Biology subjects

Asadi, F.

Publications and source records attributed to Asadi, F..

4 recordsLinked to original sources

bioRxiv2023

Neural correlates of face perception modeled with a convolutional recurrent neural network

Event-related potential (ERP) sensitivity to faces is predominantly characterized by an N170 peak that has greater amplitude and shorter latency when elicited by human faces than images of other objects. We developed a computational model of visual ERP generation to study this phenomenon which consisted of a convolutional neural network (CNN) connected to a recurrent neural network (RNN). We used open-access data to develop the model, generated synthetic images for simulating experiments, then collected additional data to validate predictions of these simulations. For modeling, visual stimuli presented during ERP experiments were represented as sequences of images (time x pixels). These were provided as inputs to the model. The CNN transformed these inputs into sequences of vectors that were passed to the RNN. The ERP waveforms evoked by visual stimuli were provided to the RNN as labels for supervised learning. The whole model was trained end-to-end using data from the open-access dataset to reproduce ERP waveforms evoked by visual events. Cross-validation model outputs strongly correlated with open-access (r = 0.98) and validation study data (r = 0.78). Open-access and validation study data correlated similarly (r = 0.81). Some aspects of model behavior were consistent with neural recordings while others were not, suggesting promising albeit limited capacity for modeling the neurophysiology of face-sensitive ERP generation.

neuroscience↗

bioRxiv2021

Misrouting of Glucagon and Stathmin-2 Towards Lysosomal System of α-Cells in Glucagon Hypersecretion of Diabetes

Glucagon hypersecretion from the pancreatic -cell is a characteristic sign of diabetes, which exacerbates fasting hyperglycemia. Thus, targeting glucagon secretion from -cells may be a promising approach for combating hyperglucagonemia. We have recently identified stathmin-2 as a protein that resides in -cell secretory granules, and showed that it regulates glucagon secretion by directing glucagon towards the endolysosomal system in TC1-6 cells. Here, we hypothesized that disruption of Stmn2-mediated trafficking of glucagon to the endolysosomes contributes to hyperglucagonemia. In isolated islets from male mice treated with streptozotocin (STZ) to induce diabetes, Arg-stimulated secretion of glucagon and Stmn2 was augmented. However, cell glucagon content was significantly increased (p<0.001), but Stmn2 levels were reduced (p<0.01) in STZ-treated mice, as measured by both ELISA and immunofluorescence intensity. Expression of Gcg mRNA increased ~4.5 times, while Stmn2 mRNA levels did not change. Using confocal immunofluorescence microscopy, the colocalization of glucagon and Stmn2 in Lamp2A+ lysosomes was dramatically reduced (p<0.001) in islets from diabetic mice, and the colocalization of Stmn2, but not glucagon, with the late endosome marker, Rab7, significantly (p<0.01) increased. Further studies were conducted in TC1-6 cells cultured in media containing high glucose (16.7 mM) for two weeks to mimic glucagon hypersecretion of diabetes. Surprisingly, treatment of TC1-6 cells with the lysosomal inhibitor bafilomycin A1 reduced K+-induced glucagon secretion, suggesting that high glucose may induce glucagon secretion from another lysosomal compartment. Both glucagon and Stmn2 co-localized with Lamp1, which marks secretory lysosomes, in cells cultured in high glucose. We propose that, in addition to enhanced trafficking and secretion through the regulated secretory pathway, the hyperglucagonemia of diabetes may also be due to re-routing of glucagon from the degradative Lamp2A+ lysosome towards the secretory Lamp1+lysosome.

cell biology↗

bioRxiv2019

Stathmin-2 Mediates Glucagon Secretion from Pancreatic α-Cells

Inhibition of glucagon hypersecretion from pancreatic -cells is an appealing strategy for the treatment of diabetes. Our hypothesis is that proteins that associate with glucagon within alpha cell secretory granules will regulate glucagon secretion, and may provide druggable targets for controlling abnormal glucagon secretion in diabetes. Recently, we identified a dynamic glucagon interactome within the secretory granules of the cell line, TC1-6, and showed that select proteins within the interactome could modulate glucagon secretion. In the present study, we show that one of these interactome proteins, the neuronal protein stathmin-2, is expressed in aTC1-6 cells and in mouse pancreatic alpha cells, and is a novel regulator of glucagon secretion. Stathmin-2 was co-secreted with glucagon in response to 55 mM K+, and immunofluorescence confocal microscopy showed co-localization of stathmin-2 with glucagon and the secretory granule markers chromogranin A and VAMP-2 in TC1-6 cells. In mouse pancreatic islets, Stathmin-2 co-localized with glucagon, but not with insulin, indicating that it is an alpha cell protein. To show a function for stathmin-2 in regulating glucagon secretion, we showed that siRNA - mediated depletion of stathmin-2 in aTC1-6 cells caused glucagon secretion to become constitutive without any effect on proglucagon mRNA levels, while overexpression of stathmin-2 completely abolished both basal and K+-stimulated glucagon secretion. Overexpression of stathmin-2 increased the localization of glucagon into the endosomal-lysosomal compartment, while depletion of stathmin-2 reduced the endosomal localization of glucagon. Therefore, we describe stathmin-2 as having a novel role as an alpha cell secretory granule protein that modulates glucagon secretion via trafficking through the endosomal-lysosomal system. These findings describe a potential new pathway for the regulation of glucagon secretion, and may have implications for controlling glucagon hypersecretion in diabetes.

cell biology↗

bioRxiv2018

Plasticity in the glucagon interactome reveals novel proteins that regulate glucagon secretion in alpha TC1-6 cells

Glucagon is stored within secretory granules of pancreatic alpha cells until a stimulus, such as a change in microenvironmental conditions, triggers its release. We hypothesized that the secretory response of the alpha cell to various stimuli could be determined by plasticity in the network of proteins that interact with glucagon within alpha cell secretory granules. To answer this question, we isolated secretory granules from alpha TC1-6 cells and identified glucagon-interacting proteins by affinity purification coupled with liquid chromatography/tandem mass spectrometry. Proteomic analyses revealed a network of cytoplasmic and histone proteins. Specifically, the interaction between glucagon and histone H4 and the ER stress protein GRP78 was confirmed through co-immunoprecipitation of secretory granule lysates, and co-localization within secretory granules using high-resolution confocal microscopy. The composition of these networks was altered at different glucose levels (25 mM vs 5.5 mM) and in response to the paracrine inhibitors of glucagon secretion, GABA and insulin. Finally, siRNA-mediated silencing of a subset of nonhistone proteins revealed novel proteins that may regulate glucagon secretion. We have therefore described a novel and dynamic glucagon interactome within alpha cell secretory granules, and suggest that plasticity in the interactome governs the alpha cell secretory response to paracrine and nutritional stimuli.

cell biology↗