Hfsp Journal最新文献

Many eukaryotic cells use pseudopodia for movement towards chemoattractants. We developed a computer algorithm to identify pseudopodia, and analyzed how pseudopodia of Dictyostelium cells are guided toward cAMP. Surprisingly, the direction of a pseudopod is not actively oriented toward the gradient, but is always perpendicular to the local cell curvature. The gradient induces a bias in the position where the pseudopod emerges: pseudopodia more likely emerge at the side of the cell closer to the gradient where perpendicular pseudopodia are pointed automatically toward the chemoattractant. A mutant lacking the formin dDia2 is not spherical but has many invaginations. Although pseudopodia still emerge at the side closer to the gradient, the surface curvature is so irregular that many pseudopodia are not extended toward cAMP. The results imply that the direction of the pseudopod extension, and therefore also the direction of cell movement, is dominated by two aspects: the position at the cell surface where a pseudopod emerges, and the local curvature of the membrane at that position.

Binding of small molecules to their targets triggers complex pathways. Computational approaches are keys for predictions of the molecular events involved in such cascades. Here we review current efforts at characterizing the molecular determinants in the largest membrane-bound receptor family, the G-protein-coupled receptors (GPCRs). We focus on odorant receptors, which constitute more than half GPCRs. The work presented in this review uncovers structural and energetic aspects of components of the cellular cascade. Finally, a computational approach in the context of radioactive boron-based antitumoral therapies is briefly described.

We propose a mechanism for tumor growth emphasizing the role of homeostatic regulation and tissue stability. We show that competition between surface and bulk effects leads to the existence of a critical size that must be overcome by metastases to reach macroscopic sizes. This property can qualitatively explain the observed size distributions of metastases, while size-independent growth rates cannot account for clinical and experimental data. In addition, it potentially explains the observed preferential growth of metastases on tissue surfaces and membranes such as the pleural and peritoneal layers, suggests a mechanism underlying the seed and soil hypothesis introduced by Stephen Paget in 1889, and yields realistic values for metastatic inefficiency. We propose a number of key experiments to test these concepts. The homeostatic pressure as introduced in this work could constitute a quantitative, experimentally accessible measure for the metastatic potential of early malignant growths.

The ability of an animal to locomote through its environment depends crucially on the interplay between its active endogenous control and the physics of its interactions with the environment. The nematode worm Caenorhabditis elegans serves as an ideal model system for studying the respective roles of neural control and biomechanics, as well as the interaction between them. With only 302 neurons in a hard-wired neural circuit, the worm's apparent anatomical simplicity belies its behavioural complexity. Indeed, C. elegans exhibits a rich repertoire of complex behaviors, the majority of which are mediated by its adaptive undulatory locomotion. The conventional wisdom is that two kinematically distinct C. elegans locomotion behaviors-swimming in liquids and crawling on dense gel-like media-correspond to distinct locomotory gaits. Here we analyze the worm's motion through a series of different media and reveal a smooth transition from swimming to crawling, marked by a linear relationship between key locomotion metrics. These results point to a single locomotory gait, governed by the same underlying control mechanism. We further show that environmental forces play only a small role in determining the shape of the worm, placing conditions on the minimal pattern of internal forces driving locomotion.

Approximately 1% of the open reading frames in the human genome encode proteins that function as DNA or RNA helicases. These enzymes act in all aspects of nucleic acid metabolism where the complementary strands of DNA:DNA or DNA:RNA duplexes require to be transiently opened. However, they perform wider roles in nucleic acid metabolism due to their ability to couple the energy derived from hydrolysis of ATP to their unidirectional translocation along strands of DNARNA. In this way, helicases can displace proteins from DNARNA, drive the migration of DNA junctions (such as the Holliday junction recombination intermediate), or generate superhelical tension in nucleic acid duplexes. Here, we review a subgroup of DNA helicase enzymes, the RecQ family, that has attracted considerable interest in recent years due to their role not only in suppression of genome instability, but also in the avoidance of human disease. We focus particularly on the protein structural motifs and the multiple assembly states that characterize RecQ helicases and discuss novel biophysical techniques to study the different RecQ structures present in solution. We also speculate on the roles of the different domains and oligomeric forms in defining which DNA structures will represent substrates for RecQ helicase-mediated transactions.

Lamellipodia are broad actin-based structures that define the protruding edge of many motile animal cells. Here we identify a Drosophila homolog of the p21-activated kinases (Paks) as a novel inhibitor of Rac-mediated lamellipodial formation: Pak3 overexpression mimics a loss of Rac activity, while Pak3 RNAi-mediated silencing enhances lamellipodial dynamics. Strikingly, the depletion of Pak3 also polarizes the cellular distribution of actin filaments, is sufficient to induce nonmotile cells to migrate, and, in cells firmly attached to the substrate, gives rise to a wave of high actin filament density that encircles the cell periphery at a steady pace. To better understand these systems level phenomena, we developed a model of the cortical actin network as an active gel whose behavior is dominated by the rate of actin filament bundling and polymer synthesis. In the presence of filament treadmilling, this system generates a propagating density wave of actin filaments like that seen in Pak3 RNAi cells. This analysis reveals an intimate relationship between local regulation of actin filament dynamics and global cytoskeletal polarity, and suggests a role for negative regulators of lamellipodial formation, like Pak3, in the maintenance of a poised state, in which regulated directional cell movement can occur.

Copper ions are essential for living organisms because they are involved in several fundamental biological processes. Biomolecules interacting with copper ions have to be characterized as such, when bound to the metal ion, and when they interact with other biomolecules or substrates. The characterization is both structural and dynamic. In this context, NMR is a preferred tool of investigation because it allows shedding light on what happens in solution. Here, the NMR contribution to the copper trafficking is described, providing precious information on biochemical pathways, which are essential to understand the mechanisms of life at the molecular level.

Sensory maps in the nervous system often connect to each other in a topographic fashion. This is most strikingly seen in the visual system, where neighboring neurons in the retina project to neighboring neurons in the target structure, such as the superior colliculus. This article discusses the developmental mechanisms that are involved in the formation of topographic maps, with an emphasis on the role of theoretical models in helping us to understand these mechanisms. Recent experimental advances in studying the roles of guidance molecules and patterns of spontaneous activity mean that there are new challenges to be addressed by theoretical models. Key questions include understanding what instructional cues are present in the patterns of spontaneous activity, and how activity and guidance molecules might interact. Our discussion concludes by comparing development of visual maps with development of maps in the olfactory system, where the influence of neural activity seems to differ.

Biomolecular motors have inspired the design and construction of artificial nanoscale motors and machines based on nucleic acids, small molecules, and inorganic nanostructures. However, the high degree of sophistication and efficiency of biomolecular motors, as well as their specific biological function, derives from the complexity afforded by protein building blocks. Here, we discuss a novel bottom-up approach to understanding biological motors by considering the construction of synthetic protein motors. Specifically, we present a design for a synthetic protein motor that moves along a linear track, dubbed the "Tumbleweed." This concept uses three discrete ligand-dependent DNA-binding domains to perform cyclically ligand-gated, rectified diffusion along a synthesized DNA molecule. Here we describe how de novo peptide design and molecular biology could be used to produce the Tumbleweed, and we explore the fundamental motor operation of such a design using numerical simulations. The construction of this and more sophisticated protein motors is an exciting challenge that is likely to enhance our understanding of the structure-function relationship in biological motors.

Apparent tissue surface tension allows the quantification of cell-cell cohesion and was reported to be a powerful indicator for the cellular rearrangements that take place during embryonic development or for cancer progression. The measurement is realized with a parallel compression plate tensiometer using the capillary laws. Although it was introduced more than a decade ago, it is based on various geometrical or physical approximations. Surprisingly, these approximations have never been tested. Using a novel tensiometer, we compare the two currently used methods to measure tissue surface tension and propose a third one, based on a local polynomial fit (LPF) of the profile of compressed droplets or cell aggregates. We show the importance of measuring the contact angle between the plate and the dropaggregate to obtain real accurate measurement of surface tension when applying existing methods. We can suspect that many reported values of surface tension are greatly affected because of not handling this parameter properly. We show then the benefit of using the newly introduced LPF method, which is not dependent on this parameter. These findings are confirmed by generating numerically compressed droplet profiles and testing the robustness and the sensitivity to errors of the different methods.