Physiological and pathological aspects of Aβ in iron homeostasis via 5'UTR in the APP mRNA and the therapeutic use of iron-chelators

Many studies have highlighted the pathological involvement of iron accumulation and iron-related oxidative stress (OS) in Alzheimer's disease (AD). Iron was further demonstrated to modulate expression of the Alzheimer's amyloid precursor holo-protein (APP) by a mechanism similar to that of regulation of ferritin-L and -H mRNA translation through an iron-responsive element (IRE) in their 5' untranslated regions (UTRs). Here, we discuss two aspects of the link between iron and AD, in relation to the recently discovered IRE in the 5'UTR of APP mRNA. The first is the physiological aspect: a compensatory neuroprotective response of amyloid-β protein (Aβ) in reducing iron-induced neurotoxicity. Thus, given that Aβ possesses iron chelation sites, it is hypothesized that OS-induced intracellular iron may stimulate APP holo-protein translation (via the APP 5'UTR) and subsequently the generation of its cleavage product, Aβ, as a compensatory response that eventually reduces OS. The second is the pathological aspect: iron chelating compounds target the APP 5'UTR and possess the capacity to reduce APP translation, and subsequently Aβ levels, and thus represent molecules with high potential in the development of drugs for the treatment of AD

A novel familial mutation in the PCSK1 gene that alters the oxyanion hole residue of proprotein convertase 1/3 and impairs its enzymatic activity.

Four siblings presented with congenital diarrhea and various endocrinopathies. Exome sequencing and homozygosity mapping identified five regions, comprising 337 protein-coding genes that were shared by three affected siblings. Exome sequencing identified a novel homozygous N309K mutation in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, encoding the neuroendocrine convertase 1 precursor (PC1/3) which was recently reported as a cause of Congenital Diarrhea Disorder (CDD). The PCSK1 mutation affected the oxyanion hole transition state-stabilizing amino acid within the active site, which is critical for appropriate proprotein maturation and enzyme activity. Unexpectedly, the N309K mutant protein exhibited normal, though slowed, prodomain removal and was secreted from both HEK293 and Neuro2A cells. However, the secreted enzyme showed no catalytic activity, and was not processed into the 66 kDa form. We conclude that the N309K enzyme is able to cleave its own propeptide but is catalytically inert against in trans substrates, and that this variant accounts for the enteric and systemic endocrinopathies seen in this large consanguineous kindred

The Informative Process Model as a New Intervention for Attitude Change in Intractable Conflicts: Theory and Empirical Evidence

Peacemaking is especially challenging in situations of intractable conflict. Collective narratives in this context contribute to coping with challenges societies face, but also fuel conflict continuation. We introduce the Informative Process Model (IPM), proposing that informing individuals about the socio-psychological processes through which conflict-supporting narratives develop, and suggesting that they can change via comparison to similar conflicts resolved peacefully, can facilitate unfreezing and change in attitudes. Study 1 established associations between awareness of conflict costs and conflict-supporting narratives, belief in the possibility of resolving the conflict peacefully and support for pursuing peace among Israeli-Jews and Palestinians. Studies 2 and 3 found that exposure to IPM-based original videos (vs. control) led Israeli-Jews to deliberation of the information presented, predicting acceptance of the IPM-based message, which, in turn, predicted support for negotiations. Study 3 also found similar effects across IPM-based messages focusing on different conflict-supporting themes. We discuss the implications to attitude change in intractable conflicts

The Paradoxical Thinking ‘Sweet Spot’: The Role of Recipients’ Latitude of Rejection in the Effectiveness of Paradoxical Thinking Messages Targeting Anti-Refugee Attitudes in Israel

