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Kynurenic acid (KYNA) plays a significant role in maintaining normal brain function, and abnormalities in KYNA levels have been associated with various central nervous system disorders. Confirmation of its causality in human diseases requires safe and effective modulation of central KYNA levels in the clinic. The kynurenine aminotransferases (KAT) II enzyme represents an attractive target for pharmacologic modulation of central KYNA levels; however, KAT II and KYNA turnover kinetics, which could contribute to the duration of pharmacologic effect, have not been reported. In this study, the kinetics of central KYNA-lowering effect in rats and nonhuman primates (NHPs, Cynomolgus macaques) was investigated using multiple KAT II irreversible inhibitors as pharmacologic probes. Mechanistic pharmacokinetic-pharmacodynamic analysis of in vivo responses to irreversible inhibition quantitatively revealed that 1) KAT II turnover is relatively slow [16-76 hours' half-life (t1/2)], whereas KYNA is cleared more rapidly from the brain (

Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (Cav,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of 30 at or above targeted efficacious plasma levels for ...

The problem of computing products of Schubert classes in the cohomology ring can be formulated as the problem of expanding skew Schur polynomials into the basis of ordinary Schur polynomials. In contrast, the problem of computing the structure constants of the Grothendieck ring of a Grassmannian variety with respect to its basis of Schubert structure sheaves is not equivalent to expanding skew stable Grothendieck polynomials into the basis of ordinary stable Grothendiecks. Instead, we show that the appropriate K-theoretic analogy is through the expansion of skew reverse plane partitions into the basis of polynomials which are Hopf-dual to stable Grothendieck polynomials. We combinatorially prove this expansion is determined by Yamanouchi set-valued tableaux. A by-product of our results is a dual approach proof for Buch's K-theoretic Littlewood-Richardson rule for the product of stable Grothendieck polynomials. Additionally we answer a question posed by Wan and Wang in 2011. The Kostka-Foulkes polynomials are ubiquitous in algebraic combinatorics, geometry, and representation theory. These polynomials in a parameter t with positive coefficients have deep connections to the Springer theory of Weyl group representations and Lusztig's q-weight multiplicity in finite dimensional irreducible representations of the general linear Lie algebra, among other things. Lascoux and Schutzenberger provided an elegant description of the Kostka-Foulkes polynomials in terms of charge, a statistic associated to Young tableaux. Wan and Wang introduced a spin counterpart, the spin Kostka polynomials, and asked that they be given a Lascoux and Schutzenberger type description by a statistic on shifted Young tableaux. The spin charge statistic given here fulfills this request.

We report water column dissolved and particulate 210 Pb and 210 Po profiles along with ancillary data from the northern Gulf of Mexico continental shelf collected during the summers of 2011 and 2012. The dissolved 210 Po/ 210 Pb ratio in bottom water was > 1 at 10 out of 12 stations whereas the 210 Po/ 210 Pb activity ratio in surface water was approximately 0.2–1.3. This lower dissolved 210 Po/ 210 Pb surface ratio indicates that 210 Po is generally more efficiently scavenged than 210 Pb in surface layers. The particulate 210 Po/ 210 Pb ratio was 1.6–5.1 in surface water and 2.5–10.4 in bottom water indicating that 210 Po tends to be more enriched in deep water particulate material as compared to surface material. The 210 Po and POC are significantly correlated (r 2 = 0.93) with the POC/ 210 Po ratio varying between 205 and 2094 μmol C dpm − 1 . These general patterns suggest that 210 Po is scavenged from the surface waters and regenerated or added to bottom waters relative to 210 Pb. The addition of Po to bottom water (either in the dissolved or particulate phase) likely requires a sedimentary source of Po, relative to Pb, to the overlying water column. Dissolved oxygen concentrations and water column stratification vary throughout the region, and we find no correlation between dissolved O 2 concentration and 210 Po excess. 210 Po enrichment does, however, appear to be coupled to the release of the redox sensitive trace metals Fe and Mn and remineralization of silica in bottom waters to some extent. We suggest that the cycling of these redox sensitive metals, coupled with the degradation of organic matter is the likely driving mechanism for 210 Po remobilization that produces the observed water column 210 Po distributions.

