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91.
Sunose M Bell K Ellard K Bergamini G Neubauer G Werner T Ramsden N 《Bioorganic & medicinal chemistry letters》2012,22(14):4613-4618
Herein, we disclose the discovery of a series of 7-substituted triazolopyridines which culminated in the identification of 14 (CZC24758), a potent, orally bioavailable small-molecule inhibitor of PI3Kγ, an attractive drug target for inflammatory and autoimmune disorders. Compound 14 has excellent selectivity across the kinome, demonstrates good potency in cell based assays and furthermore exhibits in vivo efficacy in a collagen induced arthritis model in mouse after oral dosing. 相似文献
92.
Ratner C Ettrup A Bueter M Haahr ME Compan V le Roux CW Levin B Hansen HH Knudsen GM 《Obesity (Silver Spring, Md.)》2012,20(10):2133-2141
Food intake and body weight are regulated by a complex system of neural and hormonal signals, of which the anorexigenic neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) is central. In this study, rat models of obesity and weight loss intervention were compared with regard to several 5-HT markers. Using receptor autoradiography, brain regional-densities of the serotonin transporter (SERT) and the 5-HT(2A) and 5-HT(4) receptors were measured in (i) selectively bred polygenic diet-induced obese (pgDIO) rats, (ii) outbred DIO rats, and (iii) Roux-en-Y gastric bypass (RYGB)-operated rats. pgDIO rats had higher 5-HT(4) and 5-HT(2A) receptor binding and lower SERT binding when compared to polygenic diet-resistant (pgDR) rats. The most pronounced difference between pgDIO and pgDR rats was observed in the nucleus accumbens shell (NAcS), a brain region regulating reward aspects of feeding. No differences were found in the 5-HT markers between DIO rats, chow-fed control rats, and DIO rats experiencing a weight loss. The 5-HT markers were also similar in RYGB and sham-operated rats except for a downregulation of 5-HT(2A) receptors in the NAcS. The higher receptor and lower SERT binding in pgDIO as compared to pgDR rats corresponds to what is reported in overweight humans and suggests that the dysfunctions of the 5-HT system associated with overeating or propensity to become overweight are polygenically determined. Our results support that the obesity-prone rat model has high translational value and suggests that susceptibility to develop obesity is associated with changed 5-HT tone in the brain that may also regulate hedonic aspects of feeding. 相似文献
93.
RNA-mediated gene duplication has been proposed to create processed paralogs in the plant mitochondrial genome. A processed paralog may retain signatures left by the maturation process of its RNA precursor, such as intron removal and no need of RNA editing. Whereas it is well documented that an RNA intermediary is involved in the transfer of mitochondrial genes to the nucleus, no direct evidence exists for insertion of processed paralogs in the mitochondria (i.e., processed and un-processed genes have never been found simultaneously in the mitochondrial genome). In this study, we sequenced a region of the mitochondrial gene nad1, and identified a number of taxa were two different copies of the region co-occur in the mitochondria. The two nad1 paralogs differed in their (a) presence or absence of a group II intron, and (b) number of edited sites. Thus, this work provides the first evidence of co-existence of processed paralogs and their precursors within the plant mitochondrial genome. In addition, mapping the presence/absence of the paralogs provides indirect evidence of RNA-mediated gene duplication as an essential process shaping the mitochondrial genome in plants. 相似文献
94.
Simonsen A Badawi N Anskjær GG Albers CN Sørensen SR Sørensen J Aamand J 《Applied microbiology and biotechnology》2012,94(1):237-245
Degradation and mineralisation of the groundwater contaminant 2,6-dichloro-benzamide (BAM) was investigated in two Aminobacter strains focussing on the induction of BAM degradation and mineralisation and occurrence of intermediate metabolites. The
BAM degradation rate was independent of whether the cells were pre-grown in the absence or presence of BAM, thus indicating
that the first step in the degradation pathway was constitutively expressed. In contrast, 14CO2 production was stimulated when cells were pre-grown in the presence of BAM, suggesting that one or more of the subsequent
steps in the degradation pathway were inducible. Accumulation of 2,6-dichlorobenzoate (DCBA) during degradation of BAM demonstrated
that the first step involved amidase activity. Mass balance calculations and thin-layer chromatography coupled with autoradiographic
detection indicated that degradation of DCBA and at least one unknown metabolite may comprise a bottleneck for BAM mineralisation
by Aminobacter spp. The study thus provides novel information about the BAM degradation pathway and points to the involvement of unknown
intermediate metabolites in degradation of this important groundwater contaminant. 相似文献
95.
96.
