Metamaterials are artificial substances that are structurally engineered to have properties not typically found in nature. To date, almost all metamaterials have been made from inorganic materials such as silicon and copper, which have unusual electromagnetic or acoustic properties that allow them to be used, for example, as invisible cloaks, superlenses or super absorbers for sound. Here, we show that metamaterials with unusual mechanical properties can be prepared using DNA as a building block. We used a polymerase enzyme to elongate DNA chains and weave them non-covalently into a hydrogel. The resulting material, which we term a meta-hydrogel, has liquid-like properties when taken out of water and solid-like properties when in water. Moreover, upon the addition of water, and after complete deformation, the hydrogel can be made to return to its original shape. The meta-hydrogel has a hierarchical internal structure and, as an example of its potential applications, we use it to create an electric circuit that uses water as a switch.

In primary mammalian cells, oncogenic ras induces premature senescence, depending on an active MEKextracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. It has been unclear how activation of the mitogenic MEK-ERK pathway by ras can confer growth inhibition. In this study, we have found that the stress-activated MAPK, p38, is also activated during the onset of ras-induced senescence in primary human fibroblasts. Constitutive activation of p38 by active MKK3 or MKK6 induces senescence. Oncogenic ras fails to provoke senescence when p38 activity is inhibited, suggesting that p38 activation is essential for ras-induced senescence. Furthermore, we have demonstrated that p38 activity is stimulated by ras as a result of an activated MEK-ERK pathway. Following activation of MEK and ERK, expression of oncogenic ras leads to the accumulation of active MKK3/6 and p38 activation in a MEK-dependent fashion and subsequently induces senescence. Active MEK1 induces the same set of changes and provokes senescence relying on active p38. Therefore, oncogenic ras provokes premature senescence by sequentially activating the MEK-ERK and MKK3/6-p38 pathways in normal, primary cells. These studies have defined the molecular events within the ras signaling cascade that lead to premature senescence and, thus, have provided new insights into how ras confers oncogenic transformation in primary cells.

Like apoptosis, oncogene-induced senescence is a barrier to tumor development. However, relatively little is known about the signaling pathways mediating the senescence response. p38-regulated/activated protein kinase (PRAK) is a p38 MAPK substrate whose physiological functions are poorly understood. Here we describe a role for PRAK in tumor suppression by demonstrating that PRAK mediates senescence upon activation by p38 in response to oncogenic ras. PRAK deficiency in mice enhances DMBA-induced skin carcinogenesis, coinciding with compromised senescence induction. In primary cells, inactivation of PRAK prevents senescence and promotes oncogenic transformation. Furthermore, we show that PRAK activates p53 by direct phosphorylation. We propose that phosphorylation of p53 by PRAK following activation of p38 MAPK by ras plays an important role in ras-induced senescence and tumor suppression.

DNA replication initiation is tightly controlled so that each origin only fires once per cell cycle. Cell cycle-dependent Cdt1 degradation plays an essential role in DNA replication control, as overexpression of Cdt1 leads to re-replication. In this study, we investigated the mechanisms of Cdt1 degradation in mammalian cells. We showed that the F-box protein Skp2 specifically interacted with human Cdt1 in a phosphorylation-dependent manner. The SCF Skp2 complex ubiquitinated Cdt1 both in vivo and in vitro. Down-regulation of Skp2 or disruption of the interaction between Cdt1 and Skp2 resulted in a stabilization and accumulation of Cdt1. These results suggest that the SCF Skp2 -mediated ubiquitination pathway may play an important role in the cell cycle-dependent Cdt1 degradation in mammalian cells.In all eukaryotic cells, DNA replication is tightly controlled to ensure that initiation of replication occurs only once per cell cycle (1-3). The key to this regulation is the formation of prereplication complexes (pre-RCs) 1 by loading MCM proteins to replication origins (4, 5). Studies from yeast and Xenopus showed that Cdc6 (termed as Cdc18 in Schizosaccharomyces pombe) and Cdt1 are required for MCM proteins to associate with chromatin (6 -14). In fission yeast, the protein levels of both Cdc18 and Cdt1 are tightly controlled during the cell cycle and Cdc18 and Cdt1 only appear in G 1 , which is important to prevent re-formation of pre-RCs after DNA is replicated in S phase (15)(16)(17)(18). Cdc18 is targeted for ubiquitination-mediated degradation when cells enter S phase of the cell cycle (17).In mammalian cells, Cdc6 protein levels remain almost constant throughout G 1 , S, and G 2 phases (19 -24). After the onset of S phase, Cdc6 is phosphorylated and exported to the cytoplasm (20,23,25,26). In contrast to Cdc6, the protein level of Cdt1 fluctuates during the cell cycle (27). It accumulates in early G 1 phase of the cell cycle when replication is licensed and disappears at the onset of S phase. The correlation of Cdt1 accumulation and assembly of pre-RCs in early G 1 phase suggests that Cdt1 may play an important role in the control of replication licensing in mammalian cells. This idea is further supported by the observation that overexpression of Cdt1 promotes DNA re-replication in p53 deficient cells (28).It has been shown that in mammalian cells, while Cdt1 protein level varies during the cell cycle, the mRNA level of Cdt1 remains relatively constant at different cell cycle stages (27). In the presence of proteasome inhibitors, Cdt1 accumulates in S phase when it is normally absent. This suggests that proteasome-dependent degradation may regulate the Cdt1 level during the cell cycle in mammalian cells. However, the detailed mechanisms of Cdt1 degradation remain unknown.The ubiquitin-dependent proteolytic pathway plays an important role for protein degradation (29). The conjugation of polyubiquitin chains to substrates requires enzymes, E1 (a ubiquitin-activating enzyme), E2 (a ubiquitin-conjugating enzyme...

Recent experiments have shown that hydrogels with enhanced toughness can be synthesized by incorporating self-healing physical cross-links in a chemically cross-linked gel network. These gels exhibit rate dependent mechanical behavior, suggesting that improved mechanical properties are closely tied to the breaking and reattaching of temporary crosslinks in the gel network. In this work, the connection between rate dependent mechanical behavior and kinetics of breaking and reattachment of temporary cross-links is quantified using a three-dimensional finite strain constitutive model. The parameters of the model are fitted using relaxation and constant strain rate tests in uniaxial tension of a model dualcross-link gel. The stress versus time curves of more complex strain histories, involving loading followed by unloading at different rates, is successfully and quantitatively predicted by our model. Such modeling strategy combining physically based kinetics and three-dimensional large strain mechanics shows great promise for quantitative modeling of soft biological tissues and synthetic counterparts containing dynamic bonds.