Molecular architecture of the DED chains at the DISC: regulation of procaspase-8 activation by short DED proteins c-FLIP and procaspase-8 prodomain.

The CD95/Fas/APO-1 death-inducing signaling complex (DISC), comprising CD95, FADD, procaspase-8, procaspase-10, and c-FLIP, has a key role in apoptosis induction. Recently, it was demonstrated that procaspase-8 activation is driven by death effector domain (DED) chains at the DISC. Here, we analyzed the molecular architecture of the chains and the role of the short DED proteins in regulating procaspase-8 activation in the chain model. We demonstrate that the DED chains are largely composed of procaspase-8 cleavage products and, in particular, of its prodomain. The DED chain also comprises c-FLIP and procaspase-10 that are present in 10 times lower amounts compared with procaspase-8. We show that short c-FLIP isoforms can inhibit CD95-induced cell death upon overexpression, likely by forming inactive heterodimers with procaspase-8. Furthermore, we have addressed mechanisms of the termination of chain elongation using experimental and mathematical modeling approaches. We show that neither c-FLIP nor procaspase-8 prodomain terminates the DED chain, but rather the dissociation/association rates of procaspase-8 define the stability of the chain and thereby its length. In addition, we provide evidence that procaspase-8 prodomain generated at the DISC constitutes a negative feedback loop in procaspase-8 activation. Overall, these findings provide new insights into caspase-8 activation in DED chains and apoptosis initiation.

Vaccination and antiviral treatment of neglected diseases caused by flaviviral infections.

Flaviviral infections have a re-emerging impact on the health situation in developing countries with several billions of people living at risk. In the present review, we focus on three members of the genus Flavivirus belonging to the Flaviviridae family. They are transmitted to humans by mosquito bites, namely those viruses leading to Dengue Fever, Yellow Fever and mosquito-borne Japanese encephalitis. All three virus groups have a spherical structure with a diameter of approximately 50 nm. Although sharing a similar genomic structure and intracellular life cycle, they show different clinical manifestations. Infections are incurable, as there is no antiviral treatment available for either of the three viruses. Thus, prevention and vaccination are the best defenses. The most promising vaccines are live attenuated vaccines (LAVs), such as the YF17D strain against Yellow Fever or the SA-14-14-2 strain against Japanese encephalitis. Additionally, recombinant vaccines for Japanese encephalitis are in development. Although Dengue Fever is the most prevalent arthropode-borne flaviviral infection and a lot of research to develop a vaccine against all four Dengue Fever serotypes was undertaken, no vaccine is available on the market yet. Promising tetravalent vaccine candidates are currently undergoing clinical phase trials, including LAVs, recombinant and chimeric candidates as well as non-replicating vaccine approaches. Additionally, encouraging anti-flaviviral approaches target non-structural proteins, virus-specific proteases essential for cellular maturation of viral particles. Peptide inhibitors against the highly conserved NS2B and NS3 proteases are attractive as pan-flaviviral drug candidates.

Phase transitions for flat anti-de Sitter black holes.

We reexamine the thermodynamics of anti-de Sitter (adS) black holes with Ricci flat horizons using the adS soliton as the thermal background. We find that there is a phase transition which is dependent not only on the temperature but also on the black hole area, which is an independent parameter. As in the spherical adS black hole, this phase transition is related via the adS/conformal-field-theory correspondence to a confinement-deconfinement transition in the large- N gauge theory on the conformal boundary at infinity.