Changes in the 24-h plasma cortisol rhythm in patients with cirrhosis

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Role of CD59 in experimental glomerulonephritis in rats

Role of CD59 in experimental glomerulonephritis in rats. CD59 is a molecule which is present on the host cell membranes and inhibits formation of membrane attack complex. A monoclonal antibody, 6D1, recognizes a rat analogue of human CD59. 6D1 inhibits function of rat CD59 and can enhance complement-mediated hemolysis in vitro. To assess the role of CD59 in complement-mediated glomerular injury, 6D1 was tested in a model of experimental glomerulonephritis induced by a lectin and its antibodies. The left kidney of a rat was perfused either with 200 µg of Lens culinaris hemoagglutinin (LCH) plus 1mg of 6D1 (IgGl fraction) (Group I and III) or with LCH only (Group II) through a cannula placed in the left renal artery. All the perfusate was discarded from a cannula in the renal vein. The holes in the artery and vein were repaired by microsurgery and the blood circulation was re-established. Rats were injected either with 0.125ml of rabbit anti-LCH serum (Group I and II), or with normal rabbit serum (Group III) via tail vein one minute after the recirculation. Fifteen minutes after injection, significant C9 deposition in the glomeruli was observed only in Group I, whereas C3 deposition in Group I and II were comparable. At Day 4, total glomerular cells, proliferating cells, glomerular expression of intercellular adhesion molecule-1 and fibrin deposition in Group I were all significantly increased when compared with Group II. At Day 7, number of total glomerular cells and leukocytes in the glomeruli of Group I were significantly higher than in Group II. The glomeruli in Group III appeared normal throughout experiments. These data indicate that the functional inhibition of a rat analogue of human CD59 worsens complement-mediated glomerular injury in vivo

Healthcare resource utilization and related financial costs associated with glucose lowering with either exenatide or basal insulin: a retrospective cohort study

Aims Type 2 diabetes is a major health problem placing increasing demands on healthcare systems. Our objective was to estimate healthcare resource use and related financial costs following treatment with exenatide‐based regimens prescribed as once‐weekly (EQW) or twice‐daily (EBID) formulations, compared with regimens based on basal insulin (BI). Materials and methods This retrospective cohort study used data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES). Patients with type 2 diabetes who received exenatide or BI between 2009 and 2014 as their first recorded exposure to injectable therapy were selected. Costs were attributed to primary care contacts, diabetes‐related prescriptions and inpatient admissions using standard UK healthcare costing methods (2014 prices). Frequency and costs were compared between cohorts before and after matching by propensity score using Poisson regression. Results Groups of 8723, 218 and 2180 patients receiving BI, EQW and EBID, respectively, were identified; 188 and 1486 patients receiving EQW and EBID, respectively, were matched 1:1 to patients receiving BI by propensity score. Among unmatched cohorts, total crude mean costs per patient‐year were £2765 for EQW, £2549 for EBID and £4080 for BI. Compared with BI, the adjusted annual cost ratio (aACR) was 0.92 (95% CI, 0.91‐0.92) for EQW and 0.82 (95% CI, 0.82‐0.82) for EBID. Corresponding costs for the propensity‐matched subgroups were £2646 vs £3283 (aACR, 0.80, 0.80‐0.81) for EQW vs BI and £2532 vs £3070 (aACR, 0.84, 0.84‐0.84) for EBID vs BI. Conclusion Overall, exenatide once‐weekly and twice‐daily‐based regimens were associated with reduced healthcare resource use and costs compared with basal‐insulin‐based regimens

Prevalence and diversity of TAL effector-like proteins in fungal endosymbiotic Mycetohabitans spp.

Endofungal Mycetohabitans (formerly Burkholderia) spp. rely on a type III secretion system to deliver mostly unidentified effector proteins when colonizing their host fungus, Rhizopus microsporus. The one known secreted effector family from Mycetohabitans consists of homologues of transcription activator-like (TAL) effectors, which are used by plant pathogenic Xanthomonas and Ralstonia spp. to activate host genes that promote disease. These 'Burkholderia TAL-like (Btl)' proteins bind corresponding specific DNA sequences in a predictable manner, but their genomic target(s) and impact on transcription in the fungus are unknown. Recent phenotyping of Btl mutants of two Mycetohabitans strains revealed that the single Btl in one Mycetohabitans endofungorum strain enhances fungal membrane stress tolerance, while others in a Mycetohabitans rhizoxinica strain promote bacterial colonization of the fungus. The phenotypic diversity underscores the need to assess the sequence diversity and, given that sequence diversity translates to DNA targeting specificity, the functional diversity of Btl proteins. Using a dual approach to maximize capture of Btl protein sequences for our analysis, we sequenced and assembled nine Mycetohabitans spp. genomes using long-read PacBio technology and also mined available short-read Illumina fungal-bacterial metagenomes. We show that btl genes are present across diverse Mycetohabitans strains from Mucoromycota fungal hosts yet vary in sequences and predicted DNA binding specificity. Phylogenetic analysis revealed distinct clades of Btl proteins and suggested that Mycetohabitans might contain more species than previously recognized. Within our data set, Btl proteins were more conserved across M. rhizoxinica strains than across M. endofungorum, but there was also evidence of greater overall strain diversity within the latter clade. Overall, the results suggest that Btl proteins contribute to bacterial-fungal symbioses in myriad ways

Piperazinyl quinolines as chemosensitizers to increase fluconazole susceptibility of Candida albicans clinical isolates

The effectiveness of the potent antifungal drug fluconazole is being compromised by the rise of drug-resistant fungal pathogens. While inhibition of Hsp90 or calcineurin can reverse drug resistance in Candida, such inhibitors also impair the homologous human host protein and fungal-selective chemosensitizers remain rare. The MLPCN library was screened to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. A piperazinyl quinoline was identified as a new small-molecule probe (ML189) satisfying these criteria.National Institutes of Health (U.S.) (1 R03 MH086456-01

Structure sensitivity and hydration effects in Pt/TiO2 and Pt/TiO2?SiO2 catalysts for NO and propane oxidation

The NO and propane oxidation activities of a series of 1%Pt/TiO2–SiO2 catalysts show different underlying trends as the support composition changes. Surface characterisation of the catalysts indicates that the trend for NO conversion is consistent with the oxidation rate being dependent on the degree of metallic character of the Pt nanoparticles, rather than their morphology. Although a similar correlation is expected for the total oxidation of propane, it is masked by the effects of adventitious ions originating during manufacture of the support materials. When residual chloride is present in the support, most of the exposed Pt is stabilised in its low-activity ionic form; while support materials containing W or oxidised-S ions give rise to catalysts with much higher activity than expected from their measured Pt0 content. When a Cl-containing, but SiO2-free, TiO2 support material is pre-treated hydrothermally, the propane-oxidation activity of the resultant Pt/TiO2 catalyst is substantially improved, so that it matches the performance of highly-metallic Pt supported on TiO2 containing 16 wt% SiO2. The hydrothermal pre-treatment removes residual chloride from the support material, but it also leaves the catalyst in a hydrated state. We show that, by controlling the metallic content of Pt nanoparticles, understanding the promoting and inhibiting effects of adventitious ions, and optimising the degree of catalyst hydration, the activity of 1%Pt/TiO2–SiO2 catalysts can be made to exceed that of a benchmark 2%Pt/γ-Al2O3 formulation for both NO and propane oxidation

LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells

Canonical Wnt/β-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia patients; however, some patients exhibit little or no nuclear β-catenin even where cytosolic β-catenin is abundant. Control of the subcellular localization of β-catenin therefore represents an additional mechanism regulating Wnt signaling in hematopoietic cells. To investigate the factors mediating the nuclear-localization of β-catenin we carried out the first nuclear/cytoplasmic proteomic analysis of the β-catenin interactome in myeloid leukemia cells and identified putative novel β-catenin interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear β-catenin) versus Wnt-unresponsive cells (low nuclear β-catenin) suggested the transcriptional partner, LEF-1, could direct the nuclear-localization of β-catenin. The relative levels of nuclear LEF-1 and β-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF-1 knockdown perturbed β-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF-1 overexpression was able to promote both nuclear-localization and β-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This is the first β-catenin interactome study in hematopoietic cells and reveals LEF-1 as a mediator of nuclear β-catenin level human myeloid leukemia

Tomographic phase and attenuation extraction for a sample composed of unknown materials using X-ray propagation-based phase-contrast imaging

Propagation-based phase-contrast X-ray imaging (PB-PCXI) generates image contrast by utilizing sample-imposed phase-shifts. This has proven useful when imaging weakly-attenuating samples, as conventional attenuation-based imaging does not always provide adequate contrast. We present a PB-PCXI algorithm capable of extracting the X-ray attenuation, $\beta$, and refraction, $\delta$, components of the complex refractive index of distinct materials within an unknown sample. The method involves curve-fitting an error-function-based model to a phase-retrieved interface in a PB-PCXI tomographic reconstruction, which is obtained when Paganin-type phase-retrieval is applied with incorrect values of $\delta$ and $\beta$. The fit parameters can then be used to calculate true $\delta$ and $\beta$ values for composite materials. This approach requires no a priori sample information, making it broadly applicable. Our PB-PCXI reconstruction is single distance, requiring only one exposure per tomographic angle, which is important for radiosensitive samples. We apply this approach to a breast-tissue sample, recovering the refraction component, $\delta$, with 0.6 - 2.4\% accuracy compared to theoretical values.Comment: 8 pages, 4 figures and 1 tabl