Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Robust continuous in vitro culture of the Plasmodium cynomolgi erythrocytic stages

The ability to culture pathogenic organisms substantially enhances the quest for fundamental knowledge and the development of vaccines and drugs. Thus, the elaboration of a protocol for the in vitro cultivation of the erythrocytic stages of Plasmodium falciparum revolutionized research on this important parasite. However, for P. vivax, the most widely distributed and difficult to treat malaria parasite, a strict preference for reticulocytes thwarts efforts to maintain it in vitro. Cultivation of P. cynomolgi, a macaque-infecting species phylogenetically close to P. vivax, was briefly reported in the early 1980s, but not pursued further. Here, we define the conditions under which P. cynomolgi can be adapted to long term in vitro culture to yield parasites that share many of the morphological and phenotypic features of P. vivax. We further validate the potential of this culture system for high-throughput screening to prime and accelerate anti-P. vivax drug discovery efforts

Enrichment of hydroxylated C24-and C26-acyl-chain sphingolipids mediates PIN2 apical sorting at trans-Golgi network subdomains

The post-Golgi compartment trans-Golgi Network (TGN) is a central hub divided into multiple subdomains hosting distinct trafficking pathways, including polar delivery to apical membrane. Lipids such as sphingolipids and sterols have been implicated in polar trafficking from the TGN but the underlying mechanisms linking lipid composition to functional polar sorting at TGN subdomains remain unknown. Here we demonstrate that sphingolipids with alpha-hydroxylated acyl-chains of at least 24 carbon atoms are enriched in secretory vesicle subdomains of the TGN and are critical for de novo polar secretory sorting of the auxin carrier PIN2 to apical membrane of Arabidopsis root epithelial cells. We show that sphingolipid acyl-chain length influences the morphology and interconnections of TGN-associated secretory vesicles. Our results uncover that the sphingolipids acyl-chain length links lipid composition of TGN subdomains with polar secretory trafficking of PIN2 to apical membrane of polarized epithelial cells

The centrality of social ties to climate migration and mental health

Abstract Climate change-related hazards and disasters, known to adversely impact physical and mental health outcomes, are also expected to result in human migration above current levels. Environmentally-motivated migration and displacement may lead to the disruption of existing social ties, with potentially adverse consequences for mobile populations as well as their family members who remain in places of origin. We propose that the disruption of social ties is a key mechanism by which climate-related migration may negatively impact mental health, in particular. Existing social ties may provide social and material resources that buffer mental health stressors related to both prolonged and acute climate events. Preparation for such events may also strengthen these same ties and protect mental health. Communities may leverage social ties, first to mitigate climate change, and second, to adapt and rebuild post-disaster in communities of origin. Additionally, social ties can inform migration decisions and destinations. For example, scholars have found that the drought-motivated adaptive migration of West African Fulbe herders only occurred because of the long-term development of social networks between migrants and non-migrants through trade and seasonal grazing. On the other hand, social ties do not always benefit mental health. Some migrants, including those from poor regions or communities with no formal safety net, may face considerable burden to provide financial and emotional resources to family members who remain in countries of origin. In destination communities, migrants often face significant social marginalization. Therefore, policies and programs that aim to maintain ongoing social ties among migrants and their family and community members may be critically important in efforts to enhance population resilience and adaptation to climate change and to improve mental health outcomes. Several online platforms, like Refugee Start Force, serve to integrate refugees by connecting migrants directly to people and services in destination communities. These efforts may increasingly draw upon novel technologies to support and maintain social networks in the context of population mobility due to climatic and other factors