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To understand the consequences of increased miR-322 in hypoxia, we investigated the effects of miR-322 overexpression and knockdown on the proliferation and migration in rat PASMCs. As shown in Fig. 5a, stable overexpression of miR-322 significantly accelerated the proliferation rate of PASMCs compared to its control cells both under normoxia and hypoxia by MTS assay. EdU incorporation assay, a specific assay that labels replicating cells, also showed higher fraction of proliferating cells in miR-322-expressing cells compared with control cells (Fig. 5b). FACS analysis of PI-stained cells indicated that the proportion of cells in S and G2/M phase was significantly increased, and cells in G1 phase decreased by a comparable degree (Fig. 5c). To further confirm these results, we performed the proliferation assay in PASMCs after miRNA knockdown. In contrast with miRNA overexpression studies, proliferation was significantly reduced in anti-322 transfected cells compared to that of control cells, both when exposed to normoxia or hypoxia (Fig. 5d,e,f). These data indicate that miR-322 can significantly accelerate the proliferation of PASMCs.

Celgene Corporation (NasdaqGS CELG ) Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global biopharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation.

Under Article 10a of Directive 2001/83/EC, an applicant may, in substitution for the results of its own pre-clinical and clinical research, present detailed references to published literature demonstrating that the active substance(s) of a product have a well- established medicinal use within the community for at least ten years with recognized efficacy and an acceptable level of safety in terms of the conditions set out in Annex I of Directive 2001/83/EC. In that event, the test and trial results shall be replaced by appropriate scientific literature. The applicant is entitled to refer to a variety of different types of literature, including reports of clinical trials with the same active substance(s) and epidemiological studies that indicate that the constituent or constituents of the product have an acceptable safety/efficacy profile for a particular indication. However, use of the published literature exemption is restricted by stating that in no circumstances active substances be treated as having a well- established use if they have been used for less than 10 years from the first systematic and documented use of the substance as a medicinal product in the EU. Even after 10 years’ systematic use, the threshold for well-established medicinal use might not be met. European pharmaceutical law requires the competent authorities to consider among other factors the period over which a substance has been used, the amount of patient use of the substance, the degree of scientific interest in the use of the substance (as reflected in the scientific literature) and the coherence (consistency) of all the scientific assessments made in the literature. For this reason, different substances may reach the threshold for well-established use after different periods, but the minimum period is 10 years. If the applicant seeks approval of an entirely new therapeutic use compared with that to which the published literature refers, additional pre-clinical and/or clinical results would have to be provided.

Tabrah, F., Gilbert, F., Batkin, S. & Bassett, C. A. L. Bone density changes in osteoporosis-prone women exposed to pulsed electromagnetic fields (PEMFs). J. Bone Miner. Res. 5, 437–442. (1990).

        We believe that our application of the following accounting policies, each of which require significant judgments and estimates on the part of management, is the most critical to aid in fully understanding and evaluating our reported financial results: (1) revenue recognition, (2) research and development costs, and (3) stock-based compensation.

To test the contribution of store-operated Ca2+ entry (SOCE) to the tumor cell–induced sustained Ca2+ signal, we used Baf A1 to deplete Ca2+ from acidic organelles, which are the Ca2+ stores responsible for tumor cell-mediated Ca2+ signals stimulated by ADPR (Fig. 4c and d). Depletion of Ca2+ stores by Baf A1 induced Ca2+ entry after Ca2+ was added to the bath perfusion solution, as described earlier36 (Fig. 5d). This SOCE was completely blocked by SK96365, a SOCE blocker, but not by ACA, a specific TRPM2 channel blocker. These findings indicate that the sustained Ca2+ signal is attributable to SOCE following Ca2+ mobilization by ADPR, and that TRPM2 is not involved in ADPR-mediated SOCE.

        The Company enters into certain agreements with other parties in the ordinary course of business that contain indemnification provisions. These typically include agreements with directors and officers, business partners, contractors, landlords and clinical sites. Under these provisions, the Company generally indemnifies and holds harmless the indemnified party for losses suffered or incurred by the indemnified party as a result of the Company’s activities. These indemnification provisions generally survive termination of the underlying agreement. The maximum potential amount of future payments the Company could be required to make under these indemnification provisions is unlimited. However, to date the Company has not incurred material costs to defend lawsuits or settle claims related to these indemnification provisions. As a result, the estimated fair value of these obligations is minimal.

        Concurrent with clinical trials, companies often complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the drug candidate and, among other things, the applicant must develop methods for testing the identity, strength, quality, purity, and potency of the final drug. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.

Mark-to-Market Election. Alternatively, if our ordinary shares are treated as “marketable stock,” a U.S. Holder would be allowed to make a “mark-to-market” election with respect to our ordinary shares, provided the U.S. Holder completes and files IRS Form 8621 in accordance with the relevant instructions and related Treasury Regulations. If that election is made, the U.S. Holder generally would include as ordinary income in each taxable year the excess, if any, of the fair market value of our ordinary shares at the end of the taxable year over such holder’s adjusted tax basis in such ordinary shares. The U.S. Holder would also be permitted an ordinary loss in respect of the excess, if any, of the U.S. Holder’s adjusted tax basis in our ordinary shares over their fair market value at the end of the taxable year, but only to the extent of the net amount previously included in income as a result of the mark-to- market election. A U.S. Holder’s tax basis in our ordinary shares would be adjusted to reflect any such income or loss amount. Gain realized on the sale, exchange or other disposition of our ordinary shares would be treated as ordinary income, and any loss realized on the sale, exchange or other disposition of our ordinary shares would be treated as ordinary loss to the extent that such loss does not exceed the net mark-to-market gains previously included in income by the U.S. Holder, and any loss in excess of such amount will be treated as capital loss. Amounts treated as ordinary income will not be eligible for the favorable tax rates applicable to qualified dividend income or long-term capital gains.

        Stock options granted to employees and directors under the Company’s equity plans generally have a ten-year term and vest over a period of four years, provided the individual continues to serve at the Company through the vesting dates. Options granted under all equity plans are exercisable at a price per share not less than the fair market value of the underlying common stock on the date of grant and not less than 110% of the fair market value for participants who own more than 10% of the Company’s voting power.

Schott, P. et al. Myocardial adaptation of energy metabolism to elevated preload depends on calcineurin activity : a proteomic approach. Basic Res. Cardiol. 103, 232–243, 10.1007/s00395-008-0696-1 (2008).