Deconstructing transcriptional heterogeneity in pluripotent stem cells

SUMMARY Pluripotent stem cells (PSCs) are capable of dynamic interconversion between distinct substates, but the regulatory circuits specifying these states and enabling transitions between them are not well understood. We set out to characterize transcriptional heterogeneity in PSCs by single-cell expression profiling under different chemical and genetic perturbations. Signaling factors and developmental regulators show highly variable expression, with expression states for some variable genes heritable through multiple cell divisions. Expression variability and population heterogeneity can be influenced by perturbation of signaling pathways and chromatin regulators. Strikingly, either removal of mature miRNAs or pharmacologic blockage of signaling pathways drives PSCs into a low-noise ground state characterized by a reconfigured pluripotency network, enhanced self-renewal, and a distinct chromatin state, an effect mediated by opposing miRNA families acting on the c-myc / Lin28 / let-7 axis. These data illuminate the nature of transcriptional heterogeneity in PSCs

Use of Biomarkers in the Evaluation and Treatment of Hypertensive Patients

The current definition of hypertension is based on blood pressure values, and blood pressure also drives treatment decisions, is the most important treatment monitoring tool and helps estimating risk of hypertension related organ damage. In an era of precision medicine additional biomarkers are needed in the diagnosis and management of patients with hypertension. In this review we outline the areas in which functional, imaging and circulating biomarkers could help in a more individualised definition of hypertension and associated risk. We will cover biomarkers for diagnosis; of pathophysiology and prediction of hypertension; response to treatment, organ damage; and to monitor treatment. A clear focus is on the vasculature, the heart and the kidneys, whereas we see a need to further develop biomarkers of cerebral function in order to diagnose cognition deficits and monitor changes in cognition in the future to support addressing the growing burden of hypertension associated vascular dementia

Low-temperature spin-state transition in LaCoO3 investigated using resonant x-ray absorption at the Co K edge

LaCoO3 displays two broad anomalies in the DC magnetic susceptibility chi(DC), occurring, respectively, around 50 K and 500 K. We have investigated the first of them within the 10 K < T < RT temperature range using Co K alpha(1) x-ray absorption spectroscopy (XAS) in the partial fluorescence yield mode. In contrast with previous O K-edge XAS reports, our data show the existence of abrupt changes around 50 K which can be nicely correlated with the anomaly in chi(DC). To our knowledge, this is the first time that a clear, quantitative relationship between the temperature dependence of the magnetic susceptibility and that of the XAS spectra is reported. The intensity changes in the preedge region, which are consistent with a transition from a lower to a higher spin state, have been analyzed using a minimal model including the Co 3d and O 2p hybridization in the initial state. The temperature dependence of the Co magnetic moment obtained from the estimated e(g) and t(2g) occupations could be satisfactorily reproduced. Also, the decrease of the Co 3d and O 2p hybridization by increasing temperature obtained from this simple model compares favorably with the values estimated from thermal evolution of the crystallographic structure

Haemodynamic effects of acute and chronic renin inhibition in marmosets

We have developed marmoset models for the in vivo evaluation of primate-specific inhibitors of human renin. After acute intravenous administration to normotensive sodium-depleted marmosets, renin inhibitors of different structural types induced a maximum hypotensive response of a magnitude similar to that induced after angiotensin converting enzyme (ACE) inhibition. The response was prevented by pretreatment with an ACE inhibitor. A close relationship between the inhibition of plasma renin activity (PRA) and the fall in blood pressure was observed with most of the inhibitors. CGP 29,287, a synthetic renin inhibitor, and R-3-36-16, a monoclonal antibody, both induced a selective increase in renal blood flow similar to that induced by an ACE inhibitor. A sustained reduction in blood pressure was observed during continuous administration of CGP 29,287 or R-3-36-16 over 14 days, despite an increase in immunoreactive renin and an apparent recovery of PRA. A similar blood pressure fall and an increase in plasma renin was observed during continuous administration of an ACE inhibitor. The renin inhibitor CGP 29,287 also lowered blood pressure after acute administration to hypertensive marmosets with normal PRA. Our studies demonstrate that renin inhibitors have similar haemodynamic effects to ACE inhibitors, and indicate that they may have a similar antihypertensive efficacy

alpha-gamma transition in metallic Ce studied by resonant x-ray spectroscopies

We performed bulk-sensitive x-ray absorption (XAS) in the partial fluorescence yield (PFY) mode, and resonant x-ray emission (RXES) measurements of the solid solution Sc (7 at.%):Ce at the Ce L-3 (2p-->5d) and M-4,M-5 (3d-->4f) absorption edges. We deduce an increasing 4f-band hybridization from the gamma-phase stable at room temperature to the low-temperature alpha-Ce, consistent with the "Kondo collapse" scenario for the transition. The enhanced intrinsic resolution of PFY-XAS allows us to resolve the elusive three-peak structure predicted by theory. Thanks to the selective enhancement typical of RXES, we could estimate the small but non-negligible contribution of the f(2) configuration in the hybrid ground state, and its change in the two phases. The linear dichroism effect in the M-4,M-5 RXES spectra is consistent with the observed hybridization of 4f and conduction states

Influence of the interface on the electronic channel switching of a Fe-Ag thin film on a Si substrate

FexAg100-x granular thin films, being 20 < x < 70, were prepared by pulsed laser deposition. The thermal evolution of the electric resistance shows a dramatic drop in the range of 200 < T < 300 K, completely reversible with temperature and associated to a current switching between the granular thin film and its Si substrate. High resolution transmission electron microscopy measurements have revealed an amorphous interface between the thin film and the substrate, and x-ray absorption spectroscopy studies have demonstrated an electronic localization associated to the Fe atoms in this interface, which is intrinsically responsible for the current switching