Hfsp Journal最新文献

beta-catenin acts as a critical regulator of gastrointestinal homeostasis through its control of the Wnt signaling pathway, and genetic or epigenetic lesions which activate Wnt signaling are the primary feature of colon cancer. beta-catenin is also a key element of mechanotranscription pathways, leading to upregulation of master developmental gene expression during Drosophila gastrulation, or regulating mammalian bone development and maintenance. Here we investigate the impact of mechanical stimulation on the initiation of colon cancer. Myc and Twist1, two oncogenes regulated through beta-catenin, are expressed in response to transient compression in APC deficient (APC(1638N+)) colon tissue explants, but not in wild-type colon explants. Mechanical stimulation of APC(1638N+) tissue leads to the phosphorylation of beta-catenin at tyrosine 654, the site of interaction with E-cadherin, as well as to increased nuclear localization of beta-catenin. The mechanical activation of Myc and Twist1 expression in APC(1638N+) colon can be prevented by blocking beta-catenin phosphorylation using Src kinase inhibitors. Microenvironmental signals are known to cooperate with genetic lesions to promote the nuclear beta-catenin accumulation which drives colon cancer. Here we demonstrate that when APC is limiting, mechanical strain, such as that associated with intestinal transit or tumor growth, can be interpreted by cells of preneoplastic colon tissue as a signal to initiate a beta-catenin dependent transcriptional program characteristic of cancer.

One of the central problems in the cell is how to transport molecules around the cell to desired locations. Since low Reynolds number conditions apply and diffusional times are large, without the aid of molecular motors to transport the fluid quickly cells could not survive, yet diffusion is still essential for the ultimate delivery of the goods. This paradox of low Reynolds numberlarge Peclet number has been solved by the algal weed Chara corallina in ingenious ways, as the recent paper by Goldstein, et al. [Proc. Natl. Acad. Sci. 105, 3663-3667 (2008)] discusses at a deep but accessible way using modern hydrodynamic modeling.

Proteins are the true workhorses of any cell. To carry out specific tasks, they frequently bind other molecules in their surroundings. Due to their structural complexity and flexibility, the most diverse array of interactions is seen with other proteins. The different geometries and affinities available for such interactions typically bestow specific functions on proteins. Having available a map of protein-protein interactions is therefore of enormous importance for any researcher interested in gaining insight into biological systems at the level of cells and organisms. In a recent report, a novel approach has been employed that relies on the spontaneous folding of complementary enzyme fragments fused to two different proteins to test whether these interact in their actual cellular context [Tarassov et al., Science 320, 1465-1470 (2008)]. Genome-wide application of this protein-fragment complementation assay has resulted in the first map of the in vivo interactome of Saccharomyces cerevisiae. The current data show striking similarities but also significant differences to those obtained using other large-scale approaches for the same task. This warrants a general discussion of the current state of affairs of protein-protein interaction studies and foreseeable future trends, highlighting their significance for a variety of applications and their potential to revolutionize our understanding of the architecture and dynamics of biological systems.

Signal transduction pathways are complex coupled sets of biochemical reactions evolved to transmit and process information about the state of the immediate cell environment. Can we design experiments that would inform us about the properties and limitations of signal processing? Recent studies suggest that this indeed can be achieved by exciting a cell with carefully designed oscillatory stimuli. Although this analysis has its caveats, complex temporal stimulation of signal transduction networks can serve to rapidly advance our understanding of these information channels and ultimately create intelligent ways of controlling them.

During adhesion and spreading, cells form micrometer-sized structures comprising transmembrane and intracellular protein clusters, giving rise to the formation of what is known as focal adhesions. Over the past two decades these structures have been extensively studied to elucidate their organization, assembly, and molecular composition, as well as to determine their functional role. Synthetic materials decorated with biological molecules, such as adhesive peptides, are widely used to induce specific cellular responses dependent on cell adhesion. Here, we focus on how surface patterning of such bioactive materials and organization at the nanoscale level has proven to be a useful strategy for mimicking both physical and chemical cues present in the extracellular space controlling cell adhesion and fate. This strategy for designing synthetic cellular environments makes use of the observation that most cell signaling events are initiated through recruitment and clustering of transmembrane receptors by extracellular-presented signaling molecules. These systems allow for studying protein clustering in cells and characterizing the signaling response induced by, e.g., integrin activation. We review the findings about the regulation of cell adhesion and focal adhesion assembly by micro- and nanopatterns and discuss the possible use of substrate stiffness and patterning in mimicking both physical and chemical cues of the extracellular space.

