Involvement of receptor-interacting protein 2 in innate and adaptive immune responses

Host defences to microorganisms rely on a coordinated interplay between the innate and adaptive responses of immunity. Infection with intracellular bacteria triggers an immediate innate response requiring macrophages, neutrophils and natural killer cells, whereas subsequent activation of an adaptive response through development of T-helper subtype 1 cells (TH1) proceeds during persistent infection. To understand the physiological role of receptor-interacting protein 2 (Rip2), also known as RICK and CARDIAK, we generated mice with a targeted disruption of the gene coding for Rip2. Here we show that Rip2-deficient mice exhibit a profoundly decreased ability to defend against infection by the intracellular pathogen Listeria monocytogenes. Rip2-deficient macrophages infected with L. monocytogenes or treated with lipopolysaccharide (LPS) have decreased activation of NF-kappaB, whereas dominant negative Rip2 inhibited NF-kappaB activation mediated by Toll-like receptor 4 and Nod1. In vivo, Rip2-deficient mice were resistant to the lethal effects of LPS-induced endotoxic shock. Furthermore, Rip2 deficiency results in impaired interferon-gamma production in both TH1 and natural killer cells, attributed in part to defective interleukin-12-induced Stat4 activation. Our data reflect requirements for Rip2 in multiple pathways regulating immune and inflammatory responses.     

Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine

Caffeine has been imbibed since ancient times in tea and coffee, and more recently in colas. Caffeine owes its psychostimulant action to a blockade of adenosine A(2A) receptors, but little is known about its intracellular mechanism of action. Here we show that the stimulatory effect of caffeine on motor activity in mice was greatly reduced following genetic deletion of DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein of relative molecular mass 32,000). Results virtually identical to those seen with caffeine were obtained with the selective A(2A) antagonist SCH 58261. The depressant effect of the A(2A) receptor agonist, CGS 21680, on motor activity was also greatly attenuated in DARPP-32 knockout mice. In support of a role for DARPP-32 in the action of caffeine, we found that, in striata of intact mice, caffeine increased the state of phosphorylation of DARPP-32 at Thr 75. Caffeine increased Thr 75 phosphorylation through inhibition of PP-2A-catalysed dephosphorylation, rather than through stimulation of cyclin-dependent kinase 5 (Cdk5)-catalysed phosphorylation, of this residue. Together, these studies demonstrate the involvement of DARPP-32 and its phosphorylation/dephosphorylation in the stimulant action of caffeine.     

Remains of Homo erectus from Bouri, Middle Awash, Ethiopia

The genesis, evolution and fate of Homo erectus have been explored palaeontologically since the taxon's recognition in the late nineteenth century. Current debate is focused on whether early representatives from Kenya and Georgia should be classified as a separate ancestral species ('H. ergaster'), and whether H. erectus was an exclusively Asian species lineage that went extinct. Lack of resolution of these issues has obscured the place of H. erectus in human evolution. A hominid calvaria and postcranial remains recently recovered from the Dakanihylo Member of the Bouri Formation, Middle Awash, Ethiopia, bear directly on these issues. These approximately 1.0-million-year (Myr)-old Pleistocene sediments contain abundant early Acheulean stone tools and a diverse vertebrate fauna that indicates a predominantly savannah environment. Here we report that the 'Daka' calvaria's metric and morphological attributes centre it firmly within H. erectus. Daka's resemblance to Asian counterparts indicates that the early African and Eurasian fossil hominids represent demes of a widespread palaeospecies. Daka's anatomical intermediacy between earlier and later African fossils provides evidence of evolutionary change. Its temporal and geographic position indicates that African H. erectus was the ancestor of Homo sapiens.