The current research examined whether for a message that is based on the paradoxical thinking principles—i.e., providing extreme, exaggerated, or even absurd views, that are congruent with the held views of the message recipients—to be effective, it needs to hit a ‘sweet spot’ and lead to a contrast effect. That is, it moderates the view of the message's recipients. In the framework of attitudes toward African refugees and asylum seekers in Israel by Israeli Jews, we found that compared to more moderate messages, an extreme, but not too extreme, message was effective in leading to unfreezing for high morally convicted recipients. The very extreme message similarly led to high levels of surprise and identity threat as the extreme message that was found to be effective. However, it was so extreme and absurd that it was rejected automatically. This was manifested in high levels of disagreement compared to all other messages, rendering it less effective compared to the extreme, paradoxical thinking, message. We discuss these findings’ practical and theoretical implications for the paradoxical thinking conceptual framework as an attitude change intervention, and for social judgment theory

IQOS and cigarette advertising across regulatory periods and population groups in Israel: a longitudinal analysis

BACKGROUND: Tobacco regulation recently changed in Israel, including a partial advertisement ban. We assessed the impact of regulatory changes on Philip Morris International\u27s (PMI) IQOS and cigarette advertisements. METHODS: Weekly number of ads and weekly adspend of PMI\u27s IQOS and cigarettes were analysed descriptively and using Quasi-Poisson regressions over time, across regulatory periods and in relation to subpopulations (general public, Arab, Russian and Ultra-Orthodox), from 25 December 2016 to 4 August 2020. Exponentiated coefficients (a value \u3e1 indicates an increase) and 95% CIs are reported. RESULTS: The average weekly number of ads and the average weekly adspend of IQOS were higher than cigarettes (42.22 vs 26.76 ads/week and 59 409 vs 45 613 new Israeli shekels/week; p\u3c0.001 for both) during the study period, with exclusive IQOS advertisements during market penetration (December 2016 to May 2017). Variation in both outcomes was observed with regard to regulatory decisions. After the advertisement ban, there was a significant decrease in the weekly number of ads (IQOS: ß=0.04, 95% CI 0.002 to 0.20; cigarettes: ß=0.05, 95% CI 0.01 to 0.15) and weekly adspend (IQOS: ß=0.15, 95% CI 0.07 to 0.29; cigarettes: ß=0.31, 95% CI 0.17 to 0.53) for both products. The Ultra-Orthodox had significantly higher average weekly ads compared with the Arab population (IQOS: 0.67 vs 0.07; cigarettes: 2.74 vs 0.13; p0.02 for both) but lower adspend. CONCLUSIONS: IQOS and cigarette advertisements varied over time and appeared to have been impacted by regulatory changes. PMI invested more in IQOS advertisements than in cigarettes, with a partial advertisement ban decreasing both products\u27 advertisements. PMI might be targeting the Ultra-Orthodox Jewish population which has a low smoking rate. Further research and surveillance are needed to better understand targeting strategies in order to inform tobacco control policy

A novel familial mutation in the PCSK1 gene that alters the oxyanion hole residue of proprotein convertase 1/3 and impairs its enzymatic activity.

Four siblings presented with congenital diarrhea and various endocrinopathies. Exome sequencing and homozygosity mapping identified five regions, comprising 337 protein-coding genes that were shared by three affected siblings. Exome sequencing identified a novel homozygous N309K mutation in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, encoding the neuroendocrine convertase 1 precursor (PC1/3) which was recently reported as a cause of Congenital Diarrhea Disorder (CDD). The PCSK1 mutation affected the oxyanion hole transition state-stabilizing amino acid within the active site, which is critical for appropriate proprotein maturation and enzyme activity. Unexpectedly, the N309K mutant protein exhibited normal, though slowed, prodomain removal and was secreted from both HEK293 and Neuro2A cells. However, the secreted enzyme showed no catalytic activity, and was not processed into the 66 kDa form. We conclude that the N309K enzyme is able to cleave its own propeptide but is catalytically inert against in trans substrates, and that this variant accounts for the enteric and systemic endocrinopathies seen in this large consanguineous kindred