McEvoy, N. et al. Synthesis and analysis of thin conducting pyrolytic carbon films. Carbon 50, 1216–1226 (2012).

Renal fibrogenesis is a dynamic and converging process that involves inflammatory cell infiltration, the activation and expansion of matrix-producing fibroblasts from multiple sources, ECM production and accumulation, tubular atrophy, vascular rarefaction and hypoxia15. Here, we confirmed that P311 is highly expressed in the cytoplasm of some tubular epithelial cells in renal fibrosis in both humans and mice, but not in normal human kidney tissue or in sham-operated mouse kidneys. P311 is characterized by the presence of a conserved PEST domain, and the main function of the PEST domain is to mark proteins for rapid degradation by the ubiquitin/proteasome system. In renal fibrosis, the PEST domain might be suppressive to retard P311 degradation. Then to explore the potential role of P311 in renal fibrosis, we used P311−/− mice. These mice have normal kidney organization, histological architecture, blood and urine parameters (Supplementary Figure 1), and P311 is negative in the obstructed kidneys from P311−/− mice (Supplementary Figure 2). However, interstitial collagen deposition and collagen I mRNA levels were down-regulated in obstructed kidneys from P311−/− mice. These results were consistent with our previous observations in human fibroblasts, in which P311 transfection stimulated collagen I expression10, and P311 is up-regulated in hypertrophic scar tissue compared to normal skin tissue24. These findings suggest that P311 might be involved in renal fibrogenesis. Surprisingly, P311 over-expression in two murine fibroblast cell lines decreased collagen I expression9. P311 is central to reactive oxygen species-modulated hepatic stellate cells migration, which may be involved in the development of liver fibrosis. However, P311 knock-down does not affect collagen type I and α-SMA expression28. It is difficult to explain this discrepancy with our results, which demonstrated that the different cell type dictates the different functions of P311 where it is expressed. Additional studies are required to clarify this issue.

“Telomerase activators have been reported (de Jesus et al, 2011; Fauce et al, 2008; Harley et al, 2011), however, their mechanism of action is still poorly understood. Instead, we turned into a TERT-based gene therapy strategy to extend longevity, to our knowledge unprecedented in the context of aging studies. “

All three NOS isoforms are expressed in bone and the role of NO in bone metabolism has been confirmed in intact animals with single-gene deletion of NOS isoforms53. However, which subtype of the affected NOS helps to regulate pro-inflammation (Fig. 3) and bone formation (Fig. 4) of BMSCs stimulated by the positively-charged surface (PArN) is unknown. Herein, the effects of the three isoforms on osteo-genetic expression in the presence and absence of NOS inhibition is studied in order to disclose the signaling pathway of NO. Recent studies54 indicate that targeted deletion of the eNOS isoform in mice leads to an osteoblast-driven mild osteoporotic bone phenotype. As shown in Fig. 6a, the same tendency is observed from the blank and PArN groups. Stem cells exposed to L-NAME increase the mRNA expression of Runx-2 but significantly reduce the ALP expression. Therefore, inhibition of eNOS has little effects on the OCN and BSP expressions in BMSCs cultured on PArN. When the nNOS inhibitor (Sper) is added to the cell culture medium instead of L-NAME, the nNOS expression is also suppressed on both the blank and PArN (Fig. 6b). These results are partially evidenced by those obtained from mice with global deletion of nNOS55, showing increased bone mass due to a reduced bone turnover rate and a phenotype that is repeated in mice with deletion of all three NOS genes. The same change observed from the blank and PArN indicates that nNOS is not the signal pathway for the positively-charged surface with tertiary amines (PArN) concerning regulation of the BMSCs osteogenic expression.

As noted above, we do not anticipate paying any cash dividends in the foreseeable future. If we were to pay dividends, we expect to pay such dividends in NIS. A dividend paid in NIS, including the amount of any Israeli taxes withheld, will be includible in a U.S. Holder’s income at a U.S. dollar amount calculated by reference to the exchange rate in effect on the date such dividend is received, regardless of whether the payment is in fact converted into U.S. dollars. If the dividend is converted to U.S. dollars on the date of receipt, a U.S. Holder generally will not recognize a foreign currency gain or loss. However, if the U.S. Holder converts the NIS into U.S. dollars on a later date, the U.S. Holder must include, in computing its income, any gain or loss resulting from any exchange rate fluctuations. The gain or loss will be equal to the difference between (i) the U.S. dollar value of the amount included in income when the dividend was received and (ii) the amount received on the conversion of the NIS into U.S. dollars. Such gain or loss generally will be ordinary income or loss and will be U.S. source income or loss for U.S. foreign tax credit purposes. U.S. Holders should consult their own tax advisors regarding the tax consequences to them if we pay dividends in NIS or any other non-U.S. currency.

Chang, T. M., Cooper, R. J. & Williams, E. R. Locating protonated amines in clathrates. J. Am. Chem. Soc. 135, 14821–14830 (2013).

held End-of-Phase 2 discussions with the U.S. Food and Drug Administration, or FDA, the Medicines and Healthcare Products Regulatory Agency in the United Kingdom, or the U.K., or MHRA, and Health Canada. Based on FDA feedback, as well as advice provided by MHRA and Health Canada, we announced the design of a single-arm Phase 3 study in treatment-naïve PNH patients. In January 2019, we concluded scientific advice and protocol design discussions with the European Medicines Agency (EMA). The EMA was not receptive to a single-arm study design to support approval of zilucoplan in PNH. We do not plan to alter the design of the Phase 3 PNH program, but are reassessing the likelihood of obtaining marketing authorization for PNH in the European Union, or E.U.

Under the Companies Law, and the Securities Law, 5738—1968, or the Securities Law, a company may indemnify, or undertake in advance to indemnify, an Office Holder for the following liabilities and expenses, imposed on Office Holder or incurred by Office Holder due to acts performed by him or her as an Office Holder, provided its articles of association include a provision authorizing such indemnification:

Long, L. et al. Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat models of pulmonary hypertension: potential for activin receptor-like kinase-5 inhibition in prevention and progression of disease. Circulation 119, 566–576 (2009).

(a) Cell apoptosis and (b) Cell cycle of BMSCs cultured on blank, PE, PAr, and PArN at day 1 and day 3. The figures show the cell state for triplicate experiments and 10,000 cells are analyzed.

Lin, S. Q. et al. QiShenYiQi Pills(R) prevent cardiac ischemia-reperfusion injury via energy modulation. Int. J. Cardiol. 168, 967–974, 10.1016/j.ijcard.2012.10.042 (2013).

Under the Companies Law, a person may not acquire shares in a public company if, after the acquisition, he will hold more than 90% of the shares or more than 90% of any class of shares of that company, unless a tender offer is made to purchase all of the shares or all of the shares of the particular class. The Companies Law also provides, subject to certain exceptions, that as long as a shareholder in a public company holds more than 90% of the company’s shares or of a class of shares, that shareholder shall be precluded from purchasing any additional shares unless tendering an offer to purchase all of the outstanding shares of the company or the applicable class of the shares. If the shareholders who do not respond to or accept the offer hold less than 5% of the issued and outstanding share capital of the company or of the applicable class of the shares, and more than half of the shareholders who do not have a personal interest in the offer accept the offer, all of the shares that the acquirer offered to purchase will be transferred to the acquirer by operation of law. However, a tender offer will be accepted if the shareholders who do not accept it hold less than 2% of the issued and outstanding share capital of the company or of the applicable class of the shares.