Biology subjects
Publications and source records attributed to Cox, S..
Amyloid-{beta} aggregation at the cell-membrane of neruonal cells is implicated as a source of toxicity for Alzheimers disease. Small molecules have been studied for their ability to supress amyloid aggregation and toxicity, but the presence of membranes negate their activity. Here, we have identified 5 small molecules that are active at the membrane interface.
In this study, the effect of CurDAc, a water-soluble curcumin derivative, on the formation and stability of amyloid fibers is revealed. CurDAc interaction with amyloid is structurally selective which is reflected in a strong interference with hIAPP aggregation, while showing weaker interactions with human-calcitonin and Amyloid-{beta}1-40 in comparison. Remarkably, CurDAc also exhibited potent fiber disaggregation for hIAPP generating a toxic oligomeric species.
Antibody production depends on B cell internalization and presentation of antigens to helper T cells. To acquire antigens displayed by antigen-presenting cells, B cells form immune synapses and extract antigens by the mechanical activity of the acto-myosin cytoskeleton. While cytoskeleton organization driving the initial formation of the B cell synapse has been studied, how the cytoskeleton supports antigen extraction remains poorly understood. Here we show that after initial cell spreading, F-actin in B cell synapses forms a highly dynamic pattern composed of actin foci interspersed with linear filaments and myosin IIa. The foci are generated by Arp2/3-mediated branched-actin polymerization and stochastically associate with antigen clusters to mediate internalization. However, antigen extraction also requires the activity of formins, which reside near the foci and produce the interspersed filaments. Thus, a cooperation of branched-actin foci supported by linear filaments underlies B cell mechanics during antigen extraction.
Amyloid aggregation of human islet amyloid polypeptide (hIAPP) is linked to insulin-producing islet cell death in type II diabetes. Previous studies have shown the amyloid inhibiting effects of zinc (Zn) and insulin that are co-present with hIAPP in islet cells, and the lipid membrane has been shown to significantly influence the aggregation kinetics. Increasing number of studies report the importance of developing small molecule inhibitors to suppress the hIAPPs toxicity. Particularly, the ability of epigallocatechin-gallate (EGCG) to inhibit amyloid aggregation of a variety of amyloid peptide/proteins including hIAPP initiated numerous studies including the development of compounds to potentially treat amyloid diseases. In this study, by using a combination of thioflavin-T fluorescence and transmission electron microscopy experiments, we demonstrate a significant enhancement in EGCGs efficiency, when mixed with Zn, to significantly suppress hIAPP amyloid aggregation both in presence and absence of lipid membrane. Circular dichroism experiments indicate the formation and stabilization of a helical structure of hIAPP in presence of EGCG:Zn complex. Our results also reveal the ability of EGCG or EGCG:Zn to suppress hIAPPs cellular toxicity and that the ability of EGCG to chelate with Zn suppresses zincs cellular toxicity. We suggest that the reported results would be useful to develop strategies to trap hIAPP intermediates for further biophysical and structural studies, and also to devise approaches to abolish amyloid aggregation and cellular toxicity.
Microstructural mechanisms underlying apparent cortical thinning during childhood development are unknown. Using functional, quantitative, and diffusion magnetic resonance imaging in children and adults, we tested if tissue growth (lower T1 relaxation time and mean diffusivity (MD)) or pruning (higher T1 and MD) underlies cortical thinning in ventral temporal cortex (VTC). After age 5, T1 and MD decreased in mid and deep cortex of functionally-defined regions in lateral VTC, and in their adjacent white matter. T1 and MD decreases were (i) consistent with tissue growth related to myelin proliferation, which we verified with adult postmortem histology and (ii) correlated with apparent cortical thinning. Thus, contrary to prevailing theories, cortical tissue does not thin during childhood, it becomes more myelinated, shifting the gray-white matter boundary deeper into cortex. As tissue growth is prominent in regions with protracted functional development, our data suggest an intriguing hypothesis that functional development and myelination are interlinked.
BackgroundMajor Depressive Disorder (MDD) is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome, and growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide an important route for identification of disease mechanisms by focusing on a specific process excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether MDD polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRS) and the whole genome excluding NETRIN1 pathway genes (genomic-PRS) were associated with white matter integrity.\n\nMethodsWe used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: N = 6,401; MD: N = 6,390).\n\nResultsWe found significantly lower FA in the superior longitudinal fasciculus ({beta} = -0.035, pcorrected = 0.029) and significantly higher MD in a global measure of thalamic radiations ({beta} = 0.029, pcorrected = 0.021), as well as higher MD in the superior ({beta} = 0.034, pcorrected = 0.039) and inferior ({beta} = 0.029, pcorrected = 0.043) longitudinal fasciculus and in the anterior ({beta} = 0.025, pcorrected = 0.046) and superior ({beta} = 0.027, pcorrected = 0.043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts.\n\nConclusionsOur findings indicate that variation in the NETRIN1 signaling pathway may confer risk for MDD through effects on thalamic radiation white matter microstructure.