Decreasing cytosolic translation is beneficial to yeast and human Tafazzin-deficient cells

Cardiolipin (CL) optimizes diverse mitochondrial processes, including oxidative phosphorylation (OXPHOS). To function properly, CL needs to be unsaturated, which requires the acyltransferase Tafazzin (TAZ). Loss-of-function mutations in the TAZ gene are responsible for the Barth syndrome (BTHS), a rare X-linked cardiomyopathy, presumably because of a diminished OXPHOS capacity. Herein we show that a partial inhibition of cytosolic protein synthesis, either chemically with the use of cycloheximide or by specific genetic mutations, fully restores biogenesis and the activity of the oxidative phosphorylation system in a yeast BTHS model (taz1Δ). Interestingly, the defaults in CL were not suppressed, indicating that they are not primarily responsible for the OXPHOS deficiency in taz1Δ yeast. Low concentrations of cycloheximide in the picomolar range were beneficial to TAZ-deficient HeLa cells, as evidenced by the recovery of a good proliferative capacity. These findings reveal that a diminished capacity of CL remodeling deficient cells to preserve protein homeostasis is likely an important factor contributing to the pathogenesis of BTHS. This in turn, identifies cytosolic translation as a potential therapeutic target for the treatment of this disease

The FK506-binding protein FKBP52 in vitro induces aggregation of truncated Tau forms with prion-like behavior

The KAES methodology for efficient evaluation of dependability-related properties is proposed. KAES targets systems representable by Stochastic Petri Nets-based models, composed by a large number of submodels where interconnections are managed through synchronization at action level. The core of KAES is a new numerical solution of the underlying CTMC process, based on powerful mathematical techniques, including Kronecker algebra, Tensor Trains and Exponential Sums. Specifically, advancing on existing literature, KAES addresses efficient evaluation of the Mean-Time-To-Absorption in CTMC with absorbing states, exploiting the basic idea to further pursue the symbolic representation of the elements involved in the evaluation process, so to better cope with the problem of state explosion. As a result, computation efficiency is improved, especially when the submodels are loosely interconnected and have small number of states. An instrumental case study is adopted, to show the feasibility of KAES, in particular from memory consumption point of view

The FK506-binding protein FKBP52 in vitro induces aggregation of truncated Tau forms with prion-like behavior.

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