A characterization of missingness at random in a generalized shared‐parameter joint modeling framework for longitudinal and time‐to‐event data,and sensitivity analysis

We consider a conceptual correspondence between the missing data setting, and joint modeling of longitudinal and time‐to‐event outcomes. Based on this, we formulate an extended shared random effects joint model. Based on this, we provide a characterization of missing at random, which is in line with that in the missing data setting. The ideas are illustrated using data from a study on liver cirrhosis, contrasting the new framework with conventional joint models.     

Biochemical and catalytic properties of two intracellular β-glucosidases from the fungus Penicillium decumbens active on flavonoid glucosides

In the presence of rutin as sole carbon source, Penicillium decumbens produces two intracellular β-glucosidases named G_I and G_II, with molecular masses of 56,000 and 460,000 Da, respectively. The two proteins have been purified to homogeneity. G_I and G_II composed of two and four equal sub-units, respectively and displayed optimal activity at pH 7.0 and temperature 65–75 °C. Both β-glucosidases were competitively inhibited by glucose and glucono-δ-lactone. G_I and G_II exhibited broad substrate specificity, since they hydrolyzed a range of (1,3)-, (1,4)- and (1,6)-β-glucosides as well as aryl β-glucosides. Determination of k_cat/K_m revealed that G_II hydrolyzed 3–8 times more efficiently the above-mentioned substrates. The ability of G_I and G_II to deglycosylate various flavonoid glycosides was also investigated. Both enzymes were active against flavonoids glycosylated at the 7 position but G_II hydrolyzed them 5 times more efficiently than G_I. Of the flavanols tested, both enzymes were incapable of hydrolyzing quercetrin and kaempferol-3-glucoside. The main difference between G_I and G_II as far as the hydrolysis of flavanols is concerned, was the ability of G_II to hydrolyze the quercetin-3-glucoside.     

A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors

We here conducted an image-based chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. None of the compounds up-regulated translation, which could be due to the screen being performed in cancer cells grown in full media where translation is already present at very high levels. Regarding translation down-regulators, and consistent with current knowledge, inhibitors of the mechanistic target of rapamycin (mTOR) signaling pathway were the most represented class. In addition, we identified that inhibitors of sphingosine kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. Mechanistically, this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum (ER), which activates the integrated stress response (ISR) and contributes to the toxicity of SPHK inhibitors. Surprisingly, the toxicity and activation of the ISR triggered by 2 independent SPHK inhibitors, SKI-II and ABC294640, the latter in clinical trials, are also observed in cells lacking SPHK1 and SPHK2. In summary, our study provides a useful resource on the effects of medically used drugs on translation, identified compounds capable of reducing translation independently of mTOR and has revealed that the cytotoxic properties of SPHK inhibitors being developed as anticancer agents are independent of SPHKs.

A chemical screen to evaluate how 4100 drugs modulate translation rates confirms mTOR as the main pathway regulating translation and reveals that sphingosine kinase inhibitors downregulate translation via activation of the ER-stress response. Sphingosine kinase inhibitors, including one in clinical trials, activate stress responses and kill cells independently of the cognate target.