Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP

Raf-1 phosphorylates and activates MEK-1, a kinase that activates the extracellular signal regulated kinases (ERK). This kinase cascade controls the proliferation and differentiation of different cell types. Here we describe a Raf-1-interacting protein, isolated using a yeast two-hybrid screen. This protein inhibits the phosphorylation and activation of MEK by Raf-1 and is designated RKIP (Raf kinase inhibitor protein). In vitro, RKIP binds to Raf-1, MEK and ERK, but not to Ras. RKIP co-immunoprecipitates with Raf-1 and MEK from cell lysates and colocalizes with Raf-1 when examined by confocal microscopy. RKIP is not a substrate for Raf-1 or MEK, but competitively disrupts the interaction between these kinases. RKIP overexpression interferes with the activation of MEK and ERK, induction of AP-1-dependent reporter genes and transformation elicited by an oncogenically activated Raf-1 kinase. Downregulation of endogenous RKIP by expression of antisense RNA or antibody microinjection induces the activation of MEK-, ERK- and AP-1-dependent transcription. RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK modul

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Psychological stress and health in undergraduate dental students: fifth year outcomes compared with first year baseline results from five European dental schools

Objective: To compare the levels of a series of health-related indicators from a cohort of fifth year dental students from five European schools with their first year scores, and to investigate the relationship between these follow-up measures. Methods: Burnout was measured using the Maslach Burnout Inventory (MBI), consisting of three scales: Emotional Exhaustion (EE, alpha = 0.90), Depersonalisation (alpha = 0.80) and Personal Accomplishment (alpha = 0.72). Physical health was measured by the Physical Symptoms Questionnaire (alpha = 0.82), psychological distress was measured using the General Health Questionnaire (GHQ, alpha = 0.89) and student stress was captured using seven subscales of the Dental Environment Stress questionnaire (DES, alpha = 0.92). A total of 132 fifth year students responded from five dental schools (Manchester, Belfast, Cork, Helsinki and Amsterdam), a 51% response. Results: Fifth year students showed relatively high mean MBI scores when compared with first year results, especially on EE; 39% could be labelled 'high scorers'; 44% of the students met the criteria for 'cases' on the GHQ. Highest mean scores on the DES were obtained on the subscales: Study Obligations, Patient-Related Aspects and Study Pressure respectively. Between schools interesting differences were detected on all variables. As hypothesised, a clear direct effect of stress on both burnout and physical symptoms was shown. An indirect effect of stress on mental health via burnout was shown. Conclusions: Dental students showed a negative development through the years from first to fifth year with regard to EE and psychological distress. Both burnout constructs related to physical and mental health. It is recommended that dental faculty focus on the importance of prevention and intervention of stress amongst undergraduates

Study of alleles of the second complement component (C2) on Canadian HLA haplotypes.

Typing for genetic variation in the second complement component C2 was performed on sera from HLA haplotyped Canadian families. Part of the data has been studied and analysed as a population; in addition there is a further random collection of haplotypes bearing the C2*2 allele. In the population data there were 444 separate haplotypes from unrelated parents or other founders: 4.7% of the haplotypes carried the uncommon allele C2*2; one haplotype carried the rare C2*3. Study of C2 2-1 heterozygotes in the population data revealed 59 haplotypes which carried the common C2*1 allele and one which carried a deficiency allele C2*0. The remaining haplotypes carried either C2*1 or else an undetectable C2*0 allele. In the entire data there were 281 meioses informative for C2. The only recombinant between HLA-B and C2 showed the C2 locus to be on the DR side of the B locus. Strong allelic association between C2 *2 and Bw22 and less strong association between C2 *2 and B15 suggested the possibility of two ancestral C2 mutants. Examination of other markers on these and subsequently collected haplotypes do not conflict with this idea since the B15 haplotypes mostly carry C4A *4, C4B *2 whilst the Bw22 haplotypes mostly carry C4A *4, C4B *4. The alternative idea, that there was one original mutant which crossed over from a B15 to a Bw22 haplotype or vice versa is not excluded, however. Since approximate equilibrium has been reached between Bw22 and the HLA-A locus alleles on these C2 *2 bearing haplotypes, we conclude that this mutation is at least 5000 years old. Other haplotypes carrying C2 *2 are assumed to be ancestral recombinants; if this is true, the C2 locus map position between HLA-B and HLA-DR is confirmed. Study of C2 mutation may provide a model for understanding the genetics of some disease susceptibility genes in the HLA region