CD28-B7 interactions function to co-stimulate clonal deletion of double-positive thymocytes

Negative selection of thymocytes only occurs if next to signals through the TCR, additional antigen-presenting cell (APC)-derived signals are also provided. It has been unclear which molecular interactions lead to the generation of these signals. In particular, the involvement of CD28 and its ligands B7-1 and B7-2 has been controversial. In the present study, we re-address this issue and first confirm that cross-linking CD28 molecules on thymocytes can indeed complement TCR-derived signals for induction of deletion upon TCR engagement with antibodies. Furthermore, we extend these findings by documenting that also peptide agonist-induced deletion can be co-stimulated by antibody-mediated engagement of CD28. Additionally, blocking B7-1 or B7-2 reduces negative selection induced by both anti-CD3 and peptide agonist in suspension cultures and in fetal thymic organ culture. At the same time, prominent co-stimulation of TCR-induced deletion could be provided by a B7-negative cell line. Together these results definitively demonstrate that CD28-B7 interactions can function to co-stimulate induction of clonal deletion, while yet to be identified B7-independent co-stimulatory signals can fulfil this function as well.     

The nucleus negatively controls the synthesis of mitochondrial proteins in the sea urchin egg

Enucleation of Paracentrotus lividus eggs, followed by parthenogenetic activation induces a sharp increase in the synthesis of mitochondrial proteins as shown by electrofluorography after in vivo labeling with radioactive amino acids. These results further substantiate the hypothesis that the cell nucleus negatively controls mitochondrial replication in the sea urchin egg.     

CONSISTENCY CHECKING ALONG TIME

Most model-based approaches to diagnosis require a consistency-checking procedure to perform their task. When dealing with a dynamically changing system, such a procedure must take into account time-varying data. This requires suitable techniques for reasoning over time. Additional difficulties arise when delays are involved in interactions between variables. The worst case occurs when some of the delays are completely unspecified. This report presents an approach to consistency checking that handles qualitative models of dynamic systems exhibiting time lags. A component-centered ontology is adopted to model the structure of the physical system, and an episode-based approach is adopted for representing its behavior over time. An example consisting of a physical process exhibiting transportation lags is used to illustrate the power of the approach. We present algorithms and an implementation in PROLOG called C-CAT (consistency checking along time). Some meaningful outputs from the program are used as examples. The solution proposed represents an extension to B. C. Williams' temporal constraint propagation methodology. It also extends the applicability range of existing approaches to model-based diagnosis, permitting its use in tasks such as online diagnosis of dynamic systems.     

Structure of CheA, a signal-transducing histidine kinase

BACKGROUND/AIMS: After liver transplantation for autoimmune hepatitis, the long-term results and the incidence of recurrence of primary disease are unknown. METHODS: In this retrospective study we reviewed the clinical course of 25 patients transplanted for autoimmune hepatitis and followed for a mean of 5.3 years (2-8.5 years). RESULTS: The actuarial 5-year patient and graft survival rates were 91% (+/-6%) and 83% (+/-8%). The actuarial 1-year rate of acute rejection was 50% (+/-10.2%), which was comparable to that of patients transplanted for primary biliary cirrhosis and primary sclerosing cholangitis. Autoantibodies persisted in 77% of patients, at a lower titer than before liver transplantation. Ten patients were excluded from the study of autoimmune hepatitis recurrence, one because of an early postoperative death and nine because of hepatitis C virus infection acquired before or after liver transplantation. In the remaining 15 patients, who were free of hepatitis C virus infection, 5-year patient and graft survivals were 100% and 87%, respectively. Despite triple immunosuppressive therapy, three patients (20%) developed chronic hepatitis with histological and serological features of autoimmune hepatitis in the absence of any other identifiable cause. The disease was severe in two patients, leading to graft failure and asymptomatic in another, despite marked histological abnormalities. In one of these three patients, autoimmune hepatitis recurred on the second liver graft as well. CONCLUSIONS: Patients undergoing liver transplantation for autoimmune hepatitis have an excellent survival rate although severe primary disease may recur, suggesting the need for stronger post-operative immunosuppressive therapy.     

Effects of novelty and pain on behavior and hippocampal extracellular ACh levels in male and female rats

In vivo microdialysis was used to assess the effects of novelty and pain on hippocampal ACh release in male and female rats. Experiments were carried out during the dark phase and consisted of 2 days of tests: on Day 1, after Baseline 1, animals were exposed to a new cage (Novelty) to which, 30 min later, a plastic cylinder (Object) was introduced. On Day 2, after Baseline 2, the Formalin test (50 microl of formalin 10%, s.c. injected in the dorsal hindpaw) was carried out in the animal's home cage. All behaviors were recorded. The extracellular levels of ACh in the dorsal hippocampus were estimated, in 10-min samples, by assay of ACh in the dialysates by HPLC. On Day 1 the raw values of ACh were higher in females than in males, but no sex difference was present when the percentage of change was considered. In both sexes the Novelty and Object tests induced an increase in ACh levels with respect to Baseline. Higher levels of exploration were present in females than males during the first 10 min of Novelty. On Day 2, ACh release increased in both sexes during the Formalin test. No sex difference in either ACh raw values or the percentages of change were found. Females showed higher levels of licking and lower levels of activity than males. The present study shows that novelty and pain induce similar hippocampal cholinergic activation in male and female rats but different behaviors. The results are discussed in light of the several anatomical and functional sex differences present in the hippocampus.     

Regulation of neurotrophin receptor expression by retinoic acid in mouse sympathetic neuroblasts

We have studied the effect of retinoic acid on the expression of the neurotrophin receptors trkA, trkC, and p75 by neuroblasts and neurons at different axial levels along the embryonic mouse paravertebral sympathetic chain. In dissociated cultures of sympathetic neuroblasts, retinoic acid inhibited the developmental increase in trkA mRNA expression and the developmental decrease in trkC mRNA expression that normally occurs in these cells but did not affect p75 mRNA expression. At higher concentrations, retinoic acid also increased the proliferation of sympathetic neuroblasts. After sympathetic neuroblasts became postmitotic, retinoic acid no longer affected receptor expression. Studies with retinoic acid receptor agonists and antagonists indicated that the effects of retinoic acid on neurotrophin receptor expression were mediated mainly by alpha retinoic acid receptors, not beta or gamma receptors. The observation that alpha-antagonists increased trkA mRNA expression in intact sympathetic ganglion explants suggests that endogenous retinoic acid is a physiological regulator of trkA receptor expression.