Future scientific space missions require ever more demanding large optics that work at cryogenic temperatures. In the frame of a Darwin assessment study conducted under ESA contract by TAS, the need of future very lightweight cryogenic mirrors with superior optical quality has been identified. Such mirrors need to be of size up to 3.5 m in diameter, with a mass of less than 250 kg (i.e. 25 kg/m2) and possess excellent optical quality at cryogenic temperature down to 40 K.

For space born Astronomy as well as Earth Observation from space, more and more focal plane instruments are operating in the near or mid infrared and require therefore optics operating at cryogenic temperature (down to liquid nitrogen temperature or less). Through several examples of typical past or on-going realizations for different projects requiring such cryogenics optics (e.g. MTG=Meteosat Third Generation program for ESA), the presentation will point out the main technical issues and corresponding solutions for design, manufacturing and testing of necessary lens assemblies, mirrors and relevant optical coatings. A brief review of the corresponding existing “state of the art” for these technologies in Thales Seso will conclude the presentation.

Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug–drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C–H diversification methods to drug discovery.

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). The most common LRRK2 mutation, G2019S, which is relatively rare in the total population, gives rise to increased kinase activity. As such, LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the discovery and optimization of a novel series of potent LRRK2 inhibitors, focusing on improving kinome selectivity using a surrogate crystallography approach. This resulted in the identification of 14 (PF-06447475), a highly potent, brain penetrant and selective LRRK2 inhibitor which has been further profiled in in vivo safety and pharmacodynamic studies.

Phosphodiesterases (PDEs) regulate the levels of the second messengers cAMP and cGMP and are important drug targets. PDE10A is highly enriched in medium spiny neurons of the striatum and is an attractive drug target for the treatment of basal ganglia diseases like schizophrenia, Parkinson's disease, or Huntington's disease. Here we describe the design, synthesis, and application of a variety of chemical biology probes, based on the first clinically tested PDE10A inhibitor MP-10, which were used to characterize the chemoproteomic profile of the clinical candidate in its native environment. A clickable photoaffinity probe was used to measure target engagement of MP-10 and revealed differences between whole cell and membrane preparations. Moreover, our results illustrate the importance of the linker design in the creation of functional probes. Biotinylated affinity probes allowed identification of drug-interaction partners in rodent and human tissue and quantitative mass spectrometry analysis revealed highly specific binding of MP-10 to PDE10A with virtually no off-target binding. The profiling of PDE10A chemical biology probes described herein illustrates a strategy by which high affinity inhibitors can be converted into probes for determining selectivity and target engagement of drug candidates in complex biological matrices from native sources.

Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD). The most common mutant, G2019S, increases kinase activity, thus LRRK2 kinase inhibitors are potentially useful in the treatment of PD. We herein disclose the structure, potential ligand-protein binding interactions, and pharmacological profiling of potent and highly selective kinase inhibitors based on a triazolopyridazine chemical scaffold.

THE PURPOSE OF THE STUDY WAS TO DISCOVER IF THE SUPERIOR PERFORMANCE OF STUDENT TEACHERS, WHO HAD SEEN DOCUMENTARY FILMS OF CERTAIN TECHNIQUES OF TEACHING IN THEIR UNDERGRADUATE METHODS COURSES, WOULD CARRY OVER AND COULD BE MEASURED IN THEIR FIRST YEAR OF TEACHING. EXPERIMENTAL METHODS COURSES WERE TAUGHT FOR SECONDARY LEVEL COURSES IN ENGLISH, SOCIAL STUDIES, MATHEMATICS, AND SCIENCE. ONE BASIC AND FIVE SUPPLEMENTARY EVALUATIVE INSTRUMENTS WERE USED. ONLY THE RESULTS FROM THE TEACHING TECHNIQUES EVALUATION FORM AND GRADES BY THE SUPERVISOR SHOWED A STATISTICALLY SIGNIFICANT DIFFERENCE IN FAVOR OF THE DOCUMENTARY FILM TECHNIQUE. WHILE THE UNOBSERVABLE FORMER STUDENTS MIGHT HAVE BIASED THE RESULTS, MAIN SUPPORT FOR FILM USE WAS INDICATED BY THE FAVORABLE OVERALL GRADE FOR THE FILM-VIEWING TEACHERS. (PM)

