Space-time sensors using multiple-wave atom levitation

The best clocks to date control the atomic motion by trapping the sample in an optical lattice and then interrogate the atomic transition by shining on these atoms a distinct laser of controlled frequency. In order to perform both tasks simultaneously and with the same laser field, we propose to use instead the levitation of a Bose-Einstein condensate through multiple-wave atomic interferences. The levitating condensate experiences a coherent localization in momentum and a controlled diffusion in altitude. The sample levitation is bound to resonance conditions used either for frequency or for acceleration measurements. The chosen vertical geometry solves the limitations imposed by the sample free fall in previous optical clocks using also atomic interferences. This configuration yields multiple-wave interferences enabling levitation and enhancing the measurement sensitivity. This setup, analogous to an atomic resonator in momentum space, constitutes an attractive alternative to existing atomic clocks and gravimeters.Comment: 5 pages, 4 figures.Final versio

Theoretical tools for atom laser beam propagation

We present a theoretical model for the propagation of non self-interacting atom laser beams. We start from a general propagation integral equation, and we use the same approximations as in photon optics to derive tools to calculate the atom laser beam propagation. We discuss the approximations that allow to reduce the general equation whether to a Fresnel-Kirchhoff integral calculated by using the stationary phase method, or to the eikonal. Within the paraxial approximation, we also introduce the ABCD matrices formalism and the beam quality factor. As an example, we apply these tools to analyse the recent experiment by Riou et al. [Phys. Rev. Lett. 96, 070404 (2006)]

The theory of quantum levitators

We develop a unified theory for clocks and gravimeters using the interferences of multiple atomic waves put in levitation by traveling light pulses. Inspired by optical methods, we exhibit a propagation invariant, which enables to derive analytically the wave function of the sample scattering on the light pulse sequence. A complete characterization of the device sensitivity with respect to frequency or to acceleration measurements is obtained. These results agree with previous numerical simulations and confirm the conjecture of sensitivity improvement through multiple atomic wave interferences. A realistic experimental implementation for such clock architecture is discussed.Comment: 11 pages, 6 Figures. Minor typos corrected. Final versio

Hidden symmetry and nonlinear paraxial atom optics

A hidden symmetry of the nonlinear wave equation is exploited to analyse the propagation of paraxial and uniform atom-laser beams in time-independent, quadratic and cylindrical potentials varying smoothly along the propagation axis. The quality factor and the paraxial ABCD formalism are generalized to account exactly for mean-field interaction effects in such beams. Using an approach based on moments, these theoretical tools provide a very simple and yet exact picture of the interacting beam profile evolution. Guided atom laser experiments are discussed. This treatment addresses simultaneously optical and atomic beams in a unified manner, exploiting the formal analogy between nonlinear optics and nonlinear paraxial atom optics.Comment: Final Version. Changes in the abstract and minor changes in the text with respect to the version published in PR

Mapping proteolytic processing in the secretome of gastric cancer-associated myofibroblasts reveals activation of MMP-1, MMP-2, and MMP-3

Cancer progression involves changes in extracellular proteolysis, but the contribution of stromal cell secretomes to the cancer degradome remains uncertain. We have now defined the secretome of a. specific stromal cell type, the rnyofibroblast, in gastric cancer and its modification by proteolysis. SILAC labeling and COFRADIC isolation of methionine containing peptides allowed us to quantify differences in gastric cancer-derived myofibroblasts compared with myofibroblasts from adjacent tissue, revealing increased abundance of several proteases in cancer myofibroblasts including matrix metalloproteinases (MMP)-1 and -3. Moreover, N-terminal COFRADIC analysis identified cancer-restricted proteolytic cleavages, including liberation of the active forms of MMP-1, -2, and -3 from their inactive precursors. In vivo imaging confirmed increased MMP activity when gastric cancer cells were xenografted in mice together with gastric cancer myofibroblasts. Western blot and enzyme activity assays confirmed increased MMP-1, -2, and -3 activity in cancer myofibroblasts, and cancer cell migration assays indicated stimulation by MMP-1, -2, and -3 in cancer-associated rnyofibroblast media. Thus, cancer-derived myofibroblasts differ from their normal counterparts by increased production and activation of MMP-1, -2, and -3, and this may contribute to the remodelling of the cancer cell microenvironment

Fat1 deletion promotes hybrid EMT state, tumour stemness and metastasis

FAT1, which encodes a protocadherin, is one of the most frequently mutated genes in human cancers1–5. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. Here, using mouse models of skin squamous cell carcinoma and lung tumours, we found that deletion of Fat1 accelerates tumour initiation and malignant progression and promotes a hybrid epithelial-to-mesenchymal transition (EMT) phenotype. We also found this hybrid EMT state in FAT1-mutated human squamous cell carcinomas. Skin squamous cell carcinomas in which Fat1 was deleted presented increased tumour stemness and spontaneous metastasis. We performed transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies, which revealed that loss of function of FAT1 activates a CAMK2–CD44–SRC axis that promotes YAP1 nuclear translocation and ZEB1 expression that stimulates the mesenchymal state. This loss of function also inactivates EZH2, promoting SOX2 expression, which sustains the epithelial state. Our comprehensive analysis identified drug resistance and vulnerabilities in FAT1-deficient tumours, which have important implications for cancer therapy. Our studies reveal that, in mouse and human squamous cell carcinoma, loss of function of FAT1 promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state

Mechanisms of congenital heart disease caused by NAA15 haploinsufficiency

Rationale: NAA15 is a component of the N-terminal (Nt) acetyltransferase complex, NatA. The mechanism by which NAA15 haploinsufficiency causes congenital heart disease (CHD) remains unknown. To better understand molecular processes by which NAA15 haploinsufficiency perturbs cardiac development, we introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) and assessed the consequences of these mutations on RNA and protein expression. Objective: We aim to understand the role of NAA15 haploinsufficiency in cardiac development by investigating proteomic effects on NatA complex activity, and identifying proteins dependent upon a full amount of NAA15. Methods and Results: We introduced heterozygous LoF, compound heterozygous and missense residues (R276W) in iPS cells using CRISPR/Cas9. Haploinsufficient NAA15 iPS cells differentiate into cardiomyocytes, unlike NAA15-null iPS cells, presumably due to altered composition of NatA. Mass spectrometry (MS) analyses reveal ~80% of identified iPS cell NatA targeted proteins displayed partial or complete Nt-acetylation. Between null and haploinsufficient NAA15 cells Nt-acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced, respectively. Similar acetylation loss in few proteins occurred in NAA15 R276W iPSCs. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells; eighteen were ribosomal-associated proteins. At least four proteins were encoded by genes known to cause autosomal dominant CHD. Conclusions: These studies define a set of human proteins that requires a full NAA15 complement for normal synthesis and development. A 50% reduction in the amount of NAA15 alters levels of at least 562 proteins and Nt-acetylation of only 9 proteins. One or more modulated proteins are likely responsible for NAA15-haploinsufficiency mediated CHD. Additionally, genetically engineered iPS cells provide a platform for evaluating the consequences of amino acid sequence variants of unknown significance on NAA15 function