Awada, A. | bioRxiv Science

bioRxiv2020

Septins disruption controls tumor growth and enhances efficacy of Herceptin

Septin expressions are altered in cancer cells and exhibit poor prognoses in malignancies. As the first approach to develop a septin filament targeting agent, we optimized the structure of Forchlorfenuron (FCF), a known plant cytokinin to generate UR214-9, which contrary to FCF, causes septin-2/9 filamental structural catastrophe in cancer cells without altering cellular septin protein levels. In-silico docking using septin-2/septin-2 dimer complex showed that UR214-9 displaced the guanine carbonyl oxygen from the GDP binding domain and showed increased binding energy than FCF(-8.59vs-7.21). UR214-9 reduced cancer cell growth, downregulated HER2/STAT-3 axis and controlled growth of HER2+ pancreatic, breast and ovarian cancer xenografts in NSG mice and enhanced response of Herceptin against HER2+breast cancer xenograft. Transcriptome analysis of UR214-9 exposed cells demonstrated significant perturbation of <20 genes compared to afatinib which impacted >1200 genes in JIMT-1 breast cancer cells indicating target specificity and non-transcriptional functions of UR214-9. In summary, disrupting septins via UR214-9 is a new approach to control the growth of HER2+ malignancies.

cancer biology↗

bioRxiv2019

Influence of stimulus complexity on the specificity of visual perceptual learning

Although the structure and function of the human visual system are determined in large part during early development, there is ample evidence for adult plasticity as well. Such plasticity has important consequences for restoring vision after cortical damage and for improving function in healthy people. Although these applications have shown promising results, they are often limited by pathological specificity: Improvements obtained through perceptual training fail to generalize beyond the trained stimulus feature or location. Efforts to reduce specificity have focused on the design of training tasks, but less is known about the effects of stimulus structure on the specificity of perceptual learning. Here, we leverage physiological findings from the dorsal visual pathway of the primate brain to explore the hypothesis that learning specificity is related to the complexity of the training stimulus. Specifically, because neurons in higher-level structures of the dorsal visual pathway exhibit little stimulus specificity, we reasoned that training with more complex stimuli would reduce the specificity of learning. We trained human observers on stimuli of varying complexity, ranging from simple sinewave gratings to complex optic flow fields. Our results show that training with more complex stimuli reduces specificity for spatial position and stimulus features. Such changes are associated with increased spatial integration. These findings were captured by a computational \"reweighting\" model that decoded the outputs of simulated neurons in areas MT and MST of the primate visual cortex. Our results suggest that the addition of more complex stimuli into perceptual learning paradigms provides a simple and effective way to minimize specificity in learning.

neuroscience↗