THE PREPARATION AND ASSESSMENT OF DOCUMENTARY FILMS FOR USE IN METHODS INSTRUCTION OF COLLEGE STUDENTS WAS REPORTED. FOUR GENERAL SOURCES WERE USED FOR GUIDANCE IN THE SELECTION OF TOPICS FOR THE DOCUMENTARIES. THESE SOURCES INCLUDED COLLEGE TEXTBOOKS, COLLEGE CATALOGS, INTERVIEWS WITH SPECIALISTS, AND STUDENT INTERVIEWS. POSSIBLE TITLES, FILMS, SUBJECT CONTENT, AND GUIDELINES WERE OBTAINED FROM THESE SOURCES. INSTRUCTIONAL FILMS WERE THEN PREPARED AND USED IN METHODS CLASSES. STUDENTS ENROLLED IN THE CLASSES WERE ASSIGNED TO TWO CONTROL GROUPS AND ONE EXPERIMENTAL GROUP. EACH GROUP CONSISTED OF 40 STUDENTS. THE EXPERIMENT WAS CONTINUED DURING TWO FOLLOWING SCHOOL TERMS IN FOUR SUBJECT AREAS--SOCIAL STUDIES, MATHEMATICS, SCIENCE, AND ENGLISH. EVALUATIVE MEASURES WERE DEVELOPED AND ADMINISTERED BEFORE THE USE OF THE FILMS. THESE MEASURES IMPOSED PRE- AND POST-TEST DESIGN. THE AUTHOR CONCLUDED THAT EXPERIMENTAL GROUPS WERE AIDED BY THE FILMS IN AN UNDERSTANDING OF THE TEACHING PROCESSES, ALTHOUGH THE RESULTS WERE NOT STATISTICALLY SIGNIFICANT. FURTHER STUDY WAS SUGGESTED TO DETERMINE THE USEFULNESS OF THESE FILMS FOR A PROGRAM OF INSERVICE REEDUCATION OF TEACHERS IN BASIC TECHNIQUES OF TEACHING. (RS)

A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study.

1. In early discovery stages, 2-methyl-N-(2'-(pyrrolidinyl-1-ylsulfonyl)-[1,1'-biphenyl]-4-yl)propan-1-amine (PBPA) demonstrated monoamine oxidase A (MAO-A) and cytochrome P450 (CYP)-mediated clearance. While human liver microsomes predicted low CL(b) PBPA demonstrated a moderate CL(p)/F in humans. The plasma pharmacokinetic (PK) of PBPA was characterized by unexpected high inter-individual variability. Hence, a retrospective analysis was undertaken to understand the disposition processes of PBPA, by applying in vitro mechanistic tools. 2. The in vitro-to-in vivo of rat CL(b) of PBPA was calculated as similar to that of human, suggesting rat to be a better predictor of a MAO-A/CYP substrate, but not dog or monkey; this is consistent with differences in expression of MAO-A in rat, dog, monkey and human. Fraction metabolized (f(m)) of human MAO A (hMAO-A) (50%), CYP3A4 (8%), CYP3A5 (16%) and CYP2D6 (29%) was determined, in vitro. 3. While the fm of CYP3A5 was

We provide evidence of the simultaneous occurrence of large-amplitude, quasi-parallel whistler mode waves and ion-scale magnetic structures, which have been observed by the Cluster spacecraft in the plasma sheet at 17 Earth radii, during a substorm event. It is shown that the magnetic structures are characterized by both a magnetic field strength minimum and a density hump and that they propagate in a direction quasi-perpendicular to the average magnetic field. The observed whistler mode waves are efficiently ducted by the inhomogeneity associated with such ion-scale magnetic structures. The large amplitude of the confined whistler waves suggests that electron precipitations could be enhanced locally via strong pitch angle scattering. Furthermore, electron distribution functions indicate that a strong parallel heating of electrons occurs within these ion-scale structures. This study provides new insights on the possible multiscale coupling of plasma dynamics during the substorm expansion, on the basis of the whistler mode wave trapping by coherent ion-scale structures.

