The zipper mechanism in phagocytosis: energetic requirements and variability in phagocytic cup shape

Phagocytosis is the fundamental cellular process by which eukaryotic cells bind and engulf particles by their cell membrane. Particle engulfment involves particle recognition by cell-surface receptors, signaling and remodeling of the actin cytoskeleton to guide the membrane around the particle in a zipper-like fashion. Despite the signaling complexity, phagocytosis also depends strongly on biophysical parameters, such as particle shape, and the need for actin-driven force generation remains poorly understood. Here, we propose a novel, three-dimensional and stochastic biophysical model of phagocytosis, and study the engulfment of particles of various sizes and shapes, including spiral and rod-shaped particles reminiscent of bacteria. Highly curved shapes are not taken up, in line with recent experimental results. Furthermore, we surprisingly find that even without actin-driven force generation, engulfment proceeds in a large regime of parameter values, albeit more slowly and with highly variable phagocytic cups. We experimentally confirm these predictions using fibroblasts, transfected with immunoreceptor FcyRIIa for engulfment of immunoglobulin G-opsonized particles. Specifically, we compare the wild-type receptor with a mutant receptor, unable to signal to the actin cytoskeleton. Based on the reconstruction of phagocytic cups from imaging data, we indeed show that cells are able to engulf small particles even without support from biological actin-driven processes. This suggests that biochemical pathways render the evolutionary ancient process of phagocytic highly robust, allowing cells to engulf even very large particles. The particle-shape dependence of phagocytosis makes a systematic investigation of host-pathogen interactions and an efficient design of a vehicle for drug delivery possible.Comment: Accepted for publication in BMC Systems Biology. 17 pages, 6 Figures, + supplementary informatio

Contributions à la théorie des hétérostructures supraconducteur-ferromagnétique nanométriques

Dans la théorie BCS de la supraconductivité, l'état supraconducteur est caractérisé par l'appariement d'électrons d'impulsions et de spin opposés en paires de Cooper. Ceci explique à la fois que le champ magnétique et l'ordre ferromagnétique s'opposent à la supraconductivité. Cet antagonisme est source d'une physique riche dont nous présentons ici de nouveaux aspects. Nous démontrons dans cette thèse que l'effet de proximité, qui gouverne le comportement des structures hybrides formées d'un assemblage de couches supraconductrices et ferromagnétiques, est fortement modifié lorsque l'épaisseur des couches devient de l'ordre de la distance interatomique. En particulier, nous mettons en évidence théoriquement une phase supraconductrice nouvelle produite grâce à l'application d'un fort champ magnétique, ou la présence d'un fort champ d'échange ferromagnétique à basse température.Within the BCS theory of superconductivity, the superconducting ground state results from the pairing of opposed spins and momenta electrons into Cooper pairs. This explains why external magnetic fields and ferromagnetic ordering both affect superconducting properties. The competition between these two antagonistic order parameters gives rise to many interesting physical effects. Here we present several new phenomena related to this competition, and predicted in an exact microscopic formalism. We demonstrate that the superconducting/ferromagnetic (S/F) proximity effect, which is responsible for the peculiar behaviour of nanoscopic S/F multilayered heterostructures, is appreciably modified when the layers thickness reduces to the Fermi wavelenght. As the main result, we predict the appearance, at low temperatures, of a new superconducting phase resulting from the compensation between electronic interlayer tunnel coupling and a strong applied magnetic field

Nuclear size rectification:A potential new therapeutic approach to reduce metastasis in cancer

Research on metastasis has recently regained considerable interest with the hope that single cell technologies might reveal the most critical changes that support tumor spread. However, it is possible that part of the answer has been visible through the microscope for close to 200 years. Changes in nuclear size characteristically occur in many cancer types when the cells metastasize. This was initially discarded as contributing to the metastatic spread because, depending on tumor types, both increases and decreases in nuclear size could correlate with increased metastasis. However, recent work on nuclear mechanics and the connectivity between chromatin, the nucleoskeleton, and the cytoskeleton indicate that changes in this connectivity can have profound impacts on cell mobility and invasiveness. Critically, a recent study found that reversing tumor type-dependent nuclear size changes correlated with reduced cell migration and invasion. Accordingly, it seems appropriate to now revisit possible contributory roles of nuclear size changes to metastasis

