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We investigated LaAlO3-SrTiO3 heterointerfaces grown either in oxygen-rich or -poor atmosphere by soft x-ray spectroscopy. Resonant photoemission across the Ti L2,3 absorption edge of the valence band and Ti 2p core-level spectroscopy directly monitor the impact of oxygen treatment upon the electronic structure. Two types of Ti3+ related charge carriers are identified. One is located at the Fermi energy and related to the filling of the SrTiO3 conduction band. It appears for low oxygen pressure only. The other one is centered at EB ≈ 1 eV and independent of the oxygen pressure during growth. It is probably due to defects. The magnitude of both excitations is comparable. It is shown that low oxygen pressure is detrimental for the Ti-O bonding. Our results shed light on the nature of the charge carriers in the vicinity of the LaAlO3-SrTiO3 interface. [ABSTRACT FROM AUTHOR]

The influence of an electrically controlled biaxial in-plane strain on the magnetization of superlattices of ferromagnetic La0.7Sr0.3MnO3 and SrTiO3 was studied for single-layer thicknesses of d = 1.5-13 nm. Superlattices were grown by pulsed laser deposition on both SrTiO3(001) and piezoelectric 0.72Pb(Mg1/3Nb2/3)O3-0.28PbTiO3(001), or PMN-PT(001), substrates and have been structurally characterized by x-ray diffraction (XRD) and transmission electron microscopy. Grazing-incidence XRD reveals the vertical homogeneity of the piezoelectrically controlled reversible in-plane strain, even in a 600-nm-thick superlattice containing 100 oxide interfaces. The as-grown strain is almost identical in all superlattices that are coherently grown, with small variations resulting from the partially relaxed growth of the first La0.7Sr0.3MnO3 layer on PMN-PT(001). The magnetic transition temperature decreases with the layer thickness d as a consequence of the finite layer thickness, and the strain-induced response of the magnetization changes its character from that of a long-range-ordered ferromagnet to that of a magnetically disordered (possibly electronically phase-separated) manganite. The strain response of a modified interface layer ("dead layer") of the thickness dI is distinguished from that of the layer's interior by its different temperature dependence, allowing an estimation of 10 Å < dI < 16 Å for the superlattices on PMN-PT. [ABSTRACT FROM AUTHOR]

Abstract: The energetic distribution of electronic defect states in oxide heterostructures made of ultrathin lanthanum manganite (La0.7Ca0.3MnO3, La0.7Ce0.3MnO3) films on SrTiO3 substrates is investigated by surface photovoltage (SPV) spectroscopy. Within a comparative evaluation of the SPV spectra of both the film/substrate structures and pure substrates at different temperatures we were able to elaborate a map of defect states across the SrTiO3-bandgap and we find that the defect state distribution is mainly affected by the substrate, i.e., no specific film-induced defect states were detected. Possible origins of the defect states are discussed within the framework of a semiconductor band scheme, taking into account complementary photoconductivity and SPV transient data. [Copyright &y& Elsevier]

We study the effect of elastic anisotropic biaxial strain, induced by a piezoelectric actuator, on the light emitted by neutral excitons confined in different kinds of epitaxial quantum dots. We find that the light polarization rotates by up to ∼80° and the fine structure splitting (FSS) varies nonmonotonically by several tens of μeV as the strain is varied. These findings provide the experimental proof of a recently predicted strain-induced anticrossing of the bright states of neutral excitons in quantum dots. Calculations on model dots qualitatively reproduce the observations and suggest that the minimum reachable FSS critically depends on the orientation of the strain axis relative to the dot elongation. [ABSTRACT FROM AUTHOR]

Abstract: An epitaxial magnetite (Fe3O4) film has been deposited by the pulsed laser deposition (PLD) technique on a bicrystal substrate. Magnetoresistance measurements on patterned stripes (width=20μm) across the bicrystal grain boundary have not revealed a distinguishable grain boundary contribution. Post-annealing of the film has a strong influence on the relaxation degree of the film and on the density of antiphase boundaries. Magnetotransport measurements of the micrometer-patterned annealed film show significantly enlarged high-field magnetoresistance values at low temperatures. [Copyright &y& Elsevier]

The substitutional effect of Ru on the magnetic and transport properties of double exchange ferromagnets, La0.7Sr0.3MnO3 and La0.5Sr0.5CoO3 has been investigated. It is found that substitution of 10% Ru at the Mn site of La0.7Sr0.3MnO3 decreases the Curie temperature by 20 K than that of the parent compound. However, a large decrease in the Curie temperature, ΔTc∼80 K and the system undergoes a transition from metallic state to insulating state is observed when 10% Ru is doped in La0.5Sr0.5CoO3. The marginal effect of Ru in the Mn–O–Mn sublattice in comparison to the Co–O–Co sublattice could be due to the magnetic exchange interaction between Mn and Ru by virtue of the fact that Ru exhibits variable valence states, Ru+4/Ru+5. The eg and t2g parentage of Ru+5 is similar to Mn+4 and therefore, Ru+5 ion appears to participate in the double exchange mediated ferromagnetic (FM) interaction. On the other hand, Ruthenium (IV) ion disrupts an intermediate spin state of cobalt (Co+3: t2g5eg1), forcing a double exchange FM state to anti-FM state. [Copyright &y& Elsevier]

