Summit of the N=40 Island of Inversion: precision mass measurements and ab initio calculations of neutron-rich chromium isotopes

Mass measurements continue to provide invaluable information for elucidating nuclear structure and scenarios of astrophysical interest. The transition region between the $Z = 20$ and $28$ proton shell closures is particularly interesting due to the onset and evolution of nuclear deformation as nuclei become more neutron rich. This provides a critical testing ground for emerging ab-initio nuclear structure models. Here, we present high-precision mass measurements of neutron-rich chromium isotopes using the sensitive electrostatic Multiple-Reflection Time-Of-Flight Mass Spectrometer (MR-TOF-MS) at TRIUMF's Ion Trap for Atomic and Nuclear Science (TITAN) facility. Our high-precision mass measurements of $^{59, 61-63}$Cr confirm previous results, and the improved precision in measurements of $^{64-65}$Cr refine the mass surface beyond N=40. With the ab initio in-medium similarity renormalization group, we examine the trends in collectivity in chromium isotopes and give a complete picture of the N=40 island of inversion from calcium to nickel.Comment: 12 pages, 7 figure

Mass measurements of 60–63Ga reduce x-ray burst model uncertainties and extend the evaluated T=1 isobaric multiplet mass equation

We report precision mass measurements of neutron-deficient gallium isotopes approaching the proton drip line. The measurements of Ga60–63 performed with the TITAN multiple-reflection time-of-flight mass spectrometer provide a more than threefold improvement over the current literature mass uncertainty of Ga61 and mark the first direct mass measurement of Ga60. The improved precision of the Ga61 mass has important implications for the astrophysical rp process, as it constrains essential reaction Q values near the Zn60 waiting point. Based on calculations with a one-zone model, we demonstrate the impact of the improved mass data on prediction uncertainties of x-ray burst models. The first-time measurement of the Ga60 ground-state mass establishes the proton-bound nature of this nuclide, thus constraining the location of the proton drip line along this isotopic chain. Including the measured mass of Ga60 further enables us to extend the evaluated T=1 isobaric multiplet mass equation up to A=60

Investigating nuclear structure near N=32 and N=34: Precision mass measurements of neutron-rich Ca, Ti, and V isotopes

Nuclear mass measurements of isotopes are key to improving our understanding of nuclear structure across the chart of nuclides, in particular, for the determination of the appearance or disappearance of nuclear shell closures. We present high-precision mass measurements of neutron-rich Ca, Ti, and V isotopes performed at TRIUMF's Ion Trap for Atomic and Nuclear science (TITAN) and the Low Energy Beam and Ion Trap (LEBIT) facilities. These measurements were made using the TITAN multiple-reflection time-of-flight mass spectrometer (MR-ToF-MS) and the LEBIT 9.4T Penning trap mass spectrometer. In total, 13 masses were measured, 8 of which represent increases in precision over previous measurements. These measurements refine trends in the mass surface around N=32 and N=34, and support the disappearance of the N=32 shell closure with increasing proton number. Additionally, our data do not support the presence of a shell closure at N=34.Nuclear mass measurements of isotopes are key to improving our understanding of nuclear structure across the chart of nuclides, in particular for the determination of the appearance or disappearance of nuclear shell closures. We present high-precision mass measurements of neutron-rich Ca, Ti and V isotopes performed at the TITAN and LEBIT facilities. These measurements were made using the TITAN multiple-reflection time-of-flight mass spectrometer (MR-ToF-MS) and the LEBIT 9.4T Penning trap mass spectrometer. In total, 13 masses were measured, eight of which represent increases in precision over previous measurements. These measurements refine trends in the mass surface around $N = 32$ and $N = 34$, and support the disappearance of the $N = 32$ shell closure with increasing proton number. Additionally, our data does not support the presence of a shell closure at $N = 34$

Mapping the N=40 island of inversion: Precision mass measurements of neutron-rich Fe isotopes

International audienceNuclear properties across the chart of nuclides are key to improving and validating our understanding of the strong interaction in nuclear physics. We present high-precision mass measurements of neutron-rich Fe isotopes performed at the TITAN facility. The multiple-reflection time-of-flight mass spectrometer (MR-ToF-MS), achieving a resolving power greater than 600000 for the first time, enabled the measurement of Fe63–70, including first-time high-precision direct measurements (δm/m≈10−7) of Fe68–70, as well as the discovery of a long-lived isomeric state in Fe69. These measurements are accompanied by both mean-field and ab initio calculations using the most recent realizations which enable theoretical assignment of the spin-parities of the Fe69 ground and isomeric states. Together with mean-field calculations of quadrupole deformation parameters for the Fe isotope chain, these results benchmark a maximum of deformation in the N=40 island of inversion in Fe and shed light on trends in level densities indicated in the newly refined mass surface

Bcl-2 Regulates HIF-1α Protein Stabilization in Hypoxic Melanoma Cells via the Molecular Chaperone HSP90

