2024-03-28T10:29:55Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/2370532019-08-30T11:28:51Zcom_10033_620659col_10033_620660
Fava, E
Dehghany, J
Ouwendijk, J
Müller, A
Niederlein, A
Verkade, P
Meyer-Hermann, M
Solimena, M
2012-08-02T13:06:00Z
2012-08-02T13:06:00Z
2012-04
Novel standards in the measurement of rat insulin granules combining electron microscopy, high-content image analysis and in silico modelling. 2012, 55 (4):1013-23 Diabetologia
1432-0428
22252472
10.1007/s00125-011-2438-4
http://hdl.handle.net/10033/237053
Diabetologia
Knowledge of number, size and content of insulin secretory granules is pivotal for understanding the physiology of pancreatic beta cells. Here we re-evaluated key structural features of rat beta cells, including insulin granule size, number and distribution as well as cell size.
en
Archived with thanks to Diabetologia
Novel standards in the measurement of rat insulin granules combining electron microscopy, high-content image analysis and in silico modelling.
Article
oai:repository.helmholtz-hzi.de:10033/2461512019-08-30T11:31:23Zcom_10033_620659col_10033_620660
Figge, Marc Thilo
Reichert, Andreas S
Meyer-Hermann, Michael
Osiewacz, Heinz D
2012-09-27T12:32:19Z
2012-09-27T12:32:19Z
2012-06
Deceleration of fusion-fission cycles improves mitochondrial quality control during aging. 2012, 8 (6):e1002576 PLoS Comput. Biol.
1553-7358
22761564
10.1371/journal.pcbi.1002576
http://hdl.handle.net/10033/246151
PLoS computational biology
Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging in silico. We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the 'mitochondrial infectious damage adaptation' (MIDA) model according to which a deceleration of fusion-fission cycles reflects a systemic adaptation increasing life span.
en
Archived with thanks to PLoS computational biology
Deceleration of fusion-fission cycles improves mitochondrial quality control during aging.
Article
oai:repository.helmholtz-hzi.de:10033/2488222019-08-30T11:31:18Zcom_10033_620659col_10033_620660
Dustin, Michael L
Müller, A
2012-10-15T14:36:42Z
2012-10-15T14:36:42Z
2012-01-27
Immunology. Antigen feast or famine. 2012, 335 (6067):408-9 Science
1095-9203
22282794
10.1126/science.1218165
http://hdl.handle.net/10033/248822
Science (New York, N.Y.)
en
Archived with thanks to Science (New York, N.Y.)
Immunology. Antigen feast or famine.
Article
oai:repository.helmholtz-hzi.de:10033/2788922019-08-30T11:25:42Zcom_10033_620659col_10033_620660
Hernandez-Vargas, Esteban A.
Colaneri, Patrizio
Middleton, Richard H.
2013-04-04T08:38:17Z
2013-04-04T08:38:17Z
2012-12-13
10.1109/CDC.2012.6426559
http://hdl.handle.net/10033/278892
IEEE Conference on Decision and Control
Sub-optimal switching with dwell time constraints for control of viral mutation
Article
oai:repository.helmholtz-hzi.de:10033/2813122019-08-30T11:33:05Zcom_10033_620659col_10033_620660
Hernandez-Vargas, Esteban A
Middleton, Richard H
2013-04-15T12:48:28Z
2013-04-15T12:48:28Z
2013-03-07
Modeling the three stages in HIV infection. 2013, 320:33-40 J. Theor. Biol.
1095-8541
23238280
10.1016/j.jtbi.2012.11.028
http://hdl.handle.net/10033/281312
Journal of theoretical biology
A typical HIV infection response consists of three stages: an initial acute infection, a long asymptomatic period and a final increase in viral load with simultaneous collapse in healthy CD4+T cell counts. The majority of existing mathematical models give a good representation of either the first two stages or the last stage of the infection. Using macrophages as a long-term active reservoir, a deterministic model is proposed to explain the three stages of the infection including the progression to AIDS. Simulation results illustrate how chronic infected macrophages can explain the progression to AIDS provoking viral explosion. Further simulation studies suggest that the proposed model retains its key properties even under moderately large parameter variations. This model provides important insights on how macrophages might play a crucial role in the long term behavior of HIV infection.
en
Archived with thanks to Journal of theoretical biology
Modeling the three stages in HIV infection.
Article
oai:repository.helmholtz-hzi.de:10033/2832122019-08-30T11:26:38Zcom_10033_620659col_10033_620660
Hernandez-Vargas, Esteban A.
Alanis, Alma Y.
Sanchez, Edgar N.
2013-04-19T12:30:01Z
2013-04-19T12:30:01Z
2013-04-19
978-1-4673-4497-5
http://hdl.handle.net/10033/283212
Discrete-time neural observer for HIV infection dynamic
Meetings and Proceedings
oai:repository.helmholtz-hzi.de:10033/2911312019-08-30T11:32:17Zcom_10033_620659col_10033_620660
Binder, Sebastian C
Telschow, Arndt
Meyer-Hermann, Michael
2013-05-15T09:24:01Z
2013-05-15T09:24:01Z
2012
Population Dynamics of Borrelia burgdorferi in Lyme Disease. 2012, 3:104 Front Microbiol
1664-302X
22470370
10.3389/fmicb.2012.00104
http://hdl.handle.net/10033/291131
Frontiers in microbiology
Many chronic inflammatory diseases are known to be caused by persistent bacterial or viral infections. A well-studied example is the tick-borne infection by the gram-negative spirochaetes of the genus Borrelia in humans and other mammals, causing severe symptoms of chronic inflammation and subsequent tissue damage (Lyme Disease), particularly in large joints and the central nervous system, but also in the heart and other tissues of untreated patients. Although killed efficiently by human phagocytic cells in vitro, Borrelia exhibits a remarkably high infectivity in mice and men. In experimentally infected mice, the first immune response almost clears the infection. However, approximately 1 week post infection, the bacterial population recovers and reaches an even larger size before entering the chronic phase. We developed a mathematical model describing the bacterial growth and the immune response against Borrelia burgdorferi in the C3H mouse strain that has been established as an experimental model for Lyme disease. The peculiar dynamics of the infection exclude two possible mechanistic explanations for the regrowth of the almost cleared bacteria. Neither the hypothesis of bacterial dissemination to different tissues nor a limitation of phagocytic capacity were compatible with experiment. The mathematical model predicts that Borrelia recovers from the strong initial immune response by the regrowth of an immune-resistant sub-population of the bacteria. The chronic phase appears as an equilibration of bacterial growth and adaptive immunity. This result has major implications for the development of the chronic phase of Borrelia infections as well as on potential protective clinical interventions.
en
Archived with thanks to Frontiers in microbiology
Population Dynamics of Borrelia burgdorferi in Lyme Disease.
Article
oai:repository.helmholtz-hzi.de:10033/3046622019-08-30T11:29:47Zcom_10033_620659col_10033_620660
Schmeitz, Christine
Hernandez-Vargas, Esteban Abelardo
Fliegert, Ralf
Guse, Andreas H
Meyer-Hermann, Michael
2013-10-28T15:11:25Z
2013-10-28T15:11:25Z
2013
A mathematical model of T lymphocyte calcium dynamics derived from single transmembrane protein properties. 2013, 4:277 Front Immunol
1664-3224
24065966
10.3389/fimmu.2013.00277
http://hdl.handle.net/10033/304662
Frontiers in immunology
Fate decision processes of T lymphocytes are crucial for health and disease. Whether a T lymphocyte is activated, divides, gets anergic, or initiates apoptosis depends on extracellular triggers and intracellular signaling. Free cytosolic calcium dynamics plays an important role in this context. The relative contributions of store-derived calcium entry and calcium entry from extracellular space to T lymphocyte activation are still a matter of debate. Here we develop a quantitative mathematical model of T lymphocyte calcium dynamics in order to establish a tool which allows to disentangle cause-effect relationships between ion fluxes and observed calcium time courses. The model is based on single transmembrane protein characteristics which have been determined in independent experiments. This reduces the number of unknown parameters in the model to a minimum and ensures the predictive power of the model. Simulation results are subsequently used for an analysis of whole cell calcium dynamics measured under various experimental conditions. The model accounts for a variety of these conditions, which supports the suitability of the modeling approach. The simulation results suggest a model in which calcium dynamics dominantly relies on the opening of channels in calcium stores while calcium entry through calcium-release activated channels (CRAC) is more associated with the maintenance of the T lymphocyte calcium levels and prevents the cell from calcium depletion. Our findings indicate that CRAC guarantees a long-term stable calcium level which is required for cell survival and sustained calcium enhancement.
en
Archived with thanks to Frontiers in immunology
A mathematical model of T lymphocyte calcium dynamics derived from single transmembrane protein properties.
Article
oai:repository.helmholtz-hzi.de:10033/3063992019-08-30T11:25:11Zcom_10033_620659col_10033_620660
Kempf, Harald
Hatzikirou, Haralampos
Bleicher, Marcus
Müller, A
2013-12-06T11:24:45Z
2013-12-06T11:24:45Z
2013-11
In silico analysis of cell cycle synchronisation effects in radiotherapy of tumour spheroids. 2013, 9 (11):e1003295 PLoS Comput. Biol.
1553-7358
24244120
10.1371/journal.pcbi.1003295
http://hdl.handle.net/10033/306399
PLoS computational biology
Tumour cells show a varying susceptibility to radiation damage as a function of the current cell cycle phase. While this sensitivity is averaged out in an unperturbed tumour due to unsynchronised cell cycle progression, external stimuli such as radiation or drug doses can induce a resynchronisation of the cell cycle and consequently induce a collective development of radiosensitivity in tumours. Although this effect has been regularly described in experiments it is currently not exploited in clinical practice and thus a large potential for optimisation is missed. We present an agent-based model for three-dimensional tumour spheroid growth which has been combined with an irradiation damage and kinetics model. We predict the dynamic response of the overall tumour radiosensitivity to delivered radiation doses and describe corresponding time windows of increased or decreased radiation sensitivity. The degree of cell cycle resynchronisation in response to radiation delivery was identified as a main determinant of the transient periods of low and high radiosensitivity enhancement. A range of selected clinical fractionation schemes is examined and new triggered schedules are tested which aim to maximise the effect of the radiation-induced sensitivity enhancement. We find that the cell cycle resynchronisation can yield a strong increase in therapy effectiveness, if employed correctly. While the individual timing of sensitive periods will depend on the exact cell and radiation types, enhancement is a universal effect which is present in every tumour and accordingly should be the target of experimental investigation. Experimental observables which can be assessed non-invasively and with high spatio-temporal resolution have to be connected to the radiosensitivity enhancement in order to allow for a possible tumour-specific design of highly efficient treatment schedules based on induced cell cycle synchronisation.
en
Archived with thanks to PLoS computational biology
In silico analysis of cell cycle synchronisation effects in radiotherapy of tumour spheroids.
Article
oai:repository.helmholtz-hzi.de:10033/3116162019-08-30T11:25:11Zcom_10033_620659col_10033_620660
Khailaie, Sahamoddin
Bahrami, Fariba
Janahmadi, Mahyar
Milanez-Almeida, Pedro
Huehn, Jochen
Meyer-Hermann, Michael
2014-01-21T12:58:19Z
2014-01-21T12:58:19Z
2013
A mathematical model of immune activation with a unified self-nonself concept. 2013, 4:474 Front Immunol
1664-3224
24409179
10.3389/fimmu.2013.00474
http://hdl.handle.net/10033/311616
Frontiers in immunology
The adaptive immune system reacts against pathogenic nonself, whereas it normally remains tolerant to self. The initiation of an immune response requires a critical antigen(Ag)-stimulation and a critical number of Ag-specific T cells. Autoreactive T cells are not completely deleted by thymic selection and partially present in the periphery of healthy individuals that respond in certain physiological conditions. A number of experimental and theoretical models are based on the concept that structural differences discriminate self from nonself. In this article, we establish a mathematical model for immune activation in which self and nonself are not distinguished. The model considers the dynamic interplay of conventional T cells, regulatory T cells (Tregs), and IL-2 molecules and shows that the renewal rate ratio of resting Tregs to naïve T cells as well as the proliferation rate of activated T cells determine the probability of immune stimulation. The actual initiation of an immune response, however, relies on the absolute renewal rate of naïve T cells. This result suggests that thymic selection reduces the probability of autoimmunity by increasing the Ag-stimulation threshold of self reaction which is established by selection of a low number of low-avidity autoreactive T cells balanced with a proper number of Tregs. The stability analysis of the ordinary differential equation model reveals three different possible immune reactions depending on critical levels of Ag-stimulation: a subcritical stimulation, a threshold stimulation inducing a proper immune response, and an overcritical stimulation leading to chronic co-existence of Ag and immune activity. The model exhibits oscillatory solutions in the case of persistent but moderate Ag-stimulation, while the system returns to the homeostatic state upon Ag clearance. In this unifying concept, self and nonself appear as a result of shifted Ag-stimulation thresholds which delineate these three regimes of immune activation.
en
Archived with thanks to Frontiers in immunology
A mathematical model of immune activation with a unified self-nonself concept.
Article
oai:repository.helmholtz-hzi.de:10033/3117182019-08-30T11:27:46Zcom_10033_620659col_10033_620660
Jain, Harsh Vardhan
Richardson, Alan
Müller, A
Byrne, Helen M
2014-01-23T08:59:14Z
2014-01-23T08:59:14Z
2014
Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas. 2014, 9 (1):e81582 PLoS ONE
1932-6203
24400068
10.1371/journal.pone.0081582
http://hdl.handle.net/10033/311718
PloS one
Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics.
en
Archived with thanks to PloS one
Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas.
Article
oai:repository.helmholtz-hzi.de:10033/3226962019-08-30T11:34:21Zcom_10033_620659col_10033_620660
Hernandez-Vargas, Esteban Abelardo
Colaneri, Patrizio
Middleton, Richard H.
2014-07-09T12:19:54Z
2014-07-09T12:19:54Z
2014-07-09
Optimal therapy scheduling for a simplified HIV infection model 2013, 49 (9):2874 Automatica
51098
10.1016/j.automatica.2013.06.001
http://hdl.handle.net/10033/322696
Automatica
Archived with thanks to Automatica
Optimal therapy scheduling for a simplified HIV infection model
Article
oai:repository.helmholtz-hzi.de:10033/3228192019-08-30T11:37:44Zcom_10033_620659col_10033_620660
Haering, Matthias
Hördt, Andreas
Müller, A
Hernandez-Vargas, Esteban Abelardo
2014-07-11T13:32:02Z
2014-07-11T13:32:02Z
2014
Computational Study to Determine When to Initiate and Alternate Therapy in HIV Infection. 2014, 2014:472869 Biomed Res Int
2314-6141
24900966
10.1155/2014/472869
http://hdl.handle.net/10033/322819
BioMed research international
HIV is a widespread viral infection without cure. Drug treatment has transformed HIV disease into a treatable long-term infection. However, the appearance of mutations within the viral genome reduces the susceptibility of HIV to drugs. Therefore, a key goal is to extend the time until patients exhibit resistance to all existing drugs. Current HIV treatment guidelines seem poorly supported as practitioners have not achieved a consensus on the optimal time to initiate and to switch antiretroviral treatments. We contribute to this discussion with predictions derived from a mathematical model of HIV dynamics. Our results indicate that early therapy initiation (within 2 years postinfection) is critical to delay AIDS progression. For patients who have not received any therapy during the first 3 years postinfection, switch in response to virological failure may outperform proactive switching strategies. In case that proactive switching is opted, the switching time between therapies should not be larger than 100 days. Further clinical trials are needed to either confirm or falsify these predictions.
en
Archived with thanks to BioMed research international
Computational Study to Determine When to Initiate and Alternate Therapy in HIV Infection.
Article
oai:repository.helmholtz-hzi.de:10033/3385772019-08-30T11:34:19Zcom_10033_620659col_10033_620660
Alanis, Alma Y.
Hernandez-Gonzalez, Miguel
Hernandez-Vargas, Esteban Abelardo
2015-01-20T14:41:09Z
2015-01-20T14:41:09Z
2014-11
Observers for biological systems 2014, 24:1175 Applied Soft Computing
15684946
10.1016/j.asoc.2013.10.028
http://hdl.handle.net/10033/338577
Applied Soft Computing
Observers for biological systems
Article
oai:repository.helmholtz-hzi.de:10033/3468802019-08-30T11:24:31Zcom_10033_620659col_10033_620660
Breitsprecher, Dennis
Kiesewetter, Antje K
Linkner, Joern
Vinzenz, Marlene
Stradal, Theresia E B
Small, John Victor
Curth, Ute
Dickinson, Richard B
Faix, Jan
2015-03-19T09:34:39Z
2015-03-19T09:34:39Z
2011-02-02
Molecular mechanism of Ena/VASP-mediated actin-filament elongation. 2011, 30 (3):456-67 EMBO J.
1460-2075
21217643
10.1038/emboj.2010.348
http://hdl.handle.net/10033/346880
The EMBO journal
Ena/VASP proteins are implicated in a variety of fundamental cellular processes including axon guidance and cell migration. In vitro, they enhance elongation of actin filaments, but at rates differing in nearly an order of magnitude according to species, raising questions about the molecular determinants of rate control. Chimeras from fast and slow elongating VASP proteins were generated and their ability to promote actin polymerization and to bind G-actin was assessed. By in vitro TIRF microscopy as well as thermodynamic and kinetic analyses, we show that the velocity of VASP-mediated filament elongation depends on G-actin recruitment by the WASP homology 2 motif. Comparison of the experimentally observed elongation rates with a quantitative mathematical model moreover revealed that Ena/VASP-mediated filament elongation displays a saturation dependence on the actin monomer concentration, implying that Ena/VASP proteins, independent of species, are fully saturated with actin in vivo and generally act as potent filament elongators. Moreover, our data showed that spontaneous addition of monomers does not occur during processive VASP-mediated filament elongation on surfaces, suggesting that most filament formation in cells is actively controlled.
en
Molecular mechanism of Ena/VASP-mediated actin-filament elongation.
Article
oai:repository.helmholtz-hzi.de:10033/3624832019-08-30T11:26:13Zcom_10033_620659col_10033_620660
Jain, Harsh Vardhan
Müller, A
2015-04-09T09:37:38Z
2015-04-09T09:37:38Z
2011-02-01
The molecular basis of synergism between carboplatin and ABT-737 therapy targeting ovarian carcinomas. 2011, 71 (3):705-15 Cancer Res.
1538-7445
21169413
10.1158/0008-5472.CAN-10-3174
http://hdl.handle.net/10033/362483
Cancer research
Resistance to standard chemotherapy (carboplatin + paclitaxel) is one of the leading causes of therapeutic failure in ovarian carcinomas. Emergence of chemoresistance has been shown to be mediated in part by members of the Bcl family of proteins including the antiapoptotic protein Bcl-x(L), whose expression is correlated with shorter disease-free intervals in recurrent disease. ABT-737 is an example of one of the first small-molecule inhibitors of Bcl-2/Bcl-x(L) that has been shown to increase the sensitivity of ovarian cancer cells to carboplatin. To exploit the therapeutic potential of these two drugs and predict optimal doses and dose scheduling, it is essential to understand the molecular basis of their synergistic action. Here, we build and calibrate a mathematical model of ABT-737 and carboplatin action on an ovarian cancer cell line (IGROV-1). The model suggests that carboplatin treatment primes cells for ABT-737 therapy because of an increased dependence of cells with DNA damage on Bcl-x(L) for survival. Numerical simulations predict the existence of a threshold of Bcl-x(L) below which these cells are unable to recover. Furthermore, co- plus posttreatment of ABT-737 with carboplatin is predicted to be the best strategy to maximize synergism between these two drugs. A critical challenge in chemotherapy is to strike a balance between maximizing cell-kill while minimizing patient drug load. We show that the model can be used to compute minimal doses required for any desired fraction of cell kill. These results underscore the potential of the modeling work presented here as a valuable quantitative tool to aid in the translation of novel drugs such as ABT-737 from the experimental to clinical setting and highlight the need for close collaboration between modelers and experimental scientists.
en
The molecular basis of synergism between carboplatin and ABT-737 therapy targeting ovarian carcinomas.
Article
oai:repository.helmholtz-hzi.de:10033/5662652019-08-30T11:25:11Zcom_10033_620659col_10033_620660
Dehghany, Jaber
Hoboth, Peter
Ivanova, Anna
Mziaut, Hassan
Müller, Andreas
Kalaidzidis, Yannis
Solimena, Michele
Müller, A
2015-08-13T09:04:22Z
2015-08-13T09:04:22Z
2015-08
A Spatial Model of Insulin-Granule Dynamics in Pancreatic β-Cells. 2015, 16 (8):797-813 Traffic
1600-0854
25809669
10.1111/tra.12286
http://hdl.handle.net/10033/566265
Traffic (Copenhagen, Denmark)
Insulin secretion from pancreatic β-cells in response to sudden glucose stimulation is biphasic. Prolonged secretion in vivo requires synthesis, delivery to the plasma membrane (PM) and exocytosis of insulin secretory granules (SGs). Here, we provide the first agent-based space-resolved model for SG dynamics in pancreatic β-cells. Using recent experimental data, we consider a single β-cell with identical SGs moving on a phenomenologically represented cytoskeleton network. A single exocytotic machinery mediates SG exocytosis on the PM. This novel model reproduces the measured spatial organization of SGs and insulin secretion patterns under different stimulation protocols. It proposes that the insulin potentiation effect and the rising second-phase secretion are mainly due to the increasing number of docking sites on the PM. Furthermore, it shows that 6 min after glucose stimulation, the 'newcomer' SGs are recruited from a region within less than 600 nm from the PM.
en
A Spatial Model of Insulin-Granule Dynamics in Pancreatic β-Cells.
Article
oai:repository.helmholtz-hzi.de:10033/5773122019-08-30T11:25:11Zcom_10033_620659col_10033_620660
Boianelli, Alessandro
Pettini, Elena
Prota, Gennaro
Medaglini, Donata
Vicino, Antonio
2015-09-15T08:47:04Z
2015-09-15T08:47:04Z
2015
A Stochastic Model for CD4+ T Cell Proliferation and Dissemination Network in Primary Immune Response. 2015, 10 (8):e0135787 PLoS ONE
1932-6203
26301680
10.1371/journal.pone.0135787
http://hdl.handle.net/10033/577312
PloS one
The study of the initial phase of the adaptive immune response after first antigen encounter provides essential information on the magnitude and quality of the immune response. This phase is characterized by proliferation and dissemination of T cells in the lymphoid organs. Modeling and identifying the key features of this phenomenon may provide a useful tool for the analysis and prediction of the effects of immunization. This knowledge can be effectively exploited in vaccinology, where it is of interest to evaluate and compare the responses to different vaccine formulations. The objective of this paper is to construct a stochastic model based on branching process theory, for the dissemination network of antigen-specific CD4+ T cells. The devised model is validated on in vivo animal experimental data. The model presented has been applied to the vaccine immunization context making references to simple proliferation laws that take into account division, death and quiescence, but it can also be applied to any context where it is of interest to study the dynamic evolution of a population.
en
A Stochastic Model for CD4+ T Cell Proliferation and Dissemination Network in Primary Immune Response.
Article
oai:repository.helmholtz-hzi.de:10033/5786282019-08-30T11:33:00Zcom_10033_620659col_10033_620660
Robert, Philippe A
2015-09-23T13:51:18Z
2015-09-23T13:51:18Z
2015
Commentary: "Can Selective MHC Downregulation Explain the Specificity and Genetic Diversity of NK Cell Receptors?". 2015, 6:444 Front Immunol
1664-3224
26379675
10.3389/fimmu.2015.00444
http://hdl.handle.net/10033/578628
Frontiers in immunology
en
Commentary: "Can Selective MHC Downregulation Explain the Specificity and Genetic Diversity of NK Cell Receptors?".
Article
oai:repository.helmholtz-hzi.de:10033/5801152019-08-30T11:25:43Zcom_10033_620659col_10033_620660
Nguyen, Van Kinh
Binder, Sebastian C
Boianelli, Alessandro
Müller, A
Hernandez-Vargas, Esteban Abelardo
2015-10-22T11:44:55Z
2015-10-22T11:44:55Z
2015
Ebola virus infection modeling and identifiability problems. 2015, 6:257 Front Microbiol
1664-302X
25914675
10.3389/fmicb.2015.00257
http://hdl.handle.net/10033/580115
Frontiers in microbiology
The recent outbreaks of Ebola virus (EBOV) infections have underlined the impact of the virus as a major threat for human health. Due to the high biosafety classification of EBOV (level 4), basic research is very limited. Therefore, the development of new avenues of thinking to advance quantitative comprehension of the virus and its interaction with the host cells is urgently needed to tackle this lethal disease. Mathematical modeling of the EBOV dynamics can be instrumental to interpret Ebola infection kinetics on quantitative grounds. To the best of our knowledge, a mathematical modeling approach to unravel the interaction between EBOV and the host cells is still missing. In this paper, a mathematical model based on differential equations is used to represent the basic interactions between EBOV and wild-type Vero cells in vitro. Parameter sets that represent infectivity of pathogens are estimated for EBOV infection and compared with influenza virus infection kinetics. The average infecting time of wild-type Vero cells by EBOV is slower than in influenza infection. Simulation results suggest that the slow infecting time of EBOV could be compensated by its efficient replication. This study reveals several identifiability problems and what kind of experiments are necessary to advance the quantification of EBOV infection. A first mathematical approach of EBOV dynamics and the estimation of standard parameters in viral infections kinetics is the key contribution of this work, paving the way for future modeling works on EBOV infection.
en
Ebola virus infection modeling and identifiability problems.
Article
oai:repository.helmholtz-hzi.de:10033/5969602019-08-30T11:25:43Zcom_10033_620659col_10033_620660
Nakagawa, Rinako
Leyland, Rebecca
Müller, A
Lu, Dong
Turner, Martin
Arbore, Giuseppina
Phan, Tri Giang
Brink, Robert
Vigorito, Elena
2016-02-23T10:50:23Z
2016-02-23T10:50:23Z
2016-01-04
MicroRNA-155 controls affinity-based selection by protecting c-MYC+ B cells from apoptosis. 2016, 126 (1):377-88 J. Clin. Invest.
1558-8238
26657861
10.1172/JCI82914
http://hdl.handle.net/10033/596960
The Journal of clinical investigation
The production of high-affinity antibodies by B cells is essential for pathogen clearance. Antibody affinity for antigen is increased through the affinity maturation in germinal centers (GCs). This is an iterative process in which B cells cycle between proliferation coupled with the acquisition of mutations and antigen-based positive selection, resulting in retention of the highest-affinity B cell clones. The posttranscriptional regulator microRNA-155 (miR-155) is critical for efficient affinity maturation and the maintenance of the GCs; however, the cellular and molecular mechanism by which miR-155 regulates GC responses is not well understood. Here, we utilized a miR-155 reporter mouse strain and showed that miR-155 is coexpressed with the proto-oncogene encoding c-MYC in positively selected B cells. Functionally, miR-155 protected positively selected c-MYC+ B cells from apoptosis, allowing clonal expansion of this population, providing an explanation as to why Mir155 deletion impairs affinity maturation and promotes the premature collapse of GCs. We determined that miR-155 directly inhibits the Jumonji family member JARID2, which enhances B cell apoptosis when overexpressed, and thereby promotes GC B cell survival. Our findings also suggest that there is cooperation between c-MYC and miR-155 during the normal GC response, a cooperation that may explain how c-MYC and miR-155 can collaboratively function as oncogenes.
en
MicroRNA-155 controls affinity-based selection by protecting c-MYC+ B cells from apoptosis.
Article
oai:repository.helmholtz-hzi.de:10033/6008442019-08-30T11:26:42Zcom_10033_620659col_10033_620660
Jaafoura, S
de Goër de Herve, M G
Hernandez-Vargas, Esteban Abelardo
Hendel-Chavez, H
Abdoh, M
Mateo, M C
Krzysiek, R
Merad, M
Seng, R
Tardieu, M
Delfraissy, J F
Goujard, C
Taoufik, Y
2016-03-08T09:45:52Z
2016-03-08T09:45:52Z
2014
Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4⁺ memory T Cells. 2014, 5:5407 Nat Commun
2041-1723
25382623
10.1038/ncomms6407
http://hdl.handle.net/10033/600844
Nature communications
In patients who are receiving prolonged antiretroviral treatment (ART), HIV can persist within a small pool of long-lived resting memory CD4(+) T cells infected with integrated latent virus. This latent reservoir involves distinct memory subsets. Here we provide results that suggest a progressive reduction of the size of the blood latent reservoir around a core of less-differentiated memory subsets (central memory and stem cell-like memory (TSCM) CD4(+) T cells). This process appears to be driven by the differences in initial sizes and decay rates between latently infected memory subsets. Our results also suggest an extreme stability of the TSCM sub-reservoir, the size of which is directly related to cumulative plasma virus exposure before the onset of ART, stressing the importance of early initiation of effective ART. The presence of these intrinsic dynamics within the latent reservoir may have implications for the design of optimal HIV therapeutic purging strategies.
en
Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4⁺ memory T Cells.
Article
oai:repository.helmholtz-hzi.de:10033/6009432019-08-30T11:26:12Zcom_10033_620659col_10033_620660
Binder, Sebastian C
Eckweiler, Denitsa
Schulz, Sebastian
Bielecka, Agata
Nicolai, Tanja
Franke, Raimo
Häussler, Susanne
Müller, A
2016-03-08T15:02:28Z
2016-03-08T15:02:28Z
2016
Functional modules of sigma factor regulons guarantee adaptability and evolvability. 2016, 6:22212 Sci Rep
2045-2322
26915971
10.1038/srep22212
http://hdl.handle.net/10033/600943
Scientific reports
The focus of modern molecular biology turns from assigning functions to individual genes towards understanding the expression and regulation of complex sets of molecules. Here, we provide evidence that alternative sigma factor regulons in the pathogen Pseudomonas aeruginosa largely represent insulated functional modules which provide a critical level of biological organization involved in general adaptation and survival processes. Analysis of the operational state of the sigma factor network revealed that transcription factors functionally couple the sigma factor regulons and significantly modulate the transcription levels in the face of challenging environments. The threshold quality of newly evolved transcription factors was reached faster and more robustly in in silico testing when the structural organization of sigma factor networks was taken into account. These results indicate that the modular structures of alternative sigma factor regulons provide P. aeruginosa with a robust framework to function adequately in its environment and at the same time facilitate evolutionary change. Our data support the view that widespread modularity guarantees robustness of biological networks and is a key driver of evolvability.
en
Functional modules of sigma factor regulons guarantee adaptability and evolvability.
Article
oai:repository.helmholtz-hzi.de:10033/6091252019-08-30T11:31:23Zcom_10033_620659col_10033_620660
Tas, Jeroen M J
Mesin, Luka
Pasqual, Giulia
Targ, Sasha
Jacobsen, Johanne T
Mano, Yasuko M
Chen, Casie S
Weill, Jean-Claude
Reynaud, Claude-Agnès
Browne, Edward P
Meyer-Hermann, Michael
Victora, Gabriel D
2016-05-12T08:09:36Z
2016-05-12T08:09:36Z
2016-03-04
Visualizing antibody affinity maturation in germinal centers. 2016, 351 (6277):1048-54 Science
1095-9203
26912368
10.1126/science.aad3439
http://hdl.handle.net/10033/609125
Science (New York, N.Y.)
Antibodies somatically mutate to attain high affinity in germinal centers (GCs). There, competition between B cell clones and among somatic mutants of each clone drives an increase in average affinity across the population. The extent to which higher-affinity cells eliminating competitors restricts clonal diversity is unknown. By combining multiphoton microscopy and sequencing, we show that tens to hundreds of distinct B cell clones seed each GC and that GCs lose clonal diversity at widely disparate rates. Furthermore, efficient affinity maturation can occur in the absence of homogenizing selection, ensuring that many clones can mature in parallel within the same GC. Our findings have implications for development of vaccines in which antibodies with nonimmunodominant specificities must be elicited, as is the case for HIV-1 and influenza.
en
Visualizing antibody affinity maturation in germinal centers.
Article
oai:repository.helmholtz-hzi.de:10033/6104362019-08-30T11:30:32Zcom_10033_620659col_10033_620660
Kempf, Harald
Bleicher, Marcus
Meyer-Hermann, Michael
2016-05-20T11:41:31Z
2016-05-20T11:41:31Z
2015
Spatio-Temporal Dynamics of Hypoxia during Radiotherapy. 2015, 10 (8):e0133357 PLoS ONE
1932-6203
26273841
10.1371/journal.pone.0133357
http://hdl.handle.net/10033/610436
PloS one
Tumour hypoxia plays a pivotal role in cancer therapy for most therapeutic approaches from radiotherapy to immunotherapy. The detailed and accurate knowledge of the oxygen distribution in a tumour is necessary in order to determine the right treatment strategy. Still, due to the limited spatial and temporal resolution of imaging methods as well as lacking fundamental understanding of internal oxygenation dynamics in tumours, the precise oxygen distribution map is rarely available for treatment planing. We employ an agent-based in silico tumour spheroid model in order to study the complex, localized and fast oxygen dynamics in tumour micro-regions which are induced by radiotherapy. A lattice-free, 3D, agent-based approach for cell representation is coupled with a high-resolution diffusion solver that includes a tissue density-dependent diffusion coefficient. This allows us to assess the space- and time-resolved reoxygenation response of a small subvolume of tumour tissue in response to radiotherapy. In response to irradiation the tumour nodule exhibits characteristic reoxygenation and re-depletion dynamics which we resolve with high spatio-temporal resolution. The reoxygenation follows specific timings, which should be respected in treatment in order to maximise the use of the oxygen enhancement effects. Oxygen dynamics within the tumour create windows of opportunity for the use of adjuvant chemotherapeutica and hypoxia-activated drugs. Overall, we show that by using modelling it is possible to follow the oxygenation dynamics beyond common resolution limits and predict beneficial strategies for therapy and in vitro verification. Models of cell cycle and oxygen dynamics in tumours should in the future be combined with imaging techniques, to allow for a systematic experimental study of possible improved schedules and to ultimately extend the reach of oxygenation monitoring available in clinical treatment.
en
Spatio-Temporal Dynamics of Hypoxia during Radiotherapy.
Article
oai:repository.helmholtz-hzi.de:10033/6169322019-08-30T11:33:29Zcom_10033_620659col_10033_620660
Halle, Stephan
Keyser, Kirsten Anja
Stahl, Felix Rolf
Busche, Andreas
Marquardt, Anja
Zheng, Xiang
Galla, Melanie
Heissmeyer, Vigo
Heller, Katrin
Boelter, Jasmin
Wagner, Karen
Bischoff, Yvonne
Martens, Rieke
Braun, Asolina
Werth, Kathrin
Uvarovskii, Alexey
Kempf, Harald
Meyer-Hermann, Michael
Arens, Ramon
Kremer, Melanie
Sutter, Gerd
Messerle, Martin
Förster, Reinhold
2016-07-14T10:56:31Z
2016-07-14T10:56:31Z
2016-02-16
In Vivo Killing Capacity of Cytotoxic T Cells Is Limited and Involves Dynamic Interactions and T Cell Cooperativity. 2016, 44 (2):233-45 Immunity
1097-4180
26872694
10.1016/j.immuni.2016.01.010
http://hdl.handle.net/10033/616932
Immunity
According to in vitro assays, T cells are thought to kill rapidly and efficiently, but the efficacy and dynamics of cytotoxic T lymphocyte (CTL)-mediated killing of virus-infected cells in vivo remains elusive. We used two-photon microscopy to quantify CTL-mediated killing in mice infected with herpesviruses or poxviruses. On average, one CTL killed 2-16 virus-infected cells per day as determined by real-time imaging and by mathematical modeling. In contrast, upon virus-induced MHC class I downmodulation, CTLs failed to destroy their targets. During killing, CTLs remained migratory and formed motile kinapses rather than static synapses with targets. Viruses encoding the calcium sensor GCaMP6s revealed strong heterogeneity in individual CTL functional capacity. Furthermore, the probability of death of infected cells increased for those contacted by more than two CTLs, indicative of CTL cooperation. Thus, direct visualization of CTLs during killing of virus-infected cells reveals crucial parameters of CD8(+) T cell immunity.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
openAccess
In Vivo Killing Capacity of Cytotoxic T Cells Is Limited and Involves Dynamic Interactions and T Cell Cooperativity.
Article
oai:repository.helmholtz-hzi.de:10033/6170252019-08-30T11:28:51Zcom_10033_620659col_10033_620661
Boianelli, Alessandro
Sharma-Chawla, Niharika
Bruder, Dunja
Hernandez-Vargas, Esteban Abelardo
2016-07-15T14:29:53Z
2016-07-15T14:29:53Z
2016
Oseltamivir PK/PD Modeling and Simulation to Evaluate Treatment Strategies against Influenza-Pneumococcus Coinfection. 2016, 6:60 Front Cell Infect Microbiol
2235-2988
27379214
10.3389/fcimb.2016.00060
http://hdl.handle.net/10033/617025
Frontiers in cellular and infection microbiology
Influenza pandemics and seasonal outbreaks have shown the potential of Influenza A virus (IAV) to enhance susceptibility to a secondary infection with the bacterial pathogen Streptococcus pneumoniae (Sp). The high morbidity and mortality rate revealed the poor efficacy of antiviral drugs and vaccines to fight IAV infections. Currently, the most effective treatment for IAV is by antiviral neuraminidase inhibitors. Among them, the most frequently stockpiled is Oseltamivir which reduces viral release and transmission. However, effectiveness of Oseltamivir is compromised by the emergence of resistant IAV strains and secondary bacterial infections. To date, little attention has been given to evaluate how Oseltamivir treatment strategies alter Influenza viral infection in presence of Sp coinfection and a resistant IAV strain emergence. In this paper we investigate the efficacy of current approved Oseltamivir treatment regimens using a computational approach. Our numerical results suggest that the curative regimen (75 mg) may yield 47% of antiviral efficacy and 9% of antibacterial efficacy. An increment in dose to 150 mg (pandemic regimen) may increase the antiviral efficacy to 49% and the antibacterial efficacy to 16%. The choice to decrease the intake frequency to once per day is not recommended due to a significant reduction in both antiviral and antibacterial efficacy. We also observe that the treatment duration of 10 days may not provide a clear improvement on the antiviral and antibacterial efficacy compared to 5 days. All together, our in silico study reveals the success and pitfalls of Oseltamivir treatment strategies within IAV-Sp coinfection and calls for testing the validity in clinical trials.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Oseltamivir PK/PD Modeling and Simulation to Evaluate Treatment Strategies against Influenza-Pneumococcus Coinfection.
Article
oai:repository.helmholtz-hzi.de:10033/6205622019-08-30T11:30:58Zcom_10033_620659col_10033_620660
Sukhorukov, Valerii M
Meyer-Hermann, Michael
2016-10-21T14:09:24Z
2016-10-21T14:09:24Z
2015
Structural Heterogeneity of Mitochondria Induced by the Microtubule Cytoskeleton. 2015, 5:13924 Sci Rep
2045-2322
26355039
10.1038/srep13924
http://hdl.handle.net/10033/620562
Scientific reports
By events of fusion and fission mitochondria generate a partially interconnected, irregular network of poorly specified architecture. Here, its organization is examined theoretically by taking into account the physical association of mitochondria with microtubules. Parameters of the cytoskeleton mesh are derived from the mechanics of single fibers. The model of the mitochondrial reticulum is formulated in terms of a dynamic spatial graph. The graph dynamics is modulated by the density of microtubules and their crossings. The model reproduces the full spectrum of experimentally found mitochondrial configurations. In centrosome-organized cells, the chondriome is predicted to develop strong structural inhomogeneity between the cell center and the periphery. An integrated analysis of the cytoskeletal and the mitochondrial components reveals that the structure of the reticulum depends on the balance between anterograde and retrograde motility of mitochondria on microtubules, in addition to fission and fusion. We propose that it is the combination of the two processes that defines synergistically the mitochondrial structure, providing the cell with ample capabilities for its regulative adaptation.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Structural Heterogeneity of Mitochondria Induced by the Microtubule Cytoskeleton.
Article
oai:repository.helmholtz-hzi.de:10033/6184442019-08-30T11:31:23Zcom_10033_620659col_10033_620661
Boianelli, Alessandro
Nguyen, Van Kinh
Ebensen, Thomas
Schulze, Kai
Wilk, Esther
Sharma, Niharika
Stegemann-Koniszewski, Sabine
Bruder, Dunja
Toapanta, Franklin R
Guzmán, Carlos A
Meyer-Hermann, Michael
Hernandez-Vargas, Esteban Abelardo
2016-08-16T13:41:00Z
2016-08-16T13:41:00Z
2015-10
Modeling Influenza Virus Infection: A Roadmap for Influenza Research. 2015, 7 (10):5274-304 Viruses
1999-4915
26473911
10.3390/v7102875
http://hdl.handle.net/10033/618444
Viruses
Influenza A virus (IAV) infection represents a global threat causing seasonal outbreaks and pandemics. Additionally, secondary bacterial infections, caused mainly by Streptococcus pneumoniae, are one of the main complications and responsible for the enhanced morbidity and mortality associated with IAV infections. In spite of the significant advances in our knowledge of IAV infections, holistic comprehension of the interplay between IAV and the host immune response (IR) remains largely fragmented. During the last decade, mathematical modeling has been instrumental to explain and quantify IAV dynamics. In this paper, we review not only the state of the art of mathematical models of IAV infection but also the methodologies exploited for parameter estimation. We focus on the adaptive IR control of IAV infection and the possible mechanisms that could promote a secondary bacterial coinfection. To exemplify IAV dynamics and identifiability issues, a mathematical model to explain the interactions between adaptive IR and IAV infection is considered. Furthermore, in this paper we propose a roadmap for future influenza research. The development of a mathematical modeling framework with a secondary bacterial coinfection, immunosenescence, host genetic factors and responsiveness to vaccination will be pivotal to advance IAV infection understanding and treatment optimization.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Modeling Influenza Virus Infection: A Roadmap for Influenza Research.
Article
oai:repository.helmholtz-hzi.de:10033/6205432019-08-30T11:34:48Zcom_10033_620659col_10033_620660
Marschall, Andrea L J
Dübel, Stefan
2016-10-07T13:15:15Z
2016-10-07T13:15:15Z
2016
Antibodies inside of a cell can change its outside: Can intrabodies provide a new therapeutic paradigm? 2016, 14:304-8 Comput Struct Biotechnol J
2001-0370
27570612
10.1016/j.csbj.2016.07.003
http://hdl.handle.net/10033/620543
Computational and structural biotechnology journal
Challenges posed by complex diseases such as cancer, chronic viral infections, neurodegenerative disorders and many others have forced researchers to think beyond classic small molecule drugs, exploring new therapeutic strategies such as therapy with RNAi, CRISPR/Cas9 or antibody therapies as single or as combination therapies with existing drugs. While classic antibody therapies based on parenteral application can only reach extracellular targets, intracellular application of antibodies could provide specific advantages but is so far little recognized in translational research. Intrabodies allow high specificity and targeting of splice variants or post translational modifications. At the same time off target effects can be minimized by thorough biochemical characterization. Knockdown of cellular proteins by intrabodies has been reported for a significant number of disease-relevant targets, including ErbB-2, EGFR, VEGFR-2, Metalloproteinase MMP2 and MMP9, β-amyloid protein, α-synuclein, HIV gp120, HCV core and many others. This review outlines the recent advances in ER intrabody technology and their potential use in therapy.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Antibodies inside of a cell can change its outside: Can intrabodies provide a new therapeutic paradigm?
Article
oai:repository.helmholtz-hzi.de:10033/6205462019-08-30T11:35:39Zcom_10033_620659col_10033_620660
Alfonso, J C L
Schaadt, N S
Schönmeyer, R
Brieu, N
Forestier, G
Wemmert, C
Feuerhake, F
Hatzikirou, H
2016-10-12T07:54:50Z
2016-10-12T07:54:50Z
2016-10-12
In-silico insights on the prognostic potential of immune cell infiltration patterns in the breast lobular epithelium., 6:33322 Sci Rep
2045-2322
27659691
10.1038/srep33322
http://hdl.handle.net/10033/620546
Scientific reports
Scattered inflammatory cells are commonly observed in mammary gland tissue, most likely in response to normal cell turnover by proliferation and apoptosis, or as part of immunosurveillance. In contrast, lymphocytic lobulitis (LLO) is a recurrent inflammation pattern, characterized by lymphoid cells infiltrating lobular structures, that has been associated with increased familial breast cancer risk and immune responses to clinically manifest cancer. The mechanisms and pathogenic implications related to the inflammatory microenvironment in breast tissue are still poorly understood. Currently, the definition of inflammation is mainly descriptive, not allowing a clear distinction of LLO from physiological immunological responses and its role in oncogenesis remains unclear. To gain insights into the prognostic potential of inflammation, we developed an agent-based model of immune and epithelial cell interactions in breast lobular epithelium. Physiological parameters were calibrated from breast tissue samples of women who underwent reduction mammoplasty due to orthopedic or cosmetic reasons. The model allowed to investigate the impact of menstrual cycle length and hormone status on inflammatory responses to cell turnover in the breast tissue. Our findings suggested that the immunological context, defined by the immune cell density, functional orientation and spatial distribution, contains prognostic information previously not captured by conventional diagnostic approaches.
en_US
http://creativecommons.org/licenses/by-nc-sa/4.0/
In-silico insights on the prognostic potential of immune cell infiltration patterns in the breast lobular epithelium.
Article
oai:repository.helmholtz-hzi.de:10033/6206432019-08-30T11:34:48Zcom_10033_620659col_10033_620661
Duvigneau, Stefanie
Sharma-Chawla, Niharika
Boianelli, Alessandro
Stegemann-Koniszewski, Sabine
Nguyen, Van Kinh
Bruder, Dunja
Hernandez-Vargas, Esteban Abelardo
2016-12-07T15:07:00Z
2016-12-07T15:07:00Z
2016-11-22
Hierarchical effects of pro-inflammatory cytokines on the post-influenza susceptibility to pneumococcal coinfection. 2016, 6:37045 Sci Rep
2045-2322
27872472
10.1038/srep37045
http://hdl.handle.net/10033/620643
Scientific reports
In the course of influenza A virus (IAV) infections, a secondary bacterial infection frequently leads to serious respiratory conditions provoking high hospitalization and death tolls. Although abundant pro-inflammatory responses have been reported as key contributing factors for these severe dual infections, the relative contributions of cytokines remain largely unclear. In the current study, mathematical modelling based on murine experimental data dissects IFN-γ as a cytokine candidate responsible for impaired bacterial clearance, thereby promoting bacterial growth and systemic dissemination during acute IAV infection. We also found a time-dependent detrimental role of IL-6 in curtailing bacterial outgrowth which was not as distinct as for IFN-γ. Our numerical simulations suggested a detrimental effect of IFN-γ alone and in synergism with IL-6 but no conclusive pathogenic effect of IL-6 and TNF-α alone. This work provides a rationale to understand the potential impact of how to manipulate temporal immune components, facilitating the formulation of hypotheses about potential therapeutic strategies to treat coinfections.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Hierarchical effects of pro-inflammatory cytokines on the post-influenza susceptibility to pneumococcal coinfection.
Article
oai:repository.helmholtz-hzi.de:10033/6206622019-08-30T11:36:05Zcom_10033_620659col_10033_620660
Alfonso, J C L
Köhn-Luque, A
Stylianopoulos, T
Feuerhake, F
Deutsch, A
Hatzikirou, H
2016-12-12T12:36:32Z
2016-12-12T12:36:32Z
2016-11-23
Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights. 2016, 6:37283 Sci Rep
2045-2322
27876890
10.1038/srep37283
http://hdl.handle.net/10033/620662
Scientific reports
Gliomas are highly invasive brain tumours characterised by poor prognosis and limited response to therapy. There is an ongoing debate on the therapeutic potential of vaso-modulatory interventions against glioma invasion. Prominent vasculature-targeting therapies involve tumour blood vessel deterioration and normalisation. The former aims at tumour infarction and nutrient deprivation induced by blood vessel occlusion/collapse. In contrast, the therapeutic intention of normalising the abnormal tumour vasculature is to improve the efficacy of conventional treatment modalities. Although these strategies have shown therapeutic potential, it remains unclear why they both often fail to control glioma growth. To shed some light on this issue, we propose a mathematical model based on the migration/proliferation dichotomy of glioma cells in order to investigate why vaso-modulatory interventions have shown limited success in terms of tumour clearance. We found the existence of a critical cell proliferation/diffusion ratio that separates glioma responses to vaso-modulatory interventions into two distinct regimes. While for tumours, belonging to one regime, vascular modulations reduce the front speed and increase the infiltration width, for those in the other regime, the invasion speed increases and infiltration width decreases. We discuss how these in silico findings can be used to guide individualised vaso-modulatory approaches to improve treatment success rates.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Why one-size-fits-all vaso-modulatory interventions fail to control glioma invasion: in silico insights.
Article
oai:repository.helmholtz-hzi.de:10033/6206682019-08-30T11:35:39Zcom_10033_620659col_10033_620660
Montaseri, Ghazal
Meyer-Hermann, Michael
2016-12-15T12:58:39Z
2016-12-15T12:58:39Z
2016-10
Diversity of coupled oscillators can enhance their synchronization. 2016, 94 (4-1):042213 Phys Rev E
2470-0053
27841630
10.1103/PhysRevE.94.042213
http://hdl.handle.net/10033/620668
Physical review. E
The heterogeneity of coupled oscillators is important for the degree of their synchronization. According to the classical Kuramoto model, larger heterogeneity reduces synchronization. Here, we show that in a model for coupled pancreatic β-cells, higher diversity of the cells induces higher synchrony. We find that any system of coupled oscillators that oscillates on two time scales and in which heterogeneity causes a transition from chaotic to damped oscillations on the fast time scale exhibits this property. Thus, synchronization of a subset of oscillating systems can be enhanced by increasing the heterogeneity of the system constituents.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Diversity of coupled oscillators can enhance their synchronization.
Article
oai:repository.helmholtz-hzi.de:10033/6206922019-08-30T11:35:13Zcom_10033_267632com_10033_211390com_10033_620659com_10033_311308col_10033_267633col_10033_620661col_10033_620721
Nguyen, Van Kinh
Klawonn, Frank
Mikolajczyk, Rafael
Hernandez-Vargas, Esteban Abelardo
2017-01-11T09:39:52Z
2017-01-11T09:39:52Z
2016
Analysis of Practical Identifiability of a Viral Infection Model. 2016, 11 (12):e0167568 PLoS ONE
1932-6203
28036339
10.1371/journal.pone.0167568
http://hdl.handle.net/10033/620692
PloS one
Mathematical modelling approaches have granted a significant contribution to life sciences and beyond to understand experimental results. However, incomplete and inadequate assessments in parameter estimation practices hamper the parameter reliability, and consequently the insights that ultimately could arise from a mathematical model. To keep the diligent works in modelling biological systems from being mistrusted, potential sources of error must be acknowledged. Employing a popular mathematical model in viral infection research, existing means and practices in parameter estimation are exemplified. Numerical results show that poor experimental data is a main source that can lead to erroneous parameter estimates despite the use of innovative parameter estimation algorithms. Arbitrary choices of initial conditions as well as data asynchrony distort the parameter estimates but are often overlooked in modelling studies. This work stresses the existence of several sources of error buried in reports of modelling biological systems, voicing the need for assessing the sources of error, consolidating efforts in solving the immediate difficulties, and possibly reconsidering the use of mathematical modelling to quantify experimental data.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Analysis of Practical Identifiability of a Viral Infection Model.
Article
oai:repository.helmholtz-hzi.de:10033/6208142019-08-30T11:30:58Zcom_10033_620659col_10033_620660
Hatzikirou, H
Alfonso, J C L
Mühle, S
Stern, C
Weiss, S
Meyer-Hermann, Michael
2017-02-08T15:27:26Z
2017-02-08T15:27:26Z
2015-11-06
Cancer therapeutic potential of combinatorial immuno- and vasomodulatory interventions. 2015, 12 (112) J R Soc Interface
1742-5662
26510827
10.1098/rsif.2015.0439
http://hdl.handle.net/10033/620814
Journal of the Royal Society, Interface
Currently, most of the basic mechanisms governing tumour-immune system interactions, in combination with modulations of tumour-associated vasculature, are far from being completely understood. Here, we propose a mathematical model of vascularized tumour growth, where the main novelty is the modelling of the interplay between functional tumour vasculature and effector cell recruitment dynamics. Parameters are calibrated on the basis of different in vivo immunocompromised Rag1(-/-) and wild-type (WT) BALB/c murine tumour growth experiments. The model analysis supports that tumour vasculature normalization can be a plausible and effective strategy to treat cancer when combined with appropriate immunostimulations. We find that improved levels of functional tumour vasculature, potentially mediated by normalization or stress alleviation strategies, can provide beneficial outcomes in terms of tumour burden reduction and growth control. Normalization of tumour blood vessels opens a therapeutic window of opportunity to augment the antitumour immune responses, as well as to reduce intratumoral immunosuppression and induced hypoxia due to vascular abnormalities. The potential success of normalizing tumour-associated vasculature closely depends on the effector cell recruitment dynamics and tumour sizes. Furthermore, an arbitrary increase in the initial effector cell concentration does not necessarily imply better tumour control. We evidence the existence of an optimal concentration range of effector cells for tumour shrinkage. Based on these findings, we suggest a theory-driven therapeutic proposal that optimally combines immuno- and vasomodulatory interventions.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Cancer therapeutic potential of combinatorial immuno- and vasomodulatory interventions.
Article
oai:repository.helmholtz-hzi.de:10033/6209602019-08-30T11:33:05Zcom_10033_620659col_10033_620661
Michiels, Barbara
Nguyen, Van Kinh
Coenen, Samuel
Ryckebosch, Philippe
Bossuyt, Nathalie
Hens, Niel
2017-06-19T13:56:25Z
2017-06-19T13:56:25Z
2017-01-18
Influenza epidemic surveillance and prediction based on electronic health record data from an out-of-hours general practitioner cooperative: model development and validation on 2003-2015 data. 2017, 17 (1):84 BMC Infect. Dis.
1471-2334
28100186
10.1186/s12879-016-2175-x
http://hdl.handle.net/10033/620960
BMC infectious diseases
Annual influenza epidemics significantly burden health care. Anticipating them allows for timely preparation. The Scientific Institute of Public Health in Belgium (WIV-ISP) monitors the incidence of influenza and influenza-like illnesses (ILIs) and reports on a weekly basis. General practitioners working in out-of-hour cooperatives (OOH GPCs) register diagnoses of ILIs in an instantly accessible electronic health record (EHR) system. This article has two objectives: to explore the possibility of modelling seasonal influenza epidemics using EHR ILI data from the OOH GPC Deurne-Borgerhout, Belgium, and to attempt to develop a model accurately predicting new epidemics to complement the national influenza surveillance by WIV-ISP.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Influenza epidemic surveillance and prediction based on electronic health record data from an out-of-hours general practitioner cooperative: model development and validation on 2003-2015 data.
Article
oai:repository.helmholtz-hzi.de:10033/6209612019-08-30T11:33:01Zcom_10033_620659col_10033_620661
Torres-Cerna, C. E.
Alanis, A. Y.
Poblete-Castro, I.
Hernandez-Vargas, E. A.
2017-06-20T08:55:44Z
2017-06-20T08:55:44Z
2017-04-15
Batch Cultivation Model for Biopolymer Production 2017, 31 (1):89 Chemical and Biochemical Engineering Quarterly
03529568
18465153
10.15255/CABEQ.2016.952
http://hdl.handle.net/10033/620961
Chemical and Biochemical Engineering Quarterly
http://creativecommons.org/licenses/by-nc-sa/4.0/
Batch Cultivation Model for Biopolymer Production
Article
oai:repository.helmholtz-hzi.de:10033/6210832019-08-30T11:36:33Zcom_10033_620659col_10033_620661
Nguyen, Van Kinh
Hernandez-Vargas, Esteban A
2017-08-31T13:29:28Z
2017-08-31T13:29:28Z
2017-08-21
Windows of opportunity for Ebola virus infection treatment and vaccination. 2017, 7 (1):8975 Sci Rep
2045-2322
28827623
10.1038/s41598-017-08884-0
http://hdl.handle.net/10033/621083
Scientific reports
Ebola virus (EBOV) infection causes a high death toll, killing a high proportion of EBOV-infected patients within 7 days. Comprehensive data on EBOV infection are fragmented, hampering efforts in developing therapeutics and vaccines against EBOV. Under this circumstance, mathematical models become valuable resources to explore potential controlling strategies. In this paper, we employed experimental data of EBOV-infected nonhuman primates (NHPs) to construct a mathematical framework for determining windows of opportunity for treatment and vaccination. Considering a prophylactic vaccine based on recombinant vesicular stomatitis virus expressing the EBOV glycoprotein (rVSV-EBOV), vaccination could be protective if a subject is vaccinated during a period from one week to four months before infection. For the case of a therapeutic vaccine based on monoclonal antibodies (mAbs), a single dose might resolve the invasive EBOV replication even if it was administrated as late as four days after infection. Our mathematical models can be used as building blocks for evaluating therapeutic and vaccine modalities as well as for evaluating public health intervention strategies in outbreaks. Future laboratory experiments will help to validate and refine the estimates of the windows of opportunity proposed here.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Windows of opportunity for Ebola virus infection treatment and vaccination.
Article
oai:repository.helmholtz-hzi.de:10033/6211962019-08-30T11:32:16Zcom_10033_620659col_10033_620660
He, Jin-Shu
Meyer-Hermann, Michael
Xiangying, Deng
Zuan, Lim Yok
Jones, Leigh Ann
Ramakrishna, Lakshmi
de Vries, Victor C
Dolpady, Jayashree
Aina, Hoi
Joseph, Sabrina
Narayanan, Sriram
Subramaniam, Sharrada
Puthia, Manoj
Wong, Glenn
Xiong, Huizhong
Poidinger, Michael
Urban, Joseph F
Lafaille, Juan J
Curotto de Lafaille, Maria A
2017-12-05T13:23:11Z
2017-12-05T13:23:11Z
2013-11-18
The distinctive germinal center phase of IgE+ B lymphocytes limits their contribution to the classical memory response. 2013, 210 (12):2755-71 J. Exp. Med.
1540-9538
24218137
10.1084/jem.20131539
http://hdl.handle.net/10033/621196
The Journal of experimental medicine
The mechanisms involved in the maintenance of memory IgE responses are poorly understood, and the role played by germinal center (GC) IgE(+) cells in memory responses is particularly unclear. IgE(+) B cell differentiation is characterized by a transient GC phase, a bias toward the plasma cell (PC) fate, and dependence on sequential switching for the production of high-affinity IgE. We show here that IgE(+) GC B cells are unfit to undergo the conventional GC differentiation program due to impaired B cell receptor function and increased apoptosis. IgE(+) GC cells fail to populate the GC light zone and are unable to contribute to the memory and long-lived PC compartments. Furthermore, we demonstrate that direct and sequential switching are linked to distinct B cell differentiation fates: direct switching generates IgE(+) GC cells, whereas sequential switching gives rise to IgE(+) PCs. We propose a comprehensive model for the generation and memory of IgE responses.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
The distinctive germinal center phase of IgE+ B lymphocytes limits their contribution to the classical memory response.
Article
oai:repository.helmholtz-hzi.de:10033/6212042019-08-30T11:26:42Zcom_10033_620659com_10033_620652com_10033_128109col_10033_621829col_10033_620672col_10033_620660
Zhao, Gang
Wirth, Dagmar
Schmitz, Ingo
Meyer-Hermann, Michael
2017-12-13T09:08:17Z
2017-12-13T09:08:17Z
2017-11-08
A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance. 2017, 8 (1):1362 Nat Commun
2041-1723
29118381
10.1038/s41467-017-01627-9
http://hdl.handle.net/10033/621204
Nature communications
Physiological insulin secretion exhibits various temporal patterns, the dysregulation of which is involved in diabetes development. We analyzed the impact of first-phase and pulsatile insulin release on glucose and lipid control with various hepatic insulin signaling networks. The mathematical model suggests that atypical protein kinase C (aPKC) undergoes a bistable switch-on and switch-off, under the control of insulin receptor substrate 2 (IRS2). The activation of IRS1 and IRS2 is temporally separated due to the inhibition of IRS1 by aPKC. The model further shows that the timing of aPKC switch-off is delayed by reduced first-phase insulin and reduced amplitude of insulin pulses. Based on these findings, we propose a sequential model of postprandial hepatic control of glucose and lipid by insulin, according to which delayed aPKC switch-off contributes to selective hepatic insulin resistance, which is a long-standing paradox in the field.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance.
Article
oai:repository.helmholtz-hzi.de:10033/6212112019-08-30T11:37:23Zcom_10033_620659col_10033_620660
Hatzikirou, Haralampos
López Alfonso, Juan Carlos
Leschner, Sara
Weiss, Siegfried
Meyer-Hermann, Michael
2017-12-19T14:47:16Z
2017-12-19T14:47:16Z
2017-04-01
Therapeutic Potential of Bacteria against Solid Tumors. 2017, 77 (7):1553-1563 Cancer Res.
1538-7445
28202530
10.1158/0008-5472.CAN-16-1621
http://hdl.handle.net/10033/621211
Cancer research
Intentional bacterial infections can produce efficacious antitumor responses in mice, rats, dogs, and humans. However, low overall success rates and intense side effects prevent such approaches from being employed clinically. In this work, we titered bacteria and/or the proinflammatory cytokine TNFα in a set of established murine models of cancer. To interpret the experiments conducted, we considered and calibrated a tumor-effector cell recruitment model under the influence of functional tumor-associated vasculature. In this model, bacterial infections and TNFα enhanced immune activity and altered vascularization in the tumor bed. Information to predict bacterial therapy outcomes was provided by pretreatment tumor size and the underlying immune recruitment dynamics. Notably, increasing bacterial loads did not necessarily produce better long-term tumor control, suggesting that tumor sizes affected optimal bacterial loads. Short-term treatment responses were favored by high concentrations of effector cells postinjection, such as induced by higher bacterial loads, but in the longer term did not correlate with an effective restoration of immune surveillance. Overall, our findings suggested that a combination of intermediate bacterial loads with low levels TNFα administration could enable more favorable outcomes elicited by bacterial infections in tumor-bearing subjects. Cancer Res; 77(7); 1553-63. ©2017 AACR.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Therapeutic Potential of Bacteria against Solid Tumors.
Article
oai:repository.helmholtz-hzi.de:10033/6212272019-08-30T11:37:23Zcom_10033_620659col_10033_620660
Alfonso, J C L
Talkenberger, K
Seifert, M
Klink, B
Hawkins-Daarud, A
Swanson, K R
Hatzikirou, H
Deutsch, A
2018-01-09T11:59:13Z
2018-01-09T11:59:13Z
2017-11
The biology and mathematical modelling of glioma invasion: a review. 2017, 14 (136) J R Soc Interface
1742-5662
29118112
10.1098/rsif.2017.0490
http://hdl.handle.net/10033/621227
Journal of the Royal Society, Interface
5721156
Adult gliomas are aggressive brain tumours associated with low patient survival rates and limited life expectancy. The most important hallmark of this type of tumour is its invasive behaviour, characterized by a markedly phenotypic plasticity, infiltrative tumour morphologies and the ability of malignant progression from low- to high-grade tumour types. Indeed, the widespread infiltration of healthy brain tissue by glioma cells is largely responsible for poor prognosis and the difficulty of finding curative therapies. Meanwhile, mathematical models have been established to analyse potential mechanisms of glioma invasion. In this review, we start with a brief introduction to current biological knowledge about glioma invasion, and then critically review and highlight future challenges for mathematical models of glioma invasion.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
The biology and mathematical modelling of glioma invasion: a review.
Article
oai:repository.helmholtz-hzi.de:10033/6212462019-08-30T11:34:48Zcom_10033_620659col_10033_620660
Nava-Sedeño, J M
Hatzikirou, H
Klages, R
Deutsch, A
2018-01-22T08:57:45Z
2018-01-22T08:57:45Z
2017-12-05
Cellular automaton models for time-correlated random walks: derivation and analysis. 2017, 7 (1):16952 Sci Rep
2045-2322
29209065
10.1038/s41598-017-17317-x
http://hdl.handle.net/10033/621246
Scientific reports
Many diffusion processes in nature and society were found to be anomalous, in the sense of being fundamentally different from conventional Brownian motion. An important example is the migration of biological cells, which exhibits non-trivial temporal decay of velocity autocorrelation functions. This means that the corresponding dynamics is characterized by memory effects that slowly decay in time. Motivated by this we construct non-Markovian lattice-gas cellular automata models for moving agents with memory. For this purpose the reorientation probabilities are derived from velocity autocorrelation functions that are given a priori; in that respect our approach is "data-driven". Particular examples we consider are velocity correlations that decay exponentially or as power laws, where the latter functions generate anomalous diffusion. The computational efficiency of cellular automata combined with our analytical results paves the way to explore the relevance of memory and anomalous diffusion for the dynamics of interacting cell populations, like confluent cell monolayers and cell clustering.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Cellular automaton models for time-correlated random walks: derivation and analysis.
Article
oai:repository.helmholtz-hzi.de:10033/6212492019-08-30T11:32:17Zcom_10033_620659col_10033_620660
Volk, Valery
Reppas, Andreas I
Robert, Philippe A
Spineli, Loukia M
Sundarasetty, Bala Sai
Theobald, Sebastian J
Schneider, Andreas
Gerasch, Laura
Deves Roth, Candida
Klöss, Stephan
Koehl, Ulrike
von Kaisenberg, Constantin
Figueiredo, Constanca
Hatzikirou, Haralampos
Meyer-Hermann, Michael
Stripecke, Renata
2018-01-23T14:33:35Z
2018-01-23T14:33:35Z
2017
Multidimensional Analysis Integrating Human T-Cell Signatures in Lymphatic Tissues with Sex of Humanized Mice for Prediction of Responses after Dendritic Cell Immunization. 2017, 8:1709 Front Immunol
1664-3224
29276513
10.3389/fimmu.2017.01709
http://hdl.handle.net/10033/621249
Frontiers in immunology
Mice transplanted with human cord blood-derived hematopoietic stem cells (HSCs) became a powerful experimental tool for studying the heterogeneity of human immune reconstitution and immune responses in vivo. Yet, analyses of human T cell maturation in humanized models have been hampered by an overall low immune reactivity and lack of methods to define predictive markers of responsiveness. Long-lived human lentiviral induced dendritic cells expressing the cytomegalovirus pp65 protein (iDCpp65) promoted the development of pp65-specific human CD8+ T cell responses in NOD.Cg-Rag1 tm1Mom -Il2rγ tm1Wj humanized mice through the presentation of immune-dominant antigenic epitopes (signal 1), expression of co-stimulatory molecules (signal 2), and inflammatory cytokines (signal 3). We exploited this validated system to evaluate the effects of mouse sex in the dynamics of T cell homing and maturation status in thymus, blood, bone marrow, spleen, and lymph nodes. Statistical analyses of cell relative frequencies and absolute numbers demonstrated higher CD8+ memory T cell reactivity in spleen and lymph nodes of immunized female mice. In order to understand to which extent the multidimensional relation between organ-specific markers predicted the immunization status, the immunophenotypic profiles of individual mice were used to train an artificial neural network designed to discriminate immunized and non-immunized mice. The highest accuracy of immune reactivity prediction could be obtained from lymph node markers of female mice (77.3%). Principal component analyses further identified clusters of markers best suited to describe the heterogeneity of immunization responses in vivo. A correlation analysis of these markers reflected a tissue-specific impact of immunization. This allowed for an organ-resolved characterization of the immunization status of individual mice based on the identified set of markers. This new modality of multidimensional analyses can be used as a framework for defining minimal but predictive signatures of human immune responses in mice and suggests critical markers to characterize responses to immunization after HSC transplantation.
en
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Multidimensional Analysis Integrating Human T-Cell Signatures in Lymphatic Tissues with Sex of Humanized Mice for Prediction of Responses after Dendritic Cell Immunization.
Article
oai:repository.helmholtz-hzi.de:10033/6213012019-08-30T11:25:43Zcom_10033_620659com_10033_620636col_10033_620660col_10033_620637
Ghanbari, Azadeh
Dehghany, Jaber
Schwebs, Timo
Müsken, Mathias
Häussler, Susanne
Meyer-Hermann, Michael
2018-03-02T14:24:49Z
2018-03-02T14:24:49Z
2016-09-09
Inoculation density and nutrient level determine the formation of mushroom-shaped structures in Pseudomonas aeruginosa biofilms. 2016, 6:32097 Sci Rep
2045-2322
27611778
10.1038/srep32097
http://hdl.handle.net/10033/621301
Scientific reports
Pseudomonas aeruginosa often colonises immunocompromised patients and the lungs of cystic fibrosis patients. It exhibits resistance to many antibiotics by forming biofilms, which makes it hard to eliminate. P. aeruginosa biofilms form mushroom-shaped structures under certain circumstances. Bacterial motility and the environment affect the eventual mushroom morphology. This study provides an agent-based model for the bacterial dynamics and interactions influencing bacterial biofilm shape. Cell motility in the model relies on recently published experimental data. Our simulations show colony formation by immotile cells. Motile cells escape from a single colony by nutrient chemotaxis and hence no mushroom shape develops. A high number density of non-motile colonies leads to migration of motile cells onto the top of the colonies and formation of mushroom-shaped structures. This model proposes that the formation of mushroom-shaped structures can be predicted by parameters at the time of bacteria inoculation. Depending on nutrient levels and the initial number density of stalks, mushroom-shaped structures only form in a restricted regime. This opens the possibility of early manipulation of spatial pattern formation in bacterial colonies, using environmental factors.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Inoculation density and nutrient level determine the formation of mushroom-shaped structures in Pseudomonas aeruginosa biofilms.
Article
oai:repository.helmholtz-hzi.de:10033/6213222019-08-30T11:32:41Zcom_10033_620659col_10033_620660
Binder, Sebastian C
Meyer-Hermann, Michael
2018-03-14T10:27:20Z
2018-03-14T10:27:20Z
2016
Implications of Intravital Imaging of Murine Germinal Centers on the Control of B Cell Selection and Division. 2016, 7:593 Front Immunol
1664-3224
28066409
10.3389/fimmu.2016.00593
http://hdl.handle.net/10033/621322
Frontiers in immunology
Intravital imaging of antibody optimization in germinal center (GC) reactions has set a new dimension in the understanding of the humoral immune response during the last decade. The inclusion of spatio-temporal cellular dynamics in the research on GCs required analysis using the agent-based mathematical models. In this study, we integrate the available intravital imaging data from various research groups and incorporate these into a quantitative mathematical model of GC reactions and antibody affinity maturation. Interestingly, the integration of data concerning the spatial organization of GCs and B cell motility allows to draw conclusions on the strength of the selection pressure and the control of B cell division by T follicular helper cells.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Implications of Intravital Imaging of Murine Germinal Centers on the Control of B Cell Selection and Division.
Article
oai:repository.helmholtz-hzi.de:10033/6213412019-08-30T11:34:22Zcom_10033_620659com_10033_620601col_10033_620661col_10033_620603
Samir, M
Hamed, M
Abdallah, F
Kinh Nguyen, V
Hernandez-Vargas, E A
Seehusen, F
Baumgärtner, W
Hussein, A
Ali, A A H
Pessler,, F
2018-04-10T08:09:30Z
2018-04-10T08:09:30Z
2018-01-24
An Egyptian HPAI H5N1 isolate from clade 2.2.1.2 is highly pathogenic in an experimentally infected domestic duck breed (Sudani duck). 2018 Transbound Emerg Dis
1865-1682
29363279
10.1111/tbed.12816
http://hdl.handle.net/10033/621341
Transboundary and emerging diseases
The highly pathogenic avian influenza (HPAI) H5N1 viruses continue to cause major problems in poultry and can, although rarely, cause human infection. Being enzootic in domestic poultry, Egyptian isolates are continuously evolving, and novel clades vary in their pathogenicity in avian hosts. Considering the importance of domestic ducks as natural hosts of HPAI H5N1 viruses and their likelihood of physical contact with other avian hosts and humans, it is of utmost importance to characterize the pathogenicity of newly emerged HPAI strains in the domestic duck. The most recently identified Egyptian clade 2.2.1.2 HPAI H5N1 viruses have been isolated from naturally infected pigeons, turkeys and humans. However, essentially nothing is known about their pathogenicity in domestic ducks. We therefore characterized the pathogenicity of an Egyptian HPAI H5N1 isolate A/chicken/Faquos/amn12/2011 (clade 2.2.1.2) in Sudani duck, a domestic duck breed commonly reared in Egypt. While viral transcription (HA mRNA) was highest in lung, heart and kidney peaking between 40 and 48 hpi, lower levels were detected in brain. Weight loss of infected ducks started at 16 hpi and persisted until 120 hpi. The first severe clinical signs were noted by 32 hpi and peaked in severity at 72 and 96 hpi. Haematological analyses showed a decline in total leucocytes, granulocytes, platelets and granulocyte/lymphocyte ratio, but lymphocytosis. Upon necropsy, lesions were obvious in heart, liver, spleen and pancreas and consisted mainly of necrosis and petechial haemorrhage. Histologically, lungs were the most severely affected organs, whereas brain only showed mild neuronal degeneration and gliosis at 48 hpi despite obvious neurological clinical signs. Taken together, our results provide first evidence that this HPAI H5N1 isolate (clade 2.2.1.2) is highly pathogenic to Sudani ducks and highlight the importance of this breed as potential reservoir and disseminator of HPAI strains from this clade.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
An Egyptian HPAI H5N1 isolate from clade 2.2.1.2 is highly pathogenic in an experimentally infected domestic duck breed (Sudani duck).
Article
oai:repository.helmholtz-hzi.de:10033/6214172020-07-09T08:39:43Zcom_10033_620659col_10033_620660
Hatzikirou, Haralampos
2018-06-29T09:24:58Z
2018-06-29T09:24:58Z
2191-0243
10.1515/jmbm-2018-0001
http://hdl.handle.net/10033/621417
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Statistical mechanics of cell decision-making: the cell migration force distribution
Article
oai:repository.helmholtz-hzi.de:10033/6214552019-08-30T11:29:14Zcom_10033_620659col_10033_620660
Meyer-Hermann, Michael
2018-08-27T14:21:30Z
2018-08-27T14:21:30Z
2018-08-06
2045-2322
30082874
10.1038/s41598-018-29967-6
http://hdl.handle.net/10033/621455
Rejuvenation of stem cell activity might increase life expectancy by prolonging functionality of organs. Higher stem cell replication rates also bear the risk of cancer. The extent of this risk is not known. While it is difficult to evaluate this cancer risk in experiments, it can be estimated using a mathematical model for tissue homeostasis by stem cell replication and associated cancer risk. The model recapitulates the observation that treatments targeting stem cell replication can induce a substantial delay of organ failure. The model predicts that the cancer risk is minor under particular conditions. It depends on the assumed implications for cell damage repair during treatment. The benefit of rejuvenation therapy and its impact on cancer risk depend on the biological age at the time of treatment and on the overall cell turnover rate of the organs. Different organs have to be considered separately in the planning of systemic treatments. In recent years, the transfer of blood from young to old individuals was shown to bear the potential of rejuvenation of stem cell activity. In this context, the model predicts that the treatment schedule is critical for success and that schedules successful in animal experiments are not transferable to humans. Guidelines for successful protocols are proposed. The model presented here may be used as a guidance for the development of stem cell rejuvenation treatment protocols and the identification of critical parameters for cancer risk.
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Estimation of the cancer risk induced by therapies targeting stem cell replication and treatment recommendations.
Article
oai:repository.helmholtz-hzi.de:10033/6215112019-08-30T11:29:45Zcom_10033_620659col_10033_620660
Montaseri, Ghazal
Boianelli, Alessandro
Hernandez-Vargas, Esteban A
Meyer-Hermann, Michael
2018-10-10T08:47:31Z
2018-10-10T08:47:31Z
2018-07-19
1873-1732
30031022
10.1016/j.pbiomolbio.2018.07.007
http://hdl.handle.net/10033/621511
Influenza A virus (IAV) is a latent global threat to human health. In view of the risk of pandemics, prophylactic and curative treatments are essential. Oseltamivir is a neuraminidase inhibitor efficiently supporting recovery from influenza infections. Current common clinical practice is a constant drug dose (75 or 150 mg) administered at regular time intervals twice a day. We aim to use quantitative systems pharmacology to propose an efficient adaptive drug scheduling. We combined the mathematical model for IAV infections validated by murine data, which captures the viral dynamics and the dynamics of the immune host response, with a pharmacokinetic (PK)/pharmacodynamic (PD) model of oseltamivir. Next, we applied an adaptive impulsive feedback control method to systematically calculate the adaptive dose of oseltamivir in dependence on the viral load and the number of immune effectors at the time of drug administration. Our in silico results revealed that the treatment with adaptive control-based drug scheduling is able to either increase the drug virological efficacy or reduce the drug dose while keeping the same virological efficacy. Thus, adaptive adjustment of the drug dose would reduce not only the potential side effects but also the amount of stored oseltamivir required for the prevention of outbreaks.
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Impulsive control
Influenza viral infections
Oseltamivir
PK/PD modeling
PK/PD-based adaptive tailoring of oseltamivir doses to treat within-host influenza viral infections.
Article
oai:repository.helmholtz-hzi.de:10033/6215332019-08-30T11:29:40Zcom_10033_128109com_10033_620659col_10033_128110col_10033_620660
Prajeeth, Chittappen K
Dittrich-Breiholz, Oliver
Talbot, Steven R
Robert, Philippe A
Huehn, Jochen
Stangel, Martin
2018-11-02T11:50:11Z
2018-11-02T11:50:11Z
2018-01-01
1662-5102
30364000
10.3389/fncel.2018.00352
http://hdl.handle.net/10033/621533
Autoreactive T cells that infiltrate into the central nervous system (CNS) are believed to have a significant role in mediating the pathology of neuroinflammatory diseases like multiple sclerosis. Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of neuroinflammatory processes. Our previous work demonstrated that effectors secreted by Th1 and Th17 cells have different capacities to influence the phenotype and function of glial cells. We have shown that Th1-derived effectors altered the phenotype and function of both microglia and astrocytes whereas Th17-derived effectors induced direct effects only on astrocytes but not on microglia. Here we investigated if effector molecules associated with IFN-γ producing Th1 cells induced different gene expression profiles in microglia and astrocytes. We performed a microarray analysis of RNA isolated from microglia and astrocytes treated with medium and Th-derived culture supernatants and compared the gene expression data. By using the criteria of 2-fold change and a false discovery rate of 0.01 (corrected
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Th1 cells
astrocytes
cytokines
interferon-γ
microglia
IFN-γ Producing Th1 Cells Induce Different Transcriptional Profiles in Microglia and Astrocytes.
Article
oai:repository.helmholtz-hzi.de:10033/6215342019-08-30T11:29:40Zcom_10033_620659col_10033_620660
Meyer-Hermann, Michael
Binder, Sebastian C
Mesin, Luka
Victora, Gabriel D
2018-11-02T12:06:40Z
2018-11-02T12:06:40Z
2018-01-01
1664-3224
30319600
10.3389/fimmu.2018.02020
http://hdl.handle.net/10033/621534
Clonal evolution of B cells in germinal centers (GCs) is central to affinity maturation of antibodies in response to pathogens. Permanent or tamoxifen-induced multi-color recombination of B cells based on the brainbow allele allows monitoring the degree of color dominance in the course of the GC reaction. Here, we use computer simulations of GC reactions in order to replicate the evolution of color dominance
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Attribution-NonCommercial-ShareAlike 3.0 United States
brainbow
clonal selection
computer simulation
germinal center
mathematical modeling
multiphoton imaging
sequencing
Computer Simulation of Multi-Color Brainbow Staining and Clonal Evolution of B Cells in Germinal Centers.
Article
oai:repository.helmholtz-hzi.de:10033/6216482019-08-30T11:33:54Zcom_10033_620659com_10033_620652col_10033_620666col_10033_620660
Theobald, Sebastian J
Khailaie, Sahamoddin
Meyer-Hermann, Michael
Volk, Valery
Olbrich, Henning
Danisch, Simon
Gerasch, Laura
Schneider, Andreas
Sinzger, Christian
Schaudien, Dirk
Lienenklaus, Stefan
Riese, Peggy
Guzman, Carlos A
Figueiredo, Constanca
von Kaisenberg, Constantin
Spineli, Loukia M
Glaesener, Stephanie
Meyer-Bahlburg, Almut
Ganser, Arnold
Schmitt, Michael
Mach, Michael
Messerle, Martin
Stripecke, Renata
2019-01-15T13:45:26Z
2019-01-15T13:45:26Z
2018-01-01
- Front Immunol. 2018 Nov 22;9:2734. doi: 10.3389/fimmu.2018.02734. eCollection 2018.
1664-3224
30524448
10.3389/fimmu.2018.02734
http://hdl.handle.net/10033/621648
uman cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the Gaussia luciferase reporter gene (HCMV/GLuc) in order to interrogate the viral modulatory effects on the human adaptive immunity. Humanized mice with long-term (more than 17 weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and 7 weeks later were further treated with granulocyte-colony stimulating factor (G-CSF) to induce viral reactivations. Whole body bio-luminescence imaging analyses clearly differentiated mice with latent viral infections vs. reactivations. Foci of vigorous viral reactivations were detectable in liver, lymph nodes and salivary glands. The number of viral genome copies in various tissues increased upon reactivations and were detectable in sorted human CD14+, CD169+, and CD34+ cells. Compared with non-infected controls, mice after infections and reactivations showed higher thymopoiesis, systemic expansion of Th, CTL, Treg, and Tfh cells and functional antiviral T cell responses. Latent infections promoted vast development of memory CD4+ T cells while reactivations triggered a shift toward effector T cells expressing PD-1. Further, reactivations prompted a marked development of B cells, maturation of IgG+ plasma cells, and HCMV-specific antibody responses. Multivariate statistical methods were employed using T and B cell immune phenotypic profiles obtained with cells from several tissues of individual mice. The data was used to identify combinations of markers that could predict an HCMV infection vs. reactivation status. In spleen, but not in lymph nodes, higher frequencies of effector CD4+ T cells expressing PD-1 were among the factors most suited to distinguish HCMV reactivations from infections. These results suggest a shift from a T cell dominated immune response during latent infections toward an exhausted T cell phenotype and active humoral immune response upon reactivations. In sum, this novel in vivo humanized model combined with advanced analyses highlights a dynamic system clearly specifying the immunological spatial signatures of HCMV latency and reactivations. These signatures can be merged as predictive biomarker clusters that can be applied in the clinical translation of new therapies for the control of HCMV reactivation.