We present a magnetic study of the insulating perovskite LaMn1−xTixO3+δ (0x=0.2. The time decay of the magnetization has an algebraic functional form for times up to 2 h. The specific heat also displays characteristic features of a spin–glass system by a linear low-temperature dependence and a broadened peak near the temperature of the reentrant transition. [Copyright &y& Elsevier]

Thin films of La0.7Sr0.3MnO3 were deposited by magnetron sputtering on SrTiO3(1 0 0) and LaAlO3(1 0 0) substrates. The influence of deposition parameters such as substrate temperature, chamber pressure as well as film growth rate on structural and magnetic properties was investigated. The structural characterisation by means of X-ray diffraction (θ/2θ scans, ω-scans, ϕ-scans) revealed high quality of the epitaxial LSMO films obtained at a growth rate of 2 nm/min with a small mosaicity in the plane of the substrate. By optimisation of the deposition regime, especially by decreasing the film growth rate down to 0.77–1.6 nm/min and increasing the substrate temperature up to 840°C, a further improvement of the film epitaxy as well as magnetic properties has been registered by RBS and SQUID measurements. Improved epitaxy leads to a decrease of LSMO resistivity down to values ∼100 μΩ cm comparable with those of the best-quality LSMO films. The magnetoresistance MR=[R(H)−R(0)]/R(0) of the films obtained is low at low temperature due to structural perfection. However, epitaxial strain appearing in thinner layers leads to increasing of the magnetoresistance in spite of high structural perfection. Thin LSMO films obtained by magnetron sputtering are appropriate for applications in tunnel structures and multilayers. [Copyright &y& Elsevier]

Ruthenium doped B-site deficient compound, LaMn0.95−xRuxO3, where 0≤x≤0.4 shows a ferromagnetic metal (x<0.1) to insulator (for x>0.1) transition involving rhombohedral to orthorhombic symmetry change. The ferromagnetic metallic behavior is sustained by a double exchange mediated process, while for x>0.1 a superexchange ferromagnetic interaction is observed. The conduction mechanism in the paramagnetic state for all the compounds is dominated by the 3D-variable range hopping type. The charge carrier localization length, ξ decreases from 2.88 A˚ at x=0.0 to 1.64 A˚ for x=0.4. The unusual ferromagnetic interaction between Mn and Ru is explained based on the mixed valence effect. [Copyright &y& Elsevier]

Objective: Osteoarthritis (OA) is a disease with high prevalence and an unmet medical need for disease modifying treatments. In rat models, OA-like subchondral bone and cartilage changes can be induced by instability surgery with different severity levels. Factors which determine structural changes additionally comprise the study duration and activity-impacted joint loading. Methods: A medial meniscal tear (MMT) or anterior cruciate ligament transection with partial meniscectomy (ACLT+pMx) was induced unilaterally in rats housed in a rat colony cage (RCC), allowing high activity levels including jumping and stair climbing. In parallel, ACLT+pMx rats were housed in Type IV cages. The time course of OA-related changes was investigated at 4, 8, 12, and 16 weeks after surgery by micro-CT, gait analysis and joint diameter measurements. Results: Gait disturbance was observed after 2 weeks and to a similar extend in all models. The increase in ipsilateral joint diameters peaked after 2 weeks and were more pronounced after ACLT+pMx compared to MMT-surgery, but independent of housing. Micro-CT analysis revealed that increases in osseous tibial width were most distinct after ACLT+pMx in RCC and progressed continuously until week sixteen. In contrast, osseous tibial width of ipsilateral joints in MMT RCC and ACLT+pMx Type IV groups did not increase further after week twelve. In contralateral joints, this parameter was not affected, regardless of the model or caging. However, a significant increase in bone volume fraction and trabecular thickness was observed over time in the femur and tibia of both ipsilateral and contralateral knees. Here, the medial tibial compartment of the operated joint was most affected and linear changes were most pronounced in the ACLT+pMx RCC group. Conclusion: Increased movement of animals in colony cages leads to robust structural changes in subchondral bone after surgically induced joint instability over time, while in regular Type IV housing maximal changes are reached in week twelve. The new insights into the differentiation of the models, particularly with respect to the linear progression of bone changes in ACLT+pMx in the RCC, may be useful for the design of chronic OA-studies within a longer lifespan and therefore supporting the development of novel therapies., Competing Interests: The authors SM and CB are employees of Merck Healthcare KGaA. KK-D is employed by Merck KGaA. This work was sponsored by Merck Healthcare KGaA, Darmstadt, Germany (CrossRef funder ID: 10.13039/100009945). Representatives of the sponsor were involved in the study design, collection, analysis, and interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication., (Copyright © 2024 Menges, Kleinschmidt-Dörr and Brenneis.)

