No Arabic abstract
Motile biological cells in tissue often display the phenomenon of durotaxis, i.e. they tend to move towards stiffer parts of substrate tissue. The mechanism for this behavior is not completely understood. We consider simplified models for durotaxis based on the classic persistent random walker scheme. We show that even a one-dimensional model of this type sheds interesting light on the classes of behavior cells might exhibit. Our results strongly indicate that cells must be able to sense the gradient of stiffness in order to show the effects observed in experiment. This is in contrast to the claims in recent publications that it is sufficient for cells to be more persistent in their motion on stiff substrates to show durotaxis: i.e., if would be enough to sense the value of the stiffness. We show that these cases give rise to extremely inefficient transport towards stiff regions. Gradient sensing is almost certainly the selected behavior.
The alarming growth of the antibiotic-resistant superbugs methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) is driving the development of new technologies to investigate antibiotics and their modes of action. We report the label-free detection of vancomycin binding to bacterial cell wall precursor analogues (mucopeptides) on cantilever arrays, with 10 nM sensitivity and at clinically relevant concentrations in blood serum. Differential measurements quantified binding constants for vancomycin-sensitive and vancomycin-resistant mucopeptide analogues. Moreover, by systematically modifying the mucopeptide density we gain new insights into the origin of surface stress. We propose that stress is a product of a local chemical binding factor and a geometrical factor describing the mechanical connectivity of regions affected by local binding in terms of a percolation process. Our findings place BioMEMS devices in a new class of percolative systems. The percolation concept will underpin the design of devices and coatings to significantly lower the drug detection limit and may also impact on our understanding of antibiotic drug action in bacteria.
The deep connection between thermodynamics, computation, and information is now well established both theoretically and experimentally. Here, we extend these ideas to show that thermodynamics also places fundamental constraints on statistical estimation and learning. To do so, we investigate the constraints placed by (nonequilibrium) thermodynamics on the ability of biochemical signaling networks within cells to estimate the concentration of an external signal. We show that accuracy is limited by energy consumption, suggesting that there are fundamental thermodynamic constraints on statistical inference.
Drosophila melanogaster hemocytes are highly motile cells that are crucial for successful embryogenesis and have important roles in the organisms immunological response. Hemocyte motion was measured using selective plane illumination microscopy. Every hemocyte cell in one half of an embryo was tracked during embryogenesis and analysed using a deep learning neural network. The anomalous transport of the cells was well described by fractional Brownian motion that was heterogeneous in both time and space. Hemocyte motion became less persistent over time. LanB1 and SCAR mutants disrupted the collective cellular motion and reduced its persistence due to the modification of viscoelasticity and actin-based motility respectively. The anomalous motility of the hemocytes oscillated in time with alternating epoques of varying persistent motion. Touching hemocytes experience synchronised contact inhibition of locomotion; an anomalous tango. A quantitative statistical framework is presented for hemocyte motility which provides new biological insights.
Epithelial cell clusters often move collectively on a substrate. Mechanical signals play a major role in organizing this behavior. There are a number of experimental observations in these systems which await a comprehensive explanation. These include: the internal strains are tensile even for clusters that expand by proliferation; the tractions on the substrate are often confined to the edges of the cluster; there can exist density waves within the cluster; clusters can exhibit collective durotaxis when individual cells show no effect; and for cells in an annulus there is a transition between expanding clusters with proliferation and the case where cells fill the annulus and rotate around it. We formulate a mechanical model to examine these effects. We use a molecular clutch picture which allows stalling -- inhibition of cell contraction by external forces. Stalled cells are passive from a physical point of view and the un-stalled cells are active. By attaching cells to the substrate and to each other, and taking into account contact inhibition of locomotion, we get a simple picture for many of these findings as well as predictions that could be tested. SI text/figures included, SI movies at https://rice.box.com/s/xiy3mwsfj3203lfu7pk0udfklexcgsew
Multifunctional mesoporous silica nanoparticles (MSN) have attracted substantial attention with regard to their high potential for targeted drug delivery. For future clinical applications it is crucial to address safety concerns and understand the potential immunotoxicity of these nanoparticles. In this study, we assess the biocompatibility and functionality of multifunctional MSN in freshly isolated, primary murine immune cells. We show that the functionalized silica nanoparticles are rapidly and efficiently taken up into the endosomal compartment by specialized antigen-presenting cells such as dendritic cells. The silica nanoparticles showed a favorable toxicity profile and did not affect the viability of primary immune cells from the spleen in relevant concentrations. Cargo-free MSN induced only very low immune responses in primary cells as determined by surface expression of activation markers and release of pro-inflammatory cytokines such as Interleukin-6, -12 and -1beta. In contrast, when surface-functionalized MSN with a pH-responsive polymer capping were loaded with an immune-activating drug, the synthetic Toll-like receptor 7 agonist R848, a strong immune response was provoked. We thus demonstrate that MSN represent an efficient drug delivery vehicle to primary immune cells that is both non-toxic and non-inflammagenic, which is a prerequisite for the use of these particles in biomedical applications.