Activation of neurotoxic A1-reactive astrocytes by SFTS virus infection accelerates fatal brain damage in IFNAR1-/- mice.

Severe fever with thrombocytopenia syndrome (SFTS) has a high mortality rate compared to other infectious diseases. SFTS is particularly associated with a high risk of mortality in immunocompromised individuals, while most patients who die of SFTS exhibit symptoms of severe encephalitis before death. However, the region of brain damage and mechanisms by which the SFTS virus (SFTSV) causes encephalitis remains unknown. Here, we revealed that SFTSV infects the brainstem and spinal cord, which are regions of the brain associated with respiratory function, and motor nerves in IFNAR1-/- mice. Further, we show that A1-reactive astrocytes are activated, causing nerve cell death, in infected mice. Primary astrocytes of SFTSV-infected IFNAR1-/- mice also induced neuronal cell death through the activation of A1-reactive astrocytes. Herein, we showed that SFTSV induces fatal neuroinflammation in the brain regions important for respiratory function and motor nerve, which may underlie mortality in SFTS patients. This study provides new insights for the treatment of SFTS, for which there is currently no therapeutic approach.

Particulate matter (PM10) exacerbates on MK-801-induced schizophrenia-like behaviors through the inhibition of ERK-CREB-BDNF signaling pathway.

Particulate matter (PM), released into the air by a variety of natural and human activities, is a key indicator of air pollution. Although PM is known as the extensive health hazard to affect a variety of illness, few studies have specifically investigated the effects of PM10 exposure on schizophrenic development. In the present study, we aimed to investigate the impact of PM10 on MK-801, N-methyl-D-aspartate (NMDA) receptor antagonist, induced schizophrenia-like behaviors in C57BL/6 mouse. Preadolescent mice were exposed PM10 to 3.2 mg/m3 concentration for 4 h/day for 2 weeks through a compartmentalized whole-body inhalation chamber. After PM10 exposure, we conducted behavioral tests during adolescence and adulthood to investigate longitudinal development of schizophrenia. We found that PM10 exacerbated schizophrenia-like behavior, such as psychomotor agitation, social interaction deficits and cognitive deficits at adulthood in MK-801-induced schizophrenia animal model. Furthermore, the reduced expression levels of brain-derived neurotrophic factor (BDNF) and the phosphorylation of BDNF related signaling molecules, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were exacerbated by PM10 exposure in the adult hippocampus of MK-801-treated mice. Thus, our present study demonstrates that exposure to PM10 in preadolescence exacerbates the cognitive impairment in animal model of schizophrenia, which are considered to be facilitated by the decreased level of BDNF through reduced ERK-CREB expression.

Cholesterol profiling reveals 7ß-hydroxycholesterol as a pathologically relevant peripheral biomarker of Alzheimer's disease.

AIM: Cholesterol homeostasis is associated with Alzheimer's disease (AD). Despite the multitude of cholesterol metabolites, little is known about which metabolites are directly involved in AD pathogenesis and can serve as its potential biomarkers. METHODS: To identify "hit" metabolites, steroid profiling was conducted in mice with different age, diet, and genotype and also in humans with normal cognition, mild cognitive impairment, and AD using gas chromatography-mass spectrometry. Then, using one of the "hit" molecules (7ß-hydroxycholesterol; OHC), molecular and histopathological experiment and behavioral testing were conducted in normal mice following its intracranial stereotaxic injection to see whether this molecule drives AD pathogenesis and causes cognitive impairment. RESULTS: The serum levels of several metabolites, including 7ß-OHC, were increased by aging in the 3xTg-AD unlike normal mice. Consistently, the levels of 7ß-OHC were increased in the hairs of patients with AD and were correlated with clinical severity. We found that 7ß-OHC directly affects AD-related pathophysiology; intrahippocampal injection of 7ß-OHC induced astrocyte and microglial cell activation, increased the levels of pro-inflammatory cytokines (TNF-alpha, IL-1ß, IL-6), and enhanced amyloidogenic pathway. Mice treated with 7ß-OHC also exhibited deficits in memory and frontal/executive functions assessed by object recognition and 5-choice serial reaction time task, respectively. CONCLUSIONS: Our results suggest that 7ß-OHC could serve as a convenient, peripheral biomarker of AD. As directly involved in AD pathogenesis, 7ß-OHC assay may help actualize personalized medicine in a way to identify an at-risk subgroup as a candidate population for statin-based AD treatment.

The Anti-Atopic Dermatitis Effects of Mentha arvensis Essential Oil Are Involved in the Inhibition of the NLRP3 Inflammasome in DNCB-Challenged Atopic Dermatitis BALB/c Mice.

The NLRP3 inflammasome is upregulated