FLASH Knockdown Sensitizes Cells To Fas-Mediated Apoptosis via Down-Regulation of the Anti-Apoptotic Proteins, MCL-1 and Cflip Short

FLASH (FLICE-associated huge protein or CASP8AP2) is a large multifunctional protein that is involved in many cellular processes associated with cell death and survival. It has been reported to promote apoptosis, but we show here that depletion of FLASH in HT1080 cells by siRNA interference can also accelerate the process. As shown previously, depletion of FLASH halts growth by down-regulating histone biosynthesis and arrests the cell cycle in S-phase. FLASH knockdown followed by stimulating the cells with Fas ligand or anti-Fas antibodies was found to be associated with a more rapid cleavage of PARP, accelerated activation of caspase-8 and the executioner caspase-3 and rapid progression to cellular disintegration. As is the case for most anti-apoptotic proteins, FLASH was degraded soon after the onset of apoptosis. Depletion of FLASH also resulted in the reduced intracellular levels of the anti-apoptotic proteins, MCL-1 and the short isoform of cFLIP. FLASH knockdown in HT1080 mutant cells defective in p53 did not significantly accelerate Fas mediated apoptosis indicating that the effect was dependent on functional p53. Collectively, these results suggest that under some circumstances, FLASH suppresses apoptosis

Measles transmission from an anthroposophic community to the general population, Germany 2008

<p>Abstract</p> <p>Background</p> <p>In Germany, measles vaccination coverage with two doses is not yet sufficient to prevent regional outbreaks. Among the 16 German federal states, vaccination coverage was lowest in Bavaria with 85% in 2008. From March to mid-April 2008, four neighbouring Bavarian counties reported 55 measles-cases mostly linked to an ongoing measles outbreak in an anthroposophic school in Austria. We investigated this outbreak to guide future public health action.</p> <p>Methods</p> <p>We applied the German national case-definition for measles and collected data using the national surveillance system and a questionnaire. Measles cases with disease onset a maximum of 18 days apart and spatial contact (e.g. same household, same school) were summed up in clusters. Two different interventions, which were implemented in schools and kindergartens in Bavaria, were compared by their impact on the size and duration of measles clusters. Susceptible persons were excluded from schools or kindergartens either with the first (intervention A) or second (intervention B) measles case occurring in the respective institution.</p> <p>Results</p> <p>Among the 217 Bavarian measles cases identified from March-July 2008, 28 (13%) cases were attendees of the anthroposophic school in Austria. In total, vaccination status was known in 161 (74%) cases and 156 (97%) of them were not vaccinated. The main factor for non-vaccination was "fear of vaccine-related adverse events" (33%). Twenty-nine (18%) of 161 cases suffered complications. Exclusively genotype D5 was detected. Overall, 184 cases could be epidemiologically grouped into 59 clusters. Of those, 41 clusters could be linked to households and 13 to schools or kindergartens. The effect of intervention A and B was analysed in 10 school or kindergarten clusters. Depending on the respective intervention A or B, the median number of cases per cluster was 3 versus 13 (p = 0.05), and the median duration of a cluster was 3 versus 26 days (p = 0.13).</p> <p>Conclusions</p> <p>Introduction of measles virus into a pocket of susceptible persons (e.g. vaccination opponents or sceptics) may lead to large outbreaks in the general population, if the general population's vaccination coverage is below the WHO recommended level. Education on the safety of measles vaccine needs to be strengthened to increase measles vaccination coverage. Early intervention may limit spread in schools or kindergartens. Suspected measles has to be reported immediately to the local health authorities in order to allow intervention as early as possible.</p

Mimicking microbial 'education' of the immune system: a strategy to revert the epidemic trend of atopy and allergic asthma?

Deficient microbial stimulation of the immune system, caused by hygiene, may underly the atopy and allergic asthma epidemic we are currently experiencing. Consistent with this 'hygiene hypothesis', research on immunotherapy of allergic diseases also centres on bacteria-derived molecules (eg DNA immunostimulatory sequences) as adjuvants for allergen-specific type 1 immune responses. If we understood how certain microbes physiologically 'educate' our immune system to interact safely with environmental nonmicrobial antigens, we might be able to learn to mimic their beneficial actions. Programmed 'immunoeducation' would consist of safe administration, by the correct route, dose and timing, of those microbial stimuli that are necessary to 'train' the developing mucosal immune system and to maintain an appropriate homeostatic equilibrium between its components. Overall, this would result in a prevention of atopy that is not limited to certain specific allergens. Although such a strategy is far beyond our present potential, it may in principle revert the epidemic trend of atopy and allergic asthma without jeopardizing the fight against infectious diseases

Prospect theory and tax evasion: a reconsideration of the Yitzhaki puzzle

The standard expected utility (EUT) model of tax evasion predicts that evasion is decreasing in the marginal tax rate (the Yitzhaki puzzle). Recent literature shows cases in which incorporating prospect theory (PT) does and does not overturn the Puzzle. In a general environment that nests both PT and EUT preferences, we provide a detailed study of how the elements of PT affect the Puzzle. PT does not always reverse the Puzzle, hence we give and interpret conditions for when it does and does not. When allowing for stigma and/or variable audit probability, PT reverses the Puzzle in the same way and with the same limitations as does EUT, if equally augmented

Striatal Proteomic Analysis Suggests that First L-Dopa Dose Equates to Chronic Exposure

L-3,4-dihydroxypheylalanine (L-dopa)-induced dyskinesia represent a debilitating complication of therapy for Parkinson's disease (PD) that result from a progressive sensitization through repeated L-dopa exposures. The MPTP macaque model was used to study the proteome in dopamine-depleted striatum with and without subsequent acute and chronic L-dopa treatment using two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry. The present data suggest that the dopamine-depleted striatum is so sensitive to de novo L-dopa treatment that the first ever administration alone would be able (i) to induce rapid post-translational modification-based proteomic changes that are specific to this first exposure and (ii), possibly, lead to irreversible protein level changes that would be not further modified by chronic L-dopa treatment. The apparent equivalence between first and chronic L-dopa administration suggests that priming would be the direct consequence of dopamine loss, the first L-dopa administrations only exacerbating the sensitization process but not inducing it