Insulin and serine metabolism as sex-specific hallmarks of Alzheimer's disease in the human hippocampus

Healthy aging is an ambitious aspiration for humans, but neurodegenerative disorders, such as Alzheimer's disease (AD), strongly affect quality of life. Using an integrated omics approach, we investigate alterations in the molecular composition of postmortem hippocampus samples of healthy persons and individuals with AD. Profound differences are apparent between control and AD male and female cohorts in terms of up- and downregulated metabolic pathways. A decrease in the insulin response is evident in AD when comparing the female with the male group. The serine metabolism (linked to the glycolytic pathway and generating the N-methyl-D-aspartate [NMDA] receptor coagonist D-serine) is also significantly modulated: the D-Ser/total serine ratio represents a way to counteract age-related cognitive decline in healthy men and during AD onset in women. These results show how AD changes and, in certain respects, almost reverses sex-specific proteomic and metabolomic profiles, highlighting how different pathophysiological mechanisms are active in men and women

Methionine Supplementation Affects Metabolism and Reduces Tumor Aggressiveness in Liver Cancer Cells

Liver cancer is one of the most common cancer worldwide with a high mortality. Methionine is an essential amino acid required for normal development and cell growth, is mainly metabolized in the liver, and its role as an anti-cancer supplement is still controversial. Here, we evaluate the effects of methionine supplementation in liver cancer cells. An integrative proteomic and metabolomic analysis indicates a rewiring of the central carbon metabolism, with an upregulation of the tricarboxylic acid (TCA) cycle and mitochondrial adenosine triphosphate (ATP) production in the presence of high methionine and AMP-activated protein kinase (AMPK) inhibition. Methionine supplementation also reduces growth rate in liver cancer cells and induces the activation of both the AMPK and mTOR pathways. Interestingly, in high methionine concentration, inhibition of AMPK strongly impairs cell growth, cell migration, and colony formation, indicating the main role of AMPK in the control of liver cancer phenotypes. Therefore, regulation of methionine in the diet combined with AMPK inhibition could reduce liver cancer progression

NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis

Aims NOS1AP single-nucleotide polymorphisms (SNPs) correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action-potential du-ration (APD) to facilitate arrhythmias. Here we test (i) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; (ii) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS IAP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency.Methods and results In GP-CMs, NOS1 was inhibited by S-Methyl-L-thiocitrulline acetate (SMTC) or Vinyl-L-NIO hydrochloride (L-VNIO); LQT1 was mimicked by I-Ks blockade (JNJ303) and beta-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harbouring the minor and major alleles of NOS IAP SNPs (rs16847548 and rs4657139), respectively. In GP-CMs, NOS1 inhibition prolonged APD, enhanced I-CaL and I-NaL, stowed Ca2+ decay, and induced delayed afterdepolarizations. Under action-potential damp, switching to shorter APD suppressed 'transient inward current' events induced by NOS1 inhibition and re-duced cytosolic Ca2+. In S (vs. AS) hiPSC-CMs, APD was longer and I-CaL larger; NOS1AP and NOS1 expression and co-localization were decreased.Conclusion The minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolon-gation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS IAP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes.[GRAPHICS]

Reinterpreting the relationship between centre and periphery: Pilgrimage and sacred spatialisation among Polish and Congolese communities in Britain

Pilgrimage in Britain has been transformed through the process of global migration since the end of the Second World War. In this article we focus on changes taking place within Christian pilgrimage through an analysis of the ways in which the relationship between centre and periphery has been reinterpreted. The first case study involves Polish pilgrims at a Roman Catholic shrine in the Kent countryside while the other focuses on Congolese Kimbanguists. The comparison reveals the ways in which global flows of people and ideas mediated through transnational networks have helped to blur the ideological boundaries between different Christian traditions. Furthermore, local places in the periphery are reinterpreted in conditions of increasing complexity where sacred centres in the countries of origin have to adapt to the emergence of new peripheries, which link up with other peripheries in the Kimbanguist case, and with differences between 'old' and 'new' Poles (settlers and sojourners) in the Polish example