Light-sheet-based fluorescence microscopy (LSFM) is a fluorescence technique that combines optical sectioning, the key capability of confocal and two-photon fluorescence microscopes with multiple-view imaging, which is used in optical tomography. In contrast to conventional wide-field and confocal fluorescence microscopes, a light sheet illuminates only the focal plane of the detection objective lens from the side. Excitation is, thus, restricted to the fluorophores in the volume near the focal plane. This provides optical sectioning and allows the use of regular cameras in the detection process. Compared to confocal fluorescence microscopy, LSFM reduces photo bleaching and photo toxicity by up to three orders of magnitude. In LSFM, the specimen is embedded in a transparent block of hydrogel and positioned relative to the stationary light sheet using precise motorized translation and rotation stages. This feature is used to image any plane in a specimen. Additionally, multiple views obtained along different angles can be combined into a single data set with an improved resolution. LSFMs are very well suited for imaging large live specimens over long periods of time. However, they also perform well with very small specimens such as single yeast cells. This perspective introduces the principles of LSFM, explains the challenges of specimen preparation, and introduces the basics of a microscopy that takes advantage of multiple views.

The computing power unleashed by biomolecule based massively parallel computational units has been the focus of many interdisciplinary studies that couple state of the art ideas from mathematical logic, theoretical computer science, bioengineering, and nanotechnology to fulfill some computational task. The output can influence, for instance, release of a drug at a specific target, gene expression, cell population, or be a purely mathematical entity. Analysis of the results of several studies has led to the emergence of a general set of rules concerning the implementation and optimization of in vivo computational units. Taking two recent studies on in vivo computing as examples, we discuss the impact of mathematical modeling and simulation in the field of synthetic biology and on in vivo computing. The impact of the emergence of gene regulatory networks and the potential of proteins acting as "circuit wires" on the problem of interconnecting molecular computing device subunits is also highlighted.

In this Commentary, we discuss the paper Quantitative Determination of Size and Shape of Surface-Bound DNA Using an Acoustic Wave Sensor [Tsortos et al., Biophys. J. 94(7), 2706-2715 (2008)]. The paper under discussion presents a novel theory that uses the response of a Shear-Horizontal Surface Acoustic Wave device to characterize surface-attached double- and triple-strand DNA. The authors relate the length and curvature of the DNA strands to the interfacial viscosity using classical polymer theory. In this Commentary, we discuss their results in the broader context of acoustic wave detection of biochemical interactions and some of the factors involved when probing "soft" surfaces. Specifically, we present a review of interfacial coupling and slip, and discuss how these phenomena can affect biosensors employing acoustic wave detection techniques.

Short-lived positron-emitting radiotracer techniques provide time-dependent data that are critical for developing models of metabolite transport and resource distribution in plants and their microenvironments. Until recently these techniques were applied to measure radiotracer accumulation in coarse regions along transport pathways. The recent application of positron emission tomography (PET) techniques to plant research allows for detailed quantification of real-time metabolite dynamics on previously unexplored spatial scales. PET provides dynamic information with millimeter-scale resolution on labeled carbon, nitrogen, and water transport over a small plant-size field of view. Because details at the millimeter scale may not be required for all regions of interest, hybrid detection systems that combine high-resolution imaging with other radiotracer counting technologies offer the versatility needed to pursue wide-ranging plant physiological and ecological research. In this perspective we describe a recently developed hybrid detection system at Duke University that provides researchers with the flexibility required to carry out measurements of the dynamic responses of whole plants to environmental change using short-lived radiotracers. Following a brief historical development of radiotracer applications to plant research, the role of radiotracers is presented in the context of various applications at the leaf to the whole-plant level that integrates cellular and subcellular signals andor controls.

Collective phenomena in animal groups have attracted much attention in the last years, becoming one of the hottest topics in ethology. There are various reasons for this. On the one hand, animal grouping provides a paradigmatic example of self-organization, where collective behavior emerges in absence of centralized control. The mechanism of group formation, where local rules for the individuals lead to a coherent global state, is very general and transcends the detailed nature of its components. In this respect, collective animal behavior is a subject of great interdisciplinary interest. On the other hand, there are several important issues related to the biological function of grouping and its evolutionary success. Research in this field boasts a number of theoretical models, but much less empirical results to compare with. For this reason, even if the general mechanisms through which self-organization is achieved are qualitatively well understood, a quantitative test of the models assumptions is still lacking. New analysis on large groups, which require sophisticated technological procedures, can provide the necessary empirical data.