Search

We report on the highly efficient spin-orbit torque (SOT) generation in epitaxial SrIrO$_{3}$(SIO), which is grown on an orthorhombic DyScO$_{3}$(110) substrate. By conducting harmonic Hall measurement in Co$_{20}$Fe$_{60}$B$_{20}$ (CoFeB)/SIO bilayers, we characterize two kinds of the SOTs, i.e., dampinglike (DL) and fieldlike ones to find that the former is much larger than the latter. By comparison with the Pt control sample with the same CoFeB thickness, the observed DL SOT efficiency $\xi$$_{DL}$ of SIO ($\sim$0.32) is three times higher than that of Pt ($\sim$0.093). The $\xi$$_{DL}$ is nearly constant as a function of the CoFeB thickness, suggesting that the SIO plays a crucial role in the large SOT generation. These results on the CoFeB/SIO bilayers highlight that the epitaxial SIO is promising for low-current and reliable spin-orbit torque-controlled devices., Comment: arXiv admin note: text overlap with arXiv:2305.17887

On January 26, 2023, Science issued an editorial announcing that its journal policy would be changed to restrict artificial intelligences (AIs), such as ChatGPT, from being used to write papers, in addition to disallowing authorship of AIs. Indeed, AIs are not eligible for authorship because they do not have free will and they cannot make decisions to be an author. However, several observations have been made that researchers can use ChatGPT as an English proofreader, rather than a writer of first drafts. Therefore, we discussed the usage of AIs and the way of authorship, particularly, in terms of English proofreading. Then, we wrote an eLetter for that editorial, but its eLetter section suddenly disappeared, so we released the eLetter as a preprint with additional discussion. Although AIs are a double-edged sword and they could exacerbate scholarly publishing and science, they also have potentialities to remove language barriers and improve science all over the world. The present article claimed the importance of continuous discussion about the use of AIs and the language barriers.

Scientists write research articles, process ethics reviews, evaluate proposals and research, and seek funding. Several strategies have been proposed to optimize these operations and to decentralize access to research resources and opportunities. For instance, we previously proposed the trinity review method, combining registered reports with financing and research ethics assessments. However, previously proposed systems have a number of shortcomings, including how to implement them, e.g., who manages them, how incentives for reviewers are paid, etc. Various solutions have been proposed to address these issues, employing decentralized science (DeSci) in an independent organization built on the blockchain. Decentralized approaches that exploit these developments offer potentially profound improvements to the troubled scientific ecosystem. Here, we propose a system that integrates ethics reviews, peer reviews, and funding in a decentralized manner, based on Web3 technology. This new method, named ABCDEF publishing, would enhance the speed, fairness, and transparency of scientific research and publishing.

Constant-pressure heat capacities (CPs) of crystalline benzoic acid (BAh) and its deuterated analogue (C6H5COOD, BAd) were measured by adiabatic calorimetry, and the phonon density (g(ω)) of states was determined from their CP data using a real-coded genetic algorithm (RCGA) with just generation gap + real-coded ensemble cross-over. The distribution of g(ω) was in reasonable agreement with the spectroscopic one observed for molecular vibration modes, indicating sufficient reliability of g(ω) determined by the RCGA. Based on the fact that CPs reveals an inverse-isotope effect in the temperature range 30-130 K, the determined g(ω)s were used to investigate the molecular mechanism of the effect: g(ω) of BAd revealed blue shifts in the ranges of ω = 80-100 and 150-230 K, as referred to that of BAh. It was suggested from the combined considerations on g(ω) and spectroscopic results that an anticooperative correlation exists between O-H···O hydrogen bonds and interdimer interactions in BA.

Economic inequality is associated with preferences for smaller, immediate gains over larger, delayed ones. Such temporal discounting may feed into rising global inequality, yet it is unclear whether it is a function of choice preferences or norms, or rather the absence of sufficient resources for immediate needs. It is also not clear whether these reflect true differences in choice patterns between income groups. We tested temporal discounting and five intertemporal choice anomalies using local currencies and value standards in 61 countries (N = 13,629). Across a diverse sample, we found consistent, robust rates of choice anomalies. Lower-income groups were not significantly different, but economic inequality and broader financial circumstances were clearly correlated with population choice patterns. Ruggeri et al. find in a study of 61 countries that temporal discounting patterns are globally generalizable. Worse financial environments, greater inequality and high inflation are associated with extreme or inconsistent long-term decisions.

