NF-B is a transcription factor that controls the expression of a number of genes important for mediating immune and inflammatory responses. In this study, we examined whether bortezomib and PS-1145, each of which inhibits NF-B, could protect mice from lethal graft-versus-host disease (GVHD), which is characterized by immune activation and proinflammatory cytokine production. When administered within the first 2 days after transplantation, bortezomib and PS-1145 both protected mice from fatal GVHD, did not compromise donor engraftment, and effected marked reduction in the levels of serum cytokines that are normally increased during GVHD. Extending the course of bortezomib administration or delaying the initiation of this agent for as few as 3 days after bone marrow transplantation (BMT), however, significantly exacerbated GVHD-dependent mortality because of severe pathological damage in the colon. In contrast, prolonged administration of PS-1145, which, unlike bortezomib, is a selective inhibitor of NF-B, caused no early toxicity and resulted in more complete protection than that observed with an abbreviated PS-1145 treatment schedule. These results confirm a critical role for NF-B in the pathophysiology of GVHD and indicate that targeted inhibition of NF-B may have a superior therapeutic index and may constitute a viable therapeutic approach to reduce GVHD severity. (Blood. 2006;107:827-834)

No abstract

Glutamate and its various receptors are known to play an important role in excitatory synaptic transmission throughout the CNS, including the primary visual cortex. Among subunits of the AMPA receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), subunit 2 (GluR2) is of special significance because it controls their Ca2+ permeability. In the past, this subunit has been studied mostly in conjunction with other AMPA subunits. The present study sought to determine if GluR2 alone has a distinct laminar distribution in the normal macaque visual cortex, and if its pattern correlated with that of cytochrome oxidase (CO) under normal and monocularly deprived conditions. In the normal adult cortex, GluR2 immunoreactivity (ir) had a patchy distribution in layers II/III, in register with CO-rich puffs. GluR2-ir highlighted the upper border of layer II, the lower border of layer IV (previously termed IVC(beta dark)) and, most prominently, layer VI. Labeled neurons were primarily of the pyramidal type present in the upper border and lower half of layer VI, layers II/III, and scattered in layers V and upper IVB. Labeled nonpyramidal cells were large in layer IVB and small in IVC(beta dark). Notably, the bulk of CO-rich layers IVC and IVA had very low levels of GluR2-ir. At fetal day 13, however, GluR2 labeling showed a honeycomb-like pattern in layer IVA not found in the adult. A fragment of GluR2 cDNA was generated from a human cDNA library, and in situ hybridization revealed an expression pattern similar to that of GluR2 proteins. After 1-4 weeks of monocular impulse blockade with tetrodotoxin (TTX), alternating rows of strong and weak GluR2-ir in layers VI and II/III appeared in register with CO-labeled dark and light ocular dominance columns in layer IVC and puffs in II/III, respectively. Our results indicate that various cortical layers are differentially influenced by glutamate. The bulk of the major geniculate-recipient layers IVC and IVA have low levels of GluR2, presumably favoring synaptic transmission via Ca(2+)-permeable glutamate receptors. GluR2 plays a more important role in supragranular and infragranular layers, where the initial geniculate signals are further modified and are transmitted to other cortical and subcortical centers. The maintenance of GluR2 in these output layers is governed by visual input and neuronal activity, as monocular impulse blockade induced a down-regulation of this subunit in deprived ocular dominance columns.

No abstract

The macaque visual cortex is exquisitely organized into columns, modules, and streams, much of which can be correlated with its metabolic organization revealed by cytochrome oxidase (CO). Plasticity in the adult primate visual system has also been documented by changes in CO activity. Yet, the molecular mechanism of regulating this enzyme remains not well understood. Being one of only four bigenomic enzymes in mammalian cells, the transcriptional regulation of this enzyme necessitates a potential bigenomic coordinator. Nuclear respiratory factor 2 (NRF-2) or GA-binding protein is a transcription factor that may serve such a critical role. The goal of the present study was to determine if the two major subunits of NRF-2, 2alpha and 2beta, had distinct subcellular distribution in neurons of the rat and monkey visual cortex, if major metabolic neuronal types in the macaque exhibited different levels of the two subunits, and if they would respond differently to monocular impulse blockade. Quantitative immuno-electron microscopy was used. In both rats and monkeys, nuclear labeling of alpha and beta subunits was mainly over euchromatin rather than heterochromatin, consistent with their active participation in transcriptional activity. Cytoplasmic labeling was over free ribosomes, the Golgi apparatus, and occasionally the nuclear envelope, signifying sites of synthesis and possible posttranslational modifications. The density of both subunits was much higher in the nucleus than in the cytoplasm for all neurons examined, again indicating that their major sites of cellular action is in the nucleus.