Regioselective Asao-Yamamoto benzannulations of diaryl acetylenes.
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2014 Nov 21;16(22):5926-9. doi: 10.1021/ol502938y. Epub
2014 Nov 10.Regioselective Asao-Yamamoto benzannulations of diaryl acetylenes.1, , .1Department of Chemistry and Chemical Biology, Cornell University , Baker Laboratory, Ithaca, New York , United States.AbstractAsao-Yamamoto benzannulations transform diarylalkynes into 2,3-diarylnaphthalenes, and regioselective variants of this reaction are of interest for synthesizing substituted polycyclic aromatic systems. It is shown that regioselective cycloadditions occur when one alkyne carbon preferentially stabilizes developing positive charge. Simple calculations of the relative energies of carbocations localized at each alkyne carbon of a substrate predict the regioselectivity, which is not eroded by bulky substituents, including 2,6-disubstituted aryl groups. PMID:
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External link. Please review our .Differential expression of cyclin-dependent kinase 6 in cortical thymocytes and T-cell lymphoblastic lymphoma/leukemia.
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):209-17.Differential expression of cyclin-dependent kinase 6 in cortical thymocytes and T-cell lymphoblastic lymphoma/leukemia.1, , , , , , , , , .1Istituto di Anatomia Patologica, Università di Verona, Italy. marco@anpat.univ.itAbstractCyclin-dependent kinase-6 (CDK6) is the earliest inducible member of the CDK family in human T lymphocytes, involved in growth factor stimulation and cell cycle progression. CDK6 is one of the targets of p16 and p15, CDK inhibitors encoded by MTS1 and MTS2, two tumor suppressor genes that are frequently deleted in T-cell leukemia. In this study we have investigated CDK6 expression in normal and neoplastic lymphoid tissues using immunohistochemistry and flow cytometry. In normal (six samples) and hyperplastic (four samples) thymuses, strong CDK6 expression was observed in a discrete proportion of cortical thymocytes (10 to 15%), mainly located in the peripheral (subcapsular) zone of the cortex. All tested cases of T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL) showed strong CDK6 expression in the majority (up to 100%) of neoplastic lymphoid cells. Western blot analysis confirmed the expected CDK6 protein size (40 kd). According to Southern blot analysis, CDK6 overexpression in neoplastic T lymphoblasts was not due to gene amplification. In all other lymphomas investigated (28 peripheral T-cell non-Hodgkin's lympohomas (T-NHLs), 7 CD30+ anaplastic NHLs, 22 high-grade B-NHLs, 15 low-grade B-NHLs, 25 B-cell precursor ALLs), CDK6 was not expressed or expressed at low levels, with the only exception of three nasal angiocentric T-NHLs, all exhibiting CDK6 immunoreactivity comparable to that observed in T-LBL/ALL. These data provide evidence that CDK6 is abnormally expressed in T-LBL/ALL and may be involved in the pathogenesis of this malignancy. In addition, the quantitative difference of CDK6 expression between neoplastic and non-neoplastic cortical thymocytes can be potentially useful in the differential diagnosis of thymic neoplasms on histological and cytological specimens.PMID:
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External link. Please review our .Effects of blood pressure lowering on outcome incidence in hypertension: 4. Effects of various classes of antihypertensive drugs--overview and meta...