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B cell class switch
HCMV
T cell maturation
humanized mice
linear discriminant analyses
optical imaging analyses
principal component analyses
reactivation
Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34 Cells.
Article
oai:repository.helmholtz-hzi.de:10033/6217482019-08-30T11:32:11Zcom_10033_620659col_10033_620660
Siokis, Anastasios
Robert, Philippe A
Demetriou, Philippos
Dustin, Michael L
Meyer-Hermann, Michael
2019-04-16T08:45:31Z
2019-04-16T08:45:31Z
2018-07-31
Cell Rep. 2018 Jul 31;24(5):1151-1162. doi: 10.1016/j.celrep.2018.06.114
2211-1247
30067972
10.1016/j.celrep.2018.06.114
http://hdl.handle.net/10033/621748
Cell Reports
During immunological synapse (IS) formation, T cell receptor (TCR) signaling complexes, integrins, and costimulatory molecules exhibit a particular spatial localization. Here, we develop an agent-based model for the IS formation based on TCR peptide-bound major histocompatibility complex (pMHC) and leukocyte-function-associated antigen 1 (LFA-1) intracellular activation molecule 1 (ICAM-1) dynamics, including CD28 binding to a costimulatory ligand, coupling of molecules to the centripetal actin flow, and size-based segregation (SBS). A radial gradient of LFA-1 in the peripheral supramolecular activation cluster (pSMAC) toward the central supramolecular activation cluster (cSMAC) emerged as a combined consequence of actin binding and diffusion and modified the positioning of other molecules. The simulations predict a mechanism of CD28 movement, according to which CD28-CD80 complexes passively follow TCR-pMHC microclusters. However, the characteristic CD28-CD80 localization in a ring pattern around the cSMAC only emerges with a particular CD28-actin coupling strength that induces a centripetal motion. These results have implications for the understanding of T cell activation and fate decisions.
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CD28
F-actin flow
agent-based modeling
immulogical synapse
molecular transport
pattern formation
F-Actin-Driven CD28-CD80 Localization in the Immune Synapse.
Article
oai:repository.helmholtz-hzi.de:10033/6217542019-08-30T11:32:11Zcom_10033_620659col_10033_620661
Nguyen, Van Kinh
Mikolajczyk, Rafael T
Hernandez-Vargas, Esteban Abelardo
2019-04-17T13:21:25Z
2019-04-17T13:21:25Z
2018-07-17
BMC Public Health. 2018 Jul 17;18(1):886. doi: 10.1186/s12889-018-5709-x
1471-2458
30016958
10.1186/s12889-018-5709-x
http://hdl.handle.net/10033/621754
BMC Public Health
BACKGROUND:
Recent epidemics have entailed global discussions on revamping epidemic control and prevention approaches. A general consensus is that all sources of data should be embraced to improve epidemic preparedness. As a disease transmission is inherently governed by individual-level responses, pathogen dynamics within infected hosts posit high potentials to inform population-level phenomena. We propose a multiscale approach showing that individual dynamics were able to reproduce population-level observations.
METHODS:
Using experimental data, we formulated mathematical models of pathogen infection dynamics from which we simulated mechanistically its transmission parameters. The models were then embedded in our implementation of an age-specific contact network that allows to express individual differences relevant to the transmission processes. This approach is illustrated with an example of Ebola virus (EBOV).
RESULTS:
The results showed that a within-host infection model can reproduce EBOV's transmission parameters obtained from population data. At the same time, population age-structure, contact distribution and patterns can be expressed using network generating algorithm. This framework opens a vast opportunity to investigate individual roles of factors involved in the epidemic processes. Estimating EBOV's reproduction number revealed a heterogeneous pattern among age-groups, prompting cautions on estimates unadjusted for contact pattern. Assessments of mass vaccination strategies showed that vaccination conducted in a time window from five months before to one week after the start of an epidemic appeared to strongly reduce epidemic size. Noticeably, compared to a non-intervention scenario, a low critical vaccination coverage of 33% cannot ensure epidemic extinction but could reduce the number of cases by ten to hundred times as well as lessen the case-fatality rate.
CONCLUSIONS:
Experimental data on the within-host infection have been able to capture upfront key transmission parameters of a pathogen; the applications of this approach will give us more time to prepare for potential epidemics. The population of interest in epidemic assessments could be modelled with an age-specific contact network without exhaustive amount of data. Further assessments and adaptations for different pathogens and scenarios to explore multilevel aspects in infectious diseases epidemics are underway.
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Age-structure
Contact network
Ebola virus
Epidemic
High-resolution
Simulation
Within-host infection
High-resolution epidemic simulation using within-host infection and contact data.
Article
oai:repository.helmholtz-hzi.de:10033/6217892019-11-21T12:10:44Zcom_10033_620659col_10033_620660
Schlicker, Lisa
Boers, Hanny M
Dudek, Christian-Alexander
Zhao, Gang
Barua, Arnab
Trezzi, Jean-Pierre
Meyer-Hermann, Michael
Jacobs, Doris M
Hiller, Karsten
2019-05-21T11:38:35Z
2019-05-21T11:38:35Z
2019-05-07
Metabolites. 2019 May 7;9(5). pii: metabo9050091. doi: 10.3390/metabo9050091.
2218-1989
31067731
10.3390/metabo9050091
http://hdl.handle.net/10033/621789
Metabolites
Food supplementation with a fiber mix of guar gum and chickpea flour represents a promising approach to reduce the risk of type 2 diabetes mellitus (T2DM) by attenuating postprandial glycemia. To investigate the effects on postprandial metabolic fluxes of glucose-derived metabolites in response to this fiber mix, a randomized, cross-over study was designed. Twelve healthy, male subjects consumed three different flatbreads either supplemented with 2% guar gum or 4% guar gum and 15% chickpea flour or without supplementation (control). The flatbreads were enriched with ~2% of 13C-labeled wheat flour. Blood was collected at 16 intervals over a period of 360 min after bread intake and plasma samples were analyzed by GC-MS based metabolite profiling combined with stable isotope-assisted metabolomics. Although metabolite levels of the downstream metabolites of glucose, specifically lactate and alanine, were not altered in response to the fiber mix, supplementation of 4% guar gum was shown to significantly delay and reduce the exogenous formation of these metabolites. Metabolic modeling and computation of appearance rates revealed that the effects induced by the fiber mix were strongest for glucose and attenuated downstream of glucose. Further investigations to explore the potential of fiber mix supplementation to counteract the development of metabolic diseases are warranted.
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13C-enrichment
GC-MS
chickpea flour
guar gum
metabolism
starch
wheat flour
Postprandial Metabolic Effects of Fiber Mixes Revealed by in vivo Stable Isotope Labeling in Humans.
Article
oai:repository.helmholtz-hzi.de:10033/6218302019-08-30T11:32:13Zcom_10033_620659col_10033_620660
Alfonso, J C L
Berk, L
2019-06-26T13:05:29Z
2019-06-26T13:05:29Z
2019-05-30
Radiat Oncol. 2019 May 30;14(1):88. doi: 10.1186/s13014-019-1288-y.
1748-717X
31146751
10.1186/s13014-019-1288-y
http://hdl.handle.net/10033/621830
Radiation Oncology
Standard radiobiology theory of radiation response assumes a uniform innate radiosensitivity of tumors. However, experimental data show that there is significant intratumoral heterogeneity of radiosensitivity. Therefore, a model with heterogeneity was developed and tested using existing experimental data to show the potential effects from the presence of an intratumoral distribution of radiosensitivity on radiation therapy response over a protracted radiation therapy treatment course.
en
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Accelerated repopulation
Fractionated radiotherapy
Intratumoral radiosensitivity heterogeneity
Linear-quadratic model
Radiation resistance
Modeling the effect of intratumoral heterogeneity of radiosensitivity on tumor response over the course of fractionated radiation therapy.
Article
oai:repository.helmholtz-hzi.de:10033/6218592019-08-30T11:26:40Zcom_10033_620659col_10033_620660
Mascheroni, Pietro
López Alfonso, Juan Carlos
Kalli, Maria
Stylianopoulos, Triantafyllos
Meyer-Hermann, Michael
Hatzikirou, Haralampos
2019-07-11T09:33:40Z
2019-07-11T09:33:40Z
2019-05-24
Cancers (Basel). 2019 May 24;11(5). pii: cancers11050716. doi: 10.3390/cancers11050716.
2072-6694
31137643
10.3390/cancers11050716
http://hdl.handle.net/10033/621859
Cancers
Tumor microenvironment is a critical player in glioma progression, and novel therapies for its targeting have been recently proposed. In particular, stress-alleviation strategies act on the tumor by reducing its stiffness, decreasing solid stresses and improving blood perfusion. However, these microenvironmental changes trigger chemo–mechanically induced cellular phenotypic transitions whose impact on therapy outcomes is not completely understood. In this work we analyze the effects of mechanical compression on migration and proliferation of glioma cells. We derive a mathematical model of glioma progression focusing on cellular phenotypic plasticity. Our results reveal a trade-off between tumor infiltration and cellular content as a consequence of stress-alleviation approaches. We discuss how these novel findings increase the current understanding of glioma/microenvironment interactions and can contribute to new strategies for improved therapeutic outcomes. View Full-Text
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glioma
phenotypic transitions
solid stress
stress-alleviation therapy
On the Impact of Chemo-Mechanically Induced Phenotypic Transitions in Gliomas.
Article
oai:repository.helmholtz-hzi.de:10033/6218852019-08-30T11:26:41Zcom_10033_620659col_10033_620660
Cañete, Pablo F
Sweet, Rebecca A
Gonzalez-Figueroa, Paula
Papa, Ilenia
Ohkura, Naganari
Bolton, Holly
Roco, Jonathan A
Cuenca, Marta
Bassett, Katharine J
Sayin, Ismail
Barry, Emma
Lopez, Angel
Canaday, David H
Meyer-Hermann, Michael
Doglioni, Claudio
Fazekas de St Groth, Barbara
Sakaguchi, Shimon
Cook, Matthew C
Vinuesa, Carola G
2019-07-19T10:12:00Z
2019-07-19T10:12:00Z
2019-06-17
J Exp Med. 2019 Jun 17. pii: jem.20190493. doi: 10.1084/jem.20190493.
1540-9538
31209070
10.1084/jem.20190493
http://hdl.handle.net/10033/621885
Journal of experimental Medicine
Mucosal lymphoid tissues such as human tonsil are colonized by bacteria and exposed to ingested and inhaled antigens, requiring tight regulation of immune responses. Antibody responses are regulated by follicular helper T (TFH) cells and FOXP3+ follicular regulatory T (TFR) cells. Here we describe a subset of human tonsillar follicular T cells identified by expression of TFH markers and CD25 that are the main source of follicular T (TF) cell-derived IL-10. Despite lack of FOXP3 expression, CD25+ TF cells resemble T reg cells in high CTLA4 expression, low IL-2 production, and their ability to repress T cell proliferation. CD25+ TF cell-derived IL-10 dampens induction of B cell class-switching to IgE. In children, circulating total IgE titers were inversely correlated with the frequencies of tonsil CD25+ TF cells and IL-10-producing TF cells but not with total T reg cells, TFR, or IL-10-producing T cells. Thus, CD25+ TF cells emerge as a subset with unique T and B cell regulatory activities that may help prevent atopy.
en
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Regulatory roles of IL-10-producing human follicular T cells.
Article
oai:repository.helmholtz-hzi.de:10033/6219202019-08-30T11:24:30Zcom_10033_620659col_10033_620660
Enderling, Heiko
Alfonso, Juan Carlos López
Moros, Eduardo
Caudell, Jimmy J.
Harrison, Louis B.
2019-08-27T09:13:23Z
2019-08-27T09:13:23Z
2019-08-01
24058033
10.1016/j.trecan.2019.06.006
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85068509350&origin=inward
http://hdl.handle.net/10033/621920
Trends in Cancer
2-s2.0-85068509350
2-s2.0-85059309527
SCOPUS_ID:85068509350
S2405803319301256
In current radiation oncology practice, treatment protocols are prescribed based on the average outcomes of large clinical trials, with limited personalization and without adaptations of dose or dose fractionation to individual patients based on their individual clinical responses. Predicting tumor responses to radiation and comparing predictions against observed responses offers an opportunity for novel treatment evaluation. These analyses can lead to protocol adaptation aimed at the improvement of patient outcomes with better therapeutic ratios. We foresee the integration of mathematical models into radiation oncology to simulate individual patient tumor growth and predict treatment response as dynamic biomarkers for personalized adaptive radiation therapy (RT).
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adaptive therapy
mathematical oncology
radiation
radiotherapy
systems medicine
Integrating Mathematical Modeling into the Roadmap for Personalized Adaptive Radiation Therapy
Article
oai:repository.helmholtz-hzi.de:10033/6219262019-09-04T01:34:46Zcom_10033_620659col_10033_620660
López Alfonso, Juan Carlos
Poleszczuk, Jan
Walker, Rachel
Kim, Sungjune
Pilon-Thomas, Shari
Conejo-Garcia, Jose J
Soliman, Hatem
Czerniecki, Brian
Harrison, Louis B
Enderling, Heiko
2019-09-03T08:40:40Z
2019-09-03T08:40:40Z
2019-01-01
JCO Clin Cancer Inform. 2019 Apr;3:1-16. doi: 10.1200/CCI.18.00075.
2473-4276
30964698
10.1200/CCI.18.00075
http://hdl.handle.net/10033/621926
JCO Clinical Cancer Informatics
PURPOSE Early-stage cancers are routinely treated with surgery followed by radiotherapy (SR). Radiotherapy
before surgery (RS) has been widely ignored for some cancers. We evaluate overall survival (OS) and diseasefree survival (DFS) with SR and RS for different cancer types and simulate the plausibility of RS- and SR-induced
antitumor immunity contributing to outcomes.
MATERIALS AND METHODS We analyzed a SEER data set of early-stage cancers treated with SR or RS. OS and
DFS were calculated for cancers with sufficient numbers for statistical power (cancers of lung and bronchus,
esophagus, rectum, cervix uteri, corpus uteri, and breast). We simulated the immunologic consequences of SR,
RS, and radiotherapy alone in a mathematical model of tumor-immune interactions.
RESULTS RS improved OS for cancers with low 20-year survival rates (lung: hazard ratio [HR], 0.88; P = .046)
and improved DFS for cancers with higher survival (breast: HR = 0.64; P , .001). For rectal cancer, with
intermediate 20-year survival, RS improved both OS (HR = 0.89; P = .006) and DFS (HR = 0.86; P = .04).
Model simulations suggested that RS could increase OS by eliminating cancer for a broader range of model
parameters and radiotherapy-induced antitumor immunity compared with SR for selected parameter
combinations. This could create an immune memory that may explain increased DFS after RS for certain
cancers.
CONCLUSION Study results suggest plausibility that radiation to the bulk of the tumor could induce a more robust
immune response and better harness the synergy of radiotherapy and antitumor immunity than postsurgical
radiation to the tumor bed. This exploratory study provides motivation for prospective evaluation of immune
activation of RS versus SR in controlled clinical studies
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Immunologic Consequences of Sequencing Cancer Radiotherapy and Surgery.
Article
oai:repository.helmholtz-hzi.de:10033/6219512019-09-20T01:28:29Zcom_10033_620659col_10033_620660
Schaadt, Nadine S
Alfonso, Juan Carlos López
Schönmeyer, Ralf
Grote, Anne
Forestier, Germain
Wemmert, Cédric
Krönke, Nicole
Stoeckelhuber, Mechthild
Kreipe, Hans H
Hatzikirou, Haralampos
Feuerhake, Friedrich
2019-09-19T12:06:41Z
2019-09-19T12:06:41Z
2017-07-01
Breast Cancer Res Treat. 2017 Jul;164(2):305-315. doi: 10.1007/s10549-017-4239-z. Epub 2017 Apr 25.
1573-7217
28444535
10.1007/s10549-017-4239-z
http://hdl.handle.net/10033/621951
Brest cancer research and treatment
Purpose: To improve microscopic evaluation of immune cells relevant in breast cancer oncoimmunology, we aim at distinguishing normal infiltration patterns from lymphocytic lobulitis by advanced image analysis. We consider potential immune cell variations due to the menstrual cycle and oral contraceptives in non-neoplastic mammary gland tissue.
METHODS:
Lymphocyte and macrophage distributions were analyzed in the anatomical context of the resting mammary gland in immunohistochemically stained digital whole slide images obtained from 53 reduction mammoplasty specimens. Our image analysis workflow included automated regions of interest detection, immune cell recognition, and co-registration of regions of interest.
RESULTS:
In normal lobular epithelium, seven CD8[Formula: see text] lymphocytes per 100 epithelial cells were present on average and about 70% of this T-lymphocyte population was lined up along the basal cell layer in close proximity to the epithelium. The density of CD8[Formula: see text] T-cell was 1.6 fold higher in the luteal than in the follicular phase in spontaneous menstrual cycles and 1.4 fold increased under the influence of oral contraceptives, and not co-localized with epithelial proliferation. CD4[Formula: see text] T-cells were infrequent. Abundant CD163[Formula: see text] macrophages were widely spread, including the interstitial compartment, with minor variation during the menstrual cycle.
CONCLUSIONS:
Spatial patterns of different immune cell subtypes determine the range of normal, as opposed to inflammatory conditions of the breast tissue microenvironment. Advanced image analysis enables quantification of hormonal effects, refines lymphocytic lobulitis, and shows potential for comprehensive biopsy evaluation in oncoimmunolog
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Digital pathology
Hormonal fluctuations
Lymphocytic lobulitis
Menstrual cycle
Object-based image analysis
Oncoimmunology
Image analysis of immune cell patterns in the human mammary gland during the menstrual cycle refines lymphocytic lobulitis.
Article
oai:repository.helmholtz-hzi.de:10033/6219812019-10-18T02:43:55Zcom_10033_620659col_10033_620660
Arulraj, Theinmozhi
Binder, Sebastian C
Robert, Philippe A
Meyer-Hermann, Michael
2019-10-17T10:56:26Z
2019-10-17T10:56:26Z
2019-01-01
Front Immunol. 2019 Sep 6;10:2116. doi: 10.3389/fimmu.2019.02116. eCollection 2019.
1664-3224
31555300
10.3389/fimmu.2019.02116
http://hdl.handle.net/10033/621981
Frontiers in Immunology
The germinal center reaction is an important target for modulating antibody responses. Antibody production from germinal centers is regulated by a negative feedback mechanism termed antibody feedback. By imposing antibody feedback, germinal centers can interact and regulate the output of other germinal centers. Using an agent-based model of the germinal center reaction, we studied the impact of antibody feedback on kinetics and efficiency of a germinal center. Our simulations predict that high feedback of antibodies from germinal centers reduces the production of plasma cells and subsequently the efficiency of the germinal center reaction by promoting earlier termination. Affinity maturation is only weakly improved by increased antibody feedback and ultimately interrupted because of premature termination of the reaction. The model predicts that the asynchronous onset and changes in number of germinal centers could alter the efficiency of antibody response due to changes in feedback by soluble antibodies. Consequently, late initialized germinal centers have a compromised output due to higher antibody feedback from the germinal centers formed earlier. The results demonstrate potential effects of germinal center intercommunication and highlight the importance of understanding germinal center interactions for optimizing the antibody response, in particular, in the elderly and in the context of vaccination.
en
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openAccess
Attribution-NonCommercial-ShareAlike 4.0 International
antibody production
computer simulation
germinal center
mathematical modeling
vaccination
Synchronous Germinal Center Onset Impacts the Efficiency of Antibody Responses.
Article
oai:repository.helmholtz-hzi.de:10033/6220192019-11-20T02:02:36Zcom_10033_620659col_10033_620660
Meyer-Hermann, Michael
2019-11-19T14:59:46Z
2019-11-19T14:59:46Z
2019-10-29
Cell Rep. 2019 Oct 29;29(5):1066-1073.e5. doi: 10.1016/j.celrep.2019.09.058.
2211-1247
31665624
10.1016/j.celrep.2019.09.058
http://hdl.handle.net/10033/622019
Cell Reports
Broadly neutralizing antibodies are crucial for the control of many life-threatening viral infections like HIV, influenza, or hepatitis. Their induction is a prime goal in vaccine research. Using computer simulations, we identify strategies to promote the generation of broadly neutralizing antibodies in natural germinal center (GC) reactions. The simulations predict a feedback loop based on antibodies and memory B cells from previous GC reactions that promotes GCs to focus on new epitopes. Memory-derived or injected antibodies specific for immunodominant epitopes control epitope availability, suppress the participation of memory B cells in the GC reaction, and allow for the evolution of other B cells to affinity mature for hidden or rare epitopes. This defines a natural selection mechanism for GC B cells to concentrate on new epitopes rather than refine affinity to already-covered epitopes. This principle can be used for the design and testing of future therapies and vaccination protocols.
