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Upon exhumation and cooling, contrasting compressibilities and thermal expansivities induce differential strains (volume mismatches) between a host crystal and its inclusions. These strains can be quantified in situ using Raman spectroscopy or X-ray diffraction. Knowing equations of state and elastic properties of minerals, elastic thermobarometry inverts measured strains to calculate the pressure-temperature conditions under which the stress state was uniform in the host and inclusion. These are commonly interpreted to represent the conditions of inclusion entrapment. Modeling and experiments quantify corrections for inclusion shape, proximity to surfaces, and (most importantly) crystal-axis anisotropy, and they permit accurate application of the more common elastic thermobarometers. New research is exploring the conditions of crystal growth, reaction overstepping, and the magnitudes of differential stresses, as well as inelastic resetting of inclusion and host strain, and potential new thermobarometers for lower-symmetry minerals. ▪ A physics-based method is revolutionizing calculations of metamorphic pressures and temperatures. ▪ Inclusion shape, crystal anisotropy, and proximity to boundaries affect calculations but can be corrected for. ▪ New results are leading petrologists to reconsider pressure-temperature conditions, differential stresses, and thermodynamic equilibrium.

Elastic thermobarometry (or piezobarometry) is the process of determining the P (pressure) and T (temperature) of entrapment of inclusions from their pressure, stress or strain measured when their host mineral is at room conditions. The methods and software used for piezobarometry are currently restricted to inclusions consisting of single phases. In this contribution we describe the theory of the elasticity of mixtures of different phases and combine it with the existing isotropic analysis of the elastic interactions between single-phase inclusions and their hosts to calculate the inclusion pressures of mixed-phase inclusions. The analysis shows that the reliability of calculated entrapment conditions for mixed-phase inclusions, including those containing fluid plus minerals, depends in a complex way upon the contrasts between the elastic properties of the host and the phases in the inclusion. The methods to calculate the entrapment conditions of mixed-phase inclusions have been incorporated into the EosFit7c program (version 7.6) that is available as freeware from http://www.rossangel.net.

Retinal degeneration is one of the prevalent causes of blindness worldwide, for which no effective treatment has yet been identified. Inorganic photovoltaic devices have been investigated for visual restoration in advanced stage Retinitis pigmentosa (RP), although lack of implant flexibility and foreign-object reactions have limited their application. Organic photoactive retinal prostheses may overcome these limitations, being biomimetic and tissue friendly. Inspired by organic photovoltaic strategies involving graphene, a hybrid retinal prosthesis was recently engineered consisting of a dual poly-3-hexylthiophene (P3HT) and graphene layer onto a flexible substrate. Here, this hybrid prosthesis was subretinally implanted in vivo in 5-month-old Royal College of Surgeons (RCS) rats, a rodent model of RP. Implanted dystrophic rats restored visual performances at both subcortical and cortical levels in response to light stimuli, in the absence of marked inflammatory responses. Moreover, the analysis of the physical-mechanical properties after prolonged permanence in the eye showed excellent biocompatibility and robustness of the device. Overall, the results demonstrate that graphene-enhanced organic photovoltaic devices can be suitably employed for the rescue of retinal dystrophies and supports the translation of the organic strategy into the medical practice.TABLE OF CONTENTSInspired by organic photovoltaic, a hybrid retinal prosthesis consisting of poly-3-hexylthiophene (P3HT) and graphene on a flexible substrate was subretinally implanted in vivo in Royal College of Surgeons (RCS) rats, a model of Retinitis pigmentosa. Implanted dystrophic rats restored visual performances at both subcortical and cortical levels in response to light stimuli, in the absence of marked inflammatory responses.

