Single Stranded DNA Translocation Through A Nanopore: A Master Equation Approach

We study voltage driven translocation of a single stranded (ss) DNA through a membrane channel. Our model, based on a master equation (ME) approach, investigates the probability density function (pdf) of the translocation times, and shows that it can be either double or mono-peaked, depending on the system parameters. We show that the most probable translocation time is proportional to the polymer length, and inversely proportional to the first or second power of the voltage, depending on the initial conditions. The model recovers experimental observations on hetro-polymers when using their properties inside the pore, such as stiffness and polymer-pore interaction.Comment: 7 pages submitted to PR

Stochastic volatility and leverage effect

We prove that a wide class of correlated stochastic volatility models exactly measure an empirical fact in which past returns are anticorrelated with future volatilities: the so-called ``leverage effect''. This quantitative measure allows us to fully estimate all parameters involved and it will entail a deeper study on correlated stochastic volatility models with practical applications on option pricing and risk management.Comment: 4 pages, 2 figure

Random migration and signal integration promote rapid and robust T cell recruitment

FWN – Publicaties zonder aanstelling Universiteit Leide

Anomalous Dynamics of Forced Translocation

We consider the passage of long polymers of length N through a hole in a membrane. If the process is slow, it is in principle possible to focus on the dynamics of the number of monomers s on one side of the membrane, assuming that the two segments are in equilibrium. The dynamics of s(t) in such a limit would be diffusive, with a mean translocation time scaling as N^2 in the absence of a force, and proportional to N when a force is applied. We demonstrate that the assumption of equilibrium must break down for sufficiently long polymers (more easily when forced), and provide lower bounds for the translocation time by comparison to unimpeded motion of the polymer. These lower bounds exceed the time scales calculated on the basis of equilibrium, and point to anomalous (sub-diffusive) character of translocation dynamics. This is explicitly verified by numerical simulations of the unforced translocation of a self-avoiding polymer. Forced translocation times are shown to strongly depend on the method by which the force is applied. In particular, pulling the polymer by the end leads to much longer times than when a chemical potential difference is applied across the membrane. The bounds in these cases grow as N^2 and N^{1+\nu}, respectively, where \nu is the exponent that relates the scaling of the radius of gyration to N. Our simulations demonstrate that the actual translocation times scale in the same manner as the bounds, although influenced by strong finite size effects which persist even for the longest polymers that we considered (N=512).Comment: 13 pages, RevTeX4, 16 eps figure

The Pediatric Cell Atlas: defining the growth phase of human development at single-cell resolution

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Towards estimating the true duration of dendritic cell interactions with T cells

To initiate an adaptive immune response, T cells need to interact with dendritic cells (DCs), and the duration of these interactions plays an important role. In vitro and in vivo experiments have generally tried to estimate the required period of opportunity for T cell stimulation rather than the duration of individual T cell–DC interactions. Since the application of multi-photon microscopy (MPM) to living lymphoid tissues, the interactions between immune cells, as well as the duration thereof, can directly be observed in vivo. Indeed, long-lasting interactions between T cells and DCs were shown to be important for the onset of immune responses. However, because MPM imaging is typically restricted to experiments lasting 1 h, and because T cell–DC conjugates frequently move into and out of the imaged volume, it is difficult to estimate the true duration of interactions from MPM contact data. Here, we present a method to properly make such an estimate of (the average of) the distribution of contact durations. We validate the method by applying it to spatially explicit computer simulations where the true distribution of contact duration is known. Finally, we apply our analysis to a large experimental data set of T–DC contacts, and predict an average contact time of about three hours. However, we identify a mismatch between the experimental data and the model predictions, and investigate possible causes of the mismatch, including minor tissue drift during imaging experiments. We discuss in detail how future experiments can be optimized such that MPM contact data will be minimally affected by these factors

Lymph Node Subcapsular Sinus Macrophages Confer Resistance to CNS Invasion Upon Peripheral Infection With a Neurotropic Virus

Lymph nodes (LNs) capture microorganisms that breach the body's external barriers and enter draining lymphatics, thereby limiting the systemic spread of such pathogens1. Recent work has shown that CD11b+CD169+ macrophages, which populate the subcapsular sinus (SCS) of LNs, are critical for clearance of viruses from the lymph and for initiating anti-viral humoral immune responses2,3,4. Using vesicular stomatitis virus (VSV), a relative to rabies virus that is typically transmitted by insect bites, we show here that SCS macrophages perform a third vital function; they prevent lymph-borne neurotropic viruses from infecting the CNS. Upon local depletion of SCS macrophages, ~60% of mice developed ascending paralysis and died within 7-10 days after subcutaneous infection with a small dose of VSV that was readily cleared by macrophage-sufficient control animals. VSV gained access to the nervous system via peripheral nerves in macrophage-depleted LNs. In contrast, in macrophage-sufficient LNs VSV replicated preferentially within SCS macrophages but failed to replicate in adjacent nerves. Removal of SCS macrophages did not compromise the humoral or T cell responses against VSV, but it dramatically reduced the production of type I interferon (IFN-I) within infected LNs. VSV-infected macrophages recruited IFN-I producing plasmacytoid dendritic cells to the SCS and additionally were a major source of IFN-I themselves. Experiments in bone marrow chimeric mice lacking the IFN-I receptor in either hematopoietic or stromal cells revealed that IFN-I must act on both compartments, including the intranodal nerves, to prevent lethal VSV infection. These results identify SCS macrophages as crucial gatekeepers to the CNS that prevent fatal viral neuroinvasion upon peripheral infection