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HIV
broadly neutralizing antibodies
germinal center
hepatitis
influenza
mathematical modeling
memory B cells
original antigenic sin
simulation
targeting hidden epitopes
Injection of Antibodies against Immunodominant Epitopes Tunes Germinal Centers to Generate Broadly Neutralizing Antibodies.
Article
oai:repository.helmholtz-hzi.de:10033/6221912020-04-07T05:15:09Zcom_10033_620659col_10033_620660
Schaadt, Nadine S
Schönmeyer, Ralf
Forestier, Germain
Brieu, Nicolas
Braubach, Peter
Nekolla, Katharina
Meyer-Hermann, Michael
Feuerhake, Friedrich
2020-03-06T10:51:43Z
2020-03-06T10:51:43Z
2020-02-01
PLoS Comput Biol. 2020 Feb 21;16(2):e1007385. doi: 10.1371/journal.pcbi.1007385. eCollection 2020 Feb.
1553-7358
32084130
10.1371/journal.pcbi.1007385
http://hdl.handle.net/10033/622191
PLOS computational biology
Our aim is to complement observer-dependent approaches of immune cell evaluation in microscopy images with reproducible measures for spatial composition of lymphocytic infiltrates. Analyzing such patterns of inflammation is becoming increasingly important for therapeutic decisions, for example in transplantation medicine or cancer immunology. We developed a graph-based assessment of lymphocyte clustering in full whole slide images. Based on cell coordinates detected in the full image, a Delaunay triangulation and distance criteria are used to build neighborhood graphs. The composition of nodes and edges are used for classification, e.g. using a support vector machine. We describe the variability of these infiltrates on CD3/CD20 duplex staining in renal biopsies of long-term functioning allografts, in breast cancer cases, and in lung tissue of cystic fibrosis patients. The assessment includes automated cell detection, identification of regions of interest, and classification of lymphocytic clusters according to their degree of organization. We propose a neighborhood feature which considers the occurrence of edges with a certain type in the graph to distinguish between phenotypically different immune infiltrates. Our work addresses a medical need and provides a scalable framework that can be easily adjusted to the requirements of different research questions.
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B cells
Graphs
T cells
immune cells
dentritic structure
pathologists
lymphocytes
support vector machines
Graph-based description of tertiary lymphoid organs at single-cell level.
Article
oai:repository.helmholtz-hzi.de:10033/6221952020-03-11T02:09:44Zcom_10033_620659col_10033_620660
Alfonso, Juan Carlos L
Papaxenopoulou, Lito A
Mascheroni, Pietro
Meyer-Hermann, Michael
Hatzikirou, Haralampos
2020-03-10T13:31:56Z
2020-03-10T13:31:56Z
2020-02-11
iScience. 2020 Feb 11;23(3):100897. doi: 10.1016/j.isci.2020.100897.
2589-0042
32092699
10.1016/j.isci.2020.100897
http://hdl.handle.net/10033/622195
iScience
Emerging evidence demonstrates that radiotherapy induces immunogenic death on tumor cells that emit immunostimulating signals resulting in tumor-specific immune responses. However, the impact of tumor features and microenvironmental factors on the efficacy of radiation-induced immunity remains to be elucidated. Herein, we use a calibrated model of tumor-effector cell interactions to investigate the potential benefits and immunological consequences of radiotherapy. Simulations analysis suggests that radiotherapy success depends on the functional tumor vascularity extent and reveals that the pre-treatment tumor size is not a consistent determinant of treatment outcomes. The one-size-fits-all approach of conventionally fractionated radiotherapy is predicted to result in some overtreated patients. In addition, model simulations also suggest that an arbitrary increase in treatment duration does not necessarily result in better tumor control. This study highlights the potential benefits of tumor-immune ecosystem profiling during treatment planning to better harness the immunogenic potential of radiotherapy.
en
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Bioinformatics
Cancer
Mathematical Biosciences
On the Immunological Consequences of Conventionally Fractionated Radiotherapy.
Article
oai:repository.helmholtz-hzi.de:10033/6222502020-05-11T01:28:08Zcom_10033_620659col_10033_620660
Goldberg, Amy
Rastogi, Ananya
Rosenberg, Noah A.
2020-05-10T13:48:51Z
2020-05-10T13:48:51Z
2020-04-07
Theor Popul Biol. 2020 Apr 7. pii: S0040-5809(20)30025-3. doi: 10.1016/j.tpb.2020.02.004.
0040-5809
32275920
10.1016/j.tpb.2020.02.004
http://hdl.handle.net/10033/622250
Theoretical population Biology
S0040580920300253
Populations whose mating pairs have levels of similarity in phenotypes or genotypes that differ systematically from the level expected under random mating are described as experiencing assortative mating. Excess similarity in mating pairs is termed positive assortative mating, and excess dissimilarity is negative assortative mating. In humans, empirical studies suggest that mating pairs from various admixed populations-whose ancestry derives from two or more source populations-possess correlated ancestry components that indicate the occurrence of positive assortative mating on the basis of ancestry. Generalizing a two-sex mechanistic admixture model, we devise a model of one form of ancestry-assortative mating that occurs through preferential mating based on source population. Under the model, we study the moments of the admixture fraction distribution for different assumptions about mating preferences, including both positive and negative assortative mating by population. We demonstrate that whereas the mean admixture under assortative mating is equivalent to that of a corresponding randomly mating population, the variance of admixture depends on the level and direction of assortative mating. We consider two special cases of assortative mating by population: first, a single admixture event, and second, constant contributions to the admixed population over time In contrast to standard settings in which positive assortment increases variation within a population, certain assortative mating scenarios allow the variance of admixture to decrease relative to a corresponding randomly mating population: with the three populations we consider, the variance-increasing effect of positive assortative mating within a population might be overwhelmed by a variance-decreasing effect emerging from mating preferences involving other pairs of populations. The effect of assortative mating is smaller on the X chromosome than on the autosomes because inheritance of the X in males depends only on the mother's ancestry, not on the mating pair. Because the variance of admixture is informative about the timing of admixture and possibly about sex-biased admixture contributions, the effects of assortative mating are important to consider in inferring features of population history from distributions of admixture values. Our model provides a framework to quantitatively study assortative mating under flexible scenarios of admixture over time.
en
https://www.elsevier.com/tdm/userlicense/1.0/
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Attribution-NonCommercial-ShareAlike 4.0 International
Ecology, Evolution, Behavior and Systematics
Assortative mating by population of origin in a mechanistic model of admixture
Article
oai:repository.helmholtz-hzi.de:10033/6224332020-09-28T10:51:11Zcom_10033_128109com_10033_620659com_10033_6839com_10033_620618col_10033_128110col_10033_620660col_10033_621495col_10033_620621
Bonifacius, Agnes
Goldmann, Oliver
Floess, Stefan
Holtfreter, Silva
Robert, Philippe A
Nordengrün, Maria
Kruse, Friederike
Lochner, Matthias
Falk, Christine S
Schmitz, Ingo
Bröker, Barbara M
Medina, Eva
Huehn, Jochen
2020-09-10T07:20:07Z
2020-09-10T07:20:07Z
2020-08-07
Front Immunol. 2020;11:1579. Published 2020 Aug 7. doi:10.3389/fimmu.2020.01579.
32849537
10.3389/fimmu.2020.01579
http://hdl.handle.net/10033/622433
1664-3224
Frontiers in immunology
Staphylococcus aureus can cause life-threatening diseases, and hospital- as well as community-associated antibiotic-resistant strains are an emerging global public health problem. Therefore, prophylactic vaccines or immune-based therapies are considered as alternative treatment opportunities. To develop such novel treatment approaches, a better understanding of the bacterial virulence and immune evasion mechanisms and their potential effects on immune-based therapies is essential. One important staphylococcal virulence factor is alpha-toxin, which is able to disrupt the epithelial barrier in order to establish infection. In addition, alpha-toxin has been reported to modulate other cell types including immune cells. Since CD4+ T cell-mediated immunity is required for protection against S. aureus infection, we were interested in the ability of alpha-toxin to directly modulate CD4+ T cells. To address this, murine naïve CD4+ T cells were differentiated in vitro into effector T cell subsets in the presence of alpha-toxin. Interestingly, alpha-toxin induced death of Th1-polarized cells, while cells polarized under Th17 conditions showed a high resistance toward increasing concentrations of this toxin. These effects could neither be explained by differential expression of the cellular alpha-toxin receptor ADAM10 nor by differential activation of caspases, but might result from an increased susceptibility of Th1 cells toward Ca2+-mediated activation-induced cell death. In accordance with the in vitro findings, an alpha-toxin-dependent decrease of Th1 and concomitant increase of Th17 cells was observed in vivo during S. aureus bacteremia. Interestingly, corresponding subsets of innate lymphoid cells and γδ T cells were similarly affected, suggesting a more general effect of alpha-toxin on the modulation of type 1 and type 3 immune responses. In conclusion, we have identified a novel alpha-toxin-dependent immunomodulatory strategy of S. aureus, which can directly act on CD4+ T cells and might be exploited for the development of novel immune-based therapeutic approaches to treat infections with antibiotic-resistant S. aureus strains.
en
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CD4+ T cells
Staphylococcus aureus
alpha-toxin
innate lymphoid cells
γδ T cells
Staphylococcus aureus Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses.
Article
oai:repository.helmholtz-hzi.de:10033/6224992020-10-09T01:33:40Zcom_10033_620659col_10033_620660
Siokis, Anastasios
Robert, Philippe A
Meyer-Hermann, Michael
2020-10-08T09:03:05Z
2020-10-08T09:03:05Z
2020-09-04
. Int J Mol Sci. 2020 Sep 4;21(18):E6473. doi: 10.3390/ijms21186473.
32899840
10.3390/ijms21186473
http://hdl.handle.net/10033/622499
1422-0067
International journal of molecular sciences
Immunological synapse (IS) formation is a key event during antigen recognition by T cells. Recent experimental evidence suggests that the affinity between T cell receptors (TCRs) and antigen is actively modulated during the early steps of TCR signaling. In this work, we used an agent-based model to study possible mechanisms for affinity modulation during IS formation. We show that, without any specific active mechanism, the observed affinity between receptors and ligands evolves over time and depends on the density of ligands of the antigen peptide presented by major histocompatibility complexes (pMHC) and TCR molecules. A comparison between the presence or absence of TCR-pMHC centrally directed flow due to F-actin coupling suggests that centripetal transport is a potential mechanism for affinity modulation. The model further suggests that the time point of affinity measurement during immune synapse formation is critical. Finally, a mathematical model of F-actin foci formation incorporated in the agent-based model shows that TCR affinity can potentially be actively modulated by positive/negative feedback of the F-actin foci on the TCR-pMHC association rate kon.
en
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F-actin foci
TCR cooperativity
agent-based modeling
immunological synapse
Agent-Based Modeling of T Cell Receptor Cooperativity.
Article
oai:repository.helmholtz-hzi.de:10033/6225272020-10-30T01:35:47Zcom_10033_620659com_10033_311308col_10033_620721col_10033_620660
Theobald, Sebastian J
Kreer, Christoph
Khailaie, Sahamoddin
Bonifacius, Agnes
Eiz-Vesper, Britta
Figueiredo, Constanca
Mach, Michael
Backovic, Marija
Ballmaier, Matthias
Koenig, Johannes
Olbrich, Henning
Schneider, Andreas
Volk, Valery
Danisch, Simon
Gieselmann, Lutz
Ercanoglu, Meryem Seda
Messerle, Martin
Kaisenberg, Constantin von
Witte, Torsten
Klawonn, Frank
Meyer-Hermann, Michael
Klein, Florian
Stripecke, Renata
2020-10-22T09:33:34Z
2020-10-22T09:33:34Z
2020-07-15
PLoS Pathog. 2020 Jul 15;16(7):e1008560. doi: 10.1371/journal.ppat.1008560.
32667948
10.1371/journal.ppat.1008560
http://hdl.handle.net/10033/622527
1553-7374
PLoS pathogens
Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promote de novo antiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8+ and CD4+ T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4+, liver B/IgA+ and spleen B/IgG+ cells as predictive biomarkers of immunization (≈87% accuracy). CD8+ and CD4+ T cell responses against gB were validated. Splenic gB-binding IgM-/IgG+ B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation.
en
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Attribution-NonCommercial-ShareAlike 4.0 International
Repertoire characterization and validation of gB-specific human IgGs directly cloned from humanized mice vaccinated with dendritic cells and protected against HCMV.
Article
oai:repository.helmholtz-hzi.de:10033/6225332020-11-04T04:36:58Zcom_10033_620659col_10033_620660
Rizzuti, Ilaria Francesca
Mascheroni, Pietro
Arcucci, Silvia
Ben-Mériem, Zacchari
Prunet, Audrey
Barentin, Catherine
Rivière, Charlotte
Delanoë-Ayari, Hélène
Hatzikirou, Haralampos
Guillermet-Guibert, Julie
Delarue, Morgan
2020-10-26T10:20:54Z
2020-10-26T10:20:54Z
2020-09-18
Phys Rev Lett. 2020 Sep 18;125(12):128103. doi: 10.1103/PhysRevLett.125.128103.
33016731
10.1103/PhysRevLett.125.128103
http://hdl.handle.net/10033/622533
1079-7114
Physical review letters
While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there is an increasing realization that tumor-stroma interactions also play an important role. In particular, mechanical alterations are inherent to solid cancer progression and profoundly impact cell physiology. Here, we explore the influence of compressive stress on the efficacy of chemotherapeutics in pancreatic cancer spheroids. We find that increased compressive stress leads to decreased drug efficacy. Theoretical modeling and experiments suggest that mechanical stress decreases cell proliferation which in turn reduces the efficacy of chemotherapeutics that target proliferating cells. Our work highlights a mechanical form of drug resistance and suggests new strategies for therapy.
en
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Mechanical Control of Cell Proliferation Increases Resistance to Chemotherapeutic Agents.
Article
oai:repository.helmholtz-hzi.de:10033/6226012020-11-20T01:46:27Zcom_10033_620659col_10033_620660
Reimer, Dorothea
Meyer-Hermann, Michael
Rakhymzhan, Asylkhan
Steinmetz, Tobit
Tripal, Philipp
Thomas, Jana
Boettcher, Martin
Mougiakakos, Dimitrios
Schulz, Sebastian R
Urbanczyk, Sophia
Hauser, Anja E
Niesner, Raluca A
Mielenz, Dirk
2020-11-19T15:12:26Z
2020-11-19T15:12:26Z
2020-08-11
Cell Rep. 2020 Aug 11;32(6):108030. doi: 10.1016/j.celrep.2020.108030.
32783949
10.1016/j.celrep.2020.108030
http://hdl.handle.net/10033/622601
2211-1247
Cell reports
Plasma cells secreting affinity-matured antibodies develop in germinal centers (GCs), where B cells migrate persistently and directionally over defined periods of time. How modes of GC B cell migration influence plasma cell development remained unclear. Through genetic deletion of the F-actin bundling protein Swiprosin-1/EF-hand domain family member 2 (EFhd2) and by two-photon microscopy, we show that EFhd2 restrains B cell speed in GCs and hapten-specific plasma cell output. Modeling the GC reaction reveals that increasing GC B cell speed promotes plasma cell generation. Lack of EFhd2 also reduces contacts of GC B cells with follicular dendritic cells in vivo. Computational modeling uncovers that both GC output and antibody affinity depend quantitatively on contacts of GC B cells with follicular dendritic cells when B cells migrate more persistently. Collectively, our data explain how GC B cells integrate speed and persistence of cell migration with B cell receptor affinity.
en
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B cell receptor
Swiprosin-1/EFhd2
actin cytoskeleton
differentiation
follicular dendritic cell
germinal center
migration
plasma cell
selection
synapse
B Cell Speed and B-FDC Contacts in Germinal Centers Determine Plasma Cell Output via Swiprosin-1/EFhd2.
Article
oai:repository.helmholtz-hzi.de:10033/6226022020-11-20T01:46:27Zcom_10033_620659col_10033_620660
Hoore, Masoud
Khailaie, Sahamoddin
Montaseri, Ghazal
Mitra, Tanmay
Meyer-Hermann, Michael
2020-11-19T15:23:56Z
2020-11-19T15:23:56Z
2020-07-22
Biophys J. 2020 Aug 18;119(4):862-872. doi: 10.1016/j.bpj.2020.07.011. Epub 2020 Jul 22.
32758420
10.1016/j.bpj.2020.07.011
http://hdl.handle.net/10033/622602
1542-0086
Biophysical journal
Deposition of amyloid-β (Aβ) fibers in the extracellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimer's disease (AD). Although many of the biological aspects that contribute to the formation of Aβ plaques are well addressed at the intra- and intercellular levels in short timescales, an understanding of how Aβ fibrillization usually starts to dominate at a longer timescale despite the presence of mechanisms dedicated to Aβ clearance is still lacking. Furthermore, no existing mathematical model integrates the impact of diurnal neural activity as emanated from circadian regulation to predict disease progression due to a disruption in the sleep-wake cycle. In this study, we develop a minimal model of Aβ fibrillization to investigate the onset of AD over a long timescale. Our results suggest that the diseased state is a manifestation of a phase change of the system from soluble Aβ (sAβ) to fibrillar Aβ (fAβ) domination upon surpassing a threshold in the production rate of sAβ. By incorporating the circadian rhythm into our model, we reveal that fAβ accumulation is crucially dependent on the regulation of the sleep-wake cycle, thereby indicating the importance of good sleep hygiene in averting AD onset. We also discuss potential intervention schemes to reduce fAβ accumulation in the brain by modification of the critical sAβ production rate.
en
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Attribution-NonCommercial-ShareAlike 4.0 International
Mathematical Model Shows How Sleep May Affect Amyloid-β Fibrillization.
Article
oai:repository.helmholtz-hzi.de:10033/6226102020-12-03T01:45:45Zcom_10033_620659col_10033_620660
Khailaie, Sahamoddin
Montaseri, Ghazal
Meyer-Hermann, Michael
2020-11-25T10:28:57Z
2020-11-25T10:28:57Z
2020-10-12
iScience. 2020 Oct 12;23(11):101663. doi: 10.1016/j.isci.2020.101663.
33134893
10.1016/j.isci.2020.101663
http://hdl.handle.net/10033/622610
2589-0042
iScience
Regulatory T cells (Treg) are suppressor cells that control self-reactive and excessive effector conventional T helper cell (Tconv) responses. Breakdown of the balance between Tregs and Tconvs is a hallmark of autoimmune and inflammatory diseases. Interleukin-2 (IL-2) is a growth factor for both populations and subtle leverage to restore the healthy immune balance in IL-2 therapy. By using a mechanistic mathematical model, we introduced an adaptive control strategy to design the minimal therapeutic IL-2 dosage required to increase and stabilize Treg population and restrict inflammatory response. This adaptive protocol allows for dose adjustments based on the feedback of the immune kinetics of the patient. Our simulation results showed that a minimal Treg population was required to restrict the transient side effect of IL-2 injections on the effector Tconv response. In silico results suggested that a combination of IL-2 and adoptive Treg transfer therapies can limit this side effect.
en
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Biological Sciences
Immunology
Mathematical Bioscience
An Adaptive Control Scheme for Interleukin-2 Therapy.
Article
oai:repository.helmholtz-hzi.de:10033/6226122020-12-03T01:44:26Zcom_10033_620659col_10033_620660
Xenos, Michalis A.
Petropoulou, Eugenia N.
Siokis, Anastasios
Mahabaleshwar, U. S.
2020-11-25T13:37:46Z
2020-11-25T13:37:46Z
2020-05-01
Symmetry 2020, 12, 710.
10.3390/SYM12050710
http://hdl.handle.net/10033/622612
20738994
Symmetry
2-s2.0-85085360972
SCOPUS_ID:85085360972
The physical problem under consideration is the boundary layer problem of an incompressible, laminar flow, taking place over a flat plate in the presence of a pressure gradient and radiation. For the mathematical formulation of the problem, the partial differential equations of continuity, energy, and momentum are taken into consideration with the boundary layer simplifications. Using the dimensionless Falkner–Skan transformation, a nonlinear, nonhomogeneous, coupled system of partial differential equations (PDEs) is obtained, which is solved via the homotopy analysis method. The obtained analytical solution describes radiation and pressure gradient effects on the boundary layer flow. These analytical results reveal that the adverse or favorable pressure gradient influences the dimensionless velocity and the dimensionless temperature of the boundary layer. An adverse pressure gradient causes significant changes on the dimensionless wall shear parameter and the dimensionless wall heat-transfer parameter. Thermal radiation influences the thermal boundary layer. The analytical results are in very good agreement with the corresponding numerical ones obtained using a modification of the Keller’s-box method.
en
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openAccess
Attribution 4.0 International
Approximate solution
Boundary layer
Homotopy analysis method
Pressure gradient
Thermal radiation
Solving the nonlinear boundary layer flow equations with pressure gradient and radiation
Article
oai:repository.helmholtz-hzi.de:10033/6226252020-12-02T01:41:37Zcom_10033_620659col_10033_620660
Riebisch, Anna Katharina
Mühlen, Sabrina
2020-12-01T10:08:25Z
2020-12-01T10:08:25Z
2020-07-27
Future Microbiol. 2020 Jul;15:945-958. doi: 10.2217/fmb-2019-0274. Epub 2020 Jul 27.