Hypoxia-Inducible Factor 1 (HIF-1) is a transcription factor that is a critical mediator of the cellular response to hypoxia. Enhanced levels of HIF-1alpha, the oxygen-regulated subunit of HIF-1, is often associated with increased tumour angiogenesis, metastasis, therapeutic resistance and poor prognosis. It is in this context that we previously demonstrated that under hypoxia, bcl-2 protein promotes HIF-1/Vascular Endothelial Growth Factor (VEGF)-mediated tumour angiogenesis.By using human melanoma cell lines and their stable or transient derivative bcl-2 overexpressing cells, the current study identified HIF-1alpha protein stabilization as a key regulator for the induction of HIF-1 by bcl-2 under hypoxia. We also demonstrated that bcl-2-induced accumulation of HIF-1alpha protein during hypoxia was not due to an increased gene transcription or protein synthesis. In fact, it was related to a modulation of HIF-1alpha protein expression at a post-translational level, indeed its degradation rate was faster in the control lines than in bcl-2 transfectants. The bcl-2-induced HIF-1alpha stabilization in response to low oxygen tension conditions was achieved through the impairment of ubiquitin-dependent HIF-1alpha degradation involving the molecular chaperone HSP90, but it was not dependent on the prolyl hydroxylation of HIF-1alpha protein. We also showed that bcl-2, HIF-1alpha and HSP90 proteins form a tri-complex that may contribute to enhancing the stability of the HIF-1alpha protein in bcl-2 overexpressing clones under hypoxic conditions. Finally, by using genetic and pharmacological approaches we proved that HSP90 is involved in bcl-2-dependent stabilization of HIF-1alpha protein during hypoxia, and in particular the isoform HSP90beta is the main player in this phenomenon.We identified the stabilization of HIF-1alpha protein as a mechanism through which bcl-2 induces the activation of HIF-1 in hypoxic tumour cells involving the beta isoform of molecular chaperone HSP90

Exploring the Contextual Sensitivity of Factors that Determine Cell-to-Cell Variability in Receptor-Mediated Apoptosis

Stochastic fluctuations in gene expression give rise to cell-to-cell variability in protein levels which can potentially cause variability in cellular phenotype. For TRAIL (TNF-related apoptosis-inducing ligand) variability manifests itself as dramatic differences in the time between ligand exposure and the sudden activation of the effector caspases that kill cells. However, the contribution of individual proteins to phenotypic variability has not been explored in detail. In this paper we use feature-based sensitivity analysis as a means to estimate the impact of variation in key apoptosis regulators on variability in the dynamics of cell death. We use Monte Carlo sampling from measured protein concentration distributions in combination with a previously validated ordinary differential equation model of apoptosis to simulate the dynamics of receptor-mediated apoptosis. We find that variation in the concentrations of some proteins matters much more than variation in others and that precisely which proteins matter depends both on the concentrations of other proteins and on whether correlations in protein levels are taken into account. A prediction from simulation that we confirm experimentally is that variability in fate is sensitive to even small increases in the levels of Bcl-2. We also show that sensitivity to Bcl-2 levels is itself sensitive to the levels of interacting proteins. The contextual dependency is implicit in the mathematical formulation of sensitivity, but our data show that it is also important for biologically relevant parameter values. Our work provides a conceptual and practical means to study and understand the impact of cell-to-cell variability in protein expression levels on cell fate using deterministic models and sampling from parameter distributions

Apoptotic activity is increased in parallel with the metaplasia–dysplasia–carcinoma sequence of the bronchial epithelium

A high level of apoptotic activity and an independence of apoptosis from the expression of p53 and bcl-2 have been observed in non-small-cell lung carcinoma. We examined 44 samples of normal, metaplastic and premalignant (i.e. mild, moderate and severe dysplasias and carcinoma in situ) bronchial epithelia to evaluate whether differences in the apoptotic activity could already be seen in the stages preceding squamous cell carcinoma of the lung (SQCLC). Apoptotic cells and bodies were visualized by 3′ end labelling. The expression of p53 and members of the bcl-2 gene family, such as bcl-2, bax and mcl-1, were determined immunohistochemically with specific antibodies. The relative number of apoptotic cells and bodies [apoptotic index (AI%)] was already increased threefold as the normal bronchial epithelium changed to squamous metaplasia, and the AIs of the dysplastic lesions were about four times higher than those of the normal epithelium. Apoptosis was significantly associated with cell proliferation, as determined by proliferating cell nuclear antigen (PCNA) immunohistochemistry. However, the extent of apoptosis did not correlate with the expression of p53, bcl-2, bax and mcl-1. We conclude that, in the metaplasia–dysplasia–carcinoma sequence in the lung, the elevation of the AI% is an early event associated with cell proliferation activity, but is independent of the expression of p53, bcl-2, mcl-1 and bax. © 1999 Cancer Research Campaig

Pretubulysin: From Hypothetical Biosynthetic Intermediate to Potential Lead in Tumor Therapy

Pretubulysin is a natural product that is found in strains of myxobacteria in only minute amounts. It represents the first enzyme-free intermediate in the biosynthesis of tubulysins and undergoes post-assembly acylation and oxidation reactions. Pretubulysin inhibits the growth of cultured mammalian cells, as do tubulysins, which are already in advanced preclinical development as anticancer and antiangiogenic agents. The mechanism of action of this highly potent compound class involves the depolymerization of microtubules, thereby inducing mitotic arrest. Supply issues with naturally occurring derivatives can now be circumvented by the total synthesis of pretubulysin, which, in contrast to tubulysin, is synthetically accessible in gram-scale quantities. We show that the simplified precursor is nearly equally potent to the parent compound. Pretubulysin induces apoptosis and inhibits cancer cell migration and tubulin assembly in vitro. Consequently, pretubulysin appears to be an ideal candidate for future development in preclinical trials and is a very promising early lead structure in cancer therapy