114 research outputs found

    Genetics of healthy ageing

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    Genetics of healthy ageing

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    The impact of calcination on changes in the physical and mechanical properties of the diatomites of the Leszczawka Member (the Outer Carpathians, Poland)

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    The work concerned the effects of the thermal treatment of diatomites from the Jawornik deposit (an example of the diatomites of the Leszczawka Member of the Polish Outer Carpathians). Five distinct lithological varieties were subjected to calcination at 600°C in ambient air. The thermal impact induced the following changes to the rocks. Their overall rock porosity increased, most distinctly in the initially softer varieties, and the internal pores of the siliceous frustules themselves usually became larger due to the initial melting of the silica phases. Most of the diatoms, quartz and feldspars cracked as a result of their brittle fracturing under compressive strain resulting from substantial and differing size changes of growing grains. Clay minerals were thermally transferred, changing their volume. The organic matter dispersed throughout the diatomites was partly oxidized and removed. At the same time, the structure of the rocks was strengthened, as confirmed by an increase in their microhardness. The microhardness of soft and porous diatomite varieties increased considerably on heating, but that of the hard and compact variety changed to a smaller degree. The increase is directly related to the content of the clay minerals. The impact of other mineral components was not detected. The calcination of lithologically diversified diatomites provided the mineral with raw material with deicing and antisliding properties. The technology of its production has been determined by the authors and submitted as a patent

    Growth and electronic and magnetic structure of iron oxide films on Pt(111)

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    Ultrathin (111)-oriented polar iron oxide films were grown on a Pt(111) single crystal either by the reactive deposition of iron or oxidation of metallic iron monolayers. These films were characterized using low energy electron diffraction, scanning tunneling microscopy and conversion electron Mossbauer spectroscopy. The reactive deposition of Fe led to the island growth of Fe3O4, in which the electronic and magnetic properties of the bulk material were modulated by superparamagnetic size effects for thicknesses below 2 nm, revealing specific surface and interface features. In contrast, the oxide films with FeO stoichiometry, which could be stabilized as thick as 4 nm under special preparation conditions, had electronic and magnetic properties that were very different from their bulk counterpart, w\"ustite. Unusual long range magnetic order appeared at room temperature for thicknesses between three and ten monolayers, the appearance of which requires severe structural modification from the rock-salt structure.Comment: 17 pages, 6 figures, 50 reference

    Diatomaceous rocks of the Jawornik deposit (the Polish Outer Carpathians): petrophysical and petrographical evaluation.

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    AbstractDiatomites are identified as a group of the critical minerals that are essential to many industrial applications due to a unique combination of their physical properties, i.e. porous and permeable structure, high specific surface area and adsorption capacity, low density and thermal conductivity, and chemical inertness. The present study was undertaken to analyse the relationships between the pore network characteristics, petrophysical parameters, and mineralogical variability of the Lower Miocene diatomites from the Jawornik deposit (Skole Unit, the Polish Outer Carpathians, SE Poland). Five varieties of the diatomites, distinguished on the basis of the macroscopic features, i.e., colour and fracturing effects, have been investigated by SEM, chemical and XRD analysis, mercury intrusion porosimetry, helium pycnometry, and the Vickers hardness tests. Significantly differing are two varieties. The light-coloured, massive and block-forming diatomites consist mainly of poorly cemented siliceous skeletal remains of diatoms, and represent the rocks with high porosity, low bulk density and low microhardness. The dark-gray silicified diatomites with a platy or prismatic splitting reveal obscured microfossils of diatoms and are the most compact and hard rocks, with poor porosity and higher bulk density. The spatial distribution of the field identifiable rock varieties allows selective exploitation of the diatomites with the predictable petrophysical characteristics that define their future use.

    Pathophysiological pathways related to high plasma growth differentiation factor 15 concentrations in patients with heart failure

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    Aims Elevated concentrations of growth differentiation factor 15 (GDF-15) in patients with heart failure (HF) have been consistently associated with worse clinical outcomes, but what disease mechanisms high GDF-15 concentrations represent remains unclear. Here, we aim to identify activated pathophysiological pathways related to elevated GDF-15 expression in patients with HF. Methods and results In 2279 patients with HF, we measured circulating levels of 363 biomarkers. Then, we performed a pathway over-representation analysis to identify key biological pathways between patients in the highest and lowest GDF-15 concentration quartiles. Data were validated in an independent cohort of 1705 patients with HF. In both cohorts, the strongest up-regulated biomarkers in those with high GDF-15 were fibroblast growth factor 23 (FGF-23), death receptor 5 (TRAIL-R2), WNT1-inducible signalling pathway protein 1 (WISP-1), tumour necrosis factor receptor superfamily member 11a (TNFRSF11A), leucocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), and trefoil factor 3 (TFF3). Pathway over-representation analysis revealed that high GDF-15 patients had increased activity of pathways related to inflammatory processes, notably positive regulation of chemokine production; response to interleukin-6; tumour necrosis factor and death receptor activity; and positive regulation of T-cell differentiation and inflammatory response. Furthermore, we found pathways involved in regulation of insulin-like growth factor (IGF) receptor signalling and regulatory pathways of tissue, bones, and branching structures. GDF-15 quartiles significantly predicted all-cause mortality and HF hospitalization. Conclusion Patients with HF and high plasma concentrations of GDF-15 are characterized by increased activation of inflammatory pathways and pathways related to IGF-1 regulation and bone/tissue remodelling.publishedVersio

    Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure

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    Aims Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcome in patients with heart failure (HF), but the mechanisms behind their beneficial effects are not yet fully understood. We examined the effects of empagliflozin on renal sodium and glucose handling in patients with acute HF. Methods and results This study was a pre-defined sub-study of a double-blind, randomized, placebo-controlled, multicentre study (EMPA-RESPONSE-AHF). Patients were allocated within 24 h of an acute HF admission to either empagliflozin 10 mg/day (n = 40) or placebo (n = 39) for 30 days. Markers of glucose and sodium handling were measured daily during the first 96 h and at day 30. Patients were 76 (range 38-89) years old and 33% had diabetes. The use of loop diuretics during the first 96 h was similar in both groups. Empagliflozin increased fractional glucose excretion with a peak after 24 h (21.8% vs. 0.1%; P 0.3 for all). However, empagliflozin increased plasma osmolality (delta osmolality at 72 h: 5 +/- 8 vs. 2 +/- 5 mOsm/kg; P = 0.049). Finally, there was an early decline in estimated glomerular filtration rate with empagliflozin vs. placebo (-10 +/- 12 vs. -2 +/- 12 mL/min/1.73 m(2); P = 0.009), which recovered within 30 days. Conclusion In patients with acute HF, empagliflozin increased fractional glucose excretion and plasma osmolality, without affecting fractional sodium excretion or urine osmolality and caused a temporary decline in estimated glomerular filtration rate. This suggests that empagliflozin stimulates osmotic diuresis through increased glycosuria rather than natriuresis in patients with acute HF

    Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction

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    International audienceAims: The lack of effective therapies for patients with heart failure with preserved ejection fraction (HFpEF) is often ascribed to the heterogeneity of patients with HFpEF. We aimed to identify distinct pathophysiologic clusters of HFpEF based on circulating biomarkers.Methods and results: We performed an unsupervised cluster analysis using 363 biomarkers from 429 patient with HFpEF. Relative differences in expression profiles of the biomarkers between clusters were assessed and used for pathway over-representation analyses. We identified four distinct patients subgroups based on their biomarker profiles : cluster 1 with the highest prevalence of diabetes mellitus and renal disease; cluster 2 with oldest age and frequent age-related comorbidities; cluster 3 with youngest age, largest body size, least symptoms and lowest NT-proBNP levels; and cluster 4 with highest prevalence of ischemic aetiology, smoking and chronic lung disease, most symptoms, as well as highest NT-proBNP and troponin levels. Over a median follow-up of 21 months, the occurrence of death or HF hospitalization was highest in clusters 1 and 4 (62.1% and 62.8% respectively) and lowest in cluster 3 (25.6%). Pathway over-representation analyses revealed that the biomarker profile of patients in cluster 1 was associated with activation of inflammatory pathways while the biomarker profile of patients in cluster 4 was specifically associated with pathways implicated in cell proliferation regulation and cell survival.Conclusion: Unsupervised cluster analysis based on biomarker profiles identified mutually exclusive subgroups of patients with HFpEF with distinct biomarker profiles, clinical characteristics and outcomes, suggesting different underlying pathophysiological pathway

    Locked Nucleic Acid Gapmers and Conjugates Potently Silence ADAM33, an Asthma-Associated Metalloprotease with Nuclear-Localized mRNA

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    Two mechanisms dominate the clinical pipeline for oligonucleotide-based gene silencing, namely, the antisense approach that recruits RNase H to cleave target RNA and the RNAi approach that recruits the RISC complex to cleave target RNA. Multiple chemical designs can be used to elicit each pathway. We compare the silencing of the asthma susceptibility gene ADAM33 in MRC-5 lung fibroblasts using four classes of gene silencing agents, two that use each mechanism: traditional duplex small interfering RNAs (siRNAs), single-stranded small interfering RNAs (ss-siRNAs), locked nucleic acid (LNA) gapmer antisense oligonucleotides (ASOs), and novel hexadecyloxypropyl conjugates of the ASOs. Of these designs, the gapmer ASOs emerged as lead compounds for silencing ADAM33 expression: several gapmer ASOs showed subnanomolar potency when transfected with cationic lipid and low micromolar potency with no toxicity when delivered gymnotically. The preferential susceptibility of ADAM33 mRNA to silencing by RNase H may be related to the high degree of nuclear retention observed for this mRNA. Dynamic light scattering data showed that the hexadecyloxypropyl ASO conjugates self-assemble into clusters. These conjugates showed reduced potency relative to unconjugated ASOs unless the lipophilic tail was conjugated to the ASO using a biocleavable linkage. Finally, based on the lead ASOs from (human) MRC-5 cells, we developed a series of homologous ASOs targeting mouse Adam33 with excellent activity. Our work confirms that ASO-based gene silencing of ADAM33 is a useful tool for asthma research and therapy

    The genomic origins of the world’s first farmers

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    The precise genetic origins of the first Neolithic farming populations in Europe and Southwest Asia, as well as the processes and the timing of their differentiation, remain largely unknown. Demogenomic modeling of high-quality ancient genomes reveals that the early farmers of Anatolia and Europe emerged from a multiphase mixing of a Southwest Asian population with a strongly bottlenecked western hunter-gatherer population after the last glacial maximum. Moreover, the ancestors of the first farmers of Europe and Anatolia went through a period of extreme genetic drift during their westward range expansion, contributing highly to their genetic distinctiveness. This modeling elucidates the demographic processes at the root of the Neolithic transition and leads to a spatial interpretation of the population history of Southwest Asia and Europe during the late Pleistocene and early Holocene.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
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