The Role of Cerebral Hypoperfusion in Multiple Sclerosis (ROCHIMS) Trial in Multiple Sclerosis:Insights From Negative Results

Background:Accumulating evidence indicates that mitochondrial energy failure is involved in the progressive axonal degeneration in multiple sclerosis (MS). In patients with MS, it has been shown that both levels of N-acetylaspartate (NAA), which is a marker of axonal mitochondrial energy, and cerebral blood flow (CBF) are reduced in cerebral normal appearing white matter (NAWM). The latter is likely due to the vasoconstrictive action of endothelin-1 (ET-1) produced by reactive astrocytes, which is triggered by local proinflammatory cytokines. A preliminary study in patients with MS showed that CBF could be restored to normal values after a single dose of 62.5 mg of the ET-1 antagonist bosentan. Objective:To investigate whether restoring CBF in patients with relapsing remitting MS (RRMS) increases levels of NAA in cerebral NAWM and improves clinical symptoms. Methods:27 RRMS patients were included in a 4 weeks proof-of-concept, randomized, double-blind placebo-controlled trial (ROCHIMS) to investigate whether bosentan 62.5 mg twice daily could increase the NAA/creatine (NAA/Cr) ratio in NAWM of the centrum semiovale. Magnetic resonance imaging (MRI) assessing CBF and NAA/Cr, and clinical evaluations were performed at baseline and at end of study. Separately from the clinical trial, 10 healthy controls underwent the same baseline multimodal brain MRI protocol as the MS patients. Results:Eleven patients in the bosentan arm and thirteen patients in the placebo arm completed the study. Bosentan did not increase CBF. However, we found that CBF in the patients was not different from that of the healthy controls. There were no effects on NAA levels and clinical symptoms. Conclusions:Our study showed that CBF in RRMS patients is not always decreased and that bosentan has no effect when CBF values are within the normal range. We hypothesize that in our patients there was no significant astrocytic production of ET-1 because they had a mild disease course, with minimal local inflammatory activity. Future studies with bosentan in MS should focus on patients with elevated ET-1 levels in cerebrospinal fluid or blood

Monitoring of species’ genetic diversity in Europe varies greatly and overlooks potential climate change impacts

Genetic monitoring of populations currently attracts interest in the context of the Convention on Biological Diversity but needs long-term planning and investments. However, genetic diversity has been largely neglected in biodiversity monitoring, and when addressed, it is treated separately, detached from other conservation issues, such as habitat alteration due to climate change. We report an accounting of efforts to monitor population genetic diversity in Europe (genetic monitoring effort, GME), the evaluation of which can help guide future capacity building and collaboration towards areas most in need of expanded monitoring. Overlaying GME with areas where the ranges of selected species of conservation interest approach current and future climate niche limits helps identify whether GME coincides with anticipated climate change effects on biodiversity. Our analysis suggests that country area, financial resources and conservation policy influence GME, high values of which only partially match species’ joint patterns of limits to suitable climatic conditions. Populations at trailing climatic niche margins probably hold genetic diversity that is important for adaptation to changing climate. Our results illuminate the need in Europe for expanded investment in genetic monitoring across climate gradients occupied by focal species, a need arguably greatest in southeastern European countries. This need could be met in part by expanding the European Union’s Birds and Habitats Directives to fully address the conservation and monitoring of genetic diversity

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale