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Gibson, L.

Publications and source records attributed to Gibson, L..

2 recordsLinked to original sources

Eye position signals in the dorsal pulvinar during fixation and goal-directed saccades

Most sensorimotor cortical areas contain eye position information thought to ensure perceptual stability across saccades and underlie spatial transformations supporting goal-directed actions. One pathway by which eye position signals could be relayed to and across cortical areas is via the dorsal pulvinar. Several studies demonstrated saccade-related activity in the dorsal pulvinar and we have recently shown that many neurons exhibit post-saccadic spatial preference long after the saccade execution. In addition, dorsal pulvinar lesions lead to gaze-holding deficits expressed as nystagmus or ipsilesional gaze bias, prompting us to investigate the effects of eye position. We tested three starting eye positions (-15{degrees}/0{degrees}/15{degrees}) in monkeys performing a visually-cued memory saccade task. We found two main types of gaze dependence. First, [~]50% of neurons showed an effect of static gaze direction during initial and post-saccadic fixation. Eccentric gaze preference was more common than straight ahead. Some of these neurons were not visually-responsive and might be primarily signaling the position of the eyes in the orbit, or coding foveal targets in a head/body/world-centered reference frame. Second, many neurons showed a combination of eye-centered and gaze-dependent modulation of visual, memory and saccadic responses to a peripheral target. A small subset showed effects consistent with eye position-dependent gain modulation. Analysis of reference frames across task epochs from visual cue to post-saccadic target fixation indicated a transition from predominantly eye-centered encoding to representation of final gaze or foveated locations in non-retinocentric coordinates. These results show that dorsal pulvinar neurons carry information about eye position, which could contribute to steady gaze during postural changes and to reference frame transformations for visually-guided eye and limb movements.\n\nNew & NoteworthyWork on the pulvinar focused on eye-centered visuospatial representations, but position of the eyes in the orbit is also an important factor that needs to be taken into account during spatial orienting and goal-directed reaching. Here we show that dorsal pulvinar neurons are influenced by eye position. Gaze direction modulated ongoing firing during stable fixation, as well as visual and saccade responses to peripheral targets, suggesting involvement of the dorsal pulvinar in spatial coordinate transformations.

neuroscience

Targeting the dysfunctional mitochondrial respiration in drug resistant B-cell acute lymphoblastic leukemia

Reprogramming of cellular pathways is a crucial mechanism of drug resistance and survival in refractory acute lymphoblastic leukemia (ALL) cells. In the present study, we performed an unbiased gene expression analysis and identified a dysfunctional mitochondrial respiration program in drug-resistant ALL cells grown in a co-culture system with bone marrow stromal cells (BMSC). Specifically, the activity of the complexes within the electron transport chain was significantly downregulated, correlated with decreased mitochondrial mass and ATP production in drug-resistant ALL cells. To validate mitochondrial respiration as a druggable target, we utilized pyrvinium pamoate (PP), a known inhibitor of mitochondrial respiration and documented its anti-leukemic activity in several ALL cell lines grown alone or in co-culture with BMSC. To increase the bioavailability profile of PP, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay. PP anti-leukemic activity was decreased by the addition of sodium pyruvate, and furthermore, PP was found to have an additive anti-leukemic effect when used in combination with rotenone, a mitochondrial complex I inhibitor with activity similar to PP on the mitochondrial respiration. Importantly, PPs cell death activity was found to be specific for leukemic cells as primary normal immune cells were resistant to PP-mediated cell death. In conclusion, we have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells.

cancer biology