I wrote a short article based on a recent paper by Leo Zacharski, in which he calculated that a normal ferritin, that is, one that is not associated with any form of ill health, is no more than 100. http://roguehealthandfitness.com/the-normal-value-iron-matters/

In the conduction system of the heart, HCN4 channels are the predominant isoform expressed, accounting for nearly 80% of Ih. The isoform which contributes most to the remaining current is species dependent, with HCN1 dominant in rabbit4 and HCN2 dominant in mouse7. In non-conduction tissue, HCN2 appears to be the dominant isoform with ubiquitous distribution in atrial and ventricular myocytes at low levels compared to the conduction system. Since cholesterol regulates a variety of ion channels important for cardiac function29,38,39,40,41, including rabbit HCN4 in which cholesterol depletion had previously been shown to modulate voltage dependence of activation and the kinetics of deactivation28, we systematically examined the role of cholesterol in regulating the 3 human cardiac isoforms of HCN channels. Intriguingly, we observed isoform specific differences in the regulation of these channels. While cholesterol depletion or enrichment had no effect on the voltage-dependence of human HCN1 and HCN2 activation, we observed a +10 mV shift to more depolarized potentials in human HCN4 channels. In HCN1 channels, cholesterol depletion slowed the slow-component of activation (τslow), but did not alter the deactivation kinetics. Cholesterol modulation did not affect the activation kinetics of HCN2 and HCN4 channels, but cholesterol enrichment slowed the rate of deactivation in these isoforms. The effect of cholesterol modulation on channel trafficking was striking (Fig. 4B). While HCN1 channel expression increased with cholesterol depletion, the slower activation kinetics and unchanged deactivation kinetics explain the unchanged current density compared to control (Fig. 1). In HCN2 channels, cholesterol enrichment caused a reduction in surface expression, however, channels at the surface deactivated more slowly, which likely recovers the current density to control levels (Fig. 2). Cholesterol depletion did not change the expression of channels at the surface, but decreased the current density despite no changes in kinetics. It is possible that cholesterol depletion in HCN2 channels causes a reduction in the unitary conductance, or generates a subpopulation of channels that are “silenced” (ie. Popen = 0), similarly to what is expected to occur in Kir2 channels upon cholesterol enrichment29,42. This could arise from altered sensitivity to tonic levels in cAMP, or sensitivities to changes in the physiochemical properties of membranes with decreased cholesterol43. However, it is not immediately clear why slowed deactivation and increased expression of HCN4 channels upon cholesterol enrichment does not lead to increased current densities at steady-state.

We also rely on trade secrets to protect our proprietary know-how and technological advances, especially where we do not believe patent protection is appropriate or obtainable. However, trade secrets are difficult to protect. We rely in part on confidentiality agreements with our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to protect our trade secrets and other proprietary information. These agreements may not effectively prevent disclosure of confidential information and may not provide an adequate remedy in the event of unauthorized disclosure of confidential information. In addition, others may independently discover our trade secrets and proprietary information. Costly and time-consuming litigation could be necessary to enforce and determine the scope of our proprietary rights. Failure to obtain or maintain trade secret protection could enable competitors to use our proprietary information to develop products that compete with Aramchol or any future product candidates or cause additional material adverse effects upon our competitive business position.

A deterioration in global economic conditions and uncertainties may have an adverse effect on our business. For instance, interest rates, the liquidity of the credit markets and the volatility of the capital markets could also affect the value of our investments, if any, and our ability to liquidate such investments in order to fund our operations. Interest rates and the ability to access credit markets could also adversely affect the ability of patients and distributors to purchase, pay for and effectively distribute Aramchol and any future product candidates.