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):195-211. doi: 10.1097/HJH.0447.Effects of blood pressure lowering on outcome incidence in hypertension: 4. Effects of various classes of antihypertensive drugs--overview and meta-analyses.1, , .1aDepartment of Cardiology, Helena Venizelou Hospital, Athens, Greece bDepartment of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Istituto Auxologico Italiano IRCCS cDepartment of Health Sciences, University of Milan Bicocca dScientific Direction, Istituto Auxologico Italiano IRCCS eCentro Interuniversitario di Fisiologia Clinica e Ipertensione, University of Milan, Milan, Italy.AbstractBACKGROUND AND OBJECTIVES: In 68 randomized controlled trials (RCTs), blood pressure (BP) lowering was obtained by using drugs of different classes. We have investigated whether BP lowering by any of the major drug classes is effective in reducing the cardiovascular outcomes.METHODS: A total of 55 RCTs (19,5 267 individuals) were suitable for drug-class meta-analyses. Risk ratios and their 95% confidence intervals of seven fatal and nonfatal outcomes were estimated by a random-effects model.RESULTS: Twelve RCTs (48, 898 patients) compared a diuretic with no treatment. SBP/DBP differences of about -12/-5
mmHg were accompanied by significant reductions of all outcomes, including mortality. The same results were obtained by limiting analyses to eight RCTs using low-dose diuretics. Separate analyses for thiazides, chlorthalidone and indapamide (all low dose) showed each subclass was associated with significant reduction of some major outcome. Five RCTs (18 ,724 SBP/DBP difference -10.5/-7
mmHg) showed beta-blockers significantly reduced stroke, heart failure and major cardiovascular events. In RCTs comparing calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) with placebo smaller SBP/DBP differences were achieved, mostly because in the majority of these later RCTs the antihypertensive drug and placebo were added on a background treatment with other antihypertensive agents. Nonetheless, significant reductions of stroke, major cardiovascular events, cardiovascular and all-cause death were obtained with calcium antagonists (10 RCTs, 30, 359 patients); stroke, coronary heart disease, heart failure and major cardiovascular events by ACE inhibitors (12 RCTs, 35, 707 patients); and stroke, heart failure and major cardiovascular events by ARBs (13 RCTs, 65, 256 patients).CONCLUSION: BP lowering by all classes of antihypertensive drugs is accompanied by significant reductions of stroke and major cardiovascular events. This supports the concept that reduction of these events is because of BP lowering per se rather than specific drug properties. However, evidence of risk reduction of other events and particularly mortality was obtained so far with some drug classes only. As a result of marked differences in the trial design, total cardiovascular risk, SBP/DBP differences and statistical power, comparisons of meta-analyses of different drug-specific placebo-controlled RCTs appear unwarranted.PMID:
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External link. Please review our .An Invertron-Like Linear Plasmid Mediates Intracellular Survival and Virulence in Bovine Isolates of Rhodococcus equi.
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):2725-37. doi: 10.1128/IAI.00376-15. Epub
2015 Apr 20.An Invertron-Like Linear Plasmid Mediates Intracellular Survival and Virulence in Bovine Isolates of Rhodococcus equi.1, 1, 2, 2, 3, 4, 2, 5.1Microbial Pathogenesis Unit, School of Biomedical Sciences and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom.2Division of Infection and Immunity, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.3Microbial Pathogenesis Unit, School of Biomedical Sciences and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom Division of Infection and Immunity, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.4School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland.5Microbial Pathogenesis Unit, School of Biomedical Sciences and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom Division of Infection and Immunity, Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom Grupo de Patogenómica Bacteriana, Facultad de Veterinaria, Universidad de León, León, Spain v.boland@ed.ac.uk.AbstractWe report a novel host-associated virulence plasmid in Rhodococcus equi, pVAPN, carried by bovine isolates of this facultative intracellular pathogenic actinomycete. Surprisingly, pVAPN is a 120-kb invertron-like linear replicon unrelated to the circular virulence plasmids associated with equine (pVAPA) and porcine (pVAPB variant) R. equi isolates. pVAPN is similar to the linear plasmid pNSL1 from