Residence times of receptors in dendritic spines analyzed by simulations in empirical domains

Analysis of high-density superresolution imaging of receptors reveal the organization of dendrites at the nano-scale resolution. We present here simulations in empirical live cell images, which allows converting local information extracted from short range trajectories into simulations of long range trajectories. Based on these empirical simulations, we compute the residence time of an AMPA receptor (AMPAR) in dendritic spines that accounts for receptors local interactions and geometrical organization. We report here that depending on the type of the spine, the residence time varies from one to five minutes. Moreover, we show that there exists transient organized structures, previously described as potential wells that can regulate the trafficking of AMPARs to dendritic spines.Comment: 19 page

Analysis of single particle trajectories: when things go wrong

To recover the long-time behavior and the statistics of molecular trajectories from the large number (tens of thousands) of their short fragments, obtained by super-resolution methods at the single molecule level, data analysis based on a stochastic model of their non-equilibrium motion is required. Recently, we characterized the local biophysical properties underlying receptor motion based on coarse-grained long-range interactions, corresponding to attracting potential wells of large sizes. The purpose of this letter is to discuss optimal estimators and show what happens when thing goes wrong.Comment: 4 page

Single particle trajectories reveal active endoplasmic reticulum luminal flow

The endoplasmic reticulum (ER), a network of membranous sheets and pipes, supports functions encompassing biogenesis of secretory proteins and delivery of functional solutes throughout the cell[1, 2]. Molecular mobility through the ER network enables these functionalities, but diffusion alone is not sufficient to explain luminal transport across supramicrometre distances. Understanding the ER structure–function relationship is critical in light of mutations in ER morphology-regulating proteins that give rise to neurodegenerative disorders[3, 4]. Here, super-resolution microscopy and analysis of single particle trajectories of ER luminal proteins revealed that the topological organization of the ER correlates with distinct trafficking modes of its luminal content: with a dominant diffusive component in tubular junctions and a fast flow component in tubules. Particle trajectory orientations resolved over time revealed an alternating current of the ER contents, while fast ER super-resolution identified energy-dependent tubule contraction events at specific points as a plausible mechanism for generating active ER luminal flow. The discovery of active flow in the ER has implications for timely ER content distribution throughout the cell, particularly important for cells with extensive ER-containing projections such as neurons.Wellcome Trust - 3-3249/Z/16/Z and 089703/Z/09/Z [Kaminski] UK Demential Research Institute [Avezov] Wellcome Trust - 200848/Z/16/Z, WT: UNS18966 [Ron] FRM Team Research Grant [Holcman] Engineering and Physical Sciences Research Council (EPSRC) - EP/L015889/1 and EP/H018301/1 [Kaminski] Medical Research Council (MRC) - MR/K015850/1 and MR/K02292X/1 [Kaminski

Determinants of HIV-1 broadly neutralizing antibody induction.

Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen-viral load, length of untreated infection and viral diversity-independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086-0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non-subtype B viruses (P = 1 × 10(-5)). Thus, key host, disease and viral determinants, including subtype-specific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design