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41.
Gilbert AM Bursavich MG Lombardi S Adedoyin A Dwyer JM Hughes Z Kern JC Khawaja X Rosenzweig-Lipson S Moore WJ Neal SJ Olsen M Rizzo SJ Springer D 《Bioorganic & medicinal chemistry letters》2011,21(1):195-199
A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC50: 926 nM), potent mGluR5 NAMs showing excellent potencies (IC50s <50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (Ki: 21 nM) and antagonism (IC50: 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk). 相似文献
42.
Demery ZP Chappell J Martin GR 《Proceedings. Biological sciences / The Royal Society》2011,278(1725):3687-3693
Parrots are exceptional among birds for their high levels of exploratory behaviour and manipulatory abilities. It has been argued that foraging method is the prime determinant of a bird's visual field configuration. However, here we argue that the topography of visual fields in parrots is related to their playful dexterity, unique anatomy and particularly the tactile information that is gained through their bill tip organ during object manipulation. We measured the visual fields of Senegal parrots Poicephalus senegalus using the ophthalmoscopic reflex technique and also report some preliminary observations on the bill tip organ in this species. We found that the visual fields of Senegal parrots are unlike those described hitherto in any other bird species, with both a relatively broad frontal binocular field and a near comprehensive field of view around the head. The behavioural implications are discussed and we consider how extractive foraging and object exploration, mediated in part by tactile cues from the bill, has led to the absence of visual coverage of the region below the bill in favour of more comprehensive visual coverage above the head. 相似文献
43.
Faithful segregation of homologous chromosomes during meiosis requires pairing, synapsis, and crossing-over. In C.?elegans, homolog pairing and synapsis depend on pairing centers (PCs), special regions near one end of each chromosome that interact with the nuclear envelope (NE) and cytoplasmic microtubules. Here, we report that PCs are required for nuclear reorganization at the onset of meiosis. We demonstrate that PCs recruit the Polo-like kinase PLK-2 to induce NE remodeling, chromosome pairing, and synapsis. Recruitment of PLK-2 is also required to mediate a cell cycle delay and selective apoptosis of nuclei containing unsynapsed chromosomes, establishing a molecular link between these two quality control mechanisms. This work reveals unexpected functions for the conserved family of Polo-like kinases, and advances our understanding of how meiotic processes are properly coordinated to ensure transmission of genetic information from parents to progeny. 相似文献
44.
Temporal changes in greenspace in a highly urbanized region 总被引:1,自引:0,他引:1
The majority of the world's population now lives in towns and cities, and urban areas are expanding faster than any other land-use type. In response to this phenomenon, two opposing arguments have emerged: whether cities should 'sprawl' into the wider countryside, or 'densify' through the development of existing urban greenspace. However, these greenspaces are increasingly recognized as being central to the amelioration of urban living conditions, supporting biodiversity conservation and ecosystem service provision. Taking the highly urbanized region of England as a case study, we use data from a variety of sources to investigate the impact of national-level planning policy on temporal patterns in the extent of greenspace in cities. Between 1991 and 2006, greenspace showed a net increase in all but one of 13 cities. However, the majority of this gain occurred prior to 2001, and greenspace has subsequently declined in nine cities. Such a dramatic shift in land use coincides with policy reforms in 2000, which favoured densification. Here, we illustrate the dynamic and policy-responsive nature of urban land use, thereby highlighting the need for a detailed investigation of the trade-offs associated with different mechanisms of urban densification to optimize and secure the diverse benefits associated with greenspaces. 相似文献
45.
Athanasios Tragiannidis Zoe Dorothea Pana Theodotis Papageorgiou Emmanuel Hatzipantelis Maria Hatzistilianou Fani Athanassiadou 《Journal of medical case reports》2011,5(1):407
Introduction
Transient myeloproliferative disorder is a hematologic abnormality characterized by an uncontrolled proliferation of myeloblasts in peripheral blood and bone marrow that primarily affects newborns and babies with Down syndrome. Tumor lysis syndrome is rarely associated with transient myeloproliferative disorder.Case presentation
Transient myeloproliferative disorder was diagnosed in a seven-day-old baby girl with Down syndrome, who was referred to our department due to hyperleukocytosis. Our patient developed tumor lysis syndrome, successfully treated with rasburicase, as a complication of transient myeloproliferative disorder resulting from rapid degradation of myeloid blasts after initiation of effective chemotherapy.Conclusions
Tumor lysis syndrome is rarely reported as a complication of transient myeloproliferative disorder. To the best of our knowledge, this is the first case of a newborn with Down syndrome and transient myeloproliferative disorder treated with rasburicase for developing tumor lysis syndrome.46.
