Membrane association of mitochondrial DNA facilitates base excision repair in mammalian mitochondria

Mitochondrial DNA encodes a set of 13 polypeptides and is subjected to constant oxidative stress due to ROS production within the organelle. It has been shown that DNA repair in the mitochondrion proceeds through both short- and long-patch base excision repair (BER). In the present article, we have used the natural competence of mammalian mitochondria to import DNA and study the sub-mitochondrial localization of the repair system in organello. Results demonstrate that sequences corresponding to the mtDNA non-coding region interact with the inner membrane in a rapid and saturable fashion. We show that uracil containing import substrates are taken into the mitochondrion and are used as templates for damage driven DNA synthesis. After further sub-fractionation, we show that the length of the repair synthesis patch differs in the soluble and the particulate fraction. Bona fide long patch BER synthesis occurs on the DNA associated with the particulate fraction, whereas a nick driven DNA synthesis occurs when the uracil containing DNA accesses the soluble fraction. Our results suggest that coordinate interactions of the different partners needed for BER is only found at sites where the DNA is associated with the membrane.     

A gaze bias with coarse spatial indexing during a gambling task

Researchers have used eye-tracking methods to infer cognitive processes during decision making in choice tasks involving visual materials. Gaze likelihood analysis has shown a cascading effect, suggestive of a causal role for the gaze in preference formation during evaluative decision making. According to the gaze bias hypothesis, the gaze serves to build commitment gradually towards a choice. Here, we applied gaze likelihood analysis in a two-choice version of the well-known Iowa Gambling Task. This task requires active learning of the value of different choice options. As such, it does not involve visual preference formation, but choice optimization through learning. In Experiment 1 we asked subjects to choose between two decks with different payoff structures, and to give their responses using mouse clicks. Two groups of subjects were exposed to stable versus varying outcome contingencies. The analysis revealed a pronounced gaze bias towards the chosen stimuli in both groups of subjects, plateauing at more than 400 ms before the choice. The early plateauing suggested that the gaze effect partially reflected eye-hand coordination. In Experiment 2 we asked subjects to give responses using a key press. The results again showed a clear gaze bias towards the chosen deck, this time without any influence from eye-hand coordination. In both experiments, there was a clear gaze bias towards the choice even though the gaze fixations did not narrowly focus on the spatial positions of choice options. Taken together, the data suggested a role for gaze in coarse spatial indexing during non-perceptual decision making.     

Menopausal estrogen deprivation activates steroid sensitive stem cells (3SC) and local estrogen biosynthesis: A model for breast cancer development

We propose a hypothesis for breast cancer (BC) development and its implications for BC prevention. We describe a model in which some breast cells function as both stem cells and steroid sensors (steroid sensitive stem cells). Estrogen receptors on those cells could be upregulated in women who had increased cumulative exposure to estrogen, leading to their progressive sensitization. At menopause, such women experience considerable decline of estrogen concentration in their blood. Consequently, the sensitized stem cells activate mechanisms of local estrogen synthesis including the activation of aromatase. The intracrine build-up of estrogen and its metabolites induces proliferation and genetic dysfunction. Eventually, a normal stem cell transforms into an estrogen-sensitive cancer stem cell that is capable of tumor initiation and delineation into other phenotypes of cancer cells. This hypothesis is supported by significant in-vitro and clinical research evidence. According to this model, we suggest that estrogen therapy could be protective against BC. Alternatively, aromatase inhibitors are expected to be effective in BC prevention. A combination of AIs and estrogen might augment the preventative merits of both drugs and maintain a good tolerability profile for long-term prevention protocols.