Tau protein is characterized by a complex pattern of phosphorylation and is localized in the cytoplasm and nucleus in both neuronal and non-neuronal cells. Human AT100 nuclear tau, endowed by phosphorylation in Thr212/Ser214, was recently shown to decline in cornus ammonis 1 (CA1) and dentate gyrus (DG) in Alzheimer's disease (AD), but a defined function for this nuclear tau remains unclear. Here we show that AT100 progressively increases in the nuclei of neuronal and non-neuronal cells during aging, and decreases in the more severe AD stages, as recently shown, and in cancer cells (colorectal adenocarcinoma and breast cancer). AT100, in addition to a co-localization with the DAPI-positive heterochromatin, was detected in the nucleolus of pyramidal cells from the CA1 region, shown to be at its highest level in the more senescent cells and in the first stage of AD (ADI), and disappearing in the more severe AD cases (ADIV). Taking into account the nuclear distribution of AT100 during cell aging and its relation to the chromatin changes observed in degenerated neurons, as well as in cancerous cells, which are both cellular pathologies associated with age, we can consider the Thr212/Ser214 phosphorylated nuclear tau as a molecular marker of cell aging.

We describe herein the synthesis and neuroprotective capacity of an array of 31 compounds comprising quinolyloximes, quinolylhydrazones, quinolylimines, QNs, and related heterocyclic azolylnitrones. Neuronal cultures subjected to oxygen−glucose deprivation (OGD), as experimental model for ischemic conditions, were treated with our molecules at the onset of recovery period after OGD and showed that most of these QNs, but not the azo molecules, improved neuronal viability 24 h after recovery. Especially, QN (Z)-N-tert-butyl-1-(2-chloro-6-methoxyquinolin-3-yl)methanimine oxide (23) was shown as a very potent neuroprotective agent. Antioxidant analysis based on the ability of QN 23 to trap different types of toxic radical oxygenated species supported and confirmed its strong neuroprotective capacity. Finally, QN 23 showed also neuroprotection induction in two in vivo models of cerebral ischemia, decreasing neuronal death and reducing infarct size, allowing us to conclude that QN 23 can be considered as new lead-compound for ischemic stroke treatment.

1 The role of the endothelium in the effects of cooling on the response to cholinoceptor stimulation of the rabbit central ear (cutaneous) and femoral (non-cutaneous) arteries was studied using 2 mm long cylindrical segments.2 Concentration-response curves for acetylcholine (I0-9-IO-OM), methacholine (10-9-1iO-M) and sodium nitroprusside (IO-9-IO-4M) were isometrically recorded in arteries under conditions, with and without endothelium or following pretreatment with the nitric oxide-synthesis inhibitor N0-nitro-Larginine methyl ester (L-NAME, 10-6-3 x 10-M) at 37°C and at 24°C (cooling). 3 Ear and femoral arteries showed endothelium-dependent relaxation to acetylcholine and methacholine at 37°C and 24°C. The extent of relaxation of the control ear arteries, but not of the control femoral arteries, to acetylcholine and methacholine increased during cooling. 4 L-NAME (10-6-3 x IO-4 M) reduced in a concentration-dependent way the response of ear arteries to acetylcholine at both 37°C and 24°C, this reduction being more potent at 37°C. L-Arginine (10-'-10-M) reversed in a concentration-dependent manner the inhibitor effects of 10-5 M L-NAME at both temperatures. 5 Sodium nitroprusside caused a concentration-dependent relaxation in both arteries that was endothelium-independent. However, the extent of relaxation to this nitrovasodilator in ear and femoral arteries was lower at 24°C. 6 These results suggest that cooling augments the reactivity of cutaneous (ear) arteries, but not that of non-cutaneous (femoral) arteries to cholinoceptor stimulation by endothelium-mediated mechanisms. Cooling could therefore facilitate the stimulated release of endothelial nitric oxide in cutaneous vessels.

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).

Purpose: the aim of the present study was to analyse the pattern of dietary supplements (DS) consumption on federated rugby players, including the analysis of differences based on the sex and competitive level (professional vs. amateurs). Material and methods: 144 rugby players (83 male and 61 female), of whom 69 were professionals and 75 amateurs, were recruited for the study. All the participants filled out a specific questionnaire about DS consumption including questions related to the consumption of DS and their effects on sport performance and health status. Results: 65.3% of participants declared consuming at least one DS, with a higher prevalence in males than females (77.1% vs. 49.2%) and in professionals thanin amateur players (79.7% vs. 52.0%). The main reason for consumption was to enhance sport performance (62.3%) with differences only based on sex (74.3% males vs. 43.2% females). The most common purchase sites were the Internet (45.6%) and specialised stores (39.8%). As to the moment of ingestion, professionals did this most frequently during competition and training (56.4% vs. 28.2%), whereas amateur players did so only during competition (20.5% vs. 3.6%). Moreover, professional player intake most frequently in post-exercise (65.5% vs. 35.9%), whereas amateur during pre-exercise (30.8% vs. 5.5%). The DS most consumed included whey protein (44%), caffeine (42%), sports drinks (38%), energy bars (34%) and creatine monohydrate (31%), with a higher prevalence in male and professional players of whey protein and creatine monohydrate. Conclusions: The main reason for DS consumption is for enhancing sports performance). Professional players more frequently purchase them on the Internet and consume DS during training and competition period and in the post-exercise, whereas amateur players consume during competition and pre-exercise. Related to the main form of DS consumption, it is observed that a moderate consumption of DS could be considered ergogenic, such as whey protein, sport bar and creatine, while an absence of other DS could be considered ergogenic.