Yuxuan Wang Suri Guga Kejia Wu Zoe Khaw Konstantinos Tzoumkas Phil Tombleson Mary E. Comeau Carl D. Langefeld Deborah S. Cunninghame Graham David L. Morris Timothy J. Vyse 《PLoS genetics》2022,18(11)
Genome wide association studies show there is a genetic component to severe COVID-19. We find evidence that the genome-wide genetic association signal with severe COVID-19 is correlated with that of systemic lupus erythematosus (SLE), having formally tested this using genetic correlation analysis by LD score regression. To identify the shared associated loci and gain insight into the shared genetic effects, using summary level data we performed meta-analyses, a local genetic correlation analysis and fine-mapping using stepwise regression and functional annotation. This identified multiple loci shared between the two traits, some of which exert opposing effects. The locus with most evidence of shared association is TYK2, a gene critical to the type I interferon pathway, where the local genetic correlation is negative. Another shared locus is CLEC1A, where the direction of effects is aligned, that encodes a lectin involved in cell signaling, and the anti-fungal immune response. Our analyses suggest that several loci with reciprocal effects between the two traits have a role in the defense response pathway, adding to the evidence that SLE risk alleles are protective against infection. 相似文献
47.
Roberts C Winter P Shilliam CS Hughes ZA Langmead C Maycox PR Dawson LA 《Neurochemical research》2005,30(3):371-377
LPA1 is a Gi-coupled seven transmembrane receptor with high affinity for the ligand lysophosphatidic acid. We have investigated the effect of targeted deletion at the lpa1 locus on evoked release of amino acids from hippocampal slices, using in vitro superfusion techniques, and evoked 5-HT efflux from the dorsal raphe nucleus, using in vitro fast cyclic voltammetry. Superfusion of hippocampal slices revealed that basal levels of tyrosine, aspartate and glutamate release were significantly increased while K+-evoked release of glutamate and GABA were significantly decreased in lpa1(–/–) mice. Fast cyclic voltammetry measurements in the dorsal raphe nucleus demonstrated significant decreases in electrically evoked 5-HT efflux in lpa1(–/–) mice. In summary, these data demonstrate that the lpa1 mutation produces a number of changes in neurotransmitters that have been associated with a schizophrenic-like pathology. 相似文献
48.
Martic G Karetsou Z Kefala K Politou AS Clapier CR Straub T Papamarcaki T 《The Journal of biological chemistry》2005,280(16):16143-16150
Linker histone H1 is the major factor that stabilizes higher order chromatin structure and modulates the action of chromatin-remodeling enzymes. We have previously shown that parathymosin, an acidic, nuclear protein binds to histone H1 in vitro and in vivo. Confocal laser scanning microscopy reveals a nuclear punctuate staining of the endogenous protein in interphase cells, which is excluded from dense heterochromatic regions. Using an in vitro chromatin reconstitution system under physiological conditions, we show here that parathymosin (ParaT) inhibits the binding of H1 to chromatin in a dose-dependent manner. Consistent with these findings, H1-containing chromatin assembled in the presence of ParaT has reduced nucleosome spacing. These observations suggest that interaction of the two proteins might result in a conformational change of H1. Fluorescence spectroscopy and circular dichroism-based measurements on mixtures of H1 and ParaT confirm this hypothesis. Human sperm nuclei challenged with ParaT become highly decondensed, whereas overexpression of green fluorescent protein- or FLAG-tagged protein in HeLa cells induces global chromatin decondensation and increases the accessibility of chromatin to micrococcal nuclease digestion. Our data suggest a role of parathymosin in the remodeling of higher order chromatin structure through modulation of H1 interaction with nucleosomes and point to its involvement in chromatin-dependent functions. 相似文献
49.
Kevin J. Flynn John A. Raven T. Alwyn V. Rees Zoe Finkel Antonietta Quigg John Beardall 《Journal of phycology》2010,46(1):1-12
The growth rate hypothesis (GRH) asserts, from known biochemistry, that maintaining high growth rates requires high concentrations of ribosomes. Since ribosomes are rich in phosphorus (P), the GRH predicts a positive correlation between growth rate and P content; this correlation is observed in some organisms. We consider the application of the GRH to phytoplankton and identify several key problems that require further research before the hypothesis can be accepted for these organisms. There are severe methodological problems that confound interpretation of data for testing the GRH. These problems include the measurement of protein and nucleic acids (such that ratio of these components carries a high level of uncertainty), studies of steady‐state versus dynamic systems, and the presentation of data per cell (especially as cell size varies with growth rate limitations) and the calculation of growth rates. In addition, because of the short generation times and rapid responses of these organisms to perturbations, ribosome and RNA content is expected to vary in response to (de)repression of various systems; content may increase on application of growth‐limiting stress. Finally, that most phytoplankton accumulate P when not P stressed conflicts with the GRH. In consequence, the value of the GRH for any sort of predictive role in nature appears to be severely limited. We conclude that the GRH cannot be assumed to apply to phytoplankton taxa without first performing experimental tests under transient conditions. 相似文献