Angiotensin receptor-neprilysin inhibitor improves coronary collateral perfusion

BACKGROUND: We investigated the pleiotropic effects of an angiotensin receptor-neprilysin inhibitor (ARNi) on collateral-dependent myocardial perfusion in a rat model of coronary arteriogenesis, and performed comprehensive analyses to uncover the underlying molecular mechanisms. METHODS: A rat model of coronary arteriogenesis was established by implanting an inflatable occluder on the left anterior descending coronary artery followed by a 7-day repetitive occlusion procedure (ROP). Coronary collateral perfusion was measured by using a myocardial particle infusion technique. The putative ARNi-induced pro-arteriogenic effects were further investigated and compared with an angiotensin-converting enzyme inhibitor (ACEi). Expression of the membrane receptors and key enzymes in the natriuretic peptide system (NPS), renin-angiotensin-aldosterone system (RAAS) and kallikrein-kinin system (KKS) were analyzed by quantitative polymerase chain reaction (qPCR) and immunoblot assay, respectively. Protein levels of pro-arteriogenic cytokines were measured by enzyme-linked immunosorbent assay, and mitochondrial DNA copy number was assessed by qPCR due to their roles in arteriogenesis. Furthermore, murine heart endothelial cells (MHEC5-T) were treated with a neprilysin inhibitor (NEPi) alone, or in combination with bradykinin receptor antagonists. MHEC5-T proliferation was analyzed by colorimetric assay. RESULTS: The in vivo study showed that ARNis markedly improved coronary collateral perfusion, regulated the gene expression of KKS, and increased the concentrations of relevant pro-arteriogenic cytokines. The in vitro study demonstrated that NEPis significantly promoted MHEC5-T proliferation, which was diminished by bradykinin receptor antagonists. CONCLUSION: ARNis improve coronary collateral perfusion and exert pro-arteriogenic effects via the bradykinin receptor signaling pathway

Becoming a special educator – Finnish and Swedish students' views of their future profession

Peer reviewe

Population genomics of post-glacial western Eurasia.

Western Eurasia witnessed several large-scale human migrations during the Holocene <sup>1-5</sup> . Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations

K2-290: A warm Jupiter and a mini-Neptune in a triple-star system

We report the discovery of two transiting planets orbiting K2-290 (EPIC 249624646), a bright (V = 11.11) late F-type star residing in a triple-star system. It was observed during Campaign 15 of the K2 mission, and in order to confirm and characterize the system, follow-up spectroscopy and AO imaging were carried out using the FIES, HARPS, HARPS-N, and IRCS instruments. From AO imaging and Gaia data we identify two M-dwarf companions at a separation of 113 \ub1 2 and 2467+−177155 au. From radial velocities, K2 photometry, and stellar characterization of the host star, we find the inner planet to be a mini-Neptune with a radius of 3.06 \ub1 0.16 R and an orbital period of P = 9.2 d. The radius of the mini-Neptune suggests that the planet is located above the radius valley, and with an incident flux of F ∼ 400 F, it lies safely outside the super-Earth desert. The outer warm Jupiter has a mass of 0.774 \ub1 0.047 MJ and a radius of 1.006 \ub1 0.050 RJ, and orbits the host star every 48.4 d on an orbit with an eccentricity e < 0.241. Its mild eccentricity and mini-Neptune sibling suggest that the warm Jupiter originates from in situ formation or disc migration

Clay mineralogy and magnetic susceptibility of Oxisols in geomorphic surfaces

Studies analyzing the variability of clay minerals and magnetic susceptibility provide data for the delineation of site-specific management areas since many of their attributes are important to agronomy and the environment. This study aimed to evaluate the spatial variability of clay minerals, magnetic susceptibility, adsorbed phosphorus and physical attributes in Oxisols of sandstones in different geomorphic surfaces. For that purpose, soil samples were collected every 25 m along a transect located within the area where the geomorphic surfaces were identified and mapped. The transect occupied the central portion of 500 ha, where it was also sampled for density purposes with one sample per six hectares. Soil samples were collected at a depth of 0.0-0.2 m. The results of the physical, chemical, mineralogical and magnetic susceptibility analyses were subjected to statistical and geostatistical analyses. The nature of the clay minerals and magnetic susceptibility was dependent on the variation of the soil parent material. High values of magnetic susceptibility were associated with the presence of maghemite and magnetite of coarse size. The spatial variability of crystallinity and the content of Fe oxides, as well as magnetic susceptibility, were dependent on the age of the geomorphic surfaces. The youngest surface had greater spatial variability of these attributes. The iron (goethite and hematite) and aluminum (gibbsite) oxides in the youngest geomorphic surface influenced the low values of soil density and high values of total pore volume, micropores and P adsorption. The characterization of the spatial variability of Fe oxides and susceptibility allowed for the delineation of homogeneous areas

The Discovery and Mass Measurement of a New Ultra-Short-Period Planet: K2-131b

FWN – Publicaties zonder aanstelling Universiteit LeidenStars and planetary system

Granulocyte colony-stimulating factor improves cerebrovascular reserve capacity by enhancing collateral growth in the circle of Willis

BACKGROUND AND PURPOSE: Restoration of cerebrovascular reserve capacity (CVRC) depends on the recruitment and positive outward remodeling of preexistent collaterals (arteriogenesis). With this study, we provide functional evidence that granulocyte colony-stimulating factor (G-CSF) augments therapeutic arteriogenesis in two animal models of cerebral hypoperfusion. We identified an effective dosing regimen that improved CVRC and stimulated collateral growth, thereby improving the outcome after experimentally induced stroke. METHODS: We used two established animal models of (a) cerebral hypoperfusion (mouse, common carotid artery ligation) and (b) cerebral arteriogenesis (rat, 3-vessel occlusion). Following therapeutic dose determination, both models received either G-CSF, 40 mug/kg every other day, or vehicle for 1 week. Collateral vessel diameters were measured following latex angiography. Cerebrovascular reserve capacities were assessed after acetazolamide stimulation. Mice with left common carotid artery occlusion (CCAO) were additionally subjected to middle cerebral artery occlusion, and stroke volumes were assessed after triphenyltetrazolium chloride staining. Given the vital role of monocytes in arteriogenesis, we assessed (a) the influence of G-CSF on monocyte migration in vitro and (b) monocyte counts in the adventitial tissues of the growing collaterals in vivo. RESULTS: CVRC was impaired in both animal models 1 week after induction of hypoperfusion. While G-CSF, 40 mug/kg every other day, significantly augmented cerebral arteriogenesis in the rat model, 50 or 150 mug/kg every day did not show any noticeable therapeutic impact. G-CSF restored CVRC in mice (5 +/- 2 to 12 +/- 6%) and rats (3 +/- 4 to 19 +/- 12%). Vessel diameters changed accordingly: in rats, the diameters of posterior cerebral arteries (ipsilateral: 209 +/- 7-271 +/- 57 mum; contralateral: 208 +/- 11-252 +/- 28 mum) and in mice the diameter of anterior cerebral arteries (185 +/- 15-222 +/- 12 mum) significantly increased in the G-CSF groups compared to controls. Stroke volume in mice (10 +/- 2%) was diminished following CCAO (7 +/- 4%) and G-CSF treatment (4 +/- 2%). G-CSF significantly increased monocyte migration in vitro and perivascular monocyte numbers in vivo. CONCLUSION: G-CSF augments cerebral collateral artery growth, increases CVRC and protects from experimentally induced ischemic stroke. When comparing three different dosing regimens, a relatively low dosage of G-CSF was most effective, indicating that the common side effects of this cytokine might be significantly reduced or possibly even avoided in this indication