Utilization of carbon dioxide (CO2) molecules leads to increased interest in the sustainable synthesis of methane (CH4) or methanol (CH3OH). The representative reaction intermediate consisting of a carbonyl or formate group determines yields of the fuel source during catalytic reactions. However, their selective initial surface reaction processes have been assumed without a fundamental understanding at the molecular level. Here, we report direct observations of spontaneous CO2 dissociation over the model rhodium (Rh) catalyst at 0.1 mbar CO2. The linear geometry of CO2 gas molecules turns into a chemically active bent-structure at the interface, which allows non-uniform charge transfers between chemisorbed CO2 and surface Rh atoms. By combining scanning tunneling microscopy, X-ray photoelectron spectroscopy at near-ambient pressure, and computational calculations, we reveal strong evidence for chemical bond cleavage of O‒CO* with ordered intermediates structure formation of (2 × 2)-CO on an atomically flat Rh(111) surface at room temperature. Direct observation of carbon dioxide dissociation provides an origin of catalytic conversion for industrial chemical reactions. Here, the authors reveal their molecular interactions on the rhodium catalyst at near-ambient pressure by interface science techniques and computational calculations.

This study was conducted to examine retinal sensitivity (RS) in eyes with pachychoroid diseases and to analyze its association with the presence or absence of quiescent choroidal neovascularization (CNV), that can be protective against retinal dysfunction or atrophy in other macular diseases such as age-related macular degeneration. A total of 12 eyes of 12 patients aged ≥45 years having the characteristic findings of central serous chorioretinopathy but not presenting any exudative changes were included in this study. Choroidal vascular hyper permeability (CVH) was identified by indocyanine green angiography, and the presence or absence of CNV was evaluated by optical coherence tomography angiography. RS at 68 points was examined by microperimetry. The average RS corresponding to within and outside CVH was compared. The association between the difference in RS and the presence or absence of CNV was also analyzed. CNV was detected in six eyes (50%). In eyes without CNV, the RS within CVH was similar compared with that outside CVH. However, in eyes with CNV, the RS within CVH was significantly decreased compared with that outside CVH. Multiple regression analysis revealed the presence of CNV as an independent factor associated with RS. In eyes with pachychoroid diseases, RS decreased within the CVH area under the coexistence of nonexudative CNV.

We study spin Hall magnetoresistance (SMR) in Pt/ferrimagnetic insulator Y3Fe5O12 (YIG) bilayers by focusing on crystallinity, magnetization, and interface roughness by controlling post-annealing temperatures. The SMR in the Pt/YIG grown on Si substrate is comparable to that grown on widely used Gd3Ga5O12 substrate, indicating that the large SMR can be achieved irrespective of the crystallinity. We deduced the spin mixing conductance from the Pt thickness dependence of the SMR to find the high interface quality of the optimized Pt/YIG grown on Si in terms of spin current. We also clarified that the SMR correlates well with the magnetization, the interface roughness, and carrier density. These findings highlight that optimizing YIG properties is a key to control of magnetization by spin current, leading to the development of the low power consumption spintronic device based on the magnetic insulator.

The Impella (Abiomed, Danvers, MA, USA) is a minimally invasive axial-flow catheter used in severe heart failure. We describe a case in which aortic insufficiency occurred after Impella insertion, required extra surgical intervention twice. A 33-year-old man with familial dilated cardiomyopathy was admitted to our hospital due to acute decompensation of heart failure. Despite intensive medical treatment, his hemodynamic status did not improve. Firstly, Impella was emergently implanted, and HeartMate III (Abbott, Plymouth, MN, USA) implantation was performed 2 weeks after. In the HeartMate III implantation, new aortic insufficiency had revealed and central aortic valve closure was performed concomitantly. However, on postoperative Day1, the coaptation stitch had untied, causing severe aortic insufficiency which led to another emergent operation of aortic valve replacement. We suggest that indications for Impella implantation need to be carefully discussed beforehand, especially with patients who may undergo implantation of left ventricular assist device.

The 5d transition-metal oxides are an intriguing platform to demonstrate efficient charge-to-spin-current conversion due to a unique electronic structure dominated by strong spin-orbit coupling. Here, we report on the stacking-order effect of spin-orbit torque (SOT), spin-Hall magnetoresistance, and magnetic anisotropy in bilayer ${\mathrm{Ni}}_{81}{\mathrm{Fe}}_{19}$-5d iridium oxide, ${\mathrm{Ir}\mathrm{O}}_{2}$. While all ${\mathrm{Ir}\mathrm{O}}_{2}$ and $\mathrm{Pt}$ control samples exhibit large dampinglike SOT generation, stemming from the efficient charge-to-spin-current conversion, the magnitude of the SOT is larger in the ${\mathrm{Ir}\mathrm{O}}_{2}$($\mathrm{Pt})$ bottom sample than in the ${\mathrm{Ir}\mathrm{O}}_{2}$($\mathrm{Pt})$ top one. The fieldlike SOT has an even more significant stacking-order effect, resulting in an opposite sign in the ${\mathrm{Ir}\mathrm{O}}_{2}$ samples in contrast to the same sign in the $\mathrm{Pt}$ samples. Furthermore, we observe that the magnetic anisotropy energy density and the anomalous Hall effect are increased in the ${\mathrm{Ir}\mathrm{O}}_{2}$($\mathrm{Pt})$ bottom sample, suggesting enhanced interfacial perpendicular magnetic anisotropy. Our findings highlight the significant influence of the stacking order on spin transport and the magnetotransport properties of $\mathrm{Ir}$ oxide-ferromagnet systems, providing useful information for the design of SOT devices, including 5d transition-metal oxides.

We have previously shown that podocyte injury increases the glomerular filtration of liver-derived angiotensinogen (Agt) and the generation of intrarenal angiotensin (Ang) II and that the filtered Agt is reabsorbed by proximal tubules in a manner dependent on megalin. In the present study, we aimed to study the role of megalin in the generation of renal Ang II and sodium handling during nephrotic syndrome. We generated proximal tubule-specific megalin knockout (KO) mice and crossed these animals with NEP25 mice, in which podocyte-specific injury can be induced by injection of the immunotoxin LMB2. Without podocyte injury, renal Agt staining was markedly diminished and urinary Agt increased in KO mice. However, renal Ang II was similar between KO and control mice on average: 117 (95% CI 101–134) vs. 101 (68–133) fmol/g tissue. We next tested the effect of megalin KO on intrarenal Ang II generation with podocyte injury. Control NEP25 mice showed markedly increased renal Agt staining and renal Ang II levels: 450 (336–565) fmol/g tissue. Megalin KO/NEP25 mice showed markedly diminished Agt reabsorption and attenuated renal Ang II: 199 (156–242) fmol/g tissue (p < 0.001). Compared with control NEP25 mice, megalin KO/NEP25 mice excreted 5-fold more sodium in the urine. Western blot analysis showed that megalin KO decreased NHE3 and the cleaved α and γ forms of ENaC. These data indicate that Agt reabsorbed by proximal tubules via megalin in nephrotic syndrome is converted to Ang II, which may contribute to sodium retention and edema formation by activating NHE3 and ENaC. SUMMARY: This study shows that in nephrotic syndrome, plasma angiotensinogen leaked into the renal tubular lumen is reabsorbed by proximal tubules via megalin and converted to angiotensin II, which may contribute to sodium retention and edema formation by activating NHE3 and ENaC.

This paper examines whether the economic crisis induced by the COVID-19 pandemic exhibits a Schumpeterian “cleansing” of less productive firms. Using firm-level data for 31 economies, the study finds that less productive firms have a higher probability of permanently closing during the crisis, suggesting that the process of cleansing out unproductive arrangements may be at work. The paper also uncovers a strong and negative relationship between firm exit and innovation and digital presence, especially for small firms, confirming the relevance of the ability to adapt to market conditions as a determinant of firm survival. Finally, the study finds evidence of a negative relationship between firm exit and a burdensome business environment, as well as between firm exit and age.

