5-Chloro­spiro­[indoline-3,7′-6H,7H,8H-pyrano[3,2-c:5,6-c′]di[1]benzopyran]-2,6′,8′-trione

The asymmetric unit of the title compound, C26H12ClNO6, consists of two independent mol­ecules. The central pyran rings and both the 1-benzopyran ring systems are nearly planar in both mol­ecules [r.m.s. deviations of pyan rings = 0.0264 (1) and 0.0326 (1) Å for molecules A and B, respectively; r.m.s. deviations of benzopyran rings = 0.0439 (1) and 0.0105 (1) for molecule A, 0.0146 (1) and 0.0262 (1) Å for molecule B]. In the crystal, the molecules are linked by C—H⋯O, N—H⋯O and C—H⋯π inter­actions

Annular substructures in the transition disks around LkCa 15 and J1610

We present high resolution millimeter continuum ALMA observations of the disks around the T Tauri stars LkCa 15 and J1610. These disks host dust-depleted inner regions, possibly carved by massive planets, and are of prime interest to study the imprints of planet-disk interactions. While at moderate angular resolution they appear as a broad ring surrounding a cavity, the continuum emission resolves into multiple rings at a resolution of ~60$\times$40 mas (~7.5 au for LkCa 15, ~6 au for J1610) and ~$7\,\mu$Jy beam$^{-1}$ rms at 1.3 mm. In addition to a broad extended component, LkCa 15 and J1610 host 3 and 2 narrow rings, respectively, with two bright rings in LkCa 15 being radially resolved. The rings look marginally optically thick, with peak optical depths of ~0.5 (neglecting scattering), in agreement with high angular resolution observations of full disks. We perform hydrodynamical simulations with an embedded, sub-Jovian-mass planet and show that the observed multi-ringed substructure can be qualitatively explained as the outcome of the planet-disk interaction. We note however that the choice of the disk cooling timescale alone can significantly impact the resulting gas and dust distributions around the planet, leading to different numbers of rings and gaps and different spacings between them. We propose that the massive outer disk regions of transition disks are favorable places for planetesimals and possibly second generation planet formation of objects with a lower mass than the planets carving the inner cavity (typically few $M_{\rm Jup}$), and that the annular substructures observed in LkCa 15 and J1610 may be indicative of planetary core formation within dust-rich pressure traps. Current observations are compatible with other mechanisms being at the origin of the observed substructures, in particular with narrow rings generated at the edge of the CO and N$_2$ snowlines.Comment: 17 pages, accepted for publication in Astronomy & Astrophysic

Emission-Line Galaxy Surveys as Probes of the Spatial Distribution of Dwarf Galaxies. I. The University of Michigan Survey

Objective-prism surveys which select galaxies on the basis of line-emission are extremely effective at detecting low-luminosity galaxies and constitute some of the deepest available samples of dwarfs. In this study, we confirm that emission-line galaxies (ELGs) in the University of Michigan (UM) objective-prism survey (MacAlpine et al. 1977-1981) are reliable tracers of large-scale structure, and utilize the depth of the samples to examine the spatial distribution of low-luminosity (M$_{B} >$ -18.0) dwarfs relative to higher luminosity giant galaxies (M$_{B} \leq$ -18.0) in the Updated Zwicky Catalogue (Falco et al. 1999). New spectroscopic data are presented for 26 UM survey objects. We analyze the relative clustering properties of the overall starbursting ELG and normal galaxy populations, using nearest neighbor and correlation function statistics. This allows us to determine whether the activity in ELGs is primarily caused by gravitational interactions. We conclude that galaxy-galaxy encounters are not the sole cause of activity in ELGs since ELGs tend to be more isolated and are more often found in the voids when compared to their normal galaxy counterparts. Furthermore, statistical analyses performed on low-luminosity dwarf ELGs show that the dwarfs are less clustered when compared to their non-active giant neighbors. The UM dwarf samples have greater percentages of nearest neighbor separations at large values and lower correlation function amplitudes relative to the UZC giant galaxy samples. These results are consistent with the expectations of galaxy biasing.Comment: 17 pages, 4 tables, 10 figures. Accepted for publication in the Ap

Boron Nitride Monolayer: A Strain-Tunable Nanosensor

The influence of triaxial in-plane strain on the electronic properties of a hexagonal boron-nitride sheet is investigated using density functional theory. Different from graphene, the triaxial strain localizes the molecular orbitals of the boron-nitride flake in its center depending on the direction of the applied strain. The proposed technique for localizing the molecular orbitals that are close to the Fermi level in the center of boron nitride flakes can be used to actualize engineered nanosensors, for instance, to selectively detect gas molecules. We show that the central part of the strained flake adsorbs polar molecules more strongly as compared with an unstrained sheet.Comment: 20 pages, 9 figure

An Evolutionary Reduction Principle for Mutation Rates at Multiple Loci

A model of mutation rate evolution for multiple loci under arbitrary selection is analyzed. Results are obtained using techniques from Karlin (1982) that overcome the weak selection constraints needed for tractability in prior studies of multilocus event models. A multivariate form of the reduction principle is found: reduction results at individual loci combine topologically to produce a surface of mutation rate alterations that are neutral for a new modifier allele. New mutation rates survive if and only if they fall below this surface - a generalization of the hyperplane found by Zhivotovsky et al. (1994) for a multilocus recombination modifier. Increases in mutation rates at some loci may evolve if compensated for by decreases at other loci. The strength of selection on the modifier scales in proportion to the number of germline cell divisions, and increases with the number of loci affected. Loci that do not make a difference to marginal fitnesses at equilibrium are not subject to the reduction principle, and under fine tuning of mutation rates would be expected to have higher mutation rates than loci in mutation-selection balance. Other results include the nonexistence of 'viability analogous, Hardy-Weinberg' modifier polymorphisms under multiplicative mutation, and the sufficiency of average transmission rates to encapsulate the effect of modifier polymorphisms on the transmission of loci under selection. A conjecture is offered regarding situations, like recombination in the presence of mutation, that exhibit departures from the reduction principle. Constraints for tractability are: tight linkage of all loci, initial fixation at the modifier locus, and mutation distributions comprising transition probabilities of reversible Markov chains.Comment: v3: Final corrections. v2: Revised title, reworked and expanded introductory and discussion sections, added corollaries, new results on modifier polymorphisms, minor corrections. 49 pages, 64 reference

Serum kynurenic acid is reduced in affective psychosis

A subgroup of individuals with mood and psychotic disorders shows evidence of inflammation that leads to activation of the kynurenine pathway and the increased production of neuroactive kynurenine metabolites. Depression is hypothesized to be causally associated with an imbalance in the kynurenine pathway, with an increased metabolism down the 3-hydroxykynurenine (3HK) branch of the pathway leading to increased levels of the neurotoxic metabolite, quinolinic acid (QA), which is a putative Nmethyl- D-aspartate (NMDA) receptor agonist. In contrast, schizophrenia and psychosis are hypothesized to arise from increased metabolism of the NMDA receptor antagonist, kynurenic acid (KynA), leading to hypofunction of GABAergic interneurons, the disinhibition of pyramidal neurons and striatal hyperdopaminergia. Here we present results that challenge the model of excess KynA production in affective psychosis. After rigorous control of potential confounders and multiple testing we find significant reductions in serum KynA and/or KynA/QA in acutely ill inpatients with major depressive disorder (N = 35), bipolar disorder (N = 53) and schizoaffective disorder (N = 40) versus healthy controls (N = 92). No significant difference was found between acutely ill inpatients with schizophrenia (n = 21) and healthy controls. Further, a post hoc comparison of patients divided into the categories of non-psychotic affective disorder, affective psychosis and psychotic disorder (non-affective) showed that the greatest decrease in KynA was in the affective psychosis group relative to the other diagnostic groups. Our results are consistent with reports of elevations in proinflammatory cytokines in psychosis, and preclinical work showing that inflammation upregulates the enzyme, kynurenine mono-oxygenase (KMO), which converts kynurenine into 3-hydroxykynurenine and quinolinic acid

Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma

Annotating Whole Genome Sequencing in COSMIC (The Catalogue of Somatic Mutations in Cancer)

"COSMIC, the Catalogue Of Somatic Mutations In Cancer":http://www.sanger.ac.uk/cosmic is designed to store and display somatic mutation information relating to human cancers, combining detailed information on publications, samples and mutation types. The information is curated both from the primary literature and the laboratories at the Cancer Genome Project, Sanger Institute, UK, and then semi-automatically entered into the COSMIC database. The v47 release (May 2010) contained the curation of 9202 papers describing 116,977 mutations across 466,851 samples. In order to provide consistent annotation of the data, COSMIC has developed a classification system for cancer histology and tissue ontology, and adapted HGVS mutation nomenclature recommendations to describe the multiple mutation types involved in cancer. 

Cancer genetics is moving from systematic screens of candidate gene sets to whole genome sequencing analyses, and COSMIC displays and navigates this new data; we have recently included systematic gene screens and whole genome sequencing studies. COSMIC will annotate and display somatic mutation data that will be emerging from the "International Cancer Genome Consortium (ICGC)":http://www.icgc.org/ and "The Cancer Genome Atlas (TCGA)":http://cancergenome.nih.gov/ projects. New tools are being developed to interpret this genomic data with coding mutation annotations. In addition COSMIC will be expanded to curate and display data from mouse insertional mutagenesis screening and mouse cancer model exome/genome sequencing in the future. The data within COSMIC is freely available without restriction via a website, in datasheets on the "FTP site":ftp://ftp.sanger.ac.uk/pub/CGP/cosmic and through the "COSMIC Biomart":http://www.sanger.ac.uk/genetics/CGP/cosmic/biomart/martview/, available from the "COSMIC homepage":http://www.sanger.ac.uk/cosmic 
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