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Reducing the musculoskeletal deterioration that astronauts experience in microgravity requires countermeasures that can improve the effectiveness of otherwise rigorous and time-expensive exercise regimens in space. The ability of low-intensity vibrations (LIV) to activate force-responsive signaling pathways in cells suggests LIV as a potential countermeasure to improve cell responsiveness to subsequent mechanical challenge. Mechanoresponse of mesenchymal stem cells (MSC), which maintain bone-making osteoblasts, is in part controlled by the “mechanotransducer” protein YAP (Yes-associated protein), which is shuttled into the nucleus in response to cyto-mechanical forces. Here, using YAP nuclear shuttling as a measurement outcome, we tested the effect of 72 h of clinostat-induced simulated microgravity (SMG) and daily LIV application (LIVDT) on the YAP nuclear entry driven by either acute LIV (LIVAT) or Lysophosphohaditic acid (LPA), applied after the 72 h period. We hypothesized that SMG-induced impairment of acute YAP nuclear entry would be alleviated by the daily application of LIVDT. Results showed that while both acute LIVAT and LPA treatments increased nuclear YAP entry by 50 and 87% over the basal levels in SMG-treated MSCs, nuclear YAP levels of all SMG groups were significantly lower than non-SMG controls. LIVDT, applied in parallel to SMG, restored the SMG-driven decrease in basal nuclear YAP to control levels as well as increased the LPA-induced but not LIVAT-induced YAP nuclear entry over SMG only, counterparts. These cell-level observations suggest that daily LIV treatments are a feasible countermeasure for restoring basal nuclear YAP levels and increasing the YAP nuclear shuttling in MSCs under SMG.

The nucleus, central to all cellular activity, relies on both direct mechanical input and its molecular transducers to sense and respond to external stimuli. While it has been shown that isolated nuclei can adapt to applied force ex vivo, the mechanisms governing nuclear mechanoadaptation in response to physiologic forces in vivo remain unclear. To investigate nuclear mechanoadaptation in cells, we developed an atomic force microscopy (AFM) based procedure to probe live nuclei isolated from mesenchymal stem cells (MSCs) following the application of low intensity vibration (LIV) to determine whether nuclear stiffness increases as a result of LIV. Results indicated that isolated nuclei were, on average, 30% softer than nuclei tested within intact MSCs prior to LIV. When the nucleus was isolated following LIV (0.7 g, 90 Hz, 20 min) applied four times (4×) separated by 1 h intervals, stiffness of isolated nuclei increased 75% compared to non-LIV controls. LIV-induced nuclear stiffening required functional Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, but was not accompanied by increased levels of the nuclear envelope proteins LaminA/C or Sun-2. While depleting LaminA/C or Sun-1&2 resulted in either a 47% or 39% increased heterochromatin to nuclear area ratio in isolated nuclei, the heterochromatin to nuclear area ratio was decreased by 25% in LIV-treated nuclei compared to controls, indicating LIV-induced changes in the heterochromatin structure. Overall, our findings indicate that increased apparent cell stiffness in response to exogenous mechanical challenge of MSCs in the form of LIV is in part retained by increased nuclear stiffness and changes in heterochromatin structure.

Nuclear mechanics is emerging as a key component of stem cell function and differentiation. While changes in nuclear structure can be visually imaged with confocal microscopy, mechanical characterization of the nucleus and its sub-cellular components require specialized testing equipment. A computational model permitting cell-specific mechanical information directly from confocal and atomic force microscopy of cell nuclei would be of great value. Here, we developed a computational framework for generating finite element models of isolated cell nuclei from multiple confocal microscopy scans and simple atomic force microscopy (AFM) tests. Confocal imaging stacks of isolated mesenchymal stem cells were converted into finite element models and siRNA-mediated Lamin A/C depletion isolated chromatin and Lamin A/C structures. Using AFM-measured experimental stiffness values, a set of conversion factors were determined for both chromatin and Lamin A/C to map the voxel intensity of the original images to the element stiffness, allowing the prediction of nuclear stiffness in an additional set of other nuclei. The developed computational framework will identify the contribution of a multitude of sub-nuclear structures and predict global nuclear stiffness of multiple nuclei based on simple nuclear isolation protocols, confocal images and AFM tests.

Over the last 2 decades, the role of private industry in university research has expanded dramatically throughout much of the industrialized world. In the US, technology transfer through industry-university research collaboration (IURC) is ubiquitous and actively encouraged both by university administrators and an array of federal and state policies. This paper examines the rules and organizational forms for structuring industry-university partnerships, with a focus on the problem of protecting confidential information in the context of IURC.

Japanese antitrust law is a matter of keen interest in the US. On balance, the public discussion of this issue has been critical. Japan's competition law regime has been described as weak, ineffectual, half-hearted and inadequate. The US has identified the weakness of Japan's competition policy as a trade barrier. Against this backdrop, The Japan Fair Trade Commission recently issued its first major policy statement on antitrust enforcement concerning technology licensing in a decade. This paper offers a critical examination of Japanese technology licensing antitrust law and enforcement policy.

The nucleus, central to all cellular activity, relies on both direct mechanical input and its molecular transducers to sense and respond to external stimuli. While it has been shown that isolated nuclei can adapt to force directly ex vivo, nuclear mechanoadaptation in response to physiologic forces in vivo remains unclear. To gain more knowledge regarding nuclear mechanoadaptation in cells, we have developed an atomic force microscopy (AFM) based experimental procedure to isolate live nuclei and specifically test whether nuclear stiffness increases following the application of low intensity vibration (LIV) in mesenchymal stem cells (MSCs). Results indicated that isolated nuclei, on average, were 30% softer than nuclei tested within intact MSCs. When the nucleus was isolated following LIV (0.7g, 90Hz, 20min) applied four times (4x) separated by 1h intervals, stiffness of isolated nuclei increased 75% compared to controls. LIV-induced intact MSC and nuclear stiffening required functional Linker of Nucleoskeleton and Cytoskeleton (LINC) complex but was not accompanied by increased levels of nuclear envelope proteins LaminA/C or Sun-2. Indicating LIV-induced changes in the chromatin structure, while depleting LaminA/C or Sun-1&2 resulted in a 47% and 39% increased heterochromatin to nuclear area ratio in isolated nuclei, ratio of heterochromatin to nuclear area was decreased by 25% in LIV treated nuclei compared to controls. Overall, our findings indicate that increased apparent cell stiffness in response to exogenous mechanical challenge in the form of LIV are in-part retained by increased nuclear stiffness and changes in chromatin structure in MSCs. Competing Interest Statement The authors have declared no competing interest.