We present a hybrid tri-axes magnetometer designed to measure weak magnetic fields in space from DC (direct current) up to a few kHz with a better sensitivity than fluxgate magnetometers at frequencies above a few Hz. This magnetometer combines a wire-wound ferromagnetic ribbon and a classical induction sensor. The nature of the wire-wound ferromagnetic ribbon sensor, giant magneto-impedance or magneto-inductance, is discussed. New configurations of wire-wound ferromagnetic ribbon sensors based on closed magnetic circuits are suggested and the hybrid sensor is described. The electronic conditioning of the wire-wound ribbon makes use of an alternating bias field to cancel the offset and linearize the output. Finally we summarize the main performances of the hybrid magnetometer and we discuss its advantages and drawbacks. A prototype has been built and was part of the scientific payload of the NASA rocket experiment CHARM-II (Correlation of High Frequency and Auroral Roar Measurements) launched in the auroral ionosphere. Unfortunately the launch campaign ended without any noticeable magnetic event and the rocket was eventually launched on 16 February 2010, through a very quiescent arc in the magnetic cusp and no wave activity was detected at frequencies observable by the hybrid magnetometer.

The structure-based design, synthesis, and biological evaluation of a new pyrazole series of irreversible KAT II inhibitors are described herein. The modification of the inhibitor scaffold of 1 and 2 from a dihydroquinolinone core to a tetrahydropyrazolopyridinone core led to discovery of a new series of potent KAT II inhibitors with excellent physicochemical properties. Compound 20 is the most potent and lipophilically efficient of these new pyrazole analogs, with a kinact/Ki value of 112,000 M−1 s−1 and lipophilic efficiency (LipE) of 8.53. The X-ray crystal structure of 20 with KAT II demonstrates key features that contribute to this remarkable potency and binding efficiency.

Electromagnetic ion cyclotron (EMIC) triggered chorus emissions have recently been a subject of several experimental, theoretical and simulation case studies, noting their similarities with whistler-mode chorus. We perform a survey of 8 years of Cluster data in order to increase the database of EMIC triggered emissions. The results of this is that EMIC triggered emissions have been unambiguously observed for only three different days. These three events are studied in detail. All cases have been observed at the plasmapause between 22 and 24 magnetic local time (MLT) and between − 15∘ and 15∘ magnetic latitude (λm). Triggered emissions are also observed for the first time below the local He gyrofrequency math formula. The number of events is too low to produce statistical results, nevertheless we point out a variety of common properties of those waves. The rising tones have a high level of coherence and the waves propagate away from the equatorial region. The propagation angle and degree of polarization are related to the distance from the equator, whereas the slope and the frequency extent vary from one event to the other. From the various spacecraft separations, we determine that the triggering process is a localized phenomenon in space and time. However, we are unable to determine the occurrence rates of these waves. Small frequency extent rising tones are more common than large ones. The newly reported EMIC triggered events are generally observed during periods of large AE index values and in time periods close to solar maximum.

A series of kynurenine aminotransferase II (KAT II) inhibitors has been developed replacing the hydroxamate motif with a bioisostere. Triazolinones or triazoles have proven to be effective replacements with significantly improved pharmacokinetics including reduced clearance and increased bioavailability. An X-ray crystal structure of an inhibitor bound in KAT II confirms that the irreversible binding to the co-factor is maintained and that the heterocycles make productive hydrogen bonds to the arginine-399.

Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4. The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-β42 (Aβ42) when dosed orally at 10 mg kg−1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds.