Image Slicer Performances from a Demonstrator for the SNAP/JDEM Mission - Part I: Wavelength Accuracy

A well-adapted visible and infrared spectrograph has been developed for the SNAP (SuperNova/Acceleration Probe) experiment proposed for JDEM. The instrument should have a high sensitivity to see faint supernovae but also a good redshift determination better than 0.003(1+z) and a precise spectrophotometry (2%). An instrument based on an integral field method with the powerful concept of imager slicing has been designed. A large prototyping effort has been performed in France which validates the concept. In particular a demonstrator reproducing the full optical configuration has been built and tested to prove the optical performances both in the visible and in the near infrared range. This paper is the first of two papers. The present paper focus on the wavelength measurement while the second one will present the spectrophotometric performances. We adress here the spectral accuracy expected both in the visible and in the near infrared range in such configuration and we demonstrate, in particular, that the image slicer enhances the instrumental performances in the spectral measurement precision by removing the slit effect. This work is supported in France by CNRS/INSU/IN2P3 and by the French spatial agency (CNES) and in US by the University of California.Comment: Submitted to PAS

Applications of nuclear magnetic resonance spectroscopy: from drug discovery to protein structure and dynamics.

The versatility of nuclear magnetic resonance (NMR) spectroscopy is apparent when presented with diverse applications to which it can contribute. Here, NMR is used i) as a screening/ validation tool for a drug discovery program targeting the Phosphatase of Regenerating Liver 3 (PRL3), ii) to characterize the conformational heterogeneity of p53 regulator, Murine Double Minute X (MDMX), and iii) to characterize the solution dynamics of guanosine monophosphate kinase (GMPK). Mounting evidence suggesting roles for PRL3 in oncogenesis and metastasis has catapulted it into prominence as a cancer drug target. Yet, despite significant efforts, there are no PRL3 small molecule inhibitors currently in clinical trials. This work combines screening of an FDA-approved drug panel and the identification of binders by protein-observed NMR. FDA-approved drugs salirasib and candesartan were identified as potent inhibitors in in vitro inhibition and migration assays while a weak inhibitor, olsalazine, was identified by NMR as the first small molecule inhibitor to directly bind PRL3. NMR was also used to validate the binding of additional compounds identified as experimental PRL3 inhibitors. Thienopyridone, a potent experimental inhibitor, did not show direct binding to PRL3 but instead inhibited phosphatase activity via redox mechanism. NMR also revealed that other experimental inhibitors did not engage PRL3. Thus, there remains a need to identify potent PRL3-directed inhibitors. Meanwhile, molecular modeling revealed a putative druggable site that has not been thoroughly explored before. The current study provides some scaffolds such as candesartan and particularly, olsalazine, the only binder identified, that could be the starting point of further drug discovery efforts, as well as a putative site that can be targeted in silico. MDMX, a negative regulator of p53, is another important therapeutic target in cancer, along with the homologous protein, MDM2. Inhibitors that block the MDM2-p53 interaction have been identified and despite similarities in the binding site of these homologous proteins, these inhibitors are ineffective against MDMX. It is hypothesized that the flexibility of MDMX contributes to this significant difference in response to inhibitors, despite comparable affinity to their endogenous target, p53. Examination of available inhibitor-bound structures of MDMX reveal a conserved pharmacophore but the structures adopt distinct conformations away from the binding site. This implies that global motions of the protein might contribute to molecular recognition. The conformational heterogeneity in MDMX was further confirmed by collecting residual dipolar couplings (RDCs). Further investigations on both MDMX and MDM2 are necessary to uncover whether the flexibility of MDMX contributes to the differential binding to inhibitors. Finally, NMR relaxation methods and state-of-the-art high-power Carr-Purcell-Meiboom Gill (CPMG) relaxation dispersion measurements, the first documented application on an enzyme, were used to characterize the solution dynamics of GMPK and the changes in dynamics upon GMP binding. Substrate binding resulted in restricting the amplitudes of motion for backbone amide bonds within the picosecond-nanosecond timescale. Meanwhile, CPMG showed dispersion in both in the absence and presence of GMP, such that substrate binding did not quench dynamics within the microsecond-millisecond timescale. Interestingly, more residues are observed to have dispersion in the bound form, some near the C-terminal of helix 3, which has previously been proposed to be involved in product release. Current studies show that substrate binding affect different timescales of protein motion. Future work shall follow how motions within different timescales are affected as GMPK processes its substrates – such as, for instance, binding of ATP analogs within the ATP binding site or simultaneous occupancy of both substrate binding pockets. This paves the way for a complete picture of the relationship of function and dynamics in the conformational enzymatic cycle of a bi-substrate enzyme using GMPK as a model. The current work illustrates some of the diverse applications of NMR on three unique systems that are also drug targets. Information collected here can be leveraged on future structure and dynamics studies as well as drug discovery efforts targeting any of these proteins

Generalisation through negation and predicate invention

The ability to generalise from a small number of examples is a fundamental challenge in machine learning. To tackle this challenge, we introduce an inductive logic programming (ILP) approach that combines negation and predicate invention. Combining these two features allows an ILP system to generalise better by learning rules with universally quantified body-only variables. We implement our idea in NOPI, which can learn normal logic programs with predicate invention, including Datalog programs with stratified negation. Our experimental results on multiple domains show that our approach can improve predictive accuracies and learning times

