With every beat of the heart, inflation of the lung or peristalsis of the gut, cell types of diverse function are subjected to substantial stretch. Stretch is a potent stimulus for growth, differentiation, migration, remodelling and gene expression 1,2 . Here, we report that in response to transient stretch the cytoskeleton fluidizes in such a way as to define a universal response class. This finding implicates mechanisms mediated not only by specific signalling intermediates, as is usually assumed, but also by non-specific actions of a slowly evolving network of physical forces. These results support the idea that the cell interior is at once a crowded chemical space 3 and a fragile soft material in which the effects of biochemistry, molecular crowding and physical forces are complex and inseparable, yet conspire nonetheless to yield remarkably simple phenomenological laws. These laws seem to be both universal and primitive, and thus comprise a striking intersection between the worlds of cell biology and soft matter physics.Soft materials such as tomato ketchup, shaving foam and tooth-paste tend to fluidize when subjected to shear 4-7 , as do granular materials including sugar in a bowl, coffee beans in a chute 8 and even certain geophysical strata during an earthquake 9 ; each transforms from a solidlike to a fluid-like phase, stiffness falls, and the material flows. Underlying microscopic stressbearing elements, or clusters of elements, interact with neighbours to form a network of force transmission, but how flow is initiated and the nature of energy barriers that must be overcome remain the subject of much current attention 5-9 .The response of a living cell to transient stretch would seem to be a different matter altogether. Very early literature shows that in response to application of a physical force the cell acutely softens (Supplementary Note 4), but more recent literature uniformly emphasizes stiffening Author Information Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to J.J.F. (jeffrey_fredberg@harvard.edu). Author Contributions X.T. and J.J.F. designed research and wrote the manuscript. J.P.B. conducted the theoretical analysis. X.T. and D.N. designed and implemented the experimental system. X.T., L.D. and S.S.A. optimized experimental conditions and treatments. W.T.G. and D.J.T. helped to design experimental protocols and interpret data. D.J.T. provided cells and reagents. X.T. performed all stretch experiments and data analysis. J.J.F. oversaw the project. Shear fluidization of inert matter is usually attributed to the presence of physical interactions that possess energy barriers that are so large that thermal energies by themselves are insufficient to drive microconfigurations to thermodynamic equilibrium. The material is then unable to explore its configuration space 5 , and structural rearrangements become limited by long-lived microconfigu...

Material moduli of the cytoskeleton (CSK) influence a wide range of cell functions. There is substantial evidence from reconstituted F-actin gels that a regime exists in which the moduli scale with frequency with a universal exponent of 3/4. Such behaviour is entropic in origin and is attributable to fluctuations in semiflexible polymers driven by thermal forces, but it is not obvious a priori that such entropic effects are responsible for the elasticity of the CSK. Here we demonstrate the existence of such a regime in the living cell, but only at high frequencies. Fast events scaled with frequency in a manner comparable to semiflexible-polymer dynamics, but slow events scaled with a non-universal exponent that was systematically smaller than 3/4 and probably more consistent with a soft-glass regime. These findings strongly suggest that at smaller timescales elasticity arises from entropic fluctuations of a semiflexible-filament network, whereas on longer timescales slow (soft-glass-like) dynamics of a different origin prevail. The transition between these two regimes occurred on timescales of the order of 0.01 s, thus setting within the slow glassy regime cellular events such as spreading, crawling, contracting, and invading.

Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma.As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling.Anti-inflammatory therapy, however, does not ''cure'' asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM.In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

Inflammatory bowel disease (IBD) is a high-risk con-

The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.

Introduction:The clinicopathologic features and prognostic predictors of radiological part-solid lung adenocarcinomas were unclear. Methods:We retrospectively compared the clinicopathologic features and survival times of part-solid tumors with those of pure ground glass nodules (pGGNs) and pure solid tumors treated with surgery at Fudan University Shanghai Cancer Center and evaluated the prognostic implications of consolidation-to-tumor ratio (CTR), solid component size, and tumor size for part-solid lung adenocarcinomas.Conclusions: Part-solid lung adenocarcinoma showed clinicopathologic features different from those of pure solid tumor. CTR, solid component size, and tumor size could not predict the prognosis. Part-solid lung adenocarcinomas define one special clinical subtype.

Interleukin-6 (IL-6) is a growth and survival factor in human glioblastoma cells and plays an important role in malignant progression. However, its role in glioblastoma invasion is still unknown. This study shows how IL-6 promotes cell invasion and migration in U251 and T98G glioblastoma cell lines. The underlying mechanism includes both protease-dependent and -independent manners. Stimulation with IL-6 increased MMP9 expression in the two cell lines but had no influence on MMP2 expression. Fascin-1 is a cell skeleton binding protein and plays a key role in cell migration and invasion. Its binding style directly influences cell morphology and tendency to become deformed. After IL-6 exposure, fascin-1 expression increased in an IL-6 dose-dependent manner. Immunofluorescence also revealed that the binding style of fascin-1 had changed after IL-6 exposure, resulting in a more invasive phenotype of the cells. Three most commonly emphasized invasion-associated signaling pathways, including JAK-STAT3, p42/44 MAPK, and PI3K/AKT, were verified to further illustrate its underlying mechanism. Only phosphorylation of STAT3 at ser 727 site paralleled the IL-6 stimulation, and JSI-124, a specific JAK-STAT3 pathway blocker, deterred the invasion and migration promotive effect of IL-6, indicating that the JAK/STAT3 pathway mediates signal transduction. Furthermore, IL-6 also acts in a paracrine fashion to promote vascular endothelial cell migration, thus facilitating tumor angiogenesis and invasion. These results suggest that IL-6 promotes glioblastoma cell invasion and angiogenesis and may be a potential anti-invasion target.

We tested the hypothesis that cytoskeletal reorganization induced by cyclic strain increases cytoskeletal stiffness (G′). G′ was measured by optical magnetic twisting cytometry in control cells and cells that had received mechanical strain for 10–12 days. G′ was measured before and after both contractile and relaxant agonists, and in the strained cells both parallel (Para) and perpendicular (Perp) to the aligned cytoskeleton. Before activation, G′ Para was 24 ± 5% (± SE) greater compared with Perp ( P < 0.05), and 35% ± 6 greater compared with control (Cont, P < 0.01). The difference between strained and control cells was enhanced by KCl, increasing G′ 171 ± 7% Para compared with 125 ± 6% Perp and 129 ± 8% Cont ( P < 10-5 both cases). The decrease in G′ from baseline due to relaxant agonists isoproterenol and dibutyryl cAMP was similar in all groups. Long-term oscillatory loading of airway smooth muscle (ASM) cells caused stiffness to increase and become anisotropic. These findings are consistent with the hypothesis that cytoskeletal reorganization can enhance ASM stiffness and contractility. They imply, furthermore, that oscillatory loading of ASM may contribute to airway narrowing and failure of airway dilation in asthma.