Interactions of melatonin with mammalian mitochondria. Reducer of energy capacity and amplifier of permeability transition.

Melatonin, a metabolic product of the amino acid tryptophan, induces a dose-dependent energy drop correlated with a decrease in the oxidative phosphorylation process in isolated rat liver mitochondria. This effect involves a gradual decrease in the respiratory control index and significant alterations in the state 4/state 3 transition of membrane potential (ΔΨ). Melatonin, alone, does not affect the insulating properties of the inner membrane but, in the presence of supraphysiological Ca2+, induces a ΔΨ drop and colloid-osmotic mitochondrial swelling. These events are sensitive to cyclosporin A and the inhibitors of Ca2+ transport, indicative of the induction or amplification of the mitochondrial permeability transition. This phenomenon is triggered by oxidative stress induced by melatonin and Ca2+, with the generation of hydrogen peroxide and the consequent oxidation of sulfydryl groups, glutathione and pyridine nucleotides. In addition, melatonin, again in the presence of Ca2+, can also induce substantial release of cytochrome C and AIF (apoptosis-inducing factor), thus revealing its potential as a pro-apoptotic agent

A link between the antioxidant defense system and calcium: A proposal for the biochemical function of Bcl-2.

Tumorigenesis has long been viewed as a problem of perturbed regulation of cell proliferation. It has, however, become increasingly apparent during the last years that disturbance of the equilibrium between cell survival and cell death may equally contribute to the development of a tumor. Elimination of cells has first been described by morphologists as an important physiological process in developmental biology for which the term programmed cell death (PCD) or apoptosis has been coined, and has since then been recognized as a generally important phenomenon in many different areas of biology (Wyllie et al., 1980). Apart from morphological criteria, apoptosis is only poorly defined and discrimination from other forms of cell death is often difficult. Regardless of the definition of apoptosis, it is apparent that susceptibility versus resistance to toxic conditions or death inducing signals is an extremely important property of a cell determining its fate in its environmental context.   &nbsp

Crowdsourcing language change with smartphone applications

Crowdsourcing linguistic phenomena with smartphone applications is relatively new. In linguistics, apps have predominantly been developed to create pronunciation dictionaries, to train acoustic models, and to archive endangered languages. This paper presents the first account of how apps can be used to collect data suitable for documenting language change: we created an app, Dialäkt Äpp (DÄ), which predicts users’ dialects. For 16 linguistic variables, users select a dialectal variant from a drop-down menu. DÄ then geographically locates the user’s dialect by suggesting a list of communes where dialect variants most similar to their choices are used. Underlying this prediction are 16 maps from the historical Linguistic Atlas of German-speaking Switzerland, which documents the linguistic situation around 1950. Where users disagree with the prediction, they can indicate what they consider to be their dialect’s location. With this information, the 16 variables can be assessed for language change. Thanks to the playfulness of its functionality, DÄ has reached many users; our linguistic analyses are based on data from nearly 60,000 speakers. Results reveal a relative stability for phonetic variables, while lexical and morphological variables seem more prone to change. Crowdsourcing large amounts of dialect data with smartphone apps has the potential to complement existing data collection techniques and to provide evidence that traditional methods cannot, with normal resources, hope to gather. Nonetheless, it is important to emphasize a range of methodological caveats, including sparse knowledge of users’ linguistic backgrounds (users only indicate age, sex) and users’ self-declaration of their dialect. These are discussed and evaluated in detail here. Findings remain intriguing nevertheless: as a means of quality control, we report that traditional dialectological methods have revealed trends similar to those found by the app. This underlines the validity of the crowdsourcing method. We are presently extending DÄ architecture to other languages

Analysis of an N-terminal deletion in subunit a of the Escherichia coli ATP synthase

Subunit a is a membrane-bound stator subunit of the ATP synthase and is essential for proton translocation. The N-terminus of subunit a in E. coli is localized to the periplasm, and contains a sequence motif that is conserved among some bacteria. Previous work has identified mutations in this region that impair enzyme activity. Here, an internal deletion was constructed in subunit a in which residues 6-20 were replaced by a single lysine residue, and this mutant was unable to grow on succinate minimal medium. Membrane vesicles prepared from this mutant lacked ATP synthesis and ATP-driven proton translocation, even though immunoblots showed a significant level of subunit a. Similar results were obtained after purification and reconstitution of the mutant ATP synthase into liposomes. The location of subunit a with respect to its neighboring subunits b and c was probed by introducing cysteine substitutions that were known to promote cross-linking: a_L207C + c_I55C, a_L121C + b_N4C, and a_T107C + b_V18C. The last pair was unable to form cross-links in the background of the deletion mutant. The results indicate that loss of the N-terminal region of subunit a does not generally disrupt its structure, but does alter interactions with subunit b