Complement component 3 (C3) expression in the hippocampus after excitotoxic injury: role of C/EBPβ

[Background] The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor implicated in the control of proliferation, differentiation, and inflammatory processes mainly in adipose tissue and liver; although more recent results have revealed an important role for this transcription factor in the brain. Previous studies from our laboratory indicated that CCAAT/enhancer-binding protein β is implicated in inflammatory process and brain injury, since mice lacking this gene were less susceptible to kainic acid-induced injury. More recently, we have shown that the complement component 3 gene (C3) is a downstream target of CCAAT/enhancer-binding protein β and it could be a mediator of the proinflammatory effects of this transcription factor in neural cells.[Methods] Adult male Wistar rats (8–12 weeks old) were used throughout the study. C/EBPβ+/+ and C/EBPβ–/– mice were generated from heterozygous breeding pairs. Animals were injected or not with kainic acid, brains removed, and brain slices containing the hippocampus analyzed for the expression of both CCAAT/enhancer-binding protein β and C3.[Results] In the present work, we have further extended these studies and show that CCAAT/enhancer-binding protein β and C3 co-express in the CA1 and CA3 regions of the hippocampus after an excitotoxic injury. Studies using CCAAT/enhancer-binding protein β knockout mice demonstrate a marked reduction in C3 expression after kainic acid injection in these animals, suggesting that indeed this protein is regulated by C/EBPβ in the hippocampus in vivo.[Conclusions] Altogether these results suggest that CCAAT/enhancer-binding protein β could regulate brain disorders, in which excitotoxic and inflammatory processes are involved, at least in part through the direct regulation of C3.This work was supported by MINECO, Grant SAF2014-52940-R and partially financed with FEDER funds. CIBERNED is funded by the Instituto de Salud Carlos III. JAM-G was supported by CIBERNED. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Changing Medical Education, Overnight: The Curricular Response to COVID-19 of Nine Medical Schools

Issue: Calls to change medical education have been frequent, persistent, and generally limited to alterations in content or structural re-organization. Self-imposed barriers have prevented adoption of more radical pedagogical approaches, so recent predictions of the ‘inevitability’ of medical education transitioning to online delivery seemed unlikely. Then in March 2020 the COVID-19 pandemic forced medical schools to overcome established barriers overnight and make the most rapid curricular shift in medical education’s history. We share the collated reports of nine medical schools and postulate how recent responses may influence future medical education. Evidence: While extraneous pandemic-related factors make it impossible to scientifically distinguish the impact of the curricular changes, some themes emerged. The rapid transition to online delivery was made possible by all schools having learning management systems and key electronic resources already blended into their curricula; we were closer to online delivery than anticipated. Student engagement with online delivery varied with different pedagogies used and the importance of social learning and interaction along with autonomy in learning were apparent. These are factors known to enhance online learning, and the student-centered modalities (e.g. problem-based learning) that included them appeared to be more engaging. Assumptions that the new online environment would be easily adopted and embraced by ‘technophilic’ students did not always hold true. Achieving true distance medical education will take longer than this ‘overnight’ response, but adhering to best practices for online education may open a new realm of possibilities. Implications: While this experience did not confirm that online medical education is really ‘inevitable,’ it revealed that it is possible. Thoughtfully blending more online components into a medical curriculum will allow us to take advantage of this environment’s strengths such as efficiency and the ability to support asynchronous and autonomous learning that engage and foster intrinsic learning in our students. While maintaining aspects of social interaction, online learning could enhance pre-clinical medical education by allowing integration and collaboration among classes of medical students, other health professionals, and even between medical schools. What remains to be seen is whether COVID-19 provided the experience, vision and courage for medical education to change, or whether the old barriers will rise again when the pandemic is over

Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism

Improving the control of energy homeostasis can lower cardiovascular risk in metabolically compromised individuals. To identify new regulators of whole-body energy control, we conducted a high-throughput screen in transgenic reporter zebrafish for small molecules that modulate the expression of the fasting-inducible gluconeogenic gene pck1. We show that this in vivo strategy identified several drugs that impact gluconeogenesis in humans, as well as metabolically uncharacterized compounds. Most notably, we find that the Translocator Protein (TSPO) ligands PK 11195 and Ro5-4864 are glucose lowering agents despite a strong inductive effect on pck1 expression. We show that these drugs are activators of a fasting-like energy state, and importantly that they protect high-fat diet induced obese mice from hepatosteatosis and glucose intolerance, two pathological manifestations of metabolic dysregulation. Thus, using a whole-organism screening strategy, this study has identified new small molecule activators of fasting metabolism