Total RNA was isolated from NK cells using an RNeasy Mini Kit (Qiagen, Valencia, CA). cDNA was synthesized by reverse transcription from 50 ng total RNA using a cDNA Reverse Transcriptase Kit (TaKaRa, Japan). The PCR reaction was carried out in 384-well plate using the ABI Prism 7900HT Sequence Detection System (Applied Biosystems). Real-time PCR primers for perforin, granzyme B, and GAPDH were as follows: perforin (forward, 5′-AGCACAAGTTCGTGCCAGG-3′, and reverse, 5′-GCGTCTCTCATTAGGGAGTTTTT-3′); granzyme B (forward, 5′-CCACTCTCGACCCTACATGG-3′, and reverse, 5′-GGCCCCCAAAGTGACATTTATT-3′); GAPDH (forward, 5′-CATGGCCTTCCGTGTTCCTA-3′, and reverse, 5′-ATGCCTGCTTCACCACCTTCT-3′).

In the event of a merger or consolidation of our company subsequent to which we would no longer exist as a legal entity, or a sale of all, or substantially all, of our ordinary shares or assets or other transaction having a similar effect on us, or a Transaction, any unexercised options then outstanding will be cancelled. Notwithstanding the foregoing, the Board, or the relevant committee of the Board, may determine that the options will not be cancelled but will be assumed or substituted for an appropriate number of the same type of shares or other securities of the successor company as were distributed to the Company or the shareholders in connection with the Transaction. In addition, the Board, or the relevant committee of the Board, may determine to include in certain option agreements either a clause that provides for acceleration of vesting of all or part of the unvested options in the event of a Transaction or the occurrence of another event or a clause which provides that if the optionee’s employment with the successor company is terminated by the successor company without cause within a certain period, not to exceed two years from the closing of such Transaction, all or part of the unvested options shall be accelerated.

In the 1970s, there was a lot of interest in controlled-release research for pharmaceutical applications. Much of this activity focused on the development of long-acting contraceptives. The goal was to develop formulations that released contraceptive steroids at a programmed rate for one month or longer following a single parenteral administration. Initially, researchers in the contraception field used non-biodegradable silicone materials as controlled-release excipients (2). PLG polymers were later found to have good biocompatibility and desirable bioabsorption properties; as a result, many investigators began to formulate contraceptive steroids with PLG as functional polymers. Various dosage forms, including injectable microparticles, implants, and fibers, were investigated for both systemic and local delivery (3).

Bode-Böger, S. M., Scalera, F. & Ignarro, L. J. The L-arginine paradox: importance of the L-arginine/asymmetrical dimethylarginine ratio. Pharmacology & therapeutics 114, 295–306 (2007).

        Known as our Extreme Diversity platform, our proprietary macrocyclic peptide chemistry technology allows us to produce synthetic macrocyclic peptides that combine the diversity and specificity of antibodies with the pharmacological properties of small molecules.

Cells were washed thrice with ice-cold PBS and then incubated for 30 min at 4 °C with 1 mM EZ-link sulfo-N-hydroxysuccinimide (sulfo-NHS)-SS-biotin (Pierce, Rockford, IL). After rinsing the cells twice with PBS-glycine, the cells were scraped into a lysis buffer (0.1% IGEPAL, 1% SDS, 250 mM NaCl, 50 mM Tris-HCl pH 7.5 and protease inhibitor) and incubated for 30 min at 4 °C. Three 20 secs bursts of sonication ensured complete cell rupturing. After a 30 min centrifugation at 20,800 g the protein in the supernatant was determined and 800 mg of protein was incubated overnight at 4 °C with immobilized Streptavidin (Pierce). After washing the resin at least seven times with binding buffer (PBS, 0.1% IGEPAL, 0.1% SDS), the biotinylated proteins were eluted by Laemmli buffer containing 0.5 M DTT. Samples were then probed by western blot using isoform specific anti-HCN antibodies.

Forest plot detailing weighted mean difference and 95%Cl for the impact of hydrophilic (left) and hydrophobic (right) statins on plasma concentrations of ADMA. Meta-analysis was performed using a random-effect model with inverse variance weighting.

We believe that we qualify as an “Industrial Company” within the meaning of the Industry Encouragement Law. There can be no assurance that we will continue to qualify as an Industrial Company in the future or that the benefits described above will be available to us at all.