Caspase-8 and c-FLIPL associate in lipid rafts with NF-kappaB adaptors during T cell activation

Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-kappaB signaling and proliferation. It is unknown how caspase-8 is activated following T cell stimulation, and what is the caspase-8 substrate(s) that is necessary to initiate T cell cycling. We observe that following TCR ligation, a small portion of total cellular caspase-8 and c-FLIP(L) rapidly migrate to lipid rafts where they associate in an active caspase complex. Activation of caspase-8 in lipid rafts is followed by rapid cleavage of c-FLIP(L) at a known caspase-8 cleavage site. The active caspase.c-FLIP complex forms in the absence of Fas (CD95/APO1) and associates with the NF-kappaB signaling molecules RIP1, TRAF2, and TRAF6, as well as upstream NF-kappaB regulators PKC theta, CARMA1, Bcl-10, and MALT1, which connect to the TCR. The lack of caspase-8 results in the absence of MALT1 and Bcl-10 in the active caspase complex. Consistent with this observation, inhibition of caspase activity attenuates NF-kappaB activation. The current findings define a link among TCR, caspases, and the NF-kappaB pathway that occurs in a sequestered lipid raft environment in T cells.     

Obesity, overweight, and their life course trajectories in veterans and non-veterans

Veterans comprise a large and growing segment of the US population. Results from national telephone surveys suggest higher prevalence of overweight among Veterans compared with demographically similar non-Veterans, based on self-reported height and weight. Using 1999-2008 data from the National Health and Nutrition Examination Survey (NHANES), we compared 3,768 Veterans and 21,974 non-Veterans on: (i) several measures of adiposity based on direct anthropometry; (ii) life-course of self-reported BMI; and (iii) behaviors related to weight loss or maintenance. Whether Veterans were more likely than demographically similar non-Veterans to be obese or overweight depended on the adiposity measure employed. On BMI, Veterans were about equally likely to be obese (30+ kg/m(2)), but more likely to be overweight (25-29.9 kg/m(2)) by both self-report and by direct measurement (significantly so only by self-report). On waist-stature ratio, a roughly similar pattern was observed. On waist circumference, Veterans tended to have larger values than demographically similar non-Veterans, with more Veterans in the largest two categories. But on dual-photon X-ray absorptiometry, Veterans were less likely to have 35+% body fat than non-Veterans of similar age, gender, and race/ethnicity. Life-course trends in self-reported BMI suggested a possible burst of weight gain after military discharge. These results suggest that Veterans may, on average, have less excess body fat than non-Veterans--a pattern not revealed by standard anthropometric measures.     

Extracts of black and brown rice powders improve hepatic lipid accumulation via the activation of PPARα in obese and diabetic model mice

Rice powder extract (RPE) from black and brown rice (Oryza sativa L. indica) improves hepatic lipid accumulation in obese and diabetic model mice via peroxisomal fatty acid oxidation. RPE showed PPARα agonistic activity which did not differ between black and brown RPE despite a higher anthocyanin content in black RPE.     

The chemokine SDF1 regulates migration of dentate granule cells

The dentate gyrus is the primary afferent pathway into the hippocampus, but there is little information concerning the molecular influences that govern its formation. In particular, the control of migration and cell positioning of dentate granule cells is not clear. We have characterized more fully the timing and route of granule cell migration during embryogenesis using in utero retroviral injections. Using this information, we developed an in vitro assay that faithfully recapitulates important events in dentate gyrus morphogenesis. In searching for candidate ligands that may regulate dentate granule cell migration, we found that SDF1, a chemokine that regulates cerebellar and leukocyte migration, and its receptor CXCR4 are expressed in patterns that suggest a role in dentate granule cell migration. Furthermore, CXCR4 mutant mice have a defect in granule cell position. Ectopic expression of SDF1 in our explant assay showed that it directly regulates dentate granule cell migration. Our study shows that a chemokine is necessary for the normal development of the dentate gyrus, a forebrain structure crucial for learning and memory.     

Multiple Subtypes of Excitatory Amino Acid Receptors Coupled to the Hydrolysis of Phosphoinositides in Rat Brain

Abstract: The excitatory amino acid (EAA) analogues quisqualate, ibotenate, and trans-(±)-1-amino-1, 3-cyclopentanedicarboxylate (trans-ACPD) activate the metabotropic EAA receptors that are coupled to the hydrolysis of Phosphoinositides (PI). Previous studies of hippocampal cross sections demonstrated that PI hydrolysis stimulated by these agonists can be inhibited by either L-aspartate-β- hydroxamate (L-AβHA) or DL-2-amino-3-phosphonopropionate (DL-AP3). The goal of the present studies was to determine if all metabotropic EAA receptors are sensitive to L-AβHA and DL-AP3. Two approaches were used. In the first, using cerebellar cross sections, the effects of these agonists and inhibitors were examined. The EC₅₀ values (the concentrations required to evoke half-maximal stimulation) of quisqualate, ibotenate, and trans-ACPD in cerebellum were similar to the EC₅₀ values that we observed previously in hippocampus, but neither L-AβHA nor DL- AP3 blocked PI hydrolysis. The EC₅₀ values were 0.65 ± 0.17 μM for quisqualate, 12.8 ± 2.5 μM for ibotenate, and 18.1 ± 3.1 μM for trans-ACPD. All data were best fit to theoretical curves that had Hill slopes of 1. In the second approach, another EAA analogue, D-aspartate, was identified as an agonist that stimulates PI hydrolysis. The EC₅₀for PI hydrolysis stimulated by D-aspartate was 470 ± 90 μM in hippocampus. Neither L-AβSHA nor DL-AP3 blocked PI hydrolysis stimulated by D-aspartate in hippocampus. Furthermore, antagonists of ionotropic EAA receptors, antagonists of other receptor systems coupled to PI hydrolysis, and inhibitors of the Na⁺-dependent L-glutamate transport process also did not block PI hydrolysis stimulated by D-aspartate. These data support the presence of three pharmacologically distinct metabotropic EAA receptor subtypes.