Background: Calcimimetic therapy with etelcalcetide (ETEL) has been shown to attenuate the advancement of left ventricular (LV) hypertrophy in hemodialysis patients measured by cardiac magnetic resonance (CMR). The aim of the study was to evaluate whether this effect is accompanied by alterations in LV function and myocardial composition., Methods: This was a post-hoc analysis of a randomized-controlled trial of ETEL versus Alfacalcidol (ALFA) in 62 hemodialysis patients. LV function was assessed using LV ejection fraction (LVEF) and LV global longitudinal strain (GLS) on feature-tracking (FT) CMR. Myocardial tissue characteristics were analyzed using parametric T1 and T2 mapping., Results: Of the total study cohort (n = 62), 48 subjects completed both CMR scans with sufficient quality for FT analysis. In the one-year follow-up, LV GLS deteriorated in the ALFA group, whereas the ETEL group remained stable (LV GLS change: + 2.6 ± 4.6 versus + 0.3 ± 3.8; p = 0.045 when adjusting for randomization factors and baseline LV GLS). We did not observe a difference in the change of LVEF between the two groups (p = 0.513). The impact of ETEL treatment on LV GLS over time remained significant after additional adjustment for the change in LV mass during the study period. ETEL treatment did not significantly affect other CMR parameters. There were no changes in myocardial composition between treatment groups (T1 time change: + 15 ± 42 versus + 10 ± 50; p = 0.411; T2 time change: - 0.13 ± 2.45 versus - 0.70 ± 2.43; p = 0.652)., Conclusions: In patients undergoing hemodialysis, treatment with ETEL was protective against deterioration of LV longitudinal function, as evaluated through FT CMR, when compared to the control therapy of ALFA. This effect was not mediated by the change in LV mass. Trial registration URL: https://clinicaltrials.gov/ct2/show/NCT03182699 . Unique identifier: NCT03182699., (© 2023. The Author(s).)

Complex oxide heterointerfaces contain a rich playground of novel physical properties and functionalities, which give rise to emerging technologies. Among designing and controlling the functional properties of complex oxide film heterostructures, vertically aligned nanostructure (VAN) films using a self-assembling bottom-up deposition method presents great promise in terms of structural flexibility and property tunability. Here, the bottom-up self-assembly is extended to a new approach using a mixture containing a 2Dlayer-by-layer film growth, followed by a 3D VAN film growth. In this work, the two-phase nanocomposite thin films are based on LaAlO 3 :LaBO 3 , grown on a lattice-mismatched SrTiO 3001 (001) single crystal. The 2D-to-3D transient structural assembly is primarily controlled by the composition ratio, leading to the coexistence of multiple interfacial properties, 2D electron gas, and magnetic anisotropy. This approach provides multidimensional film heterostructures which enrich the emergent phenomena for multifunctional applications., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Objective: Osteoarthritis (OA) is a common joint disorder often affecting the knee. It is characterized by alterations of various joint tissues including subchondral bone and by chronic pain. Anti-nerve growth factor (NGF) antibodies have demonstrated improvement in pain associated with OA in phase 3 clinical trials but have not been approved due to an increased risk of developing rapidly progressive OA. The aim of this study was to investigate effects of systemic anti-NGF-treatment on structure and symptoms in rabbits with surgically induced joint instability. Methods: This was elicited by anterior cruciate ligament transection and partial resection of the medial meniscus in right knee of 63 female rabbits, housed altogether in a 56 m 2 floor husbandry. Rabbits received either 0.1, 1 or 3 mg/kg anti-NGF antibody intra-venously at weeks 1, 5 and 14 after surgery or vehicle. During in-life phase, static incapacitance tests were performed and joint diameter was measured. Following necropsy, gross morphological scoring and micro-computed tomography analysis of subchondral bone and cartilage were performed. Results: After surgery, rabbits unloaded operated joints, which was improved with 0.3 and 3 mg/kg anti-NGF compared to vehicle injection during the first half of the study. The diameter of operated knee joints increased over contralateral measures. This increase was bigger in anti-NGF treated rabbits beginning 2 weeks after the first IV injection and became dose-dependent and more pronounced with time. In the 3 mg/kg anti-NGF group, the bone volume fraction and trabecular thickness increased in the medio-femoral region of operated joints compared to contralateral and to vehicle-treated animals, while cartilage volume and to a lesser extent thickness decreased. Enlarged bony areas were found in right medio-femoral cartilage surfaces of animals receiving 1 and 3 mg/kg anti-NGF. Alterations of all structural parameters were particularly distinct in a subgroup of three rabbits, which also exhibited more prominent symptomatic improvement. Conclusion: This study showed that anti-NGF administration exerted negative impact on structure in destabilized joints of rabbits, while pain-induced unloading of joints was improved. Our findings open up the possibility to better understand the effects of systemic anti-NGF, particularly on subchondral bone, and thus the occurrence of rapidly progressive OA in patients., Competing Interests: The author SM is an employee of Merck Healthcare KGaA. KK-D is employed by Merck KGaA. MM was an employee of Merck Healthcare KGaA until his retirement in 2022. This work was sponsored by Merck Healthcare KGaA, Darmstadt, Germany. Representatives of the sponsor were involved in the study design, collection, analysis, and interpretation of data, in the writing of the manuscript, and in the decision to submit the manuscript for publication., (Copyright © 2023 Menges, Michaelis and Kleinschmidt-Dörr.)

