Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo

Objective: Gut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in inflammatory bowel diseases. We aimed to analyze the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via α4β7 and GPR15. Design: We assessed the expression of homing receptors on T cells in peripheral blood and inflamed mucosa. We studied the migration pattern and homing of Teff and Treg cells to the inflamed gut using intravital confocal microscopy and FACS in a humanized mouse model in DSS-treated NSG (NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ) mice. Results: Expression of GPR15 and α4β7 was significantly increased on Treg rather than Teff cells in peripheral blood of patients with ulcerative colitis (UC) as compared to Crohn´s disease and controls. In vivo analysis in a humanized mouse model showed augmented gut homing of UC Treg cells as compared to controls. Moreover, suppression of UC (but not control) Teff and Treg cell homing was noted upon treatment with the α4β7 antibody vedolizumab. In contrast, siRNA blockade of GPR15 had only effects on homing of Teff cells but did not affect Treg homing in UC. Clinical vedolizumab treatment was associated with marked expansion of UC Treg cells in peripheral blood. Conclusion: α4β7 rather than GPR15 is crucial for increased colonic homing of UC Treg cells in vivo, while both receptors control UC Teff homing. Vedolizumab treatment impairs homing of UC Treg cells leading to their accumulation in peripheral blood with subsequent suppression of systemic effector T cell expansion

Exaptation and emergence as mechanisms to cross fitness valleys during evolution: an example using simulated homing behaviour

Evolution is often considered a gradual hill climbing process, slowly increasing the fitness of organisms. I investigate the evolution of homing behaviour in simulated intertidal limpets. In order to evolve path integration as a homing mechanism, a temporary reduction in an organism’s fitness is required – since high developmental costs occur before a successful homing strategy evolves. Simple hill-climbing algorithms, therefore, only rarely result in the evolution of a functional homing behaviour. The inclusion of a second behaviour (trail-following) greatly increases the frequency of success of evolution of a path integration strategy. Initially an emergent homing behaviour is formed combining path integration with trail following. This also demonstrates evolution through exaptation, since the original role of trail following is likely to be unrelated to homing. Analysis of the fitness landscapes of homing in the presence of trail-following behaviour shows a high variability of fitness, which results in the formation of ‘stepping-stones’ of high fitness across fitness valleys. By using these stepping-stones, simple hill-climbing algorithms can reach the global maximum fitness value

Impaired bone marrow homing of cytokine-activated CD34⁺ cells in the NOD/SCID model

The reduced engraftment potential of hematopoietic stem/progenitor cells (HSPCs) after exposure to cytokines may be related to the impaired homing ability of actively cycling cells. We tested this hypothesis by quantifying the short-term horning of human adult CD34+ cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) animals. We show that the loss of engraftment ability of cytokine-activated CD34+ cells is associated with a reduction in homing of colony-forming cells (CFCs) to bone marrow (BM) at 24 hours after transplantation (from median 2.8% [range, 1.9%-6.1%] to 0.3% [0.0%-0.7%]; n = 3; P < .01), coincident with an increase in CFC accumulation in the lungs (P < .01). Impaired BM homing of cytokine-activated cells was not restored by using sorted cells in G 0G1 or by inducing cell cycle arrest at the G 1/S border. Blocking Fas ligation in vivo did not increase the BM homing of cultured cells. Finally, we tested cytokine combinations or culture conditions previously reported to restore the engraftment of cultured cells but did not find that any of these was able to reverse the changes in homing behavior of cytokine-exposed cells. We suggest that these changes in homing and, as a consequence, engraftment result from the increased migratory capacity of infused activated cells, leading to the loss of selectivity of the homing process. © 2004 by The American Society of Hematology

Saving Grace on Feathered Wings: Homing Pigeons in the First World War

Soldiers of the First World War came in all shapes and sizes. The humble homing pigeon is one of the more unique and critical examples of such. They served in the armed forces of both the Allies and the Central Powers. Used as a last-ditch form of communication, the homing pigeons were exceptional in the work of sending messages back and forth between the battle lines. Little has been written about their vital role and even less in the rigorous training the birds and their handlers both endured. Understanding their training is critical to understanding how the homing pigeons performed so well under the extreme conditions of combat

