No abstract

Neurotrophic factors (NTFs) can protect against or sensitize neurons to excitotoxicity. We studied the role played by various NTFs in the excitotoxic death of purified embryonic rat motor neurons. Motor neurons cultured in brain-derived neurotrophic factor, but not neurotrophin 3, glial-derived neurotrophic factor, or cardiotrophin 1, were sensitive to excitotoxic insult. BDNF also induces excitotoxic sensitivity (ES) in motor neurons when BDNF is combined with these other NTFs. The effect of BDNF depends on de novo protein and mRNA synthesis. Reagents that either activate or inhibit the 75-kDa NTF receptor p75 NTR do not affect BDNF-induced ES. The low EC 50 for BDNF-induced survival and ES suggests that TrkB mediates both of these biological activities. BDNF does not alter glutamate-evoked rises of intracellular Ca 2ϩ , suggesting BDNF acts downstream. Both wortmannin and LY294002, which specifically block the phosphatidylinositol 3-kinase (PI3K) intracellular signaling pathway in motor neurons, inhibit BDNF-induced ES. We confirm this finding using a herpes simplex virus (HSV) that expresses the dominant negative p85 subunit of PI3K. Infecting motor neurons with this HSV, but not a control HSV, blocks activation of the PI3K pathway and BDNF-induced ES. Through the activation of TrkB and the PI3K signaling pathway, BDNF renders developing motor neurons susceptible to glutamate receptor-mediated cell death. Key Words: Ionotropic glutamate receptors-Motor neurons-Excitotoxicity-Phosphatidylinositol 3-kinase-TrkB-Low-affinity neurotrophin receptor.

CT-1 can protect cardiac cells when added either prior to simulated ischaemia or at the time of reoxygenation following simulated ischaemia and these effects are dependent upon its ability to activate the p42/p44 MAPK pathway. Hence CT-1 may have therapeutic potential when added at the time of reperfusion following ischaemic damage.

Objectives: To determine whether the cytokine cardiotrophin-1 (CT-1) can protect the adult heart against ischaemia / reperfusion when added either prior to ischaemia or at reperfusion. Background: CT-1 has previously been shown to protect cultured embryonic or neonatal cardiocytes from cell death. To assess the therapeutic potential of CT-1, it is necessary to determine whether this effect can be observed in adult cardiac cells both in culture and most importantly in the intact heart. Methods: We examined the protective effect of CT-1 both in cultured adult rat cardiocytes and in the rat intact heart. In both cases, the cardiac cells were exposed to hypoxia / ischaemia followed by reoxygenation / reperfusion and CT-1 was administered either prior to hypoxia / ischaemia or at reoxygenation / reperfusion. Results: CT-1 has a protective effect in reducing ischaemic damage in the intact heart ex vivo as assayed by infarct size to area at risk ratio (20% compared to 35%). Similar protective effects against cell death were noted in adult cells in vitro. Both in vitro and ex vivo CT-1 can exert a protective effect when added at the time of reoxygenation / reperfusion as well as prior to the hypoxic / ischaemic stimulus (cell death reduced from 50 to 20% in TUNEL assay, infarct size to zone at risk ratio reduced from 35 to 20%). These protective effects are blocked by an inhibitor of the p42 / p44 MAPK pathway. Conclusion: CT-1 can protect adult cardiac cells both in vitro and in vivo when added both prior to or after the hypoxic / ischaemic stimulus. The potential therapeutic benefit of CT-1 when added at the time of reperfusion following ischaemic damage is discussed. Condensed abstractThe cytokine cardiotrophin-1 (CT-1) has previously been shown to have protective effects in embryonic or neonatal cardiac cells in culture. Here we show for the first time that CT-1 can protect adult cardiac cells both in culture and in the intact heart exposed to ischaemia / reperfusion. Moreover, this protective effect can be observed when CT-1 is added at reperfusion after ischaemia as well as prior to ischaemia. The ability of CT-1 to protect the intact adult heart when given at reperfusion suggests it may have therapeutic potential in the clinical situation.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).