Introduction: Increased left atrial (LA) size is a risk factor for cardiovascular events and all-cause mortality. It is closely related to left ventricular hypertrophy and chronic volume overload, both of which are common in hemodialysis. Calcimimetic treatment with etelcalcetide (ETL) previously showed an inhibitory effect on left ventricular mass index (LVMI) progression in this population., Methods: This is a post hoc analysis of the EtECAR-HD trial, where 62 patients were randomized to ETL or alfacalcidol (ALFA) for 1 year. LA volume index (LAVI) was measured using cardiac magnetic resonance imaging. The aim of the study was to investigate whether ETL was associated with a change of LAVI., Results: Median baseline levels of LAVI were 40 mL/m2 (31, 54 IQR) in the ETL group and 36 mL/m2 (26, 46 IQR) in the ALFA group. In the ITT population, the change of LAVI was 5.0 mL/m2 [95% CI: -0.04, 10] lower under ETL, compared to ALFA (p = 0.052, R2adj = 0.259). In the PP population, the difference in LAVI changes widened to 5.8 [95% CI: 0.36, 11], p = 0.037, R2adj = 0.302). Secondary analysis showed that the study delta of LVMI was correlated with the LAVI delta (r = 0.387) and that an inclusion of LVMI delta in the ANCOVA model mediated the effect on LAVI delta to β = 3.3 [95% CI: -0.04, 10] (p = 0.2, R2adj = 0.323). The same could not be observed for parameters assessing the volume status., Conclusions: The analysis indicates that ETL could inhibit LAVI progression compared with ALFA. This effect was mediated by the change of LVMI., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Secondary hyperparathyroidism in chronic kidney disease poses a major risk factor for vascular calcification and high bone turnover, leading to mineralization defects. The aim was to analyze the effect of active vitamin D and calcimimetic treatment on fibroblast growth factor 23 (FGF23), serum calcification propensity (T50), a surrogate marker of calcification stress and bone specific alkaline phosphatase (BAP) in hemodialysis. This is a subanalysis of a randomized trial comparing etelcalcetide vs. alfacalcidol in 62 hemodialysis patients for 1 year. We compared the change of BAP and serum calcification propensity between the two medications and assessed the influence of FGF23 change over time. We found no significant differences in the change of BAP or serum calcification propensity (T50) levels from baseline to study end between treatment arms (difference in change of marker between treatment with etelcalcetide vs. alfacalcidol: BAP : 2.0 ng/ml [95% CI-1.5,5.4], p = 0.3; T50: -15 min [95% CI -49,19], p = 0.4). Using FGF23 change over time, we could show that BAP levels at study end were associated with FGF23 change (-0.14 [95% CI -0.21, -0.08], p < 0.001). We did not observe the same association between FGF23 change and T50 (effect of FGF23 change on T50: 3.7 [95% CI -5.1, 12], p = 0.4; R 2 = 0.07 vs. R 2 = 0.06). No significant difference was found in serum calcification propensity (T50) values between treatment arms. FGF23 was not associated with serum calcification propensity (T50), but was negatively correlated with BAP underlying its role in the bone metabolism., Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03182699]., Competing Interests: RO reports grants from Amgen during the conduct of the study. In addition, RO, KD, and RR-S have a patent “Methods of treating left ventricle hypertrophy” pending. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dörr, Hödlmoser, Kammer, Reindl-Schwaighofer, Lorenz, Reiskopf, Jagoditsch, Marculescu and Oberbauer.)