Optimal receptor-cluster size determined by intrinsic and extrinsic noise

Biological cells sense external chemical stimuli in their environment using cell-surface receptors. To increase the sensitivity of sensing, receptors often cluster, most noticeably in bacterial chemotaxis, a paradigm for signaling and sensing in general. While amplification of weak stimuli is useful in absence of noise, its usefulness is less clear in presence of extrinsic input noise and intrinsic signaling noise. Here, exemplified on bacterial chemotaxis, we combine the allosteric Monod-Wyman- Changeux model for signal amplification by receptor complexes with calculations of noise to study their interconnectedness. Importantly, we calculate the signal-to-noise ratio, describing the balance of beneficial and detrimental effects of clustering for the cell. Interestingly, we find that there is no advantage for the cell to build receptor complexes for noisy input stimuli in absence of intrinsic signaling noise. However, with intrinsic noise, an optimal complex size arises in line with estimates of the sizes of chemoreceptor complexes in bacteria and protein aggregates in lipid rafts of eukaryotic cells.Comment: 15 pages, 12 figures,accepted for publication on Physical Review

Quiescent Saccharomyces cerevisiae forms telomere hyperclusters at the nuclear membrane vicinity through a multifaceted mechanism involving Esc1, the Sir complex, and chromatin condensation

Like other eukaryotes, Saccharomyces cerevisiae spatially organizes its chromosomes within the nucleus. In G(1) phase, the yeast’s 32 telomeres are clustered into 6–10 foci that dynamically interact with the nuclear membrane. Here we show that, when cells leave the division cycle and enter quiescence, telomeres gather into two to three hyperclusters at the nuclear membrane vicinity. This localization depends on Esc1 but not on the Ku proteins. Telomere hypercluster formation requires the Sir complex but is independent of the nuclear microtubule bundle that specifically assembles in quiescent cells. Importantly, mutants deleted for the linker histone H1 Hho1 or defective in condensin activity or affected for histone H4 Lys-16 deacetylation are impaired, at least in part, for telomere hypercluster formation in quiescence, suggesting that this process involves chromosome condensation. Finally, we establish that telomere hypercluster formation is not necessary for quiescence establishment, maintenance, and exit, raising the question of the physiological raison d’être of this nuclear reorganization

Reduction in Nuclear Size by DHRS7 in Prostate Cancer Cells and by Estradiol Propionate in DHRS7-Depleted Cells

Increased nuclear size correlates with lower survival rates and higher grades for prostate cancer. The short-chain dehydrogenase/reductase (SDR) family member DHRS7 was suggested as a biomarker for use in prostate cancer grading because it is largely lost in higher-grade tumors. Here, we found that reduction in DHRS7 from the LNCaP prostate cancer cell line with normally high levels of DHRS7 increases nuclear size, potentially explaining the nuclear size increase observed in higher-grade prostate tumors where it is lost. An exogenous expression of DHRS7 in the PC3 prostate cancer cell line with normally low DHRS7 levels correspondingly decreases nuclear size. We separately tested 80 compounds from the Microsource Spectrum library for their ability to restore normal smaller nuclear size to PC3 cells, finding that estradiol propionate had the same effect as the re-expression of DHRS7 in PC3 cells. However, the drug had no effect on LNCaP cells or PC3 cells re-expressing DHRS7. We speculate that separately reported beneficial effects of estrogens in androgen-independent prostate cancer may only occur with the loss of DHRS7/ increased nuclear size, and thus propose DHRS7 levels and nuclear size as potential biomarkers for the likely effectiveness of estrogen-based treatments

Chemical interrogation of nuclear size identifies compounds with cancer cell line specific effects on migration and invasion

[Image: see text] Background: Lower survival rates for many cancer types correlate with changes in nuclear size/scaling in a tumor-type/tissue-specific manner. Hypothesizing that such changes might confer an advantage to tumor cells, we aimed at the identification of commercially available compounds to guide further mechanistic studies. We therefore screened for Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved compounds that reverse the direction of characteristic tumor nuclear size changes in PC3, HCT116, and H1299 cell lines reflecting, respectively, prostate adenocarcinoma, colonic adenocarcinoma, and small-cell squamous lung cancer. Results: We found distinct, largely nonoverlapping sets of compounds that rectify nuclear size changes for each tumor cell line. Several classes of compounds including, e.g., serotonin uptake inhibitors, cyclo-oxygenase inhibitors, β-adrenergic receptor agonists, and Na(+)/K(+) ATPase inhibitors, displayed coherent nuclear size phenotypes focused on a particular cell line or across cell lines and treatment conditions. Several compounds from classes far afield from current chemotherapy regimens were also identified. Seven nuclear size-rectifying compounds selected for further investigation all inhibited cell migration and/or invasion. Conclusions: Our study provides (a) proof of concept that nuclear size might be a valuable target to reduce cell migration/invasion in cancer treatment and (b) the most thorough collection of tool compounds to date reversing nuclear size changes specific to individual cancer-type cell lines. Although these compounds still need to be tested in primary cancer cells, the cell line-specific nuclear size and migration/invasion responses to particular drug classes suggest that cancer type-specific nuclear size rectifiers may help reduce metastatic spread