The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation

Alzheimer’s disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid-β peptide (Aβ) aggregates that can perforate the plasma membrane of cells, increasing the intracellular calcium levels and releasing synaptic vesicles that finally lead to a delayed synaptic failure. Several membrane proteins and lipids interact with Aβ affecting its toxicity in neurons. Here, we focus on NMDA receptors (NMDARs) as proteins that could be modulating the association and neurotoxic perforation induced by Aβ on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA approaches, increased the association of Aβ to the neurons. Furthermore, overexpression of NMDARs also resulted in an enhanced association between NMDA and Aβ. Functionally, the reduction in membrane NMDARs augmented the process of membrane perforation. On the other hand, overexpressing NMDARs had a protective effect because Aβ was now unable to cause membrane perforation, suggesting a complex relationship between Aβ and NMDARs. Because previous studies have recognized that Aβ oligomers are able to increase membrane permeability and produce amyloid pores, the present study supports the conclusion that NMDARs play a critical protective role on Aβ actions in hippocampal neurons. These results could explain the lack of correlation between brain Aβ burden and clinically observed dementia

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

On the pharmacogenetics of non-small cell lung cancer treatment

Abstract: Introduction. Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well-established chemotherapeutic regimens, has been limited by inherited/acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR-inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches

Search for unbound 15Be states in the 3n+12Be channel

15Be is expected to have low-lying 3/2+ and 5/2+ states. A first search did not observe the 3/2+ [A. Spyrou et al., Phys. Rev. C 84, 044309 (2011)], however, a resonance in 15Be was populated in a second attempt and determined to be unbound with respect to 14Be by 1.8(1) MeV with a tentative spin-parity assignment of 5/2+ [J. Snyder et al., Phys. Rev. C 88, 031303(R) (2013)]. Search for the predicted 15Be 3/2+ state in the three-neutron decay channel. A two-proton removal reaction from a 55 MeV/u 17C beam was used to populate neutron-unbound states in 15Be. The two-, three-, and four-body decay energies of the 12Be + neutron(s) detected in coincidence were reconstructed using invariant mass spectroscopy. Monte Carlo simulations were performed to extract the resonance and decay properties from the observed spectra. The low-energy regions of the decay energy spectra can be described with the first excited unbound state of 14Be (E_x=1.54 MeV, E_r=0.28 MeV). Including a state in 15Be that decays through the first excited 14Be state slightly improves the fit at higher energies though the cross section is small. A 15Be component is not needed to describe the data. If the 3/2+ state in 15Be is populated, the decay by three-neutron emission through 14Be is weak, less than or equal to 11% up to 4 MeV. In the best fit, 15Be is unbound with respect to 12Be by 1.4 MeV (unbound with respect to $14Be by 2.66 MeV) with a strength of 7%.Comment: 6 pages, 5 figures, accepted in Physical Review

PAR1 Agonists Stimulate APC-Like Endothelial Cytoprotection and Confer Resistance to Thromboinflammatory Injury

Stimulation of protease-activated receptor 1 (PAR1) on endothelium by activated protein C (APC) is protective in several animal models of disease, and APC has been used clinically in severe sepsis and wound healing. Clinical use of APC, however, is limited by its immunogenicity and its anticoagulant activity. We show that a class of small molecules termed “parmodulins” that act at the cytosolic face of PAR1 stimulates APC-like cytoprotective signaling in endothelium. Parmodulins block thrombin generation in response to inflammatory mediators and inhibit platelet accumulation on endothelium cultured under flow. Evaluation of the antithrombotic mechanism showed that parmodulins induce cytoprotective signaling through Gβγ, activating a PI3K/Akt pathway and eliciting a genetic program that includes suppression of NF-κB–mediated transcriptional activation and up-regulation of select cytoprotective transcripts. STC1 is among the up-regulated transcripts, and knockdown of stanniocalin-1 blocks the protective effects of both parmodulins and APC. Induction of this signaling pathway in vivo protects against thromboinflammatory injury in blood vessels. Small-molecule activation of endothelial cytoprotection through PAR1 represents an approach for treatment of thromboinflammatory disease and provides proof-of-principle for the strategy of targeting the cytoplasmic surface of GPCRs to achieve pathway selective signaling

First observation of 13^{13}Li ground state

The ground state of neutron-rich unbound $^{13}$Li was observed for the first time in a one-proton removal reaction from $^{14}$Be at a beam energy of 53.6 MeV/u. The $^{13}$Li ground state was reconstructed from $^{11}$Li and two neutrons giving a resonance energy of 120$^{+60}_{-80}$ keV. All events involving single and double neutron interactions in the Modular Neutron Array (MoNA) were analyzed, simulated, and fitted self-consistently. The three-body ($^{11}$Li+$n+n$) correlations within Jacobi coordinates showed strong dineutron characteristics. The decay energy spectrum of the intermediate $^{12}$Li system ($^{11}$Li+$n$) was described with an s-wave scattering length of greater than -4 fm, which is a smaller absolute value than reported in a previous measurement.Comment: Accepted for publication in Phys. Rev. C as a Rapid Communicatio

Structure and Decay Correlations of Two-Neutron Systems Beyond the Dripline

The two-neutron unbound systems of 16Be, 13Li, 10He, and 26O have been measured using the Modular Neutron Array (MoNA) and 4 Tm Sweeper magnet setup. The correlations of the 3-body decay for the 16Be and 13Li were extracted and demonstrated a strong correlated enhancement between the two neutrons. The measurement of the 10He ground state resonance from a 14Be(−2p2n) reaction provided insight into previous predictions that wavefunction of the entrance channel, projectile, can influence the observed decay energy spectrum for the unbound system. Lastly, the decay-in-target (DiT) technique was utilized to extract the lifetime of the 26O ground state. The measured lifetime of 4.5+1.1 −1.5 (stat.)±3(sys.) ps provides the first indication of two-neutron radioactivity

Atom gravimeters and gravitational redshift

In a recent paper, H. Mueller, A. Peters and S. Chu [A precision measurement of the gravitational redshift by the interference of matter waves, Nature 463, 926-929 (2010)] argued that atom interferometry experiments published a decade ago did in fact measure the gravitational redshift on the quantum clock operating at the very high Compton frequency associated with the rest mass of the Caesium atom. In the present Communication we show that this interpretation is incorrect.Comment: 2 pages, Brief Communication appeared in Nature (2 September 2010