No abstract

Transcript changes and altered pathways in schizophrenia prefrontal cortex. (a) Mitochondria are the most affected cellular components at the transcript level in schizophrenia. Cellular localization of the significantly altered genes (both up-and downregulated) that passed RMA and filtering procedures were analyzed and visualized using GO Surfer (http://biosun1.harvard.edu/complab/gosurfer/). Branches and nodes represent pathways containing greater than five genes. Significantly altered 'cellular components' (Po0.05) are highlighted in red and their categories are indicated. (b) Metabolic categories found to be most significantly altered at the transcript level. EASE (http://david.niaid.nih.gov/david/ease.htm) was used for pathway analysis of microarray results and to determine significantly up-and/or downregulated GO biological processes and KEGG metabolic pathways. (c) Hierarchical clustering tree of schizophrenia (vertical blue lines) and controls (vertical gray lines) microarray chips on the basis of 59 significantly altered genes related to energy metabolism and oxidative stress. Drug-naive schizophrenia patients are denoted by ** (n ¼ 7), while minimally treated patients are marked by * (o6000 lifetime fluphenazine units; n ¼ 4). Note that the schizophrenia group appears to fall into two subclusters with respect to lowered transcript expression as indicated by the prominent blue shading. For more information on this topic, please see the article by Prabakaran et al on pp 684-697.

Single-nucleotide variations in C13orf31 (LACC1) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.

Death receptor 3 (DR3), a member of the TNF receptor (TNFR) superfamily, is induced in human renal tubular epithelial cells (TEC) in response to injury. This study examined the expression and actions of TL1A, the principal ligand for DR3. In histologically normal tissue from biopsy or nephrectomy specimens of renal allografts, TL1A mRNA and protein were expressed in vascular endothelial cells but not in TEC. In specimens of acute or antibody-mediated allograft rejection, vascular endothelial cells and infiltrating leukocytes expressed increased TL1A mRNA and protein, but TEC expressed TL1A protein without mRNA, consistent with uptake of exogenous ligand. Addition of TL1A to organ cultures of human or mouse kidney caused activation of NF-B, expression of TNFR2, activation of caspase-3, and apoptosis in TEC. Inhibition of NF-B activation increased TL1A-mediated caspase-3 activation and apoptosis of TEC, but it did not reduce the induction of TNFR2. In organ culture of DR3-deficient mouse kidneys, addition of TL1A induced TNFR2 but did not activate NF-B and did not increase apoptosis of TEC. These data suggest that TL1A may contribute to renal inflammation and injury through DR3-mediated activation of NF-B and caspase-3, respectively, but that an unidentified receptor may mediate the NF-B-independent induction of TNFR2 in TEC.

Metabolomics helped in deciphering the metabolic response to weight loss treatments. Moving from association to causation is the next challenge to move to a further level of clinical application.