art industrial results by over 4% and surpass academically published results by up to 35%. Finally, we give lower bounds that offer insights into the amount of available further improvements.