Purpose of Review: Patients with end-stage kidney disease (ESKD) frequently develop left ventricular hypertrophy (LVH), which is associated with an exceptionally high risk of cardiovascular events and mortality. This review focuses on interventional studies that modify levels of fibroblast growth factor 23 (FGF23) and examine effects on myocardial hypertrophy, cardiovascular events and mortality., Recent Findings: Quantitative evaluations of trials of calcimimetics found no effects on cardiovascular events and cardiovascular and all-cause mortality when compared with placebo. However, a recent randomized, controlled trial of etelcalcetide versus alfacalcidol showed that etelcalcetide effectively inhibited the progression of LVH in comparison to vitamin D in patients on haemodialysis after 1 year of treatment. Prior to that, oral calcimimetic treatment has already been shown to reduce left ventricular mass in patients on haemodialysis, whereas treatment with active vitamin D or mineralocorticoids was ineffective in patients with ESKD., Summary: Data from a recent trial of etelcalcetide on LVH suggest that FGF23 may be a possible therapeutic target for cardiac risk reduction in patients on haemodialysis. If these findings are confirmed by further research, it might be speculated that a treatment shift from active vitamin D towards FGF23-lowering therapy may occur in patients on haemodialysis., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Fibroblast growth factor 23 (FGF23) is elevated in patients with chronic kidney disease and contributes to left ventricular hypertrophy (LVH). The aim of the analysis was to determine whether this effect is mediated by the renin-angiotensin-aldosterone system (RAAS) in hemodialysis. Serum samples from 62 randomized hemodialysis patients with LVH were analyzed for plasma renin activity (PRA-S), angiotensin II (AngII), and metabolites, angiotensin-converting enzyme-2 (ACE2) and aldosterone using a high throughput mass spectrometry assay. Compared to healthy individuals, levels of the RAAS parameters PRA-S, AngII and aldosterone were generally lower [median (IQR) PRA-S 130 (46-269) vs. 196 (98, 238) pmol/L; AngII 70 (28-157) vs. 137 (76, 201) pmol/L; Aldosterone 130 (54, 278) vs. 196 (98, 238) pmol/L]. We did not find an indication that the effect of FGF23 on LVH was mediated by RAAS parameters, with all estimated indirect effects virtually zero. Furthermore, FGF23 was not associated with RAAS parameter levels throughout the study. While there was a clear association between FGF23 levels and left ventricular mass index (LVMI) at the end of the study and in the FGF23 fold change and LVMI change analysis, no association between RAAS and LVMI was observed. Serum concentrations of PRA-S, AngII, and aldosterone were below the ranges measured in healthy controls suggesting that RAAS is not systemically activated in hemodialysis patients. The effect of FGF23 on LVMI was not mediated by systemic RAAS activity. These findings challenge the current paradigm of LVH progression and treatment with RAAS blockers in dialysis., Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT03182699], identifier [NCT03182699]., Competing Interests: RO reported grants from Amgen during the conduct of the study. In addition, RO, KD, and RR-S had a patent “Methods of treating left ventricle hypertrophy” pending. MP was employed by Attoquant Diagnostics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dörr, Kammer, Reindl-Schwaighofer, Lorenz, Marculescu, Poglitsch, Beitzke and Oberbauer.)

[Figure: see text].

The growth and differentiation factor 5 (GDF-5) is known to play a key role in cartilage morphogenesis and homeostasis, and a single-nucleotide polymorphism in its promoter sequence was found to be associated with osteoarthritis (OA). In addition, GDF-5 was shown to promote extracellular matrix (ECM) production in healthy chondrocytes, to stimulate chondrogenesis of mesenchymal stem cells (MSCs) and to protect against OA progression in vivo. Therefore, GDF-5 appears to be a promising treatment for osteoarthritis. However, GDF-5 also promotes osteogenesis and hypertrophy, limiting its therapeutic utility. To circumvent this, a GDF-5 mutant with lower hypertrophic and osteogenic properties was engineered: M1673. The present study aimed to evaluate and compare the effects of GDF-5 and M1673 on primary porcine and human OA chondrocytes. We found that both GDF-5 and M1673 can robustly stimulate ECM accumulation, type II collagen and aggrecan expression in porcine and human OA chondrocytes in 3D culture. In addition, both molecules also down-regulated MMP13 and ADAMTS5 expression. These results suggest that M1673 retained the anabolic and anti-catabolic effects of GDF-5 on chondrocytes and is an alternative to GDF-5 for osteoarthritis., (© 2020 Merck KGaA. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Osteoarthritis (OA) is a common disease worldwide with large unmet medical needs. To bring innovative treatments to OA patients, we at Merck have implemented a comprehensive strategy for drug candidate evaluation. We have a clear framework for decision-making in our preclinical pipeline, to design our clinical proof-of-concept trials for OA patients. We have qualified our strategy to define and refine dose and dosing regimen, for treatments administered either systemically or intra-articularly (IA). We do this through preclinical in vitro and in vivo studies, and by back-translating results from clinical studies in OA patients., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Fibroblast growth factor 23 (FGF23) is associated with left ventricular hypertrophy (LVH) in patients with chronic kidney disease, and calcimimetic therapy reduces plasma concentrations of FGF23. It remains unknown whether treatment with the calcimimetic etelcalcetide (ETL) reduces LVH in patients on hemodialysis., Methods/design: This single-blinded randomized trial of 12 months duration will test the effects of ETL compared with alfacalcidol on LVH and cardiac fibrosis in maintenance hemodialysis patients with secondary hyperparathyroidism. Both treatment regimens will be titrated to equally suppress secondary hyperparathyroidism while alfacalcidol treatment causes an increase and ETL a decrease in FGF23, respectively. Patients treated thrice weekly with hemodialysis for ≥ 3 months and ≤ 3 years with parathyroid hormone levels ≥ 300 pg/ml and LVH will be enrolled in the study. The primary study endpoint is change from baseline to 12 months in left ventricular mass index (LVMI; g/m 2 ) measured by cardiac magnetic resonance imaging. Sample size calculations showed that 62 randomized patients will be necessary to detect a difference in LVMI of at least 20 g/m 2 between the two groups at 12 months. Due to the strong association of volume overload and LVH, randomization will be stratified by residual kidney function, and regular body composition monitoring will be performed to control the volume status of patients. Study medication will be administered intravenously by the dialysis nurses after every hemodialysis session, thus omitting adherence issues. Secondary study endpoints are cardiac parameters measured by echocardiography, biomarker concentrations of bone metabolism (FGF23, vitamin D, parathyroid hormone, calcium, phosphate, s-Klotho), cardiac markers (pro-brain natriuretic peptide, pre- and postdialysis troponin T) and metabolites of the renin-angiotensin-aldosterone cascade (angiotensin I (Ang I), Ang II, Ang-(1-7), Ang-(1-5), Ang-(1-9), and aldosterone)., Discussion: The causal inference and pathophysiology of LVH regression by FGF23 reduction using calcimimetic treatment has not yet been shown. This intervention study has the potential to discover a new strategy for the treatment of cardiac hypertrophy and fibrosis in patients on maintenance hemodialysis. It might be speculated that successful treatment of cardiac morphology will also reduce the risk of cardiac death in this population., Trial Registration: European Clinical Trials Database, EudraCT number 2017-000222-35; ClinicalTrials.gov, NCT03182699 . Registered on.

