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71.
Ronald C. Bernotas Robert R. Singhaus David H. Kaufman John Ullrich Horace Fletcher Elaine Quinet Ponnal Nambi Rayomand Unwalla Anna Wilhelmsson Annika Goos-Nilsson Mathias Farnegardh Jay Wrobel 《Bioorganic & medicinal chemistry》2009,17(4):1663-1670
A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate substitution with amide groups provided high affinity LXR ligands, some with excellent potency and efficacy in functional assays of LXR activity. Novel amide 4g had a binding IC50 = 1.9 nM for LXRβ and EC50 = 34 nM (96% efficacy relative to T0901317) in an ABCA1 gene expression assay in mouse J774 cells, demonstrating that 4-(biarylether)-quinolines with appropriate amide substitution are potent LXR agonists 相似文献
72.
C Kohl R Lesnik A Brinkmann A Ebinger A Radonić A Nitsche K Mühldorfer G Wibbelt A Kurth 《PloS one》2012,7(8):e43106
In recent years novel human respiratory disease agents have been described in South East Asia and Australia. The causative pathogens were classified as pteropine orthoreoviruses with strong phylogenetic relationship to orthoreoviruses of flying foxes inhabiting these regions. Subsequently, a zoonotic bat-to-human transmission has been assumed. We report the isolation of three novel mammalian orthoreoviruses (MRVs) from European bats, comprising bat-borne orthoreovirus outside of South East Asia and Australia and moreover detected in insectivorous bats (Microchiroptera). MRVs are well known to infect a broad range of mammals including man. Although they are associated with rather mild and clinically unapparent infections in their hosts, there is growing evidence of their ability to also induce more severe illness in dogs and man. In this study, eight out of 120 vespertilionid bats proved to be infected with one out of three novel MRV isolates, with a distinct organ tropism for the intestine. One isolate was analyzed by 454 genome sequencing. The obtained strain T3/Bat/Germany/342/08 had closest phylogenetic relationship to MRV strain T3D/04, isolated from a dog. These novel reoviruses provide a rare chance of gaining insight into possible transmission events and of tracing the evolution of bat viruses. 相似文献
73.
Robert R. Singhaus Ronald C. Bernotas Robert Steffan Edward Matelan Elaine Quinet Ponnal Nambi Irene Feingold Christine Huselton Anna Wilhelmsson Annika Goos-Nilsson Jay Wrobel 《Bioorganic & medicinal chemistry letters》2010,20(2):521-525
Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional assays of LXR activity, good agonist potency and efficacy were found for several analogs. 相似文献
74.
Bryophytes achieve substantial biomass and play several key functional roles in boreal forests that can influence how carbon (C) and nitrogen (N) cycling respond to atmospheric deposition of reactive nitrogen (Nr). They associate with cyanobacteria that fix atmospheric N2, and downregulation of this process may offset anthropogenic Nr inputs to boreal systems. Bryophytes also promote soil C accumulation by thermally insulating soils, and changes in their biomass influence soil C dynamics. Using a unique large-scale (0.1 ha forested plots), long-term experiment (16 years) in northern Sweden where we simulated anthropogenic Nr deposition, we measured the biomass and N2-fixation response of two bryophyte species, the feather mosses Hylocomium splendens and Pleurozium schreberi. Our data show that the biomass declined for both species; however, N2-fixation rates per unit mass and per unit area declined only for H. splendens. The low and high treatments resulted in a 29% and 54% reduction in total feather moss biomass, and a 58% and 97% reduction in total N2-fixation rate per unit area, respectively. These results help to quantify the sensitivity of feather moss biomass and N2 fixation to chronic Nr deposition, which is relevant for modelling ecosystem C and N balances in boreal ecosystems. 相似文献
75.