Integrating a Global Induction Mechanism into a Sequent Calculus

Most interesting proofs in mathematics contain an inductive argument which requires an extension of the LK-calculus to formalize. The most commonly used calculi for induction contain a separate rule or axiom which reduces the valid proof theoretic properties of the calculus. To the best of our knowledge, there are no such calculi which allow cut-elimination to a normal form with the subformula property, i.e. every formula occurring in the proof is a subformula of the end sequent. Proof schemata are a variant of LK-proofs able to simulate induction by linking proofs together. There exists a schematic normal form which has comparable proof theoretic behaviour to normal forms with the subformula property. However, a calculus for the construction of proof schemata does not exist. In this paper, we introduce a calculus for proof schemata and prove soundness and completeness with respect to a fragment of the inductive arguments formalizable in Peano arithmetic.Comment: 16 page

Volatile profile and consumer acceptability of natural yoghurts elaborated with chilean native cultures of enterococcus sp. strain BB3 and lactobacillus sp. strain BB6

According to WHO, in 2016 around 13% of the world's adult population (11% of men and 15% of women) were obese. The global prevalence of obesity almost tripled between 1975 and 2016. In this context, it is important to note that the continuous increase in life expectancy, the desire for a better quality of life, and the high cost of medical care have led to a growing demand for functional foods in the market. People have started to realize that their food choices and their unhealthy lifestyles have consequences for their health. An important role in this scenario is associated with functional foods containing probiotic strains, reported to benefit human health. Here we report the development of natural yogurts based on native probiotic starter cultures of Enterococcus sp. strain BB3 (MK681869) and Lactobacillus sp. strain BB6 (MK681868), isolated from raw cow milk of La Araucanía region of Chile. The odor and taste were the main parameters criticized by the consumer, the analysis of CG-MS elucidated that the yogurt produced by the strain Enterococcus sp. strain BB3 (MK681869) produced a higher amount of heptan-2-one, associated with a cheesy type odor, with less acceptance by the consumers. The acceptability of 6 types of yogurt was evaluated with a randomized analysis of 60 participants. The development of a functional dairy product based on probiotics is of interest because of its relation with positive changes in gut microbiota, and at the same time with a possible decrease in body weight

Spin-to-Orbital Angular Momentum Conversion in Semiconductor Microcavities

We experimentally demonstrate a technique for the generation of optical beams carrying orbital angular momentum using a planar semiconductor microcavity. Despite being isotropic systems, the transverse electric - transverse magnetic (TE-TM) polarization splitting featured by semiconductor microcavities allows for the conversion of the circular polarization of an incoming laser beam into the orbital angular momentum of the transmitted light field. The process implies the formation of topological entities, a pair of optical half-vortices, in the intracavity field

Limits on the neutrino magnetic moment from the MUNU experiment

The MUNU experiment was carried out at the Bugey nuclear power reactor. The aim was the study of electron antineutrino-electron elastic scattering at low energy. The recoil electrons were recorded in a gas time projection chamber, immersed in a tank filled with liquid scintillator serving as veto detector, suppressing in particular Compton electrons. The measured electron recoil spectrum is presented. Upper limits on the neutrino magnetic moment were derived and are discussed.Comment: 9 pages, 7 figures Added reference: p.3, 1st col., TEXONO Added sentence: p.4, 1st col., electron attachement Modified sentence: p.5, 1st col., readout sequence Added sentence: p.5, 1st col., fast rise time cu

Sub MeV Particles Detection and Identification in the MUNU detector ((1)ISN, IN2P3/CNRS-UJF, Grenoble, France, (2)Institut de Physique, Neuch\^atel, Switzerland, (3) INFN, Padova Italy, (4) Physik-Institut, Z\"{u}rich, Switzerland)

We report on the performance of a 1 m$^{3}$ TPC filled with CF$_{4}$ at 3 bar, immersed in liquid scintillator and viewed by photomultipliers. Particle detection, event identification and localization achieved by measuring both the current signal and the scintillation light are presented. Particular features of $\alpha$ particle detection are also discussed. Finally, the ${54}$Mn photopeak, reconstructed from the Compton scattering and recoil angle is shown.Comment: Latex, 19 pages, 20 figure

Moderate-to-Vigorous Physical Activity is Related With Retinal Neuronal and Axonal Integrity in Persons With Multiple Sclerosis

Background Moderate-to-vigorous physical activity (MVPA) may confer benefits for axonal and/or neuronal integrity in adults with multiple sclerosis (MS). Purpose Examine the association between device-measured MVPA with optical coherence tomography (OCT) metrics of retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) in persons with and without MS. Methods Adults with MS (N = 41), along with sex-matched healthy control (HC) participants (N = 79), underwent measurements of retinal morphology via OCT and wore an accelerometer for a period of 7 days as a measure of MVPA. Results Persons with MS had significantly lower MVPA, RNFL thickness, and TMV compared with HCs. MVPA was correlated with RNFL (r = .38, P \u3c .01) thickness and TMV (r = .49, P \u3c .01). Hierarchical linear regression analyses indicated that addition of MVPA attenuated the Group effect on RNFL and TMV. MVPA accounted for 8% and 3% of the variance in TMV (β = .343, P \u3c .01) and RNFL thickness (β = .217, P = .03), respectively. Conclusion MVPA was positively associated with axonal and neuronal integrity assessed by OCT and partially explained group differences in those metrics. These results present possible future targets for MS management by increasing MVPA