Precise intracellular calcium signaling is crucial to numerous cellular functions. In non-excitable cells, store-operated calcium entry (SOCE) is a key step in the generation of intracellular calcium signals. Tight regulation of SOCE is important, and dysregulation is involved in several pathophysiological cellular malfunctions. The current underlying SOCE, calcium release-activated calcium current (I CRAC ), was first discovered almost three decades ago. Since its discovery, the molecular components of I CRAC , Orai1 and stromal interaction molecule 1 (STIM1), have been extensively investigated. Several regulatory mechanisms and proteins contribute to alterations in SOCE and cellular malfunctions in cancer, immune and neurodegenerative diseases, inflammation, and neuronal disorders. This review summarizes these regulatory mechanisms, including glycosylation, pH sensing, and the regulatory proteins golli, α-SNAP, SARAF, ORMDL3, CRACR2A, and TRPM4 channels., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A surge in interest of oxide-based materials is testimony for their potential utility in a wide array of device applications and offers a fascinating landscape for tuning the functional properties through a variety of physical and chemical parameters. In particular, selective electronic/defect doping has been demonstrated to be vital in tailoring novel functionalities, not existing in the bulk host oxides. Here, an extraordinary interstitial doping effect is demonstrated centered around a light element, boron (B). The host matrix is a novel composite system, made from discrete bulk LaAlO 3 :LaBO 3 compounds. The findings show a spontaneous ordering of the interstitial B cations within the host LaAlO 3 lattices, and subsequent spin-polarized charge injection into the neighboring cations. This leads to a series of remarkable cation-dominated electrical switching and high-temperature ferromagnetism. Hence, the induced interstitial doping serves to transform a nonmagnetic insulating bulk oxide into a ferromagnetic ionic-electronic conductor. This unique interstitial B doping effect upon its control is proposed to be as a general route for extracting/modifying multifunctional properties in bulk oxides utilized in energy and spin-based applications., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Store-operated Ca(2+) entry mediated by STIM1-gated Orai1 channels is essential to activate immune cells and its inhibition or gain-of-function can lead to immune dysfunction and other pathologies. Reactive oxygen species interacting with cysteine residues can alter protein function. Pretreatment of the Ca(2+) selective Orai1 with the oxidant H2O2 reduces ICRAC with C195, distant to the pore, being its major redox sensor. However, the mechanism of inhibition remained elusive. Here we combine experimental and theoretical approaches and show that oxidation of Orai1 leads to reduced subunit interaction, slows diffusion and that either oxidized C195 or its oxidomimetic mutation C195D located at the exit of transmembrane helix 3 virtually eliminates channel activation by intramolecular interaction with S239 of transmembrane helix 4, thereby locking the channel in a closed conformation. Our results demonstrate a novel mechanistic model for ROS-mediated inhibition of Orai1 and identify a candidate residue for pharmaceutical intervention.

N-glycosylation of cell surface proteins affects protein function, stability, and interaction with other proteins. Orai channels, which mediate store-operated Ca(2+) entry (SOCE), are composed of N-glycosylated subunits. Upon activation by Ca(2+) sensor proteins (stromal interaction molecules STIM1 or STIM2) in the endoplasmic reticulum, Orai Ca(2+) channels in the plasma membrane mediate Ca(2+) influx. Lectins are carbohydrate-binding proteins, and Siglecs are a family of sialic acid-binding lectins with immunoglobulin-like repeats. Using Western blot analysis and lectin-binding assays from various primary human cells and cancer cell lines, we found that glycosylation of Orai1 is cell type-specific. Ca(2+) imaging experiments and patch-clamp experiments revealed that mutation of the only glycosylation site of Orai1 (Orai1N223A) enhanced SOCE in Jurkat T cells. Knockdown of the sialyltransferase ST6GAL1 reduced α-2,6-linked sialic acids in the glycan structure of Orai1 and was associated with increased Ca(2+) entry in Jurkat T cells. In human mast cells, inhibition of sialyl sulfation altered the N-glycan of Orai1 (and other proteins) and increased SOCE. These data suggest that cell type-specific glycosylation influences the interaction of Orai1 with specific lectins, such as Siglecs, which then attenuates SOCE. In summary, the glycosylation state of Orai1 influences SOCE-mediated Ca(2+) signaling and, thus, may contribute to pathophysiological Ca(2+) signaling observed in immune disease and cancer., (Copyright © 2016, American Association for the Advancement of Science.)