Adaptive Homing is in P

Homing preset and adaptive experiments with Finite State Machines (FSMs) are widely used when a non-initialized discrete event system is given for testing and thus, has to be set to the known state at the first step. The length of a shortest homing sequence is known to be exponential with respect to the number of states for a complete observable nondeterministic FSM while the problem of checking the existence of such sequence (Homing problem) is PSPACE-complete. In order to decrease the complexity of related problems, one can consider adaptive experiments when a next input to be applied to a system under experiment depends on the output responses to the previous inputs. In this paper, we study the problem of the existence of an adaptive homing experiment for complete observable nondeterministic machines. We show that if such experiment exists then it can be constructed with the use of a polynomial-time algorithm with respect to the number of FSM states.Comment: In Proceedings MBT 2015, arXiv:1504.0192

Tying in Two-Sided Markets with Multi-Homing

This paper analyzes the effects of tying arrangements on market competition and social welfare in two-sided markets when economic agents can engage in multi-homing; that is, they can participate in multiple platforms in order to reap maximal network benefits. The model shows that tying induces more consumers to multi-home and makes platform-specific exclusive contents available to more consumers, which is also beneficial to content providers. As a result, tying can be welfare-enhancing if multi-homing is allowed, even in cases where its welfare impacts are negative in the absence of multi-homing. The analysis thus can have important implications for recent antitrust cases in industries where multi-homing is prevalent.tying, two-sided markets, (indirect) network effects, multi-homing

Large Scale Homing in Honeybees

Honeybee foragers frequently fly several kilometres to and from vital resources, and communicate those locations to their nest mates by a symbolic dance language. Research has shown that they achieve this feat by memorizing landmarks and the skyline panorama, using the sun and polarized skylight as compasses and by integrating their outbound flight paths. In order to investigate the capacity of the honeybees' homing abilities, we artificially displaced foragers to novel release spots at various distances up to 13 km in the four cardinal directions. Returning bees were individually registered by a radio frequency identification (RFID) system at the hive entrance. We found that homing rate, homing speed and the maximum homing distance depend on the release direction. Bees released in the east were more likely to find their way back home, and returned faster than bees released in any other direction, due to the familiarity of global landmarks seen from the hive. Our findings suggest that such large scale homing is facilitated by global landmarks acting as beacons, and possibly the entire skyline panorama.This study was supported by the ARC COE in Vision Sciences (CE0561903), ARC DP-0450535 to SWZ, MP, and HZ (http://www.vision.edu.au/). MP was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, Würzburg University (http://www.graduateschools.uni-wuerzburg.de/life_sciences). This publication was funded by the German Research Foundation (DFG) and the University of Wuerzburg in the funding programme Open Access Publishing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The navigation of homing pigeons: Do they use sun Navigation?

Experiments to determine the dependence of homing pigeons on the sun as a navigational cue are discussed. Various methods were employed to interrupt the circadian rhythms of the pigeons prior to release. It was determined that the sun may serve as a compass, but that topographic features are more important for navigation. The effects of a magnetic field produced by electric equipment carried by the bird were also investigated. It was concluded that magnetic fields may have a small effect on the homing ability. The exact nature of the homing pigeon's navigational ability is still unknown after years of elaborate experimentation

Multi-homing tunnel broker

A proper support for communications has to provide fault tolerance capabilities such as the preservation of established connections in case of failures. Multihoming addresses this issue, but the currently available solution based in massive BGP route injection presents serious scalability limitations, since it contributes to the exponential growth of the BGP table size. An alternative solution based on the configuration of tunnels between the multihomed site exit routers and the ISP border routers has been proposed for IPv6 in RFC 3178. However, the amount of manual configuration imposed by this solution on the ISP side prevents its wide adoption. In particular, this solution requires at the ISP the manual configuration of a tunnel endpoint per each multihomed client that it serves. We present a multihoming tunnel broker (MHTB) that provides automatic creation of the tunnel endpoint at the ISP side.This work was supported by the SAM (Advanced Servers with Mobility)project, funded by the Spanish National research and Development Programme as TIC2002-04531-C04-03.Publicad