EntraPT is a web-based application for elastic geobarometry freely accessible at the “Fiorenzo Mazzi” experimental mineralogy lab website (http://www.mineralogylab.com/software/). It provides an easy-to-use tool to calculate the entrapment conditions of inclusions, with error propagation, from the residual strain measured in mineral inclusions. EntraPT establishes a method and a workflow to import and analyze the measured residual strains, correctly calculates the mean stress in the inclusions, computes the entrapment isomekes with uncertainty estimation, and visualizes all the results in relevant graphs. It enables the user to avoid the many possible errors that can arise from manual handling of the data and from the numerous steps required in geobarometry calculations. All of the data, parameters, and settings are stored in a consistent format and can be exported as project files and spreadsheets, and imported back to EntraPT for further analysis. This allows researchers to store and/or share their data easily, making the checking and the comparison of data and results reliable. EntraPT is an online tool that does not require any download and/or installation, and it will be updated in the future with new functionalities made available from advances in the development of elastic geobarometry.

Mountain building, earthquake generation, and volcanic eruptions occur in Earth’s lithosphere and have direct impacts on society. Understanding the mechanism of geodynamic processes relies on the determination of the pressure-temperature history which is recorded by rocks that have been involved in geodynamic processes. In most cases, the interpretation of the conditions attained by rocks is based on the assumption that the stresses in the Earth are hydrostatic. However, non-hydrostatic stresses are observed in the lithosphere, and the significance of the magnitude of the differential stress on phase equilibria is still actively contested among researchers who hold completely incompatible views about the use of various thermodynamic potentials (e.g. [1-3]).The problem of phase equilibria under non-hydrostatic stress has been explored in several rock-deformation experiments (on mm scale), in which recrystallization of minerals was observed under an applied non-hydrostatic stress [4-6]. However, during experiments, stress and pressure heterogeneities may develop in the sample (e.g. [6]). Therefore, the direct effect of the applied non-hydrostatic stress on the thermodynamics of the reactions cannot be separated from the effect caused by local pressure variations in the sample itself.Here, we explore the effect of non-hydrostatic stress on the thermodynamics of mineral reactions by investigating a system at the molecular scale. With Molecular Dynamics (MD) we perform coexistence simulations in which two phases are brought in contact and equilibrated at given temperature, pressure, and stress conditions. As expected, the obtained stress component normal to the phase-phase interfaces is homogeneous across the system. Our data suggest that the direct effect of non-hydrostatic stress on the solid-liquid equilibria is rather minor for geological applications, consistent with theoretical predictions [7,8]. However, our analysis does not take into account the indirect effect of stress heterogeneities at the sample scale. Spatial variations of stress can reach GPa level and can therefore indirectly affect phase equilibria.M.L. Mazzucchelli is supported by an Alexander von Humboldt research fellowship.References[1] Wheeler, J. Geology 42, 647–650 (2014);[2] Hobbs, B. et al. Geology 43, e372 (2015);[3] Tajčmanová, L. et al. Lithos 216–217, 338–351 (2015)[4] Hirth, G. et al. J. Geophys. Res. 99, 11731–11747 (1994)[5] Richter, B. et al. J. Geophys. Res. Solid Earth 121, 8015–8033 (2016)[6] Cionoiu, S. et al. Sci. Rep. 9, 1–6 (2019)[7] Sekerka, R. et al. Acta Mater., 52(6), 1663–1668 (2004)[8] Frolov, T. et al. Phys. Rev. B Condens. Matter Mater. Phys. 82, 1–14 (2010)

Graphene conductive properties have been long exploited in the field of organic photovoltaics and optoelectronics by the scientific community worldwide. We engineered and characterized a hybrid biointerface in which graphene is coupled with photosensitive polymers, and tested its ability to elicit lighttriggered neural activity modulation in primary neurons and blind retina explants. We designed such a graphene-based device by modifying a photoactive P3HT-based retinal interface, previously reported to rescue light sensitivity in blind rodents, with a CVD graphene layer replacing the conductive PEDOT:PSS layer to enhance charge separation. The new graphene-based device was characterized for its electrochemical features and for the ability to photostimulate primary neurons and blind retina explants, while preserving biocompatibility. Light-triggered responses, recorded by patch-clamp in vitro or MEA ex vivo, show a stronger light-transduction efficiency when the neurons are interfaced with the graphene-based device with respect to the PEDOT:PSS-based one. The possibility to ameliorate flexible photo-stimulating devices via the insertion of graphene, paves the way for potential biomedical applications of graphenebased neuronal interfaces in the context of retinal implants., Comment: 10 pages, 5 figures