Morten Frederiksen Børge Moe Francis Daunt Richard A. Phillips Robert T. Barrett Maria I. Bogdanova Thierry Boulinier John W. Chardine Olivier Chastel Lorraine S. Chivers Signe Christensen‐Dalsgaard Céline Clément‐Chastel Kendrew Colhoun Robin Freeman Anthony J. Gaston Jacob González‐Solís Aurélie Goutte David Grémillet Tim Guilford Gitte H. Jensen Yuri Krasnov Svein‐Håkon Lorentsen Mark L. Mallory Mark Newell Bergur Olsen Deryk Shaw Harald Steen Hallvard Strøm Geir H. Systad Thorkell L. Thórarinsson Tycho Anker‐Nilssen 《Diversity & distributions》2012,18(6):530-542
Aim An understanding of the non‐breeding distribution and ecology of migratory species is necessary for successful conservation. Many seabirds spend the non‐breeding season far from land, and information on their distribution during this time is very limited. The black‐legged kittiwake, Rissa tridactyla, is a widespread and numerous seabird in the North Atlantic and Pacific, but breeding populations throughout the Atlantic range have declined recently. To help understand the reasons for the declines, we tracked adults from colonies throughout the Atlantic range over the non‐breeding season using light‐based geolocation. Location North Atlantic. Methods Geolocation data loggers were deployed on breeding kittiwakes from 19 colonies in 2008 and 2009 and retrieved in 2009 and 2010. Data from 236 loggers were processed and plotted using GIS. Size and composition of wintering populations were estimated using information on breeding population size. Results Most tracked birds spent the winter in the West Atlantic, between Newfoundland and the Mid‐Atlantic Ridge, including in offshore, deep‐water areas. Some birds (mainly local breeders) wintered in the North Sea and west of the British Isles. There was a large overlap in winter distributions of birds from different colonies, and colonies closer to each other showed larger overlap. We estimated that 80% of the 4.5 million adult kittiwakes in the Atlantic wintered west of the Mid‐Atlantic Ridge, with only birds from Ireland and western Britain staying mainly on the European side. Main conclusions The high degree of mixing in winter of kittiwakes breeding in various parts of the Atlantic range implies that the overall population could be sensitive to potentially deteriorating environmental conditions in the West Atlantic, e.g. owing to lack of food or pollution. Our approach to estimating the size and composition of wintering populations should contribute to improved management of birds faced with such challenges. 相似文献
97.
Sanne Skov Jensen Anders Fomsgaard Marie Borggren Jeanette Linnea Tingstedt Jan Gerstoft Gitte Kronborg Line Dahlerup Rasmussen Court Pedersen Ingrid Karlsson 《PloS one》2015,10(12)
Understanding alterations in HIV-specific immune responses during antiretroviral therapy (ART), such as antibody-dependent cellular cytotoxicity (ADCC), is important in the development of novel strategies to control HIV-1 infection. This study included 53 HIV-1 positive individuals. We evaluated the ability of effector cells and antibodies to mediate ADCC separately and in combination using the ADCC-PanToxiLux assay. The ability of the peripheral blood mononuclear cells (PBMCs) to mediate ADCC was significantly higher in individuals who had been treated with ART before seroconversion, compared to the individuals initiating ART at a low CD4+ T cell count (<350 cells/μl blood) and the ART-naïve individuals. The frequency of CD16 expressing natural killer (NK) cells correlated with both the duration of ART and Granzyme B (GzB) activity. In contrast, the plasma titer of antibodies mediating ADCC declined during ART. These findings suggest improved cytotoxic function of the NK cells if initiating ART early during infection, while the levels of ADCC mediating antibodies declined during ART. 相似文献
98.
The lengths of roots and root hairs and the extent of root-induced processes affect phosphorus (P) uptake efficiency by plants. To assess the influence of variation in the lengths of roots and root hairs and rhizosphere processes on the efficiency of soil phosphorus (P) uptake, a pot experiment with a low-P soil and eight selected genotypes of cowpea (Vigna unguiculata (L) WALP) was conducted. Root length, root diameter and root hair length were measured to estimate the soil volume exploited by roots and root hairs. The total soil P was considered as a pool of Olsen-P, extractable with 0.5 M NaHCO3 at pH 8.5, and a pool of non-Olsen-P. Model calculations were made to estimate P uptake originated from Olsen-P in the root hair zone and the Olsen-P moving by diffusion into the root hair cylinder and non-Olsen-P uptake. The mean uptake rate of P and the mean rate of non-Olsen-P depletion were also estimated. The genotypes differed significantly in lengths of roots and root hairs, and in P uptake, P uptake rates and growth. From 6 to 85% of total P uptake in the soil volume exploited by roots and root hairs was absorbed from the pool of non-Olsen-P. This indicates a considerable activity of root-induced rhizosphere processes. Hence the large differences show that traits for more P uptake-efficient plants exist in the tested cowpea genotypes. This opens the possibility to breed for more P uptake-efficient varieties as a way to bring more sparingly soluble soil P into cycling in crop production and obtain capitalisation of soil P reserves. 相似文献
99.
Gitte Van Baelen Steven Hostyn Liene Dhooghe Pál Tapolcsányi Péter Mátyus Guy Lemière Roger Dommisse Marcel Kaiser Reto Brun Paul Cos Louis Maes György Hajós Zsuzsanna Riedl Ildikó Nagy Bert U.W. Maes Luc Pieters 《Bioorganic & medicinal chemistry》2009,17(20):7209-7217
Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-β-carboline, showed the best in vitro activity, with an IC50 value of 0.45 μM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI > 1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure–activity relationships are discussed and compared with related naturally occurring compounds. 相似文献
100.
Erbs G Jensen TT Silipo A Grant W Dow JM Molinaro A Parrilli M Newman MA 《Microbes and infection / Institut Pasteur》2008,10(5):571-574
Lipopolysaccharides, the ubiquitous part of the outer membrane of Gram-negative bacteria, and their derivatives are recognised by plants to trigger or potentiate particular defence responses such as induction of genes encoding pathogenesis-related proteins. The molecular mechanisms of LPS perception that underpin these effects in plants are, however, unknown. Here, lipid A from Halomonas magadiensis, which is an antagonist of lipid A action in human cells, was used to investigate lipid A action in plants. Our findings offer an insight into the different structural requirements for direct induction and potentiation of plant defences by lipid A. 相似文献