Neutrophil String Formation: Hydrodynamic Thresholding and Cellular Deformation during Cell Collisions

Neutrophils unexpectedly display flow-enhanced adhesion (hydrodynamic thresholding) to L-selectin in rolling or aggregation assays. We report that the primary collision efficiency (ε) of flowing neutrophils with preadhered neutrophils on intercellular adhesion molecule-1 (ICAM-1) or fibrinogen also displayed a maximum of ε ~ 0.4–0.45 at a wall shear rate of 100 s-1, an example of thresholding. Primary collision lifetime with no detectable bonding decreased from 130 to 10 ms as wall shear rate increased from 30 to 300 s-1, whereas collision lifetimes with bonding decreased from 300 to 100 ms over this shear range using preadhered neutrophils on ICAM-1, with similar results for fibrinogen. Antibodies against L-selectin, but not against CD11a, CD11b, or CD18, reduced ε at 100 s-1 by \u3e85%. High resolution imaging detected large scale deformation of the flowing neutrophil during the collision at 100 s-1 with the apparent contact area increasing up to ~40 μm2. We observed the formation of long linear string assemblies of neutrophils downstream of neutrophils preadhered to ICAM-1, but not fibrinogen, with a maximum in string formation at 100 s-1. Secondary capture events to the ICAM-1 or fibrinogen coated surfaces after primary collisions were infrequent and short lived, typically lasting from 500 to 3500 ms. Between 5 and 20% of neutrophil interactions with ICAM-1 substrate converted to firm arrest (\u3e3500 ms) and greatly exceeded that observed for fibrinogen, thus defining the root cause of poor string formation on fibrinogen at all shear rates. Additionally, neutrophils mobilized calcium after incorporation into strings. Static adhesion also caused calcium mobilization, as did the subsequent onset of flow. To our knowledge, this is the first report of 1), hydrodynamic thresholding in neutrophil string formation; 2), string formation on ICAM-1 but not on fibrinogen; 3), large cellular deformation due to collisions at a venous shear rate; and 4), mechanosensing through neutrophil β2-integrin/adhesion. The increased contact area during deformation was likely responsible for the hydrodynamic threshold observed in the primary collision efficiency since no increase in primary collision lifetime was detected as shear forces were increased (for either surface coating)

Collateral and Debt Maturity Choice. A Signaling Model

This paper derives optimal loan policies under asymmetric information where banks offer loan contracts of long and short duration, backed or unbacked with collateral. The main novelty of the paper is that it analyzes a setting in which high quality firms use collateral as a complementary device along with debt maturity to signal their superiority. The least-cost signaling equilibrium depends on the relative costs of the signaling devices, the difference in firm quality and the proportion of good firms in the market. Model simulations suggest a non-monotonic relationship between firm quality and debt maturity, in which high quality firms have both long-term secured debt and short-term secured or non-secured debt.

Self-Organized States in Cellular Automata: Exact Solution

The spatial structure, fluctuations as well as all state probabilities of self-organized (steady) states of cellular automata can be found (almost) exactly and {\em explicitly} from their Markovian dynamics. The method is shown on an example of a natural sand pile model with a gradient threshold.Comment: 4 pages (REVTeX), incl. 2 figures (PostScript

Clearance of chikungunya virus infection in lymphoid tissues is promoted by treatment with an agonistic anti-CD137 antibody

CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV RNA that are not cleared efficiently by adaptive immune responses. Analysis of viral tropism revealed that CHIKV RNA was present preferentially in splenic B cells and follicular dendritic cells during the persistent phase of infection, and animals lacking B cells did not develop persistent CHIKV infection in lymphoid tissue. Anti-CD137 MAb treatment resulted in T cell-dependent clearance of CHIKV RNA in lymphoid tissue, although this effect was not observed in musculoskeletal tissue. The clearance of CHIKV RNA from lymphoid tissue by anti-CD137 MAb was associated with reductions in the numbers of germinal center B cells and follicular dendritic cells. Similar results were observed with anti-CD137 MAb treatment of mice infected with Mayaro virus, a related arthritogenic alphavirus. Thus, anti-CD137 MAb treatment promotes resolution of chronic alphavirus infection in lymphoid tissues by reducing the numbers of target cells for infection and persistence

The 3-D kinematics of water masers around the semiregular variable RT Virginis

We report observations of water masers around the semiregular variable RT Virginis (RT Vir), which have been made with the Very Long Baseline Array (VLBA) of the National Radio Astronomy Observatory (NRAO) at five epochs, each separated by three weeks of time. We detected about 60 maser features at each epoch. Overall, 61 features, detected at least twice, were tracked by their radial velocities and proper motions. The 3-D maser kinematics exhibited a circumstellar envelope that is expanding roughly spherically with a velocity of about 8 km/s. Asymmetries in both the spatial and velocity distributions of the maser features were found in the envelope, but less significant than that found in other semiregular variables. Systematic radial-velocity drifts of individual maser features were found with amplitudes of <= 2 km/s/yr. For one maser feature, we found a quadratic position shift with time along a straight line on the sky. This apparent motion indicates an acceleration with an amplitude of 33 km/s/yr, implying the passage of a shock wave driven by the stellar pulsation of RT Vir. The acceleration motion is likely seen only on the sky plane because of a large velocity gradient formed in the accelerating maser region. We estimated the distance to RT Vir to be about 220 pc on the basis of both the statistical parallax and model-fitting methods for the maser kinematics.Comment: 18 pages, 8 figures. Accepted to appear in the Astrophysical Journa

Key Challenges in Agile Requirements Engineering

Agile Software Development (ASD) is becoming more popular in all fields of industry. For an agile transformation, organizations need to continuously improve their established approaches to Requirements Engineering (RE) as well as their approaches to software development. This is accompanied by some chal‐lenges in terms of agile RE. The main objective of this paper is to identify the most important challenges in agile RE industry has to face today. Therefore, we conducted an iterative expert judgement process with 26 experts in the field of ASD, comprising three complementary rounds. In sum, we identified 20 challenges in three rounds. Six of these challenges are defined as key challenges. Based on the results, we provide options for dealing with those key challenges by means of agile techniques and tools. The results show that the identified challenges are often not limited to ASD, but they rather refer to software development in general. Therefore, we can conclude that organ‐izations still struggle with agile transition and understanding agile values, in particular, in terms of stakeholder and user involvement.Ministerio de Economía y Competitividad TIN2013-46928-C3-3-RMinisterio de Economía y Competitividad TIN2016-76956-C3-2-RMinisterio de Economía y Competitividad TIN2015-71938-RED