Rhodococcus sp. NS1 and harbors six new vap multigene family members (vapN to vapS) in a vap pathogenicity locus presumably acquired via en bloc mobilization from a direct predecessor of equine pVAPA. Loss of pVAPN rendered R. equi avirulent in macrophages and mice. Mating experiments using an in vivo transconjugant selection strategy demonstrated that pVAPN transfer is sufficient to confer virulence to a plasmid-cured R. equi recipient. Phylogenetic analyses assigned the vap multigene family complement from pVAPN, pVAPA, and pVAPB to seven monophyletic clades, each containing plasmid type-specific allelic variants of a precursor vap gene carried by the nearest vap island ancestor. Deletion of vapN, the predicted "bovine-type" allelic counterpart of vapA, essential for virulence in pVAPA, abrogated pVAPN-mediated intramacrophage proliferation and virulence in mice. Our findings support a model in which R. equi virulence is conferred by host-adapted plasmids. Their central role is mediating intracellular proliferation in macrophages, promoted by a key vap determinant present in the common ancestor of the plasmid-specific vap islands, with host tropism as a secondary trait selected during coevolution with specific animal species. Copyright (C) 2015, American Society for Microbiology. All Rights Reserved.PMID:
[PubMed - indexed for MEDLINE] Detection of pVAPN by PFGE. (A) Genomic DNA of bovine isolate 1571 and equine isolate 103S; three and two independent lysates per strain are shown. Relevant positions of the lambda PFGE marker (New England BioLabs) are indicated. pVAPN is observable as a distinct band of ≈100 kb in the bovine isolate. (B) Southern blot analysis of bovine isolates PAM1571, PAM1533, and PAM1554 (strain 103S was used as a negative control). (Left) Relevant sections of the PFGE (right) membrane hybridized with a pVAPN-specific DNA probe (600-bp fragment encompassing the 3′ region of vapN and the 5′ region of vapQ). The arrow indicates the pVAPN band.Infect Immun. ):.Genome alignments of the linear virulence plasmid pVAPN, circular virulence plasmids pVAPA and pVAPB, and the respective closest homologs from nonpathogenic rhodococcal species (pNSL1 from Rhodococcus sp. NS1 [] and pREC1 from R. erythropolis []). The alignments were built with EasyFig (http://easyfig.sourceforge.net/). The circular plasmids (pVAPA, pVAPB, and pREC1) were linearized starting from the first conserved gene of the housekeeping backbone. Regions with significant similarity between plasmids are connected by gray stripes (tblastx E value threshold of 0.1); grayscale indicates percent similarity. ORFs are color coded as follows: hypothetical proteins (gray), conjugation or DNA replication/recombination/metabolism (red), DNA mobility genes (magenta), transcriptional regulators (blue), secreted proteins (dark green), membrane proteins (pale green), metabolic functions (yellow), vap family genes (black), and pseudogenes (brown). Green and pale red bars below the genes indicate conjugation and replication/partitioning functional modules, dashed underline indicates HGT regions identified by Alien_hunter (); and the triangle indicates a putative origin of replication. Abbreviations: 3oxoACPr, 3-oxoacyl-ACP 3oxoACPs, 3-oxoacyl-ACP Endo, Exo, Lig, LT, ly MT, Mtase, PK, PR, pentape ssRec, site- TPR, TPR FA met, fatty acid metabolism.Infect Immun. ):.ML trees of Rhodococcus plasmid backbones (A) and the R. equi vap multigene family (B). The Hasegawa-Kishino-Yano with gamma distribution (HKY+G) evolutionary model was used. (A) ML tree based on a concatenated alignment of orthologs from a selection of rhodococcal extrachromosomal replicons (total of 7,802 nucleotides). The genes used are indicated by dots in . Values &50 for 100 bootstrap replicates are indicated. Symbols: triangles, circles, circular plasmids. (B) vap family members derived from each of the predicted seven precursor vap genes in the MRCA of the extant pVAPA, pVAPB, and pVAPN PAIs are in gray balloons.Infect Immun. ):.pVAPN telomeric sequences. (A) ClustalΩ alignment of the left- and right-end 200 terminal nucleotides. Identical nucleotides are shaded (dark and light blue, purines and pyrimidines, respectively). Inverted repeats are indicated above the sequence. In red are four conserved palindromic sequences with the central motif GCTNCGC identified in the binding site of telomere-associated proteins involved in Streptomyces linear plasmid replication (). Several “GCTNCGC” palindromic sequences are normally present in the telomeres of rhodococcal linear plasmids () (see Fig. S2 in the supplemental material). (B) Secondary structures potentially formed by the palindromic sequences in pVAPN telomeres, as numbered in panel