Propulsion in a viscoelastic fluid

Flagella beating in complex fluids are significantly influenced by viscoelastic stresses. Relevant examples include the ciliary transport of respiratory airway mucus and the motion of spermatozoa in the mucus-filled female reproductive tract. We consider the simplest model of such propulsion and transport in a complex fluid, a waving sheet of small amplitude free to move in a polymeric fluid with a single relaxation time. We show that, compared to self-propulsion in a Newtonian fluid occurring at a velocity U_N, the sheet swims (or transports fluid) with velocity U / U_N = [1+De^2 (eta_s)/(eta) ]/[1+De^2], where eta_s is the viscosity of the Newtonian solvent, eta is the zero-shear-rate viscosity of the polymeric fluid, and De is the Deborah number for the wave motion, product of the wave frequency by the fluid relaxation time. Similar expressions are derived for the rate of work of the sheet and the mechanical efficiency of the motion. These results are shown to be independent of the particular nonlinear constitutive equations chosen for the fluid, and are valid for both waves of tangential and normal motion. The generalization to more than one relaxation time is also provided. In stark contrast with the Newtonian case, these calculations suggest that transport and locomotion in a non-Newtonian fluid can be conveniently tuned without having to modify the waving gait of the sheet but instead by passively modulating the material properties of the liquid.Comment: 21 pages, 1 figur

The fate of murine double minute X (MdmX) is dictated by distinct signaling pathways through murine double minute 2 (Mdm2)

Mouse double minute 2 (Mdm2) and MdmX dimerize in response to low levels of genotoxic stress to function in a ubiquitinating complex, which signals for destabilization of p53. Under growth conditions, Mdm2 functions as a neddylating ligase, but the importance and extent of MdmX involvement in this process are largely unknown. Here we show that when Mdm2 functions as a neddylating enzyme, MdmX is stabilized. Furthermore, we demonstrate that under growth conditions, MdmX enhances the neddylation activity of Mdm2 on p53 and is a substrate for neddylation itself. Importantly, MdmX knockdown in MCF-7 breast cancer cells resulted in diminished neddylated p53, suggesting that MdmX is important for Mdm2-mediated neddylation. Supporting this finding, the lack of MdmX in transient assays or in p53/MdmX-/- MEFs results in decreased or altered neddylation of p53 respectively; therefore, MdmX is a critical component of the Mdm2-mediated neddylating complex. c-Src is the upstream activator of this Mdm2-MdmX neddylating pathway and loss of Src signaling leads to the destabilization of MdmX that is dependent on the RING (Really Interesting New Gene) domain of MdmX. Treatment with a small molecule inhibitor of neddylation, MLN4924, results in the activation of Ataxia Telangiectasia Mutated (ATM). ATM phosphorylates Mdm2, converting Mdm2 to a ubiquitinating enzyme which leads to the destabilization of MdmX. These data show how distinct signaling pathways engage neddylating or ubiquitinating activities and impact the Mdm2-MdmX axis

Mutant and wild-type p53 form complexes with p73 upon phosphorylation by the kinase JNK

The transcription factors p53 and p73 are critical to the induction of apoptotic cell death, particularly in response to cell stress that activates c-Jun N-terminal kinase (JNK). Mutations in the DNA-binding domain of p53, which are commonly seen in cancers, result in conformational changes that enable p53 to interact with and inhibit p73, thereby suppressing apoptosis. In contrast, wild-type p53 reportedly does not interact with p73. We found that JNK-mediated phosphorylation of Thr81 in the proline-rich domain (PRD) of p53 enabled wild-type p53, as well as mutant p53, to form a complex with p73. Structural algorithms predicted that phosphorylation of Thr81 exposes the DNA-binding domain in p53 to enable its binding to p73. The dimerization of wild-type p53 with p73 facilitated the expression of apoptotic target genes [such as those encoding p53–up-regulated modulator of apoptosis (PUMA) and Bcl-2-associated X protein (BAX)] and, subsequently, the induction of apoptosis in response to JNK activation by cell stress in various cells. Thus, JNK phosphorylation of mutant and wild-type p53 promotes the formation of a p53/p73 complex that determines cell fate: apoptosis in the context of wild-type p53 or cell survival in the context of the mutant. These findings refine our current understanding of both the mechanistic links between p53 and p73 and the functional role for Thr81 phosphorylation

Report from the PredictER Expert Panel Meeting, November 2, 2007

On November 2, 2007, the Indiana University Center for Bioethics convened an expert panel on predictive health research (PHR) as part of the Center’s Program in Predictive Health Ethics Research (http://www.bioethics.iu.edu/predicter.asp) which is supported by a grant from the Richard M. Fairbanks Foundation. The goal of this meeting was to identify the major obstacles and opportunities for engaging the community in PHR. PredictER intends to use the results of this meeting as a first step toward more fully engaging the Indianapolis community in discussions about PHR.Richard M. Fairbanks Foundatio