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Osteoarthritis (OA) is the most prevalent degenerative joint disease with multifactorial etiology caused by risk factors such as ageing, obesity and trauma. Previously, it was reported that the inhibition of microRNA-34a (miR-34a) may reduce rat chondrocyte apoptosis induced by IL-1β, whereas the molecular mechanism and the role of miR-34a in human chondrocyte as well as in OA progression remains to be determined. In the current study, using MTT, luciferase reporter assays and western blot analysis we identified that miR-34a was upregulated while silent information regulator 1 (SIRT1) was inhibited in chondrocytes from 12 OA patients compared with healthy chondrocytes from 10 trauma amputees. Overexpression of miR-34a promoted apoptosis and inhibited cell proliferation in human chondrocytes. Transfection with miR-34a mimic inhibited SIRT1 expression, which attenuated the deacetylation of p53, leading to the upregulation of Bax and downregulation of Bcl-2. Furthermore, results from the western blot analysis and luciferase reporter assay demonstrated that SIRT1 was directly regulated by miR-34a in human chondrocytes. A rat model of OA was induced through anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx). The results showed that the intra-articular injection of lentiviral vector encoding anti-miR-34a sequence effectively ameliorated the progression of OA. The results suggest that miR-34a has a crucial role in the pathogenesis of OA through direct regulation of the SIRT1/p53 signaling pathway and serves as a potential therapeutic target of OA.

[1] We test hypothetical tsunami scenarios against a 4,600-year record of sandy deposits in a southern Oregon coastal lake that offer minimum inundation limits for prehistoric Cascadia tsunamis. Tsunami simulations constrain coseismic slip estimates for the southern Cascadia megathrust and contrast with slip deficits implied by earthquake recurrence intervals from turbidite paleoseismology. We model the tsunamigenic seafloor deformation using a three-dimensional elastic dislocation model and test three Cascadia earthquake rupture scenarios: slip partitioned to a splay fault; slip distributed symmetrically on the megathrust; and slip skewed seaward. Numerical tsunami simulations use the hydrodynamic finite element model, SELFE, that solves nonlinear shallow-water wave equations on unstructured grids. Our simulations of the 1700 Cascadia tsunami require >12-13 m of peak slip on the southern Cascadia megathrust offshore southern Oregon. The simulations account for tidal and shoreline variability and must crest the $6-m-high lake outlet to satisfy geological evidence of inundation. Accumulating this slip deficit requires ≥360-400 years at the plate convergence rate, exceeding the 330-year span of two earthquake cycles preceding 1700. Predecessors of the 1700 earthquake likely involved >8-9 m of coseismic slip accrued over >260 years. Simple slip budgets constrained by tsunami simulations allow an average of 5.2 m of slip per event for 11 additional earthquakes inferred from the southern Cascadia turbidite record. By comparison, slip deficits inferred from time intervals separating earthquake-triggered turbidites are poor predictors of coseismic slip because they meet geological constraints for only 4 out of 12 ($33%) Cascadia tsunamis.Citation: Witter, R. C., Y. Zhang, K. Wang, C. Goldfinger, G. R. Priest, and J. C. Allan (2012), Coseismic slip on the southern Cascadia megathrust implied by tsunami deposits in an Oregon lake and earthquake-triggered marine turbidites,

To explore the local tsunami hazard from the Cascadia subduction zone we (1) evaluate geologically reasonable variability of the earthquake rupture process, (2) specify 25 deterministic earthquake sources, and (3) use resulting vertical coseismic deformations for simulation of tsunami inundation at Cannon Beach, Oregon. Maximum runup was 9-30 m (NAVD88) from earthquakes with slip of *8-38 m and M w *8.3-9.4. Minimum subduction zone slip consistent with three tsunami deposits was 14-15 m. By assigning variable weights to the source scenarios using a logic tree, we derived percentile inundation lines that express the confidence level (percentage) that a Cascadia tsunami will not exceed the line. Ninety-nine percent of Cascadia tsunami variation is covered by runup B30 m and 90% B16 m with a ''preferred'' (highest weight) value of *10 m. A hypothetical maximum-considered distant tsunami had runup of *11 m, while the historical maximum was *6.5 m.

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[1] As integral capability within an end-to-end observatory for the Columbia River estuary-plume-shelf system, we routinely create simulation databases of 3-D baroclinic circulation with unstructured grid models SELFE (Semi-implicit Eulerian-Lagrangian Finite Element) and ELCIRC (Eulerian-Lagrangian Circulation). Here, 1999-2006 simulations are used to study plume variability at multiple temporal scales: interannual, seasonal, and event scale. Time series of plume metrics, together with climatology and anomalies of surface salinity, suggest that simulations usefully capture key features of plume dynamics. In particular, simulations capture seasonal variability around two known trends: a coastally attached northward winter plume and a detached southward summer plume. Results show significant interannual variability of the plume orientation and extent, with potential implications on the variability of productivity in the system. An empirical orthogonal function analysis confirms that a bidirectional plume is prevalent in summer, showing that the result holds true regardless of interannual variability. Short-term bidirectional plumes, previously observed or modeled only in summer, can also occasionally develop in winter as a result of episodically strong upwelling-favorable winds. Across years, the predominantly coastal attached northward plume in late fall and winter is found to separate frequently from the coast, during wind relaxation events or weak wind reversals. Multiple skill scores are used to evaluate the quality of the simulations against earlier circulation databases and data. Analysis of root-mean-square error and bias suggests overall superiority of SELFE-generated over ELCIRC-generated simulation databases, but the generality of the conclusions is limited by (1) models not being the only difference between simulation databases and (2) no model prevailing across all error metrics.