Endoplasmic reticulum stress in insulin resistance and diabetes

The endoplasmic reticulum is the main intracellular Ca²⁺ store for Ca²⁺ release during cell signaling. There are different strategies to avoid ER Ca²⁺ depletion. Release channels utilize first Ca²⁺-bound to proteins and this minimizes the reduction of the free luminal [Ca²⁺]. However, if release channels stay open after exhaustion of Ca²⁺-bound to proteins, then the reduction of the free luminal ER [Ca²⁺] (via STIM proteins) activates Ca²⁺ entry at the plasma membrane to restore the ER Ca²⁺ load, which will work provided that SERCA pump is active. Nevertheless, there are several noxious conditions that result in decreased activity of the SERCA pump such as oxidative stress, inflammatory cytokines, and saturated fatty acids, among others. These conditions result in a deficient restoration of the ER [Ca²⁺] and lead to the ER stress response that should facilitate recovery of the ER. However, if the stressful condition persists then ER stress ends up triggering cell death and the ensuing degenerative process leads to diverse pathologies; particularly insulin resistance, diabetes and several of the complications associated with diabetes. This scenario suggests that limiting ER stress should decrease the incidence of diabetes and the mobility and mortality associated with this illness.     

What Do We Know About Metal Recycling Rates?

The recycling of metals is widely viewed as a fruitful sustainability strategy, but little information is available on the degree to which recycling is actually taking place. This article provides an overview on the current knowledge of recycling rates for 60 metals. We propose various recycling metrics, discuss relevant aspects of recycling processes, and present current estimates on global end‐of‐life recycling rates (EOL‐RR; i.e., the percentage of a metal in discards that is actually recycled), recycled content (RC), and old scrap ratios (OSRs; i.e., the share of old scrap in the total scrap flow). Because of increases in metal use over time and long metal in‐use lifetimes, many RC values are low and will remain so for the foreseeable future. Because of relatively low efficiencies in the collection and processing of most discarded products, inherent limitations in recycling processes, and the fact that primary material is often relatively abundant and low‐cost (which thereby keeps down the price of scrap), many EOL‐RRs are very low: Only for 18 metals (silver, aluminum, gold, cobalt, chromium, copper, iron, manganese, niobium, nickel, lead, palladium, platinum, rhenium, rhodium, tin, titanium, and zinc) is the EOL‐RR above 50% at present. Only for niobium, lead, and ruthenium is the RC above 50%, although 16 metals are in the 25% to 50% range. Thirteen metals have an OSR greater than 50%. These estimates may be used in considerations of whether recycling efficiencies can be improved; which metric could best encourage improved effectiveness in recycling; and an improved understanding of the dependence of recycling on economics, technology, and other factors.     

A Two-Layered Targeting Mechanism Underlies Nuclear RNA Sorting by the Human Exosome

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Repeated strand invasion and extensive branch migration are hallmarks of meiotic recombination

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Structural basis for the N‐degron specificity of ClpS1 from Arabidopsis thaliana

The N‐degron pathway determines the half‐life of proteins in both prokaryotes and eukaryotes by precisely recognizing the N‐terminal residue (N‐degron) of substrates. ClpS proteins from bacteria bind to substrates containing hydrophobic N‐degrons (Leu, Phe, Tyr, and Trp) and deliver them to the caseinolytic protease system ClpAP. This mechanism is preserved in organelles such as mitochondria and chloroplasts. Bacterial ClpS adaptors bind preferentially to Leu and Phe N‐degrons; however, ClpS1 from Arabidopsis thaliana (AtClpS1) shows a difference in that it binds strongly to Phe and Trp N‐degrons and only weakly to Leu. This difference in behavior cannot be explained without structural information due to the high sequence homology between bacterial and plant ClpS proteins. Here, we report the structure of AtClpS1 at 2.0 Å resolution in the presence of a bound N‐degron. The key determinants for α‐amino group recognition are conserved among all ClpS proteins, but the α3‐helix of eukaryotic AtClpS1 is significantly shortened, and consequently, a loop forming a pocket for the N‐degron is moved slightly outward to enlarge the pocket. In addition, amino acid replacement from Val to Ala causes a reduction in hydrophobic interactions with Leu N‐degron. A combination of the fine‐tuned hydrophobic residues in the pocket and the basic gatekeeper at the entrance of the pocket controls the N‐degron selectivity of the plant ClpS protein.     

Curcumin improves memory deficits by inhibiting HMGB1-RAGE/TLR4-NF-κB signalling pathway in APPswe/PS1dE9 transgenic mice hippocampus

Amyloid-β (Aβ) deposition in the brain has been implicated in the development of Alzheimer's disease (AD), and neuroinflammation generates AD progression. Therapeutic effects of anti-inflammatory approaches in AD are still under investigation. Curcumin, a potent anti-inflammatory and antioxidant, has demonstrated therapeutic potential in AD models. However, curcumin's anti-inflammatory molecular mechanisms and its associated cognitive impairment mechanisms in AD remain unclear. The high-mobility group box-1 protein (HMGB1) participates in the regulation of neuroinflammation. Herein, we attempted to evaluate the anti-inflammatory effects of chronic oral administration of curcumin and HMGB1 expression in APP/PS1 transgenic mice AD model. We found that transgenic mice treated with a curcumin diet had shorter escape latencies and showed a significant increase in percent alternation, when compared with transgenic mice, in the Morris water maze and Y-maze tests. Additionally, curcumin treatment could effectively decrease HMGB1 protein expression, advanced glycosylation end product-specific receptor (RAGE), Toll-like receptors-4 (TLR4) and nuclear factor kappa B (NF-κB) in transgenic mice hippocampus. However, amyloid plaques detected with thioflavin-S staining in transgenic mice hippocampus were not affected by curcumin treatment. In contrast, curcumin significantly decreased GFAP-positive cells, as assessed by immunofluorescence staining. Taken together, these data indicate that oral administration of curcumin may be a promising agent to attenuate memory deterioration in AD mice, probably inhibiting the HMGB1-RAGE/TLR4-NF-κB inflammatory signalling pathway.     

Assisted Suicide in Switzerland: Clarifying Liberties and Claims

Assisting suicide is legal in Switzerland if it is offered without selfish motive to a person with decision‐making capacity. Although the ‘Swiss model’ for suicide assistance has been extensively described in the literature, the formally and informally protected liberties and claims of assistors and recipients of suicide assistance in Switzerland are incompletely captured in the literature. In this article, we describe the package of rights involved in the ‘Swiss model’ using the framework of Hohfeldian rights as modified by Wenar. After outlining this framework, we dissect the rights involved in suicide assistance in Switzerland, and compare it with the situation in England and Germany. Based on this approach, we conclude that in Switzerland, claim rights exist for those requesting suicide assistance, and for those who are considering providing such assistance, even though no entitlements exist toward suicide assistance. We then describe the implementation of the ‘Swiss model’ and difficulties arising within it. Clarifying these issues is important to understand the Swiss situation, to evaluate what features of it may or may not be worth correcting or emulating, and to understand how it can impact requests for suicide assistance in other countries due to ‘suicide tourism’. It is also important to understand exactly what sets Switzerland apart from other countries with different legislations regarding suicide assistance.