A. Structures were determined with mFold. Free energy (ΔG) values: -33.84 kcal/mol (left), -37.95 kcal/mol (right).Infect Immun. ):.Genetic structure of the vap PAIs from pVAPN (15.1 kb), pVAPA (21.5 kb), and pVAPB (15.9 kb). Color codes of genes: vap family (black), DNA conjugation/partitioning (red), DNA mobility/recombination (magenta), transcriptional regulators (blue), other regulators (cyan), membrane proteins (green), metabolic reactions (yellow). Orthologs are in the same color shade and linked by gray bands. ORFs encoding hypothetical proteins are represented in light blue-gray and in white if they are outside the PAI. White arrowheads point to the first and last genes of the consensus PAI. The traA pseudogene/phage excisionase-rep-copG HGT cluster presumably acquired by pVAPN from the pVAPA backbone is boxed. The figure also schematizes the probable evolutionary relationships of the vap multigene family as inferred from phylogenetic analyses (; see also Fig. S4 and S5 in the supplemental material) and PAI the model minimizes the number of vap gene loss events. Solid lines/arrows connect vap genes belonging to the same monophyletic group (thus likely representing allelic variants of a common vap gene ancestor). Curved lines/arrows indicate vap gene duplications within a PAI. Crosses denote vap genes that were lost, and asterisks indicate pseudogenes. Two alternative evolutionary paths are shown for vapA-vapB-vapK1-vapK2-vapN (see the legend of Fig. S5 in the supplemental material for additional details). The black dots indicate the non-vap genes used for the MLSA shown in Fig. S4B in the supplemental material.Infect Immun. ):.Hypothetical reconstruction of vap PAI evolution. (A) Model of vap multigene family evolution. Lines indicate the evolutionary path of the vap genes between ancestral PAIs, the most recent common ancestor (MRCA), and extant PAIs. Pre-pVAPA designates the hypothetical direct precursor of the current pVAPA PAI. Gene duplication events are indicated by red squares, gene loss events by crosses, and pseudogenes by asterisks and white borders. (B) Fate of the vap PAI and R. equi virulence plasmid evolution. (a) Acquisition by rhodococcal circular replicon of vap PAI ancestor conferring the ability to
(b) mobilization of vap PAI from pre-pVAPA plasmid to rhodoco (c) evolution of species specificity.Infect Immun. ):.Intracellular proliferation in murine (J774A.1) and human (THP-1) macrophages. Data are expressed as normalized IGC values (see Materials and Methods). Means of data from three duplicate experiments ± standard errors are shown. Statistical significance was analyzed by 2-way ANOVA; P values determined by ?idák post hoc multiple-comparison tests at each time point are shown if ≤0.05. (A) Plasmidless derivative and in-frame ΔvapN mutant of bovine isolate 1571. Two-way ANOVA P values = 0.0007 for J774A.1 and 0.0160 for THP-1. (B) Plasmidless derivative and in-frame ΔvapA mutant of equine isolate 103S. Two-way ANOVA P values = 0.0112 for J774A.1 cells and &0.0001 for THP-1 cells.Infect Immun. ):.Competitive virulence assay in mouse lung. BALB/c mice (n = 4 per time point) were infected intranasally with a ≈1:1 mixture of the test bacteria, and the competing populations were monitored 60 min after infection (t = 0) and then on four consecutive days. Bar height denotes total lung CFU, and the light and dark gray areas within bars indicate the proportions of the competing bacteria. Corresponding CI values are shown in . (A) Competition between wild-type bovine isolate 1571 and the isogenic plasmidless derivative 1571- at an infection dose of 3.7 × 107 CFU/mouse (2.3 × 107 and 1.4 × 107 CFU, respectively). (B) Competition between the avirulent 1571- strain and an in-frame 1571ΔvapN deletion mutant at an infection dose of 7.8 × 107 CFU/mouse (3.2 × 107 and 4.6 × 107 CFU, respectively).Infect Immun. ):.Transfer of pVAPN by mating confers virulence to a plasmid-negative R. equi recipient strain. (A) In vivo selection of pVAPN transconjugants in mice. Note the progressive enrichment of the recipient 103S-RmpR strain upon acquisition of the pVAPN plasmid. Time zero is 60 min after infection. (B) Intracellular proliferation in J774A.1 macrophages. Acquisition of pVAPN (and control pVAPA) promotes intracellular proliferation in the recipient 103S-RmpR strain. Data are expressed as normalized IGC values (see Materials and Methods). Means of data from three duplicate experiments ± P values (determined by 2-way ANOVA and ?idák post hoc multiple-comparison tests) are indicated. ns, not significant.Infect Immun. ):.Publication TypesMeSH TermsSubstancesSecondary Source IDGrant SupportFull Text Sources
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