@article{6983, abstract = {Malaria, a disease caused by parasites of the Plasmodium genus, begins when Plasmodium-infected mosquitoes inject malaria sporozoites while searching for blood. Sporozoites migrate from the skin via blood to the liver, infect hepatocytes, and form liver stages which in mice 48 h later escape into blood and cause clinical malaria. Vaccine-induced activated or memory CD8 T cells are capable of locating and eliminating all liver stages in 48 h, thus preventing the blood-stage disease. However, the rules of how CD8 T cells are able to locate all liver stages within a relatively short time period remains poorly understood. We recently reported formation of clusters consisting of variable numbers of activated CD8 T cells around Plasmodium yoelii (Py)-infected hepatocytes. Using a combination of experimental data and mathematical models we now provide additional insights into mechanisms of formation of these clusters. First, we show that a model in which cluster formation is driven exclusively by T-cell-extrinsic factors, such as variability in “attractiveness” of different liver stages, cannot explain distribution of cluster sizes in different experimental conditions. In contrast, the model in which cluster formation is driven by the positive feedback loop (i.e., larger clusters attract more CD8 T cells) can accurately explain the available data. Second, while both Py-specific CD8 T cells and T cells of irrelevant specificity (non-specific CD8 T cells) are attracted to the clusters, we found no evidence that non-specific CD8 T cells play a role in cluster formation. Third and finally, mathematical modeling suggested that formation of clusters occurs rapidly, within few hours after adoptive transfer of CD8 T cells, thus illustrating high efficiency of CD8 T cells in locating their targets in complex peripheral organs, such as the liver. Taken together, our analysis provides novel insights into and attempts to discriminate between alternative mechanisms driving the formation of clusters of antigen-specific CD8 T cells in the liver.}, author = {Kelemen, Réka K and Rajakaruna, H and Cockburn, IA and Ganusov, VV}, issn = {1664-3224}, journal = {Frontiers in Immunology}, publisher = {Frontiers}, title = {{Clustering of activated CD8 T cells around Malaria-infected hepatocytes is rapid and is driven by antigen-specific cells}}, doi = {10.3389/fimmu.2019.02153}, volume = {10}, year = {2019}, } @article{6972, abstract = {We give fault-tolerant algorithms for establishing synchrony in distributed systems in which each of thennodes has its own clock. Our algorithms operate in a very strong fault model: we require self-stabilisation, i.e.,the initial state of the system may be arbitrary, and there can be up to f> r eff and show that these systems obey universal scaling laws different from neutral particles. An accurate description of these states requires both the Coulomb-modified scattering length and the effective range unless the Coulomb interaction is very weak (D -> ). Our findings are relevant for bound states whose spatial extent is significantly larger than the range of the attractive potential. These states enjoy universality – their character is independent of the shape of the short-range potential.}, author = {Schmickler, C.H. and Hammer, H.-W. and Volosniev, Artem}, issn = {0370-2693}, journal = {Physics Letters B}, publisher = {Elsevier}, title = {{Universal physics of bound states of a few charged particles}}, doi = {10.1016/j.physletb.2019.135016}, volume = {798}, year = {2019}, } @article{7005, abstract = {Activity-dependent bulk endocytosis generates synaptic vesicles (SVs) during intense neuronal activity via a two-step process. First, bulk endosomes are formed direct from the plasma membrane from which SVs are then generated. SV generation from bulk endosomes requires the efflux of previously accumulated calcium and activation of the protein phosphatase calcineurin. However, it is still unknown how calcineurin mediates SV generation. We addressed this question using a series of acute interventions that decoupled the generation of SVs from bulk endosomes in rat primary neuronal culture. This was achieved by either disruption of protein–protein interactions via delivery of competitive peptides, or inhibition of enzyme activity by known inhibitors. SV generation was monitored using either a morphological horseradish peroxidase assay or an optical assay that monitors the replenishment of the reserve SV pool. We found that SV generation was inhibited by, (i) peptides that disrupt calcineurin interactions, (ii) an inhibitor of dynamin I GTPase activity and (iii) peptides that disrupt the phosphorylation-dependent dynamin I–syndapin I interaction. Peptides that disrupted syndapin I interactions with eps15 homology domain-containing proteins had no effect. This revealed that (i) calcineurin must be localized at bulk endosomes to mediate its effect, (ii) dynamin I GTPase activity is essential for SV fission and (iii) the calcineurin-dependent interaction between dynamin I and syndapin I is essential for SV generation. We therefore propose that a calcineurin-dependent dephosphorylation cascade that requires both dynamin I GTPase and syndapin I lipid-deforming activity is essential for SV generation from bulk endosomes.}, author = {Cheung, Giselle T and Cousin, Michael A.}, issn = {1471-4159}, journal = {Journal of Neurochemistry}, number = {5}, pages = {570--583}, publisher = {Wiley}, title = {{Synaptic vesicle generation from activity‐dependent bulk endosomes requires a dephosphorylation‐dependent dynamin–syndapin interaction}}, doi = {10.1111/jnc.14862}, volume = {151}, year = {2019}, } @article{7000, abstract = {The main contributions of this paper are the proposition and the convergence analysis of a class of inertial projection-type algorithm for solving variational inequality problems in real Hilbert spaces where the underline operator is monotone and uniformly continuous. We carry out a unified analysis of the proposed method under very mild assumptions. In particular, weak convergence of the generated sequence is established and nonasymptotic O(1 / n) rate of convergence is established, where n denotes the iteration counter. We also present some experimental results to illustrate the profits gained by introducing the inertial extrapolation steps.}, author = {Shehu, Yekini and Iyiola, Olaniyi S. and Li, Xiao-Huan and Dong, Qiao-Li}, issn = {1807-0302}, journal = {Computational and Applied Mathematics}, number = {4}, publisher = {Springer Nature}, title = {{Convergence analysis of projection method for variational inequalities}}, doi = {10.1007/s40314-019-0955-9}, volume = {38}, year = {2019}, } @article{7009, abstract = {Cell migration is essential for physiological processes as diverse as development, immune defence and wound healing. It is also a hallmark of cancer malignancy. Thousands of publications have elucidated detailed molecular and biophysical mechanisms of cultured cells migrating on flat, 2D substrates of glass and plastic. However, much less is known about how cells successfully navigate the complex 3D environments of living tissues. In these more complex, native environments, cells use multiple modes of migration, including mesenchymal, amoeboid, lobopodial and collective, and these are governed by the local extracellular microenvironment, specific modalities of Rho GTPase signalling and non- muscle myosin contractility. Migration through 3D environments is challenging because it requires the cell to squeeze through complex or dense extracellular structures. Doing so requires specific cellular adaptations to mechanical features of the extracellular matrix (ECM) or its remodelling. In addition, besides navigating through diverse ECM environments and overcoming extracellular barriers, cells often interact with neighbouring cells and tissues through physical and signalling interactions. Accordingly, cells need to call on an impressively wide diversity of mechanisms to meet these challenges. This Review examines how cells use both classical and novel mechanisms of locomotion as they traverse challenging 3D matrices and cellular environments. It focuses on principles rather than details of migratory mechanisms and draws comparisons between 1D, 2D and 3D migration.}, author = {Yamada, KM and Sixt, Michael K}, issn = {1471-0080}, journal = {Nature Reviews Molecular Cell Biology}, number = {12}, pages = {738–752}, publisher = {Springer Nature}, title = {{Mechanisms of 3D cell migration}}, doi = {10.1038/s41580-019-0172-9}, volume = {20}, year = {2019}, } @article{6988, abstract = {Platelets are central players in thrombosis and hemostasis but are increasingly recognized as key components of the immune system. They shape ensuing immune responses by recruiting leukocytes, and support the development of adaptive immunity. Recent data shed new light on the complex role of platelets in immunity. Here, we summarize experimental and clinical data on the role of platelets in host defense against bacteria. Platelets bind, contain, and kill bacteria directly; however, platelet proinflammatory effector functions and cross-talk with the coagulation system, can also result in damage to the host (e.g., acute lung injury and sepsis). Novel clinical insights support this dichotomy: platelet inhibition/thrombocytopenia can be either harmful or protective, depending on pathophysiological context. Clinical studies are currently addressing this aspect in greater depth.}, author = {Nicolai, Leo and Gärtner, Florian R and Massberg, Steffen}, issn = {1471-4906}, journal = {Trends in Immunology}, number = {10}, pages = {922--938}, publisher = {Cell Press}, title = {{Platelets in host defense: Experimental and clinical insights}}, doi = {10.1016/j.it.2019.08.004}, volume = {40}, year = {2019}, } @article{7002, abstract = {Multiple Importance Sampling (MIS) is a key technique for achieving robustness of Monte Carlo estimators in computer graphics and other fields. We derive optimal weighting functions for MIS that provably minimize the variance of an MIS estimator, given a set of sampling techniques. We show that the resulting variance reduction over the balance heuristic can be higher than predicted by the variance bounds derived by Veach and Guibas, who assumed only non-negative weights in their proof. We theoretically analyze the variance of the optimal MIS weights and show the relation to the variance of the balance heuristic. Furthermore, we establish a connection between the new weighting functions and control variates as previously applied to mixture sampling. We apply the new optimal weights to integration problems in light transport and show that they allow for new design considerations when choosing the appropriate sampling techniques for a given integration problem.}, author = {Kondapaneni, Ivo and Vevoda, Petr and Grittmann, Pascal and Skrivan, Tomas and Slusallek, Philipp and Křivánek, Jaroslav}, issn = {0730-0301}, journal = {ACM Transactions on Graphics}, number = {4}, publisher = {ACM}, title = {{Optimal multiple importance sampling}}, doi = {10.1145/3306346.3323009}, volume = {38}, year = {2019}, } @article{6978, abstract = {In pipes and channels, the onset of turbulence is initially dominated by localizedtransients, which lead to sustained turbulence through their collective dynamics. In thepresent work, we study numerically the localized turbulence in pipe flow and elucidate astate space structure that gives rise to transient chaos. Starting from the basin boundaryseparating laminar and turbulent flow, we identify transverse homoclinic orbits, thepresence of which necessitates a homoclinic tangle and chaos. A direct consequence ofthe homoclinic tangle is the fractal nature of the laminar-turbulent boundary, which wasconjectured in various earlier studies. By mapping the transverse intersections between thestable and unstable manifold of a periodic orbit, we identify the gateways that promote anescape from turbulence.}, author = {Budanur, Nazmi B and Dogra, Akshunna and Hof, Björn}, journal = {Physical Review Fluids}, number = {10}, pages = {102401}, publisher = {American Physical Society}, title = {{Geometry of transient chaos in streamwise-localized pipe flow turbulence}}, doi = {10.1103/PhysRevFluids.4.102401}, volume = {4}, year = {2019}, }