mTOR: from growth signal integration to cancer, diabetes and ageing

In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.National Institutes of Health (U.S.)Howard Hughes Medical InstituteWhitehead Institute for Biomedical ResearchJane Coffin Childs Memorial Fund for Medical Research (Postdoctoral Fellowship)Human Frontier Science Program (Strasbourg, France

Cytokine production pattern of T lymphocytes in neonatal arterial ischemic stroke during the first month of life

BACKGROUND: The perinatal period carries the highest risk for stroke in childhood; however, the pathophysiology is poorly understood and preventive, prognostic, and therapeutic strategies are not available. A new pathophysiological model describes the development of neonatal arterial ischemic stroke (NAIS) as the combined result of prenatal inflammation and hypoxic-ischemic insult. Neuroinflammation and a systemic inflammatory response are also important features of NAIS. Identifying key players of the inflammatory system is in the limelight of current research. CASE PRESENTATION: We present four NAIS cases, in whom detailed analysis of intracellular and plasma cytokine levels are available from the first month of life. All neonates were admitted with the initial diagnosis of hypoxic ischemic encephalopathy (HIE); however, early MRI examination revealed NAIS. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Peripheral blood mononuclear cells were assessed with flow cytometry and plasma cytokine levels were measured. Pooled data from the cohort of four NAIS patients were compared to infants with HIE. At 6 and 72 h of age, the prevalence of IL10+ CD8+ lymphocytes remained lower in NAIS. At 6 h, CD8+ lymphocytes in NAIS produced more IL-17. At 72 h, CD8+ cells produced more IL-6 in severe HIE than in NAIS, but IL-6 production remained elevated in CD8 cells at 1 month in NAIS, while it decreased in HIE. At 1 week, the prevalence of TGF-beta + lymphocytes prone to enter the CNS was elevated in NAIS. On the other hand, by 1 month of age, the prevalence of TGF-beta + CD4+ lymphocytes decreased in NAIS compared to HIE. At 72 h, we found elevated plasma levels of IL-5, MCP-1, and IL-17 in NAIS. By 1 month, plasma levels of IL-4, IL-12, and IL-17 decreased in NAIS but remained elevated in HIE. CONCLUSIONS: Differences in the cytokine network are present between NAIS and HIE. CD8 lymphocytes appear to shift towards the pro-inflammatory direction in NAIS. The inflammatory response appears to be more pronounced at 72 h in NAIS but decreases faster, reaching lower plasma levels of inflammatory markers at 1 month

Low-cost mobile augmented reality service for building information modeling

Informed decision-making is crucial for construction site operators. Cyber-physical systems, including various technologies such as augmented reality and building automation tools, are gathering popularity within the infrastructure management sector. However, such advanced technologies are expensive and inaccessible to adopt for most small organizations. This paper describes the development of a novel low-cost mobile augmented reality service for BIM and demonstrates its usability by implementing a prototype for a pipe maintenance case study which supports inspection, workflow management, data reduction, and augmented reality for on-site operators. Decision and integration support and the ease of use were further analyzed through semi-structured interviews with five organizations in the UK and South Korea. The results showed that the prototype is easy to use and the augmented reality service integrated with the building automation tool and the BIMserver enhances decision-making and data integration for on-site operations by generating a closed loop. This paper also highlights the need for developing low-cost digital solutions to foster digitalization in construction organizations with limited budgets.The research was supported by the KIAT (Korea Institu- tion for Advanced of Technology) grant funded by the Korea Government (MOTIE: Ministry of Trade Industry and En- ergy). (Advanced Training Program for Smart Factory, No. N0002429

food allergy and atopic dermatitis

Background/aim: Filaggrin is a protein complex involved in epidermal differentiation and skin barrier formation. Mutations of the filaggrin gene (FLG) arc associated with allergen sensitization and allergic diseases like atopic dermatitis (AD), allergic rhinitis, food allergy (FA), and asthma. The aim of the study is to reveal the frequency of change in the FIG gene and determine the association between FIG loss-of-function (LOF) mutations and FA and/or AD in Turkish children.Materials and methods: Four PLC loss-of-function (WO mutations known to be common in European populations were analyzed in 128 healthy children, 405 food-allergic children with or without atopic dermatitis, and 61 children with atopic dermatitis. PCRRFLP was performed for genotyping R501X, 2282del14, and R2447X mutations; 53247X was genotyped using a TaqMan-based allelic discrimination assay. Results were confirmed by DNA sequence analysis in 50 randomly chosen patients for all mutations.Results: A total of 466 patients [(67% male, 1 (0.7-2.8) years] and 128 healthy controls [59% male, 2.4 (1.4-3.5) years)] were included in this study. Two patients were heterozygous carriers of wild-type R501X, but none of the controls carried this mutation. Three patients and one healthy control were heterozygous carriers of wild-type 2282del4. Neither patients nor controls carried R2447X or S3247X PLC mutations. There were no combined mutations determined in heterozygous mutation carriers.Conclusions: Although R501X, 2282del4, R2447X, and S3247X mutations are very common in European populations, we found that FIG mutations were infrequent and there is no significant association with food allergy and/or atopic dermatitis in Turkish individuals.C1 [Acar, Nese Vardar; Karaaslan, Cagatay] Hacettepe Univ, Fac Sci, Dept Biol, Ankara, Turkey.[Cavkaytar, Ozlem; Yilmaz, Ebru Arik; Buyuktiryaki, Betul; Soyer, Ozge; Sahiner, Umit Murat; Sekerel, Bulent Enis] Hacettepe Univ, Fac Med, Dept Pediat Allergy, Ankara, Turkey.[Cavkaytar, Ozlem] Istanbul Medeniyet Univ, Fac Med, Dept Pediat Allergy & Immunol, Istanbul, Turkey.[Yilmaz, Ebru Arik] Pamukkale Univ, Fac Med, Dept Pediat Allergy, Denizli, Turkey.[Sackesen, Cansin] Koc Univ, Fac Med, Dept Pediat Allergy, Istanbul, Turkey

Requirement for ribosomal protein S6 kinase 1 to mediate glycolysis and apoptosis resistance induced by Pten deficiency

Pten inactivation promotes cell survival in leukemia cells by activating glycolytic metabolism. We found that targeting ribosomal protein S6 kinase 1 (S6K1) in Pten-deficient cells suppressed glycolysis and induced apoptosis. S6K1 knockdown decreased expression of HIF-1α, and HIF-1α was sufficient to restore glycolysis and survival of cells lacking S6K1. In the Ptenfl/fl Mx1-Cre+ mouse model of leukemia, S6K1 deletion delayed the development of leukemia. Thus, S6K1 is a critical mediator of glycolytic metabolism, cell survival, and leukemogenesis in Pten-deficient cells