In prostate cancer, reactive oxygen species (ROS) are elevated and Ca(2+) signaling is impaired. Thus, several novel therapeutic strategies have been developed to target altered ROS and Ca(2+) signaling pathways in prostate cancer. Here, we investigate alterations of intracellular Ca(2+) and inhibition of cell viability caused by ROS in primary human prostate epithelial cells (hPECs) from healthy tissue and prostate cancer cell lines (LNCaP, DU145, and PC3). In hPECs, LNCaP and DU145 H2O2 induces an initial Ca(2+) increase, which in prostate cancer cells is blocked at high concentrations of H2O2. Upon depletion of intracellular Ca(2+) stores, store-operated Ca(2+) entry (SOCE) is activated. SOCE channels can be formed by hexameric Orai1 channels; however, Orai1 can form heteromultimers with its homolog, Orai3. Since the redox sensor of Orai1 (Cys-195) is absent in Orai3, the Orai1/Orai3 ratio in T cells determines the redox sensitivity of SOCE and cell viability. In prostate cancer cells, SOCE is blocked at lower concentrations of H2O2 compared with hPECs. An analysis of data from hPECs, LNCaP, DU145, and PC3, as well as previously published data from naive and effector TH cells, demonstrates a strong correlation between the Orai1/Orai3 ratio and the SOCE redox sensitivity and cell viability. Therefore, our data support the concept that store-operated Ca(2+) channels in hPECs and prostate cancer cells are heteromeric Orai1/Orai3 channels with an increased Orai1/Orai3 ratio in cells derived from prostate cancer tumors. In addition, ROS-induced alterations in Ca(2+) signaling in prostate cancer cells may contribute to the higher sensitivity of these cells to ROS., (Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

180° domain wall motion in a tetragonal ferroelectric oxide is accelerated by an order of magnitude using in situ strain in a force microscope. Single-domain PbZr0.2 Ti0.8 O3 films on piezoelectric (001)-oriented 0.72PbMg1/3 Nb2/3 O3 -0.28PbTiO3 substrates allow for direct investigation of strain-dependent domain dynamics. The strain effect depends on the sign of applied field through strain-dependent electrode built-in potentials and a suggested charging of tilted walls., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Films of cerium-doped LaMnO3, which has been intensively discussed as an electron-doped counterpart to hole-doped mixed-valence lanthanum manganites during the past decade, were analyzed by x-ray photoemission spectroscopy with respect to their manganese valence under photoexcitation. The comparative analysis of the Mn 3s exchange splitting of La0.7Ce0.3MnO3 (LCeMO) films in the dark and under illumination clearly shows that both oxygen reduction and illumination are able to decrease the Mn valence towards a mixed 2+/3+ state, independently of the film thickness and the degree of CeO2 segregation. Charge-injection from the photoconductive SrTiO3 substrate into the Mn eg band with carrier lifetimes in the range of tens of seconds and intrinsic generation of electron-hole pairs within the films are discussed as two possible sources of the Mn valence shift and the subsequent electron doping.

The role of elastic strain for magnetoelectric materials and devices is twofold. It can induce ferroic orders in thin films of otherwise non-ferroic materials. On the other hand, it provides the most exploited coupling mechanism in two-phase magnetoelectric materials and devices today. Complex oxide films (perovskites, spinels) are promising for both routes. The strain control of magnetic order in complex oxide films is a young research field, and few ab initio simulations are available for magnetic order in dependence on lattice parameters and lattice symmetry. Here, an experimental approach for the evaluation of how elastic strain in thin epitaxial films alters their magnetic order is introduced. The magnetic films are grown epitaxially in strain states controlled by buffer layers onto piezoelectric substrates of 0.72Pb(Mg1/3Nb2/3)O3-0.28PbTiO3(001). As an example, the strain dependence of the ordered magnetic moment of SrRuO3 has been investigated. At a tensile strain level of approximately 1%, SrRuO3 is tetragonal, and biaxial elastic strain induces a pronounced suppression of the ordered magnetic moment. As a second example, a strain-driven transition from a ferromagnetic to a magnetically disordered phase has been observed in epitaxial La0.8Sr0.2CoO3 films.