Benjamin Heuberger Annika Paukner Lauren J. Wooddell Matt Kasman Ross A. Hammond 《American journal of primatology》2020,82(8):e23165
Capuchins, like other primates, use feedback from sensory cues and digestion to make decisions about which foods to consume and which to avoid. However, little is known about how capuchins make consumption decisions when simultaneously presented with novel and familiar foods, or how food familiarity and macronutrient concentration together influence food choice, topics with potential implications for developmental and health research. In this study, we evaluated the role of familiarity, as well as fat and sugar concentration, in the food selections of captive tufted capuchins (Sapajus apella). In the first experiment, over 10 sessions, subjects were assigned to either a group that chose between one familiar and one novel food item both high in fat or sugar (high condition), or to a group that chose between one familiar and one novel food item both low in fat or sugar (low condition). In the second experiment, subjects were divided into three groups, familiarized with food over five feeding sessions, and then offered the familiarized food and a novel food that varied in fat or sugar for 10 sessions. When offered foods high in fat, capuchins showed no clear signs of neophobia, forming an initial preference for the novel food, rejecting foods less frequently, and selecting foods faster than when offered foods low in fat. These trends were generally not observed in response to foods with sugar. When presented with options that varied in macronutrient concentration, subjects showed an initial interest in the novel food irrespective of whether it was high in fat or sugar, yet formed a final preference for the higher-concentration item. Findings suggest that the concentration of fat or sugar in novel foods may be an important mediator of exploratory behavior and that capuchins rely on immediate feedback from taste and other sensory cues to make consumption decisions. 相似文献
76.
IFN-gamma and IL-10 mediate parasite-specific immune responses of cord blood cells induced by pregnancy-associated Plasmodium falciparum malaria 总被引:4,自引:0,他引:4
Brustoski K Möller U Kramer M Petelski A Brenner S Palmer DR Bongartz M Kremsner PG Luty AJ Krzych U 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(3):1738-1745
Available evidence suggests that immune cells from neonates born to mothers with placental Plasmodium falciparum (Pf) infection are sensitized to parasite Ag in utero but have reduced ability to generate protective Th1 responses. In this study, we detected Pf Ag-specific IFN-gamma(+) T cells in cord blood from human neonates whose mothers had received treatment for malaria or who had active placental Pf infection at delivery, with responses being significantly reduced in the latter group. Active placental malaria at delivery was also associated with reduced expression of monocyte MHC class I and II in vivo and following short term in vitro coculture with Pf Ag compared with levels seen in neonates whose mothers had received treatment during pregnancy. Given that APC activation and Th1 responses are driven in part by IFN-gamma and down-regulated by IL-10, we examined the role of these cytokines in modulating the Pf Ag-specific immune responses in cord blood samples. Exogenous recombinant human IFN-gamma and neutralizing anti-human IL-10 enhanced T cell IFN-gamma production, whereas recombinant human IFN-gamma also restored MHC class I and II expression on monocytes from cord blood mononuclear cells cocultured with Pf Ag. Accordingly, active placental malaria at delivery was associated with increased frequencies of Pf Ag-specific IL-10(+)CD4(+) T cells in cord blood mononuclear cell cultures from these neonates. Generation and maintenance of IL-10(+) T cells in utero may thus contribute to suppression of APC function and Pf Ag-induced Th1 responses in newborns born to mothers with placental malaria at delivery, which may increase susceptibility to infection later in life. 相似文献
77.
Hanage WP Kaijalainen T Herva E Saukkoriipi A Syrjänen R Spratt BG 《Journal of bacteriology》2005,187(17):6223-6230
We investigated the genetic relationships between serotypeable pneumococci and nonserotypeable presumptive pneumococci using multilocus sequence typing (MLST) and partial sequencing of the pneumolysin gene (ply). Among 121 nonserotypeable presumptive pneumococci from Finland, we identified isolates of three classes: those with sequence types (STs) identical to those of serotypeable pneumococci, suggesting authentic pneumococci in which capsular expression had been downregulated or lost; isolates that clustered among serotypeable pneumococci on a tree based on the concatenated sequences of the MLST loci but which had STs that differed from those of serotypeable pneumococci in the MLST database; and a more diverse collection of isolates that did not cluster with serotypeable pneumococci. The latter isolates typically had sequences at all seven MLST loci that were 5 to 10% divergent from those of authentic pneumococci and also had distinct and divergent ply alleles. These isolates are proposed to be distinct from pneumococci but cannot be resolved from them by optochin susceptibility, bile solubility, or the presence of the ply gene. Complete resolution of pneumococci from the related but distinct population is problematic, as recombination between them was evident, and a few isolates of each population possessed alleles at one or occasionally more MLST loci from the other population. However, a tree based on the concatenated sequences of the MLST loci in most cases unambiguously distinguished whether a nonserotypeable isolate was or was not a pneumococcus, and the sequence of the ply gene fragment was found to be useful to resolve difficult cases. 相似文献
78.
