The P2X7 receptor antagonist JNJ-47965567 administered thrice weekly from disease onset does not alter progression of amyotrophic lateral sclerosis in SOD1G93A mice

Purinergic Signalling - The ATP-gated P2X7 ion channel has emerging roles in amyotrophic lateral sclerosis (ALS) progression. Pharmacological blockade of P2X7 with Brilliant Blue G can ameliorate...     

Impaired mitophagosome–lysosome fusion mediates olanzapine-induced aging

The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome–lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome–lysosome fusion in olanzapine-induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD-induced adverse effects associated with accelerated aging.     

Sharing the safe operating space: Exploring ethical allocation principles to operationalize the planetary boundaries and assess absolute sustainability at individual and industrial sector levels

In the light of increasing human pressures on the Earth system, the issue of sharing in the face of scarcity is more pressing than ever. The planetary boundary framework identifies and quantifies nine environmental boundaries and corresponding human pressures. However, when aiming to make the concept operational for decision support it is unclear how this safe operating space (SOS) within each of the planetary boundaries should be shared. This study proposes a two‐step approach, where the operating space is first downscaled to the individual level using ethical allocation principles and next scaled up to a higher organizational level using different upscaling methods. For the downscaling, three allocation principles are demonstrated: egalitarian (equal per capita); grandfathering (proportional to current share of the total impacts); and ability to pay (proportional to economic activity). For upscaling from the individual level final consumption expenditure is used as a proxy for the priority that the individual gives to the product or sector. In an alternative upscaling approach, an additional upscaling factor is based on the eco‐efficiency (ratio between turnover and environmental impact) of the product or sector. A demonstration of the method's application is given by applying the framework to two of the planetary boundaries, climate change and biogeochemical flows, with the Danish, Indian and global dairy sectors as cases. It is demonstrated how the choices of allocation and upscaling approaches influence the results differently in the three cases. The developed framework is shown to support an informed and transparent selection of allocation principles and upscaling methods and it provides a step toward standardization of distributing the SOS in absolute environmental sustainability assessments.