Many organs with a high cell turnover (for example, skin, intestine and blood) are composed of short-lived cells that require continuous replenishment by somatic stem cells. Ageing results in the inability of these tissues to maintain homeostasis and it is believed that somatic stem-cell ageing is one underlying cause of tissue attrition with age or age-related diseases. Ageing of haematopoietic stem cells (HSCs) is associated with impaired haematopoiesis in the elderly. Despite a large amount of data describing the decline of HSC function on ageing, the molecular mechanisms of this process remain largely unknown, which precludes rational approaches to attenuate stem-cell ageing. Here we report an unexpected shift from canonical to non-canonical Wnt signalling in mice due to elevated expression of Wnt5a in aged HSCs, which causes stem-cell ageing. Wnt5a treatment of young HSCs induces ageing-associated stem-cell apolarity, reduction of regenerative capacity and an ageing-like myeloid-lymphoid differentiation skewing via activation of the small Rho GTPase Cdc42. Conversely, Wnt5a haploinsufficiency attenuates HSC ageing, whereas stem-cell-intrinsic reduction of Wnt5a expression results in functionally rejuvenated aged HSCs. Our data demonstrate a critical role for stem-cell-intrinsic non-canonical Wnt5a signalling in HSC ageing.

A drop of endoplasmic reticulum Ca(2+) concentration triggers its Ca(2+) ssensor protein stromal interaction molecule 1 (STIM1) to oligomerize and accumulate within endoplasmic reticulum-plasma membrane junctions where it activates Orai1 channels, providing store-operated Ca(2+) entry. To elucidate the functional significance of N-glycosylation sites of STIM1, we created different mutations of asparagine-131 and asparagine-171. STIM1 NN/DQ resulted in a strong gain of function. Patch clamp, Total Internal Reflection Fluorescent (TIRF) microscopy, and fluorescence recovery after photobleaching (FRAP) analyses revealed that expression of STIM1 DQ mutants increases the number of active Orai1 channels and the rate of STIM1 translocation to endoplasmic reticulum-plasma membrane junctions with a decrease in current latency. Surprisingly, co-expression of STIM1 DQ decreased Orai1 protein, altering the STIM1:Orai1 stoichiometry. We describe a novel mathematical tool to delineate the effects of altered STIM1 or Orai1 diffusion parameters from stoichiometrical changes. The mutant uncovers a novel mechanism whereby "superactive" STIM1 DQ leads to altered oligomerization rate constants and to degradation of Orai1 with a change in stoichiometry of activator (STIM1) to effector (Orai1) ratio leading to altered Ca(2+) homeostasis.

The decline in hematopoietic function seen during aging involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, and has been linked to aging of hematopoietic stem cells (HSCs). The molecular mechanisms underlying HSC aging remain unclear. Here we demonstrate that elevated activity of the small RhoGTPase Cdc42 in aged HSCs is causally linked to HSC aging and correlates with a loss of polarity in aged HSCs. Pharmacological inhibition of Cdc42 activity functionally rejuvenates aged HSCs, increases the percentage of polarized cells in an aged HSC population, and restores the level and spatial distribution of histone H4 lysine 16 acetylation to a status similar to that seen in young HSCs. Our data therefore suggest a mechanistic role for Cdc42 activity in HSC biology and epigenetic regulation, and identify Cdc42 activity as a pharmacological target for ameliorating stem cell aging., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The molecular and cellular mechanisms of the age-associated increase in the incidence of acute myeloid leukemia (AML) remain poorly understood. Multiple studies support that the bone marrow (BM) microenvironment has an important influence on leukemia progression. Given that the BM niche itself undergoes extensive functional changes during lifetime, we hypothesized that one mechanism for the age-associated increase in leukemia incidence might be that an aged niche promotes leukemia progression. The most frequent genetic alteration in AML is the t(8;21) translocation, resulting in the expression of the AML1-ETO fusion protein. Expression of the fusion protein in hematopoietic cells results in mice in a myeloproliferative disorder. Testing the role of the age of the niche on leukemia progression, we performed both transplantation and in vitro co-culture experiments. Aged animals transplanted with AML1-ETO positive HSCs presented with a significant increase in the frequency of AML-ETO positive early progenitor cells in BM as well as an increased immature myeloid cell load in blood compared to young recipients. These findings suggest that an aged BM microenvironment allows a relative better expansion of pre-leukemic stem and immature myeloid cells and thus imply that the aged microenvironment plays a role in the elevated incidence of age-associated leukemia.

The mechanisms of the age-associated exponential increase in the incidence of leukemia are not known in detail. Leukemia as well as aging are initiated and regulated in multi-factorial fashion by cell-intrinsic and extrinsic factors. The role of aging of the microenvironment for leukemia initiation/progression has not been investigated in great detail so far. Clonality in hematopoiesis is tightly linked to the initiation of leukemia. Based on a retroviral-insertion mutagenesis approach to generate primitive hematopoietic cells with an intrinsic potential for clonal expansion, we determined clonality of transduced hematopoietic progenitor cells (HPCs) exposed to a young or aged microenvironment in vivo. While HPCs displayed primarily oligo-clonality within a young microenvironment, aged animals transplanted with identical pool of cells displayed reduced clonality within transduced HPCs. Our data show that an aged niche exerts a distinct selection pressure on dominant HPC-clones thus facilitating the transition to mono-clonality, which might be one underlying cause for the increased age-associated incidence of leukemia.