The TGF-β/Smad signaling pathway plays a key role in fibrotic disease pathogenesis33. TGF-β1 binds to TβR II and then recruits TβR I. The activated complex directly phosphorylates downstream intracellular molecules, including Smad2 and Smad3. Phosphorylated Smad2/3 associates with Smad4 to form a complex that translocates into the nucleus to initiate gene transcription and regulate cell behavior33,34. TGF-β receptor activation mediates many physiological and pathological processes, including CKD18. Increased TβR II expression aggravates ECM accumulation in fibrotic tissue. Inhibition of TGF-β1/Smad2 signaling pathways modulates the development of fibrosis in adriamycin-induced nephropathy35. TGF-β/Smad3 signaling promotes renal fibrosis by inhibiting miR-29 and up-regulating miR-2136,37. Furthermore, inhibiting the endothelial-mesenchymal transition with a Smad3-specific inhibitor (SIS3) delays the early development of diabetic nephropathy20. Herein, we found that TβR I and TβR II mRNA expression was induced in the UUO model, but P311 knockout significantly inhibited this up-regulation in this mouse model. Similarly, obstructed kidneys from P311−/− mice showed obviously impaired TGF-β1, p-Smad2, Smad2, p-Smad3, Smad3 and Smad4 protein expression compared to those from P311+/+ mice. Taken together, these results indicated that P311 regulates not only TGF-β1 but also the corresponding receptors and the Smad signaling pathway, which may be involved in the regulation of renal fibrosis by P311. However, Meng XM et al. found that Smad2 deletion promotes collagen I and III expression in a mouse UUO model38. This finding differs from our previous data, and additional studies are required to clarify this discrepancy. TGF-β signaling pathway activation results in the protein expression of inhibitory Smads, such as Smad6 and Smad7. The inhibitor Smad7 can bind to activated TβR I to interfere with TGF-β-induced Smad2/3 activation. In renal fibrosis, Smad7 is renoprotective and blocks the fibrotic effect of TGF-β in renal tubular epithelial cells by inhibiting Smad2 activation and altering TGF-β/Smad3-regulated microRNA expression39,40. Smad7 over-expression restores the balance of TGF/Smad signaling and exerts a therapeutic effect in CKD41. We found that Smad7 protein expression in both P311+/+ and P311−/− mice decreased after UUO compared to sham operation, but the decrease was more marked in P311−/− mice. This result was unexpected. Notably, P311 differentially regulated TGF-β1 and Smad proteins. We also found that TGFβ1-positive regions seem to be co-localized with P311-positive regions, α-SMA positive regions and acidophilic degeneration in some tubular epithelial cells within obstructed kidney tissue. We hypothesize that TGF-β/Smad signaling is involved in P311-induced EMT in renal fibrogenesis.

If our ordinary shares become a “penny stock,” it may be more difficult for investors to sell their ordinary shares, and the market price of our ordinary shares may be adversely affected.

Well Aldebaran it’s hard to argue with your very logical mathematical mind. I like option 1. Being 105 in good health is good stuff. I’ll take it.

(d)      Disclosed in this report any change in the Company’s internal control over financial reporting that occurred during the period covered by the annual report that has materially affected, or is reasonably likely to materially affect, the Company’s internal control over financial reporting; and

Our Articles provide that a director may, by written notice to the Company, appoint another person to serve as an alternate director provided that such appointment is approved by a majority of the directors then in office, and that such appointing director may remove such alternate director. Any alternate director shall be entitled to notice of meetings of the Board and of relevant committees and to attend and vote accordingly, except that the alternate has no standing at any meeting at which the appointing director is present or at which the appointing director is not entitled to participate as provided in the Companies Law. A person who is not qualified to be appointed as a director, or a person who already serves as a director or an alternate director, may not be appointed as an alternate director.

The agenda for a shareholder meeting is determined by the Board and must include matters in respect of which the convening of a shareholder meeting was demanded and any matter requested to be included by holder(s) of 1% of the Company’s voting rights. According to regulations promulgated pursuant to the Companies Law and governing the terms of notice and publication of shareholder meetings of public companies, or the General Meeting Regulations, holder(s) of one percent or more of the Company’s voting rights may propose any matter appropriate for deliberation at a shareholder meeting to be included on the agenda of a shareholder meeting, generally by submitting a proposal within seven days of publicizing the convening of a shareholder meeting, or, if the Company publishes a preliminary notice at least 21 days prior to publicizing the convening of a meeting (stating its intention to convene such meeting and the agenda thereof), within 14 days of such preliminary notice. Any such proposal must further comply with the information requirements under applicable law and the Articles.

        We do not own or operate manufacturing facilities for the production of clinical or commercial quantities of our product candidates, and we lack the resources and the capabilities to do so. As a result, we currently rely on third parties for supply of the active pharmaceutical ingredients, or API, in our product candidates. Our current strategy is to outsource all manufacturing of our product candidates and products to third parties.

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Our product candidates may cause undesirable side effects or have other properties that could delay or prevent their regulatory approval, limit the commercial profile of an approved label, or result in significant negative consequences following marketing approval, if any.

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        We have never declared or paid cash dividends on our common stock, and we do not expect to pay any cash dividends on our common stock in the foreseeable future. Payment of future dividends, if any, on our common stock will be at the discretion of our board of directors after taking into account various factors, including our financial condition, operating results, anticipated cash needs, and plans for expansion.

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