Purpose To investigate the three-dimensional distribution and associating demographic factors of depolarization, using polarization-sensitive optical coherence tomography (PS-OCT), to evaluate melanin pigmentation in the retinal pigment epithelium (RPE) and choroid in healthy eyes. Methods In total, 39 unaffected healthy eyes of 39 subjects were examined using a PS-OCT clinical prototype. The degree of depolarization, expressed as the polarimetric entropy, was assessed in the RPE, the superficial and the total choroid layer, especially in the center, the inner, or the outer areas centered at the fovea. The values and their association with the demographic data were analyzed. Near-infrared fundus autofluorescence (NIRAF) was also used, in the same manner, for the comparison. Twenty-eight of 39 eyes were measured twice to evaluate intrasession repeatability. Results Both the polarimetric entropy in the RPE and the gray level in NIRAF, decreased from the center to the periphery (P < 0.001). The polarimetric entropy in the RPE was significantly associated with age in each area (P ≤ 0.001). In the RPE and the superficial choroid, the polarimetric entropy was negatively associated with axial length in each area (P ≤ 0.002). The intraclass correlation coefficient of the polarimetric entropy in the same session was excellent in each area of the RPE, superficial choroid, or total choroid layer (0.94-0.98). Conclusions The distribution of fundus melanin pigment-related depolarization was evaluated using PS-OCT. The depolarization was associated with the subjects' demographic data, such as age or axial length. Translational Relevance The presented information in healthy eyes provides an essential basis for the investigation into a variety of chorioretinal pathologies.

Purpose To report the clinical findings of the patients with retinal pigment epithelium (RPE) aperture secondary to age-related macular degeneration (AMD). Methods A retrospective data analysis was conducted of patients at the University of Tokyo Hospital eye clinic, from the year September 1st, 2012 to 2019. Review of the medical records of patients with RPE aperture accompanied by AMD was performed. We investigated age, best-corrected visual acuity (BCVA), images of spectral domain optical coherence tomography, short-wave fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography, and retinal sensitivity measured with microperimetry. The change in visual acuity or the area of the aperture during the follow-up period was analyzed. Results Five eyes of 5 patients (4 men, one woman) were included in the analysis. The mean age at presentation was 78.6 ± 9.1 years. The average length of follow-up was 23.6 ± 17.9 months. The RPE apertures appeared as round, either at the apex or at the base of PED, with no evidence of accompanying CNV but subretinal detachment (SRD) above the aperture. On FAF, the apertures appeared as sharply demarcated round areas of hypoautofluorescence. The FA revealed sharply demarcated round areas of window defects in the early and mid-phase with leakage in the late phase corresponding to SRD. The area of apertures enlarged during the follow-up period. Mean BCVA got worse from 0.20 logMAR at the initial presentation to 0.39 logMAR at the last visit. The retinal sensitivity was reduced but partly preserved above the area of aperture. Conclusions and importance RPE aperture was found in some patients with drusenoid PED secondary to AMD. It enlarged during follow-up. Visual acuity was declined. Retinal sensitivity was decreased but partly preserved.

A method was proposed to derive the phonon density [g(ω)] of states of materials from their heat capacity data by using Real-Coded Genetic Algorithm (RCGA) with Just Generation Gap + Real-Coded Ensemble Crossover. The performance of the method was confirmed by testing whether or not the RCGA reproduces a reasonable g(ω) by analyzing the set of heat capacity data evaluated from an initially assumed model g0(ω) composed of Debye and optical modes. As an example, constant-pressure heat capacities (CPs) were measured for soft molecular materials, diphenyl phosphate (DPP) and diphenylphosphinic acid, in the condensed state, and their g(ω)s were determined from the CP data by applying the RCGA. The unusual behavior that the CP value of glass was smaller than the one of the crystal in the temperature range from 10 to 70 K was observed in DPP; the behavior is contrary to that expected ordinarily for the glass as compared with the crystal. The g(ω)s determined by the RCGA demonstrated that the unusual behavior was attributed to the blue shift in g(ω) of ω = 30-240 K in the glass compared with the crystal. The blue shift and other effects were discussed reasonably as originating from the competitive concurrence of strong and weak intermolecular hydrogen bonds in DPP, with the help of determination of their intramolecular vibrations for the isolated molecule by the density functional theory calculation. It was concluded that the method using the RCGA is of value for obtaining the microscopic information of g(ω) from the precise heat capacity data and for investigating any difference between the details of g(ω)s in different phases of materials.

The $5d$ transition-metal oxides have a unique electronic structure dominated by strong spin-orbit coupling and hence they can be an intriguing platform to explore spin-current physics. Here, we report on room-temperature generation of spin-orbit torque (SOT) from a conductive $5d$ iridium oxide, $\mathrm{Ir}{\mathrm{O}}_{2}$. By measuring second-harmonic Hall resistance of ${\mathrm{Ni}}_{81}{\mathrm{Fe}}_{19}/\mathrm{Ir}{\mathrm{O}}_{2}$ bilayers, we find both dampinglike and fieldlike SOTs. The former is larger than the latter, enabling easier control of magnetization. We also observe that the dampinglike SOT efficiency has a significant dependence on $\mathrm{Ir}{\mathrm{O}}_{2}$ thickness, which is well described by the drift-diffusion model based on the bulk spin Hall effect. We deduce the effective spin Hall angle of +0.093 \ifmmode\pm\else\textpm\fi{} 0.003 and the spin-diffusion length of 1.7 \ifmmode\pm\else\textpm\fi{} 0.2 nm. By comparison with control samples Pt and Ir, we show that the effective spin Hall angle of $\mathrm{Ir}{\mathrm{O}}_{2}$ is comparable to that of Pt and seven times higher than that of Ir. The fieldlike SOT efficiency has a negative sign without appreciable dependence on the thickness, in contrast to the dampinglike SOT. This suggests that the fieldlike SOT likely stems from the interface. These experimental findings suggest that the uniqueness of the electronic structure of $5d$ transition-metal oxides is crucial for highly efficient charge to spin-current conversion.

Genome-wide analysis of renal sodium-transporting system has identified specific variations of Mendelian hypertensive disorders, including HSD11B2 gene variants in apparent mineralocorticoid excess. However, these genetic variations in extrarenal tissue can be involved in developing hypertension, as demonstrated in former studies using global and brain-specific Hsd11b2 knockout rodents. To re-examine the importance of renal dysfunction on developing hypertension, we generated kidney-specific Hsd11b2 knockout mice. The knockout mice exhibited systemic hypertension, which was abolished by reducing salt intake, suggesting its salt-dependency. In addition, we detected an increase in renal membrane expressions of cleaved epithelial sodium channel-α and T53-phosphorylated Na + -Cl − cotransporter in the knockout mice. Acute intraperitoneal administration of amiloride-induced natriuresis and increased urinary sodium/potassium ratio more in the knockout mice compared with those in the wild-type control mice. Chronic administration of amiloride and high-KCl diet significantly decreased mean blood pressure in the knockout mice, which was accompanied with the correction of hypokalemia and the resultant decrease in Na + -Cl − cotransporter phosphorylation. Accordingly, a Na + -Cl − cotransporter blocker hydrochlorothiazide significantly decreased mean blood pressure in the knockout mice. Chronic administration of mineralocorticoid receptor antagonist spironolactone significantly decreased mean blood pressure of the knockout mice along with downregulation of cleaved epithelial sodium channel-α and phosphorylated Na + -Cl − cotransporter expression in the knockout kidney. Our data suggest that kidney-specific deficiency of 11β-HSD2 leads to salt-dependent hypertension, which is attributed to mineralocorticoid receptor–epithelial sodium channel–Na + -Cl − cotransporter activation in the kidney, and provides evidence that renal dysfunction is essential for developing the phenotype of apparent mineralocorticoid excess.

