Activin A, a multifunctional cytokine, plays an important role in hepatocyte growth suppression and is involved in liver size control. The present study was aimed to determine the cell location of activin A in the normal rat liver microenvironment and the contribution of activin A signaling to the hepatocyte phenotype to obtain insight into molecular mechanisms. Immunohistochemical and in situ hybridization analyses identified hepatocytes as the major activin A‐positive cell population in normal liver and identified mast cells as an additional activin A source. To investigate paracrine and autocrine activin A‐stimulated effects, hepatocytes were cocultured with engineered activin A‐secreting cell lines (RF1, TL8) or transduced with an adeno‐associated virus vector encoding activin βA, which led to strikingly altered expression of cell cycle‐related genes (Ki‐67, E2F transcription factor 1 [E2F1], minichromosome maintenance complex component 2 [Mcm2], forkhead box M1 [FoxM1]) and senescence‐related genes (cyclin‐dependent kinase inhibitor 2B [p15INK4b/CDKN2B], differentiated embryo‐chondrocyte expressed gene 1 [DEC1]) and reduced proliferation and induction of senescence. Microarray analyses identified 453 differentially expressed genes, many of which were not yet recognized as activin A downstream targets (e.g., ADAM metallopeptidase domain 12 [Adam12], semaphorin 7A [Sema7a], LIM and cysteine‐rich domains‐1 [Lmcd1], DAB2, clathrin adaptor protein [Dab2]). Among the main activin A‐mediated molecular/cellular functions are cellular growth/proliferation and movement, molecular transport, and metabolic processes containing highly down‐regulated genes, such as cytochrome P450, subfamily 2, polypeptide 11 (Cyp2C11), sulfotransferase family 1A, member 1 (Sult1a1), glycine‐N‐acyltransferase (Glyat), and bile acid‐CoA:amino acid N‐acyltransferase (Baat). Moreover, Ingenuity Pathway Analyses identified particular gene networks regulated by hepatocyte nuclear factor (HNF)‐4α and peroxisome proliferator‐activated receptor gamma (PPARγ) as key targets of activin A signaling. Conclusion: Our in vitro models demonstrated that activin A‐stimulated growth inhibition and cellular senescence is mediated through p15INK4b/CDKN2B and is associated with up‐ and down‐regulation of numerous target genes involved in multiple biological processes performed by hepatocytes, suggesting that activin A fulfills a critical role in normal liver function. (Hepatology Communications 2017;1:852‐870)

Dynamic biplane radiographic (DBR) imaging measures continuous vertebral motion during in vivo, functional tasks with sub-millimeter accuracy, offering the potential to develop novel biomechanical markers for lower back disorders based on true dynamic motion rather than metrics based on static end-range of motion. Nevertheless, the reliability of DBR metrics is unclear due to the inherent variability in movement over multiple repetitions and a need to minimize radiation exposure associated with each movement repetition. The objectives of this study were to determine the margin of uncertainty (MOU) in estimating the typical intervertebral kinematics waveforms based upon only a small number of movement repetitions, and to determine the day-to-day repeatability of intervertebral kinematics waveforms measured using DBR. Lumbar spine kinematics data were collected from two participant groups who performed multiple trials of flexion-extension or lateral bending to assess the uncertainty in the mean estimated waveform. The first group performed ten repetitions on the same day. Data from that group was used to estimate MOU as a function of the number of repetitions. The second group performed five repetitions on each of two separate days. MOU was not only movement-specific, but also motion segment-specific. Using just one or two trials yielded a relatively high MOU (e.g. > 4& or 4 mm), however, collecting at least three repetitions reduced the MOU by 40% or more. Results demonstrate the reproducibility of DBR-derived measurements is greatly improved by collecting at least three repetitions, while simultaneously minimizing radiation exposure.