Roland Reinehr Holger Gohlke Annika Sommerfeld Stephan vom Dahl Dieter H?ussinger 《The Journal of biological chemistry》2010,285(38):29348-29356
High concentrations of urea were shown to induce a paradoxical regulatory volume decrease response with K+ channel opening and subsequent hepatocyte shrinkage (Hallbrucker, C., vom Dahl, S., Ritter, M., Lang, F., and Häussinger, D. (1994) Pflügers Arch. 428, 552–560), although the hepatocyte plasma membrane is thought to be freely permeable to urea. The underlying mechanisms remained unclear. As shown in the present study, urea (100 mmol/liter) induced within 1 min an activation of β1 integrins followed by an activation of focal adhesion kinase, c-Src, p38MAPK, extracellular signal-regulated kinases, and c-Jun N-terminal kinase. Because α5β1 integrin is known to act as a volume/osmosensor in hepatocytes, which becomes activated in response to hepatocyte swelling, the findings suggest that urea at high concentrations induces a nonosmotic activating perturbation of this osmosensor, thereby triggering a volume regulatory K+ efflux. In line with this, similar to hypo-osmotic hepatocyte swelling, urea induced an inhibition of hepatic proteolysis, which was sensitive to p38MAPK inhibition. Molecular dynamics simulations of a three-dimensional model of the ectodomain of α5β1 integrin in water, urea, or thiourea solutions revealed significant conformational changes of α5β1 integrin in urea and thiourea solutions, in contrast to the simulation of α5β1 in water. These changes lead to an unbending of the integrin structure around the genu, which may suggest activation, whereas the structures of single domains remained essentially unchanged. It is concluded that urea at high concentrations affects hepatic metabolism through direct activation of the α5β1 integrin system. 相似文献
79.
Wilhelmson A Häkkinen ST Kallio PT Oksman-Caldentey KM Nuutila AM 《Biotechnology progress》2006,22(2):350-358
Fast-growing hairy root cultures of Hyoscyamus muticus induced by Agrobacterium rhizogenes offer a potential production system for tropane alkaloids. Oxygen deficiency has been shown to limit growth and biomass accumulation of hairy roots, whereas little experimental data is available on the effect of oxygen on alkaloid production. We have investigated the effect of Vitreoscilla hemoglobin (VHb) expression and cultivation conditions on the complete alkaloid profile of H. muticus hairy roots in shake flasks and in a laboratory scale bioreactor. We optimized the growth medium composition and studied the effects of sucrose, ammonium, nitrate, and phosphate on growth and alkaloid production. Maximum biomass accumulation was achieved with the highest and maximum hyoscyamine content with the lowest sucrose concentration. The optimum nitrate concentration for growth was higher for the VHb line than the control. Neither VHb expression nor aeration improved the hyoscyamine content significantly, thus suggesting that hyoscyamine biosynthesis is not limited by oxygen availability. Interestingly, the effect of VHb expression on the alkaloid profile was slightly different from that of aeration. VHb expression did not affect the concentrations of cuscohygrine, which was increased by aeration. Therefore, the effect of VHb is probably not related only to its ability to increase the intracellular effective oxygen concentration. 相似文献
80.
Weak telomerase activity in malignant cells in metastatic serous effusions: correlation to short survival time 总被引:1,自引:0,他引:1
OBJECTIVE: The purpose of this study was to evaluate whether the intensity of telomerase activity measured on the cellular level in effusions correlates to survival time in cases of metastatic spread to the serous cavities. STUDY DESIGN: Telomere repeat amplification protocol (TRAP) in situ was applied to 46 effusions containing metastatic cancer cells. RESULTS: Weak telomerase activity in tumor cells was seen in 7 cases, and moderate or strong activity in 39 cases. The intensity of the enzyme activity correlated significantly to survival (Kaplan-Meier survival analysis), the median survival time being 18 days for patients with weakly positive tumors and 100 days for patients with moderately or strongly positive tumors (Kruskal-Wallis test, p = 0.021). CONCLUSION: The strong relationship between telomerase activity in tumor cells in effusions and survival time has never been described before. Determination of telomerase activity on the cellular level provides a way to identify a subgroup of patients with a high probability of short survival. 相似文献