Aging is associated with a high prevalence of hypertension due to elevated susceptibility of BP to dietary salt, but its mechanism is unknown. Serum levels of Klotho, an anti-aging factor, decline with age. We found that high salt (HS) increased BP in aged mice and young heterozygous Klotho-knockout mice and was associated with increased vascular expression of Wnt5a and p-MYPT1, which indicate RhoA activity. Not only the Wnt inhibitor LGK974 and the Wnt5a antagonist Box5 but Klotho supplementation inhibits HS-induced BP elevation, similarly to the Rho kinase inhibitor fasudil, associated with reduced p-MYPT1 expression in both groups of mice. In cultured vascular smooth muscle cells, Wnt5a and angiotensin II (Ang II) increased p-MYPT1 expression but knockdown of Wnt5a with siRNA abolished Ang II–induced upregulation of p-MYPT1, indicating that Wnt5a is indispensable for Ang II–induced Rho/ROCK activation. Notably, Klotho inhibited Wnt5a- and Ang II–induced upregulation of p-MYPT1. Consistently, Klotho supplementation ameliorated HS-induced augmentation of reduced renal blood flow (RBF) response to intra-arterial infusion of Ang II and the thromboxane A(2) analog U46619, which activated RhoA in both groups of mice and were associated with the inhibition of BP elevation, suggesting that abnormal response of RBF to Ang II contributes to HS-induced BP elevation. Thus, Klotho deficiency underlies aging-associated salt-sensitive hypertension through vascular non-canonical Wnt5a/RhoA activation.

Background Regulation of sodium chloride transport in the aldosterone-sensitive distal nephron is essential for fluid homeostasis and BP control. The chloride-bicarbonate exchanger pendrin in β-intercalated cells, along with sodium chloride cotransporter (NCC) in distal convoluted tubules, complementarily regulate sodium chloride handling, which is controlled by the renin-angiotensin-aldosterone system. Methods Using mice with mineralocorticoid receptor deletion in intercalated cells, we examined the mechanism and roles of pendrin upregulation via mineralocorticoid receptor in two different models of renin-angiotensin-aldosterone system activation. We also used aldosterone-treated NCC knockout mice to examine the role of pendrin regulation in salt-sensitive hypertension. Results Deletion of mineralocorticoid receptor in intercalated cells suppressed the increase in renal pendrin expression induced by either exogenous angiotensin II infusion or endogenous angiotensin II upregulation via salt restriction. When fed a low-salt diet, intercalated cell-specific mineralocorticoid receptor knockout mice with suppression of pendrin upregulation showed BP reduction that was attenuated by compensatory activation of NCC. In contrast, upregulation of pendrin induced by aldosterone excess combined with a high-salt diet was scarcely affected by deletion of mineralocorticoid receptor in intercalated cells, but depended instead on hypokalemic alkalosis through the activated mineralocorticoid receptor-epithelial sodium channel cascade in principal cells. In aldosterone-treated NCC knockout mice showing upregulation of pendrin, potassium supplementation corrected alkalosis and inhibited the pendrin upregulation, thereby lowering BP. Conclusions In conjunction with NCC, the two pathways of pendrin upregulation, induced by angiotensin II through mineralocorticoid receptor activation in intercalated cells and by alkalosis through mineralocorticoid receptor activation in principal cells, play important roles in fluid homeostasis during salt depletion and salt-sensitive hypertension mediated by aldosterone excess.

International audience; The surface chemical states of Pd(100) during CO oxidation were investigated using ambient pressure x-ray photoelectron spectroscopy and mass spectroscopy. Under the reactant ratio of CO/O2 = 0.1, i.e. an oxygen-rich reaction condition, the formation of surface oxides was observed with the onset of CO oxidation reaction at T = 525 K. As the reactant ratio (CO/O2) increased from 0.1 to 1.0, ∼ 90 % surface oxides remains on surface during the reaction. Upon the formation of surface oxides, the core level shift of oxygen gas phase peak was observed, indicating that change of surface work function. As CO oxidation takes places, i.e. making a transition from CO covered surface to the oxidic surface, the work functions of surface oxide on Pd(100) and Pt(110) display opposite behavior.

High-intensity focused ultrasound (HIFU) treatment is a non-invasive method of cancer treatment. In a HIFU treatment, ultrasound is focused on a target tumor tissue leading to temperature rise that coagulates the tissue. The treatment has a problem of long treatment time because a tumor is usually larger than the focal spot of HIFU. To reduce the treatment time, cavitation bubbles can be used for accelerating ultrasonic heating. Additionally, the heat conducting away from a focal spot can be utilized by properly scanning the focus. In this study, three sequences of scanning the focus to form six foci were compared by observing cavitation bubbles and measuring temperature rise in an excised chicken breast tissue and an agarose gel as well as a thin slice of tissue sandwiched between agarose gels. The results showed that there were differences in the behavior of bubbles and the efficient sequence between the tissue and the gel.

Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We identified that meclizine hydrochloride inhibited FGFR3 signaling in various chondrocytic cells and promoted longitudinal bone growth in mouse model of ACH. Meclizine has safely been used for more than 50 years, but it lacks the safety data for repeated administration and pharmacokinetics (PK) when administered to children. We performed a phase Ia study to evaluate the PK and safety of meclizine administered orally to ACH children. Twelve ACH children aged from 5 to younger than 11 years were recruited, and the first 6 subjects received once a day of meclizine in the fasted condition, subsequent 6 subjects received twice a day of meclizine in the fed condition. Meclizine was well tolerated in ACH children with no serious adverse events. The mean Cmax, Tmax, AUC0-24h, t1/2 during 24 hours in the fasted condition were 130 ng/mL, 1.7 hours, 761 ng·h/mL, and 8.5 hours respectively. The simulation of repeated administration of meclizine for 14 days demonstrated that plasma concentration apparently reached steady state around 10 days after the first dose both at once a day and twice a day administration. The AUC0-10h of the fasting and fed condition were 504 ng·h/mL and 813 ng·h/mL, respectively, indicating exposure of meclizine increased with the diet. Although higher drug exposure was confirmed in ACH children compared to adults, a single administration of meclizine seemed to be well tolerated.

Maternal malnutrition, which causes prenatal exposure to excessive glucocorticoid, induces adverse metabolic programming, leading to hypertension in offspring. In offspring of pregnant rats receiving a low-protein diet or dexamethasone, a synthetic glucocorticoid, mRNA expression of angiotensin receptor type 1a (Agtr1a) in the paraventricular nucleus (PVN) of the hypothalamus was upregulated, concurrent with reduced expression of DNA methyltransferase 3a (Dnmt3a), reduced binding of DNMT3a to the Agtr1a gene, and DNA demethylation. Salt loading increased BP in both types of offspring, suggesting that elevated hypothalamic Agtr1a expression is epigenetically modulated by excessive glucocorticoid and leads to adult-onset salt-sensitive hypertension. Consistent with this, dexamethasone treatment of PVN cells upregulated Agtr1a, while downregulating Dnmt3a, and decreased DNMT3a binding and DNA demethylation at the Agtr1a locus. In addition, Dnmt3a knockdown upregulated Agtr1a independently of dexamethasone. Hypothalamic neuron-specific Dnmt3a-deficient mice exhibited upregulation of Agtr1a in the PVN and salt-induced BP elevation without dexamethasone treatment. By contrast, dexamethasone-treated Agtr1a-deficient mice failed to show salt-induced BP elevation, despite reduced expression of Dnmt3a. Thus, epigenetic modulation of hypothalamic angiotensin signaling contributes to salt-sensitive hypertension induced by prenatal glucocorticoid excess in offspring of mothers that are malnourished during pregnancy.

In an isostructural series of anion radical salts β′-(Me4-xEtxZ)[Pd(dmit)2]2 (Z = P, As, Sb; x = 0, 1, 2), [Pd(dmit)2]2− units form a two-dimensional Mott insulator layer with a quasi-isosceles triangular lattice. The anisotropy of the triangular lattice is characterized by a ratio of interdimer transfer integrals, t′/t. The crystal structures of EtMe3Sb, Me4Sb, Me4As, and Et2Me2As salts were determined in the range of 5–295 K by the single crystal X-ray diffraction technique. Interdimer transfer integrals, Fermi surface, and band structures at low temperatures were calculated by the tight binding method and the first-principles density-functional theory (DFT) method based on experimentally obtained crystal structures. Interdimer transfer integrals increased with lowering temperature. At 5 K, the ratio t′/t decreased by about 15% from the room temperature value in every salt. The relationship between the transfer integrals and interdimer S⋯S distances indicated that the change of the t′/t value with temperature was due to a thermal contraction, rather than the arch-shaped molecular distortion of the Pd(dmit)2 molecule associated with the cation dependence of t′/t.