In the complex geodynamic processes occurring at convergent plate margins, rocks can be subducted at depth into the Earth experiencing metamorphism. A mineral inhomogeneity entrapped into another mineral, after exhumation to the Earth surface, will exhibit stress and strain fields different from those of the host because of the different thermoelastic properties. In the present paper, we propose a finite-element-based approach to determine the Eshelby and the relaxations tensors for any morphology of the inhomogeneity and for any crystallographic symmetry of the host. The proposed procedure can be directly applied in the framework of elastic geobarometry to estimate, on the basis of the Eshelby theory, the entrapment conditions (pressure and temperature) from the residual strain field measured in the inhomogeneity. This aspect represents a step forward to currently available models for geobarometry allowing the investigation of complex morphologies of the inhomogeneity in systems with general material anisotropy. We validate the proposed approach versus Eshelby analytical solutions available for spherical and ellipsoidal inclusions and we show the application to a real geological case of high pressure metamorphic rocks.

Purpose\ud \ud In Sheffield (UK), we introduced the PINP monitoring algorithm for the management of osteoporosis treatment delivered in primary care. Our aims were to evaluate whether this algorithm was associated with better osteoporosis outcomes and was cost-effective compared to standard care.\ud \ud \ud \ud Methods\ud \ud Inclusion criteria were referral from Sheffield GPs, BMD scans performed between 2012 and 2013 and a report advising initiation of oral bisphosphonate and PINP monitoring. 906 patients were identified and retrospectively divided into Group A (intention to monitor, with baseline PINP, n = 588) and Group B (no intention to monitor, without baseline PINP, n = 318). The model described by Davis and colleagues was used to extrapolate life-time costs and quality-adjusted life-years (QALYs).\ud \ud \ud \ud Results\ud \ud No differences were found in baseline characteristics between groups (age, gender, BMI, BMD and major risk factors for fractures). More patients in Group A started oral treatment (77.4% vs 49.1%; p < 0.001), but there were no differences between groups in the presence of a gap in treatment >3 months or in treatment duration. Patients in Group A were more likely to have follow-up DXA scan at 4–6 years from baseline (46.9% vs 29.2%; p < 0.000) and had a greater increase in total hip BMD (+2.74% vs + 0.42%; p value = 0.003). Fewer new fractures occurred in Group A but this was not statistically significant, but the numbers of fractures were small. Patients in Group A were more likely to change management (p = 0.005) including switching to zoledronate (p = 0.03). The PINP measurement and increased prescribing in Group A resulted in increases in both costs (£30.19) and QALYs (0.0039) relative to Group B, giving an incremental cost effectiveness ratio (ICER) of £7660 in the probabilistic sensitivity analysis.\ud \ud \ud \ud Conclusions\ud \ud Patients monitored with PINP are more likely to start oral bisphosphonate treatment, switch to zoledronate, have follow-up DXA scans and a greater increase of hip BMD. PINP monitoring has the potential to be cost-effective in a UK NHS setting given that interventions with an ICER under £20,000 are generally considered to be cost-effective.

BackgroundGray mouse lemurs (Microcebus murinus) are the smallest and most ancestral primates known. Their size falls in between that of mice and rats, and their genetic proximity to humans makes them an emerging model to study age-related neurodegeneration. Since mouse lemurs replicate similar senescence processes of humans, they constitute a useful model for studying cardiovascular dysfunctions. However, their cardiac physiology is unknown. Thus, we investigated the cardiac pacemaker activity generated by the sinoatrial node (SAN) of mouse lemurs, presenting the first characterization of heart automaticity in nonhuman primates.Methods and ResultsWe recorded cardiac automaticity in mouse lemurs and in their SAN tissues and pacemaker myocytes. Mouse lemurs have a heart rate (HR) in between those of mice and rats and a similar generation of the SAN electrical impulse. Their SAN myocytes express the main pacemaker currents at densities similar to mice: the hyperpolarization-activated current (If) and the L-type (Ica,L) and T-type (Ica,T) calcium currents. Conversely, their ventricular depolarization resembles that of large mammals and despite the small size of mouse lemurs, the total number of heartbeats in their life corresponds to what can be attained by humans.Using muscle-derived stem cells (MDSCs) from mouse lemurs, we also differentiated pacemaker-like (PML) cells showing spontaneous automaticity and expressing markers of native SAN myocytes (HCN4 and connexin-45).ConclusionsOur characterization of heart automaticity in Microcebus murinus provides new opportunities for comparative cardio-physiology studies in primates and with humans and for testing molecules that could modulate age-related dysfunctions of heart rate.

International audience; Since its first description in 1979, the hyperpolarization-activated funny current (If) has been the object of intensive research aimed at understanding its role in cardiac pacemaker activity and its modulation by the sympathetic and parasympathetic branches of the autonomic nervous system. If was described in isolated tissue strips of the rabbit sinoatrial node using the double-electrode voltage-clamp technique. Since then, the rabbit has been the principal animal model for studying pacemaker activity and If for more than 20 years. In 2001, the first study describing the electrophysiological properties of mouse sinoatrial pacemaker myocytes and those of If was published. It was soon followed by the description of murine myocytes of the atrioventricular node and the Purkinje fibres. The sinoatrial node of genetically modified mice has become a very popular model for studying the mechanisms of cardiac pacemaker activity. This field of research benefits from the impressive advancement of in-vivo exploration techniques of physiological parameters, imaging, genetics, and large-scale genomic approaches. The present review discusses the influence of mouse genetics based on the most recent knowledge of the funny current's role in the physiology and pathophysiology of cardiac pacemaker activity. Genetically modified mice have provided important insights into the role of If in determining intrinsic automaticity in vivo and in myocytes of the conduction system. In addition, gene targeting of f-(HCN) channel isoforms have contributed to elucidating the current's role in the regulation of heart rate by the parasympathetic nervous system. This review is dedicated to Dario DiFrancesco on his retirement.

Human-induced pluripotent stem cell (hiPSC)-derived retinal pigment epithelium (RPE) is a powerful tool for pathophysiological studies and preclinical therapeutic screening, as well as a source for clinical cell transplantation. Thus, it must be validated for maturity and functionality to ensure correct data readouts and clinical safety. Previous studies have validated hiPSC-derived RPE as morphologically characteristic of the tissue in the human eye. However, information concerning the expression and functionality of ion channels is still limited. We screened hiPSC-derived RPE for the polarized expression of a panel of L-type (CaV 1.1, CaV 1.3) and T-type (CaV 3.1, CaV 3.3) Ca2+ channels, K+ channels (Maxi-K, Kir4.1, Kir7.1), and the Cl- channel ClC-2 known to be expressed in native RPE. We also tested the roles of these channels in key RPE functions using specific inhibitors. In addition to confirming the native expression profiles and function of certain channels, such as L-type Ca2+ channels, we show for the first time that T-type Ca2+ channels play a role in both phagocytosis and vascular endothelial growth factor (VEGF) secretion. Moreover, we demonstrate that Maxi-K and Kir7.1 channels are involved in the polarized secretion of VEGF and pigment epithelium-derived factor (PEDF). Furthermore, we show a novel localization for ClC-2 channel on the apical side of hiPSC-derived RPE, with an overexpression at the level of fluid-filled domes, and demonstrate that it plays an important role in phagocytosis, as well as VEGF and PEDF secretion. Taken together, hiPSC-derived RPE is a powerful model for advancing fundamental knowledge of RPE functions.