SummaryPrevious studies have suggested that breast cancer stem cells (BCSCs) mediate metastasis, are resistant to radiation and chemotherapy, and contribute to relapse. Although several BCSC markers have been described, it is unclear whether these markers identify the same or independent BCSCs. Here, we show that BCSCs exist in distinct mesenchymal-like (epithelial-mesenchymal transition [EMT]) and epithelial-like (mesenchymal-epithelial transition [MET]) states. Mesenchymal-like BCSCs characterized as CD24−CD44+ are primarily quiescent and localized at the tumor invasive front, whereas epithelial-like BCSCs express aldehyde dehydrogenase (ALDH), are proliferative, and are located more centrally. The gene-expression profiles of mesenchymal-like and epithelial-like BCSCs are remarkably similar across different molecular subtypes of breast cancer, and resemble those of distinct basal and luminal stem cells found in the normal breast. We propose that the plasticity of BCSCs that allows them to transition between EMT- and MET-like states endows these cells with the capacity for tissue invasion, dissemination, and growth at metastatic sites.

[1] Aseismic deformation transients can emerge as a natural outcome of the rate and state friction processes revealed in laboratory fault-sliding experiments. When that constitutive formulation is applied to model subduction earthquake sequences, transients can arise spontaneously for certain effective stress (s) variations with depth. We show that if interstitial fluids are present and pore pressure is near-lithostatic around and downdip from the frictional stability transition, transients with recurrence intervals of $1 year are predicted on the basis of laboratory friction parameters and their temperature (hence depth) variations. The recurrence interval decreases with s and reaches 14 months when s is $2-3 MPa. Dimensional analysis and numerical studies show that the fault response primarily depends on a parameter W/h*. Here the high pore pressure zone extends distance W updip from the stability transition, and h* is the stable patch size for steady sliding. Evidence that such fluid conditions may actually be present is independently provided by the occurrence of nonvolcanic tremors as apparent responses to extremely small stress changes and by petrological constraints on expected regions of dehydration for the shallow dipping subduction zones where transients are observed. Transient sequences can also be triggered by a modest, one-time, step-like interseismic stress perturbation on the subduction fault, due to nearby earthquakes, or to pore pressure changes, e.g., during episodes of metamorphic fluid release. Properties of triggered transients and future thrust earthquakes depend on the interseismic time when the perturbation is introduced, its relative location along the subduction fault, and its magnitude.Citation: Liu, Y., and J. R. Rice (2007), Spontaneous and triggered aseismic deformation transients in a subduction fault model,

Summary N 6 -methyladenosine (m 6 A), the most prevalent internal RNA modification on mammalian messenger RNAs (mRNAs), regulates fates and functions of modified transcripts through m 6 A-specific binding proteins 1 – 5 . m 6 A is abundant in the nervous system and modulates various neural functions 6 – 11 . While m 6 A marks groups of mRNAs for coordinated degradation in various physiological processes 12 – 15 , the relevance of m 6 A in mRNA translation remains largely unknown in vivo . Here we show that, through its binding protein Ythdf1, m 6 A promotes protein synthesis of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 ( Ythdf1 -KO) exhibit learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Ythdf1 re-expression in the hippocampus of adult Ythdf1 -KO mice rescues behavioral and synaptic defects, while hippocampus-specific acute knockdown of Ythdf1 or Mettl3 , the catalytic component of m 6 A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of Ythdf1 binding sites and m 6 A sites on hippocampal mRNAs uncovered key neuronal genes. Nascent protein labeling and tether reporter assays in hippocampal neurons revealed that Ythdf1 enhances protein synthesis in a neuronal-stimulus-dependent manner. Collectively, our results uncover a pathway of mRNA m 6 A methylation in learning and memory, which is mediated through Ythdf1 in response to stimuli.