32716209
10.2217/fmb-2019-0274
http://hdl.handle.net/10033/622625
1746-0921
Future microbiology
The innate immune response resembles an essential barrier to bacterial infection. Many bacterial pathogens have, therefore, evolved mechanisms to evade from or subvert the host immune response in order to colonize, survive and multiply. The attaching and effacing pathogens enteropathogenic Escherichia coli, enterohaemorrhagic E. coli, Escherichia albertii and Citrobacter rodentium are Gram-negative extracellular gastrointestinal pathogens. They use a type III secretion system to inject effector proteins into the host cell to manipulate a variety of cellular processes. Over the last decade, considerable progress was made in identifying and characterizing the effector proteins of attaching and effacing pathogens that are involved in the inhibition of innate immune signaling pathways, in determining their host cell targets and elucidating the mechanisms they employ. Their functions will be reviewed here.
en
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AE pathogens
apoptosis
inflammasome
inflammatory response
innate immune response
necroptosis
Attaching and effacing pathogens: the effector ABC of immune subversion.
Review
oai:repository.helmholtz-hzi.de:10033/6226662021-01-08T15:56:37Zcom_10033_620659col_10033_620660
Pae, Juhee
Ersching, Jonatan
Castro, Tiago B R
Schips, Marta
Mesin, Luka
Allon, Samuel J
Ordovas-Montanes, Jose
Mlynarczyk, Coraline
Melnick, Ari
Efeyan, Alejo
Shalek, Alex K
Meyer-Hermann, Michael
Victora, Gabriel D
2021-01-07T11:00:27Z
2021-01-07T11:00:27Z
2021-04-01
The Journal of Experimental Medicine. 2021 Apr;218(4). DOI: 10.1084/jem.20201699.
33332554
10.1084/jem.20201699
http://hdl.handle.net/10033/622666
1540-9538
The Journal of experimental medicine
During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by "inertia." We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma-associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.
en
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©2021 Pae et al. Originally published in he Journal of Experimental Medicine. https://doi.org/10.1084/jem.20201699
Attribution-NonCommercial-ShareAlike 4.0 International
Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells.
Article
oai:repository.helmholtz-hzi.de:10033/6226802021-01-15T01:54:29Zcom_10033_620659col_10033_620660
Barua, Arnab
Nava-Sedeño, Josue M
Meyer-Hermann, Michael
Hatzikirou, Haralampos
2021-01-14T12:59:00Z
2021-01-14T12:59:00Z
2020-12-22
Sci Rep. 2020 Dec 22;10(1):22371. doi: 10.1038/s41598-020-79119-y.
33353977
10.1038/s41598-020-79119-y
http://hdl.handle.net/10033/622680
2045-2322
Scientific reports
Collective migration is commonly observed in groups of migrating cells, in the form of swarms or aggregates. Mechanistic models have proven very useful in understanding collective cell migration. Such models, either explicitly consider the forces involved in the interaction and movement of individuals or phenomenologically define rules which mimic the observed behavior of cells. However, mechanisms leading to collective migration are varied and specific to the type of cells involved. Additionally, the precise and complete dynamics of many important chemomechanical factors influencing cell movement, from signalling pathways to substrate sensing, are typically either too complex or largely unknown. The question is how to make quantitative/qualitative predictions of collective behavior without exact mechanistic knowledge. Here we propose the least microenvironmental uncertainty principle (LEUP) that may serve as a generative model of collective migration without precise incorporation of full mechanistic details. Using statistical physics tools, we show that the famous Vicsek model is a special case of LEUP. Finally, to test the biological applicability of our theory, we apply LEUP to construct a model of the collective behavior of spherical Serratia marcescens bacteria, where the underlying migration mechanisms remain elusive.
en
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Attribution 4.0 International
A least microenvironmental uncertainty principle (LEUP) as a generative model of collective cell migration mechanisms.
Article
oai:repository.helmholtz-hzi.de:10033/6227182021-02-06T01:58:19Zcom_10033_620659col_10033_620660
Nakagawa, Rinako
Toboso-Navasa, Amparo
Schips, Marta
Young, George
Bhaw-Rosun, Leena
Llorian-Sopena, Miriam
Chakravarty, Probir
Sesay, Abdul Karim
Kassiotis, George
Meyer-Hermann, Michael
Calado, Dinis Pedro
2021-02-05T11:11:57Z
2021-02-05T11:11:57Z
2021-01-12
Proc Natl Acad Sci U S A. 2021 Jan 12;118(2):e2016425118. doi: 10.1073/pnas.2016425118.
33419925
10.1073/pnas.2016425118
http://hdl.handle.net/10033/622718
1091-6490
Proceedings of the National Academy of Sciences of the United States of America
Affinity maturation depends on how efficiently germinal centers (GCs) positively select B cells in the light zone (LZ). Positively selected GC B cells recirculate between LZs and dark zones (DZs) and ultimately differentiate into plasmablasts (PBs) and memory B cells (MBCs). Current understanding of the GC reaction presumes that cMyc-dependent positive selection of LZ B cells is a competitive affinity-dependent process; however, this cannot explain the production of GC-derived lower-affinity MBCs or retention of GC B cells with varied affinities. Here, by combining single-cell/bulk RNA sequencing and flow cytometry, we identified and characterized temporally and functionally distinct positively selected cMyc+ GC B cell subpopulations. cMyc+ LZ B cell subpopulations enriched with either higher- or lower-affinity cells diverged soon after permissive positive selection. The former subpopulation contained PB precursors, whereas the latter comprised less proliferative MBC precursors and future DZ entrants. The overall affinity of future DZ entrants was enhanced in the LZ through preferential proliferation of higher-affinity cells. Concurrently, lower-affinity cells were retained in GCs and protected from apoptosis. These findings redefine positive selection as a dynamic process generating three distinct B cell fates and elucidate how positive selection ensures clonal diversity for broad protection.
en
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Attribution-NonCommercial-NoDerivatives 4.0 International
GC B cells
affinity maturation
clonal diversity
memory B cells
positive selection
Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth.
Article
oai:repository.helmholtz-hzi.de:10033/6227272021-02-10T02:32:31Zcom_10033_211390com_10033_620659col_10033_211409col_10033_620660
Khailaie, Sahamoddin
Mitra, Tanmay
Bandyopadhyay, Arnab
Schips, Marta
Mascheroni, Pietro
Vanella, Patrizio
Lange, Berit
Binder, Sebastian C
Meyer-Hermann, Michael
2021-02-09T10:22:58Z
2021-02-09T10:22:58Z
2021-01-28
BMC Med. 2021 Jan 28;19(1):32. doi: 10.1186/s12916-020-01884-4.
33504336
10.1186/s12916-020-01884-4
http://hdl.handle.net/10033/622727
1741-7015
BMC medicine
Background: SARS-CoV-2 has induced a worldwide pandemic and subsequent non-pharmaceutical interventions (NPIs) to control the spread of the virus. As in many countries, the SARS-CoV-2 pandemic in Germany has led to a consecutive roll-out of different NPIs. As these NPIs have (largely unknown) adverse effects, targeting them precisely and monitoring their effectiveness are essential. We developed a compartmental infection dynamics model with specific features of SARS-CoV-2 that allows daily estimation of a time-varying reproduction number and published this information openly since the beginning of April 2020. Here, we present the transmission dynamics in Germany over time to understand the effect of NPIs and allow adaptive forecasts of the epidemic progression.
Methods: We used a data-driven estimation of the evolution of the reproduction number for viral spreading in Germany as well as in all its federal states using our model. Using parameter estimates from literature and, alternatively, with parameters derived from a fit to the initial phase of COVID-19 spread in different regions of Italy, the model was optimized to fit data from the Robert Koch Institute.
Results: The time-varying reproduction number (Rt) in Germany decreased to <1 in early April 2020, 2-3 weeks after the implementation of NPIs. Partial release of NPIs both nationally and on federal state level correlated with moderate increases in Rt until August 2020. Implications of state-specific Rt on other states and on national level are characterized. Retrospective evaluation of the model shows excellent agreement with the data and usage of inpatient facilities well within the healthcare limit. While short-term predictions may work for a few weeks, long-term projections are complicated by unpredictable structural changes.
Conclusions: The estimated fraction of immunized population by August 2020 warns of a renewed outbreak upon release of measures. A low detection rate prolongs the delay reaching a low case incidence number upon release, showing the importance of an effective testing-quarantine strategy. We show that real-time monitoring of transmission dynamics is important to evaluate the extent of the outbreak, short-term projections for the burden on the healthcare system, and their response to policy changes.
en
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Attribution 4.0 International
COVID-19
Epidemiology
Healthcare usage
Modeling
Non-pharmaceutical interventions
Reproduction number
SARS-CoV-2
Development of the reproduction number from coronavirus SARS-CoV-2 case data in Germany and implications for political measures.
Article
oai:repository.helmholtz-hzi.de:10033/6227282021-02-10T02:32:43Zcom_10033_620659com_10033_311308col_10033_620721col_10033_620660
Volk, Valery
Theobald, Sebastian J
Danisch, Simon
Khailaie, Sahamoddin
Kalbarczyk, Maja
Schneider, Andreas
Bialek-Waldmann, Julia
Krönke, Nicole
Deng, Yun
Eiz-Vesper, Britta
Dragon, Anna Christina
von Kaisenberg, Constantin
Lienenklaus, Stefan
Bleich, Andre
Keck, James
Meyer-Hermann, Michael
Klawonn, Frank
Hammerschmidt, Wolfgang
Delecluse, Henri-Jacques
Münz, Christian
Feuerhake, Friedrich
Stripecke, Renata
2021-02-09T11:10:59Z
2021-02-09T11:10:59Z
2021-01-12
Front Oncol. 2021 Jan 12;10:614876. doi: 10.3389/fonc.2020.614876.
2234-943X
33511078
10.3389/fonc.2020.614876
http://hdl.handle.net/10033/622728
Frontiers in oncology
Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to develop and combat EBV. If this is not effective, approaches include immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells. Immune checkpoint inhibition (ICI) to treat EBV+ PTLD was not established clinically due to the risks of organ rejection and graft-versus-host disease. Previously, blockade of the programmed death receptor (PD)-1 by a monoclonal antibody (mAb) during ex vivo infection of mononuclear cells with the EBV/M81+ strain showed lower xenografted lymphoma development in mice. Subsequently, fully humanized mice infected with the EBV/B95-8 strain and treated in vivo with a PD-1 blocking mAb showed aggravation of PTLD and lymphoma development. Here, we evaluated vis-a-vis in fully humanized mice after EBV/B95-8 or EBV/M81 infections the effects of a clinically used PD-1 blocker. Fifteen to 17 weeks after human CD34+ stem cell transplantation, Nod.Rag.Gamma mice were infected with two types of EBV laboratory strains expressing firefly luciferase. Dynamic optical imaging analyses showed systemic EBV infections and this triggered vigorous human CD8+ T cell expansion. Pembrolizumab administered from 2 to 5 weeks post-infections significantly aggravated EBV systemic spread and, for the M81 model, significantly increased the mortality of mice. ICI promoted Ki67+CD30+CD20+EBER+PD-L1+ PTLD with central nervous system (CNS) involvement, mirroring EBV+ CNS PTLD in humans. PD-1 blockade was associated with lower frequencies of circulating T cells in blood and with a profound collapse of CD4+ T cells in lymphatic tissues. Mice treated with pembrolizumab showed an escalation of exhausted T cells expressing TIM-3, and LAG-3 in tissues, higher levels of several human cytokines in plasma and high densities of FoxP3+ regulatory CD4+ and CD8+ T cells in the tumor microenvironment. We conclude that PD-1 blockade during acute EBV infections driving strong CD8+ T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV+ PTLD.
en
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Attribution 4.0 International
Epstein-Barr Virus (EBV)
PD-1
humanized mice
immune checkpoint inhibition (ICI)
immuno-oncology
lymphoma
pembrolizumab
post-transplant lymphoproliferative disease (PTLD)
PD-1 Blockade Aggravates Epstein-Barr Virus Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4 T Cell Dysregulations.
Article
oai:repository.helmholtz-hzi.de:10033/6227772021-03-20T03:35:54Zcom_10033_620659com_10033_211390col_10033_211409col_10033_620660
Dorn, Florian
et al.
2021-03-19T12:05:26Z
2021-03-19T12:05:26Z
2020-05-12
http://hdl.handle.net/10033/622777
ifo Schnelldienst digital
[No Abstract available]
de
http://creativecommons.org/licenses/by-nc-sa/4.0/
Attribution-NonCommercial-ShareAlike 4.0 International
Das gemeinsame Interesse von Gesundheit und Wirtschaft: Eine Szenarienrechnung zur Eindämmung der Corona Pandemie
Article
oai:repository.helmholtz-hzi.de:10033/6227902021-03-25T01:32:00Zcom_10033_620659col_10033_620660
Merino Tejero, Elena
Lashgari, Danial
García-Valiente, Rodrigo
Gao, Xuefeng
Crauste, Fabien
Robert, Philippe A
Meyer-Hermann, Michael
Martínez, María Rodríguez
van Ham, S Marieke
Guikema, Jeroen E J
Hoefsloot, Huub
van Kampen, Antoine H C
2021-03-24T10:58:20Z
2021-03-24T10:58:20Z
2021-02-05
Front Immunol. 2021 Feb 5;11:620716. doi: 10.3389/fimmu.2020.620716.
33613551
10.3389/fimmu.2020.620716
http://hdl.handle.net/10033/622790
1664-3224
Frontiers in immunology
Germinal centers play a key role in the adaptive immune system since they are able to produce memory B cells and plasma cells that produce high affinity antibodies for an effective immune protection. The mechanisms underlying cell-fate decisions are not well understood but asymmetric division of antigen, B-cell receptor affinity, interactions between B-cells and T follicular helper cells (triggering CD40 signaling), and regulatory interactions of transcription factors have all been proposed to play a role. In addition, a temporal switch from memory B-cell to plasma cell differentiation during the germinal center reaction has been shown. To investigate if antigen affinity-based Tfh cell help recapitulates the temporal switch we implemented a multiscale model that integrates cellular interactions with a core gene regulatory network comprising BCL6, IRF4, and BLIMP1. Using this model we show that affinity-based CD40 signaling in combination with asymmetric division of B-cells result in switch from memory B-cell to plasma cell generation during the course of the germinal center reaction. We also show that cell fate division is unlikely to be (solely) based on asymmetric division of Ag but that BLIMP1 is a more important factor. Altogether, our model enables to test the influence of molecular modulations of the CD40 signaling pathway on the production of germinal center output cells.
en
http://creativecommons.org/licenses/by/4.0/
openAccess
Attribution 4.0 International
CD40 signaling
T follicular helper cell
germinal center
multiscale model
plasma cell differentiation
Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help.
Article
oai:repository.helmholtz-hzi.de:10033/6228212021-04-07T01:29:41Zcom_10033_620659col_10033_620660
Rastogi, Ananya
Robert, Philippe A
Halle, Stephan
Meyer-Hermann, Michael
2021-04-06T11:29:54Z
2021-04-06T11:29:54Z
2020-12-28
PLoS Comput Biol. 2020 Dec 28;16(12):e1008428. doi: 10.1371/journal.pcbi.1008428.
33370254
10.1371/journal.pcbi.1008428
http://hdl.handle.net/10033/622821
1553-7358
PLoS computational biology
In vivo imaging of cytotoxic T lymphocyte (CTL) killing activity revealed that infected cells have a higher observed probability of dying after multiple contacts with CTLs. We developed a three-dimensional agent-based model to discriminate different hypotheses about how infected cells get killed based on quantitative 2-photon in vivo observations. We compared a constant CTL killing probability with mechanisms of signal integration in CTL or infected cells. The most likely scenario implied increased susceptibility of infected cells with increasing number of CTL contacts where the total number of contacts was a critical factor. However, when allowing in silico T cells to initiate new interactions with apoptotic target cells (zombie contacts), a contact history independent killing mechanism was also in agreement with experimental datasets. The comparison of observed datasets to simulation results, revealed limitations in interpreting 2-photon data, and provided readouts to distinguish CTL killing models.
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Evaluation of CD8 T cell killing models with computer simulations of 2-photon imaging experiments.
Article
oai:repository.helmholtz-hzi.de:10033/6228232021-04-08T01:40:59Zcom_10033_128109com_10033_620659com_10033_620591col_10033_128110col_10033_620724col_10033_620660
Elfaki, Yassin
Robert, Philippe A
Binz, Christoph
Falk, Christine S
Bruder, Dunja
Prinz, Immo
Floess, Stefan
Meyer-Hermann, Michael
Huehn, Jochen
2021-04-07T14:24:38Z
2021-04-07T14:24:38Z
2021-02-26
Eur J Immunol. 2021 Feb 26. doi: 10.1002/eji.202048981. Epub ahead of print.
33638148
10.1002/eji.202048981
http://hdl.handle.net/10033/622823
1521-4141
European journal of immunology
Foxp3+ Treg cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25+ Foxp3- or CD25- Foxp3+ Treg cell precursors. Although it is known that infections can cause transient thymic involution, the impact of infection-induced thymus atrophy on thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenza A virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient thymic involution, dominated by a loss of CD4+ CD8+ double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25+ Foxp3+ tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T-cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.
en
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Attribution 4.0 International
Foxp3+ Treg cells ⋅ Influenza A virus ⋅ Mathematical modeling ⋅ Ordinary differential equations ⋅ Thymus atrophy
Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T-cell development in mice.
Article
oai:repository.helmholtz-hzi.de:10033/6228532021-05-04T01:38:20Zcom_10033_620659col_10033_620660
Barua, Arnab
Syga, Simon
Mascheroni, Pietro
Kavallaris, Nikos
Meyer-Hermann, Michael
Deutsch, Andreas
Hatzikirou, Haralampos
2021-05-03T13:21:14Z
2021-05-03T13:21:14Z
2020-12-01
(2020) New Journal of Physics,22(12)art.no: 123034.
13672630
10.1088/1367-2630/abcb2e
http://hdl.handle.net/10033/622853
New Journal of Physics
2-s2.0-85097945599
SCOPUS_ID:85097945599
Cellular decision making allows cells to assume functionally different phenotypes in response to microenvironmental cues, with or without genetic change. It is an open question, how individual cell decisions influence the dynamics at the tissue level. Here, we study spatio-temporal pattern formation in a population of cells exhibiting phenotypic plasticity, which is a paradigm of cell decision making. We focus on the migration/resting and the migration/proliferation plasticity which underly the epithelial-mesenchymal transition and the go or grow dichotomy. We assume that cells change their phenotype in order to minimize their microenvironmental entropy following the LEUP (Least microEnvironmental Uncertainty Principle) hypothesis. In turn, we study the impact of the LEUP-driven migration/resting and migration/proliferation plasticity on the corresponding multicellular spatio-temporal dynamics with a stochastic cell-based mathematical model for the spatio-temporal dynamics of the cell phenotypes. In the case of the go or rest plasticity, a corresponding mean-field approximation allows to identify a bistable switching mechanism between a diffusive (fluid) and an epithelial (solid) tissue phase which depends on the sensitivity of the phenotypes to the environment. For the go or grow plasticity, we show the possibility of Turing pattern formation for the ‘solid’ tissue phase and its relation with the parameters of the LEUP-driven cell decisions.
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Attribution 4.0 International
Cell-decision making
Fluid-to-solid transition
Langevin equations
Least microEnvironmental uncertainty principle (LEUP)
Mean-field theory
Phenotypic plasticity
Entropy-driven cell decision-making predicts ‘fluid-to-solid’ transition in multicellular systems
Article
oai:repository.helmholtz-hzi.de:10033/6228702021-05-13T01:51:34Zcom_10033_620659col_10033_620660
Tretter, Felix
Wolkenhauer, Olaf
Meyer-Hermann, Michael
Dietrich, Johannes W
Green, Sara
Marcum, James
Weckwerth, Wolfram
2021-05-12T11:33:02Z
2021-05-12T11:33:02Z
2021-03-29
Front Med (Lausanne). 2021 Mar 29;8:640974. doi: 10.3389/fmed.2021.640974.
2296-858X
33855036
10.3389/fmed.2021.640974
http://hdl.handle.net/10033/622870
Frontiers in medicine
Precision medicine and molecular systems medicine (MSM) are highly utilized and successful approaches to improve understanding, diagnosis, and treatment of many diseases from bench-to-bedside. Especially in the COVID-19 pandemic, molecular techniques and biotechnological innovation have proven to be of utmost importance for rapid developments in disease diagnostics and treatment, including DNA and RNA sequencing technology, treatment with drugs and natural products and vaccine development. The COVID-19 crisis, however, has also demonstrated the need for systemic thinking and transdisciplinarity and the limits of MSM: the neglect of the bio-psycho-social systemic nature of humans and their context as the object of individual therapeutic and population-oriented interventions. COVID-19 illustrates how a medical problem requires a transdisciplinary approach in epidemiology, pathology, internal medicine, public health, environmental medicine, and socio-economic modeling. Regarding the need for conceptual integration of these different kinds of knowledge we suggest the application of general system theory (GST). This approach endorses an organism-centered view on health and disease, which according to Ludwig von Bertalanffy who was the founder of GST, we call Organismal Systems Medicine (OSM). We argue that systems science offers wider applications in the field of pathology and can contribute to an integrative systems medicine by (i) integration of evidence across functional and structural differentially scaled subsystems, (ii) conceptualization of complex multilevel systems, and (iii) suggesting mechanisms and non-linear relationships underlying the observed phenomena. We underline these points with a proposal on multi-level systems pathology including neurophysiology, endocrinology, immune system, genetics, and general metabolism. An integration of these areas is necessary to understand excess mortality rates and polypharmacological treatments. In the pandemic era this multi-level systems pathology is most important to assess potential vaccines, their effectiveness, short-, and long-time adverse effects. We further argue that these conceptual frameworks are not only valid in the COVID-19 era but also important to be integrated in a medicinal curriculum.
en
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Attribution 4.0 International
Organismal Systems Medicine
dynamic equilibrium
excess mortality rate
multi organ disease
multi-level view model
polypharmacology
systems theory
The Quest for System-Theoretical Medicine in the COVID-19 Era.
Article
oai:repository.helmholtz-hzi.de:10033/6229322021-07-10T01:44:11Zcom_10033_620659col_10033_620660
Linden, Matthias
Dehning, Jonas
Mohr, Sebastian B
Mohring, Jan
Meyer-Hermann, Michael
Pigeot, Iris
Schöbel, Anita
Priesemann, Viola
2021-07-09T09:14:26Z
2021-07-09T09:14:26Z
Dtsch Arztebl Int 2020; 117: 790–1. DOI: 10.3238/arztebl.2020.0790
33533714
10.3238/arztebl.2020.0790
http://hdl.handle.net/10033/622932
1866-0452
Deutsches Arzteblatt international
PMC7930464
[No abstract available]
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Case Numbers Beyond Contact Tracing Capacity Are Endangering the Containment of COVID-19.
Letter
oai:repository.helmholtz-hzi.de:10033/6229472021-08-04T10:24:30Zcom_10033_620659col_10033_620660
Arulraj, Theinmozhi
Binder, Sebastian C
Meyer-Hermann, Michael
2021-07-21T10:05:30Z
2021-07-21T10:05:30Z
2021-02-19
J Immunol. 2021 Apr 1;206(7):1436-1442. doi: 10.4049/jimmunol.2001355. Epub 2021 Feb 19.
33608455
10.4049/jimmunol.2001355
http://hdl.handle.net/10033/622947
1550-6606
Journal of immunology (Baltimore, Md. : 1950)
en
http://creativecommons.org/licenses/by/4.0/
openAccess
Attribution 4.0 International
Rate of Immune Complex Cycling in Follicular Dendritic Cells Determines the Extent of Protecting Antigen Integrity and Availability to Germinal Center B Cells.
Article
oai:repository.helmholtz-hzi.de:10033/6230172021-09-09T01:53:12Zcom_10033_128109com_10033_620659col_10033_128110col_10033_620660
Arulraj, Theinmozhi
Binder, Sebastian C
Robert, Philippe A
Meyer-Hermann, Michael
2021-09-08T12:17:09Z
2021-09-08T12:17:09Z
2021-07-07
Front Immunol. 2021 Jul 7;12:705240. doi: 10.3389/fimmu.2021.705240.
34305944
10.3389/fimmu.2021.705240
http://hdl.handle.net/10033/623017
1664-3224
Frontiers in immunology
Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are responsible for protective antibody responses, dysregulated GC reactions are associated with autoimmune disease and B cell lymphoma. Typically, 'normal' GCs persist for a limited period of time and eventually undergo shutdown. In this review, we focus on an important but unanswered question - what causes the natural termination of the GC reaction? In murine experiments, lack of antigen, absence or constitutive T cell help leads to premature termination of the GC reaction. Consequently, our present understanding is limited to the idea that GCs are terminated due to a decrease in antigen access or changes in the nature of T cell help. However, there is no direct evidence on which biological signals are primarily responsible for natural termination of GCs and a mechanistic understanding is clearly lacking. We discuss the present understanding of the GC shutdown, from factors impacting GC dynamics to changes in cellular interactions/dynamics during the GC lifetime. We also address potential missing links and remaining questions in GC biology, to facilitate further studies to promote a better understanding of GC shutdown in infection and immune dysregulation.
en
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Attribution 4.0 International
B cell lymphoma
antibody responses
chronic germinal centres
ectopic germinal centres
germinal centre shutdown
vaccination
Germinal Centre Shutdown.
Article
oai:repository.helmholtz-hzi.de:10033/6230402021-09-22T01:53:11Zcom_10033_620659col_10033_620660
Meyer-Hermann, Michael
2021-09-21T09:04:49Z
2021-09-21T09:04:49Z
2021-08-24
Cell Rep. 2021 Aug 24;36(8):109552. doi: 10.1016/j.celrep.2021.109552. PMID: 34433043.
34433043
10.1016/j.celrep.2021.109552
http://hdl.handle.net/10033/623040
2211-1247
Cell reports
The selection of B cells (BCs) in germinal centers (GCs) is pivotal to the generation of high-affinity antibodies and memory BCs, but it lacks global understanding. Based on the idea of a single Tfh-cell signal that controls BC selection and division, experiments appear contradictory. Here, we use the current knowledge on the molecular pathways of GC BCs to develop a theory of GC BC selection and division based on the dynamics of molecular factors. This theory explains the seemingly contradictory experiments by the separation of signals for BC fate decision from signals controlling the number of BC divisions. Three model variants are proposed and experiments are predicted that allow one to distinguish those. Understanding information processing in molecular BC states is critical for targeted immune interventions, and the proposed theory implies that selection and division can be controlled independently in GC reactions.
en
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Attribution 4.0 International
B cell division
B cell selection
B cell signaling
FoxO1
affinity maturation
c-Myc
computer simulation
germinal center
mTOR
mathematical model
A molecular theory of germinal center B cell selection and division.
Article
oai:repository.helmholtz-hzi.de:10033/6230602021-10-05T03:23:31Zcom_10033_620659col_10033_620660
Priesemann, Viola
Meyer-Hermann, Michael
Pigeot, Iris
Schöbel, Anita
2021-10-04T14:27:18Z
2021-10-04T14:27:18Z
2021-07-30
Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2021 Sep;64(9):1058-1066. German. doi: 10.1007/s00103-021-03390-1. Epub 2021 Jul 30.
34328524
10.1007/s00103-021-03390-1
http://hdl.handle.net/10033/623060
1437-1588
Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz
After the global outbreak of the COVID-19 pandemic, an infection dynamic of immense extent developed. Since then, numerous measures have been taken to bring the infection under control. This was very successful in the spring of 2020, while the number of infections rose sharply the following autumn. To predict the occurrence of infections, epidemiological models are used. These are in principle a very valuable tool in pandemic management. However, they still partly need to be based on assumptions regarding the transmission routes and possible drivers of the infection dynamics. Despite numerous individual approaches, systematic epidemiological data are still lacking with which, for example, the effectiveness of individual measures could be quantified. Such information generated in studies is needed to enable reliable predictions regarding the further course of the pandemic. Thereby, the complexity of the models could develop hand in hand with the complexity of the available data. In this article, after delineating two basic classes of models, the contribution of epidemiological models to the assessment of various central aspects of the pandemic, such as the reproduction rate, the number of unreported cases, infection fatality rate, and the consideration of regionality, is shown. Subsequently, the use of the models to quantify the impact of measures and the effects of the "test-trace-isolate" strategy is described. In the concluding discussion, the limitations of such modelling approaches are juxtaposed with their advantages.
de
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Attribution 4.0 International
Agent-based models
Compartmental models
Dark figure
Infection fatality rate
Reproductive number
[The contribution of epidemiological models to the description of the outbreak of the COVID-19 pandemic].
Review
oai:repository.helmholtz-hzi.de:10033/6230682021-10-09T01:59:22Zcom_10033_620659col_10033_620660
Kühn, Martin J
Abele, Daniel
Mitra, Tanmay
Koslow, Wadim
Abedi, Majid
Rack, Kathrin
Siggel, Martin
Khailaie, Sahamoddin
Klitz, Margrit
Binder, Sebastian
Spataro, Luca
Gilg, Jonas
Kleinert, Jan
Häberle, Matthias
Plötzke, Lena
Spinner, Christoph D
Stecher, Melanie
Zhu, Xiao Xiang
Basermann, Achim
Meyer-Hermann, Michael
2021-10-08T14:09:34Z
2021-10-08T14:09:34Z
2021-06-30
Math Biosci. 2021 Sep;339:108648. doi: 10.1016/j.mbs.2021.108648. Epub 2021 Jun 30. PMID: 34216635.
34216635
10.1016/j.mbs.2021.108648
http://hdl.handle.net/10033/623068
1879-3134
Mathematical biosciences
on-pharmaceutical interventions (NPIs) are important to mitigate the spread of infectious diseases as long as no vaccination or outstanding medical treatments are available. We assess the effectiveness of the sets of non-pharmaceutical interventions that were in place during the course of the Coronavirus disease 2019 (Covid-19) pandemic in Germany. Our results are based on hybrid models, combining SIR-type models on local scales with spatial resolution. In order to account for the age-dependence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we include realistic prepandemic and recently recorded contact patterns between age groups. The implementation of non-pharmaceutical interventions will occur on changed contact patterns, improved isolation, or reduced infectiousness when, e.g., wearing masks. In order to account for spatial heterogeneity, we use a graph approach and we include high-quality information on commuting activities combined with traveling information from social networks. The remaining uncertainty will be accounted for by a large number of randomized simulation runs. Based on the derived factors for the effectiveness of different non-pharmaceutical interventions over the past months, we provide different forecast scenarios for the upcoming time.
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
Coronavirus disease
Covid-19
Forecast
Mitigation
Non-pharmaceutical interventions
SARS-CoV-2
Assessment of effective mitigation and prediction of the spread of SARS-CoV-2 in Germany using demographic information and spatial resolution.
Article
oai:repository.helmholtz-hzi.de:10033/6231182021-12-14T03:20:36Zcom_10033_128109com_10033_620659col_10033_621771col_10033_128110col_10033_620660
Formaglio, Pauline
Alabdullah, Mohamad
Siokis, Anastasios
Handschuh, Juliane
Sauerland, Ina
Fu, Yan
Krone, Anna
Gintschel, Patricia
Stettin, Juliane
Heyde, Sandrina
Mohr, Juliane
Philipsen, Lars
Schröder, Anja
Robert, Philippe A
Zhao, Gang
Khailaie, Sahamoddin
Dudeck, Anne
Bertrand, Jessica
Späth, Gerald F
Kahlfuß, Sascha
Bousso, Philippe
Schraven, Burkhart
Huehn, Jochen
Binder, Sebastian
Meyer-Hermann, Michael
Müller, Andreas J
2021-12-13T14:09:55Z
2021-12-13T14:09:55Z
2021-10-15
mmunity. 2021 Oct 15:S1074-7613(21)00406-4. doi: 10.1016/j.immuni.2021.09.021. Epub ahead of print.
34687607
10.1016/j.immuni.2021.09.021
http://hdl.handle.net/10033/623118
1097-4180
Immunity
Nitric oxide (NO) is an important antimicrobial effector but also prevents unnecessary tissue damage by shutting down the recruitment of monocyte-derived phagocytes. Intracellular pathogens such as Leishmania major can hijack these cells as a niche for replication. Thus, NO might exert containment by restricting the availability of the cellular niche required for efficient pathogen proliferation. However, such indirect modes of action remain to be established. By combining mathematical modeling with intravital 2-photon biosensors of pathogen viability and proliferation, we show that low L. major proliferation results not from direct NO impact on the pathogen but from reduced availability of proliferation-permissive host cells. Although inhibiting NO production increases recruitment of these cells, and thus pathogen proliferation, blocking cell recruitment uncouples the NO effect from pathogen proliferation. Therefore, NO fulfills two distinct functions for L. major containment: permitting direct killing and restricting the supply of proliferation-permissive host cells.
en
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Attribution 4.0 International
2-photon microscopy
Leishmania
biosensor
iNOS
inflammation
intracellular pathogen
monocyte
nitric oxide
phagocyte
Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells.
Article
oai:repository.helmholtz-hzi.de:10033/6231292022-01-07T01:48:30Zcom_10033_620659col_10033_620660
Knabl, Ludwig
Mitra, Tanmay
Kimpel, Janine
Rössler, Annika
Volland, André
Walser, Andreas
Ulmer, Hanno
Pipperger, Lisa
Binder, Sebastian C
Riepler, Lydia
Bates, Katie
Bandyopadhyay, Arnab
Schips, Marta
Ranjan, Mrinalini
Falkensammer, Barbara
Borena, Wegene
Meyer-Hermann, Michael
von Laer, Dorothee
2022-01-06T17:06:42Z
2022-01-06T17:06:42Z
2021-06-30
Commun Med (London). 2021;1(1):4. doi: 10.1038/s43856-021-00007-1. Epub 2021 Jun
34870284
10.1038/s43856-021-00007-1
http://hdl.handle.net/10033/623129
2730-664X
Communications medicine
Between April 21st and 27th 2020, a cross-sectional epidemiologic study targeting the full population of Ischgl (n = 1867), of which 79% could be included (n = 1473, incl. 214 children), was performed. For each individual, the study involved a SARS-CoV-2 PCR, antibody testing and structured questionnaires. A mathematical model was used to help understand the influence of the determined seroprevalence on virus transmission.
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
SARS virus
Viral epidemiology
Viral infection
High SARS-CoV-2 seroprevalence in children and adults in the Austrian ski resort of Ischgl.
Article
oai:repository.helmholtz-hzi.de:10033/6232062022-06-14T01:57:09Zcom_10033_620659col_10033_620660
Mascheroni, Pietro
Meyer-Hermann, Michael
Hatzikirou, Haralampos
2022-06-13T09:23:31Z
2022-06-13T09:23:31Z
2020-06-04
1664-302X
32582070
10.3389/fmicb.2020.01083
http://hdl.handle.net/10033/623206
Frontiers in microbiology
Tumor-targeting bacteria elicit anticancer effects by infiltrating hypoxic regions, releasing
toxic agents and inducing immune responses. Although current research has largely
focused on the influence of chemical and immunological aspects on the mechanisms
of bacterial therapy, the impact of physical effects is still elusive. Here, we propose a
mathematical model for the anti-tumor activity of bacteria in avascular tumors that takes
into account the relevant chemo-mechanical effects. We consider a time-dependent
administration of bacteria and analyze the impact of bacterial chemotaxis and killing rate.
We show that active bacterial migration toward tumor hypoxic regions provides optimal
infiltration and that high killing rates combined with high chemotactic values provide the
smallest tumor volumes at the end of the treatment.We highlight the emergence of steady
states in which a small population of bacteria is able to constrain tumor growth. Finally,
we show that bacteria treatment works best in the case of tumors with high cellular
proliferation and low oxygen consumption.
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
bacterial therapy
cancer
chemotaxis
mathematical modeling
space competition
Investigating the Physical Effects in Bacterial Therapies for Avascular Tumors.
Article
oai:repository.helmholtz-hzi.de:10033/6232232022-06-15T02:53:16Zcom_10033_620659col_10033_620660
Freudenhammer, Mirjam
Voll, Reinhard E
Binder, Sebastian C
Keller, Baerbel
Warnatz, Klaus
2022-06-14T09:15:04Z
2022-06-14T09:15:04Z
2020-09-09
32907998
10.4049/jimmunol.2000343
http://hdl.handle.net/10033/623223
1550-6606
Journal of immunology (Baltimore, Md. : 1950)
An expansion of CD21low B cells has been described in a variety of diseases associated with persistent immune stimulation as in chronic infection, immunodeficiency, or autoimmunity. Different developmental stages of CD21low B cells have been highlighted in specific diseases; however, a systematic comparison of distribution, phenotype, and signaling capacity of these populations has not yet been performed to delineate the pivotal character of this unusual B cell population. Screening of more than 200 patients with autoimmune disease demonstrated that the prevalence of patients with expanded CD21low B cells varies between diseases. The expansion was frequent in patients with systemic lupus erythematosus, in which it correlated to relative B cell lymphopenia and duration of disease. Different proportions of distinct developmental stages of CD21low B cells co-occur in nearly all patients with autoimmune disease. Although in most patients, naive-like and CD27- switched memory B cells were the most prominent CD21low subpopulations, there was no detectable association of the pattern with the underlying disease. Despite their distinct developmental stage, all CD21low B cells share a common core phenotype including the increased expression of inhibitory receptors, associated with an elevated constitutive phosphorylation of proximal signaling molecules downstream of the BCR but impaired Ca2+ mobilization and NF-κB activation after BCR stimulation. Further, this was accompanied by impaired upregulation of CD69, although CD86 upregulation was preserved. Beyond maturation-associated differences, the common core characteristics of all CD21low B cell populations suggests either a common ancestry or a shared sustained imprint by the environment they originated in.
en
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Attribution 4.0 International
Naive- and Memory-like CD21 B Cell Subsets Share Core Phenotypic and Signaling Characteristics in Systemic Autoimmune Disorders.
Article
oai:repository.helmholtz-hzi.de:10033/6232262022-06-15T02:52:29Zcom_10033_620659col_10033_620660
Montaseri, Ghazal
Alfonso, Juan Carlos López
Hatzikirou, Haralampos
Meyer-Hermann, Michael
2022-06-14T13:44:32Z
2022-06-14T13:44:32Z
2020-02-07
31790681
10.1016/j.jtbi.2019.110099
http://hdl.handle.net/10033/623226
1095-8541
Journal of theoretical biology
en
http://creativecommons.org/licenses/by/4.0/
Attribution 4.0 International
A minimal modeling framework of radiation and immune system synergy to assist radiotherapy planning.
Article
oai:repository.helmholtz-hzi.de:10033/6232382022-08-11T01:55:06Zcom_10033_620659col_10033_620660
Demetriou, Philippos
Abu-Shah, Enas
Valvo, Salvatore
McCuaig, Sarah
Mayya, Viveka
Kvalvaag, Audun
Starkey, Thomas
Korobchevskaya, Kseniya
Lee, Lennard Y W
Friedrich, Matthias
Mann, Elizabeth
Kutuzov, Mikhail A
Morotti, Matteo
Wietek, Nina
Rada, Heather
Yusuf, Shamsideen
Afrose, Jehan
Siokis, Anastasios
Meyer-Hermann, Michael
Ahmed, Ahmed Ashour
Depoil, David
Dustin, Michael L
2022-08-10T08:40:34Z
2022-08-10T08:40:34Z
2020-09-14
32929275
10.1038/s41590-020-0770-x
http://hdl.handle.net/10033/623238
1529-2916
Nature immunology
The CD2-CD58 recognition system promotes adhesion and signaling and counters exhaustion in human T cells. We found that CD2 localized to the outer edge of the mature immunological synapse, with cellular or artificial APC, in a pattern we refer to as a 'CD2 corolla'. The corolla captured engaged CD28, ICOS, CD226 and SLAM-F1 co-stimulators. The corolla amplified active phosphorylated Src-family kinases (pSFK), LAT and PLC-γ over T cell receptor (TCR) alone. CD2-CD58 interactions in the corolla boosted signaling by 77% as compared with central CD2-CD58 interactions. Engaged PD-1 invaded the CD2 corolla and buffered CD2-mediated amplification of TCR signaling. CD2 numbers and motifs in its cytoplasmic tail controlled corolla formation. CD8+ tumor-infiltrating lymphocytes displayed low expression of CD2 in the majority of people with colorectal, endometrial or ovarian cancer. CD2 downregulation may attenuate antitumor T cell responses, with implications for checkpoint immunotherapies.
en
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Attribution-ShareAlike 4.0 International
A dynamic CD2-rich compartment at the outer edge of the immunological synapse boosts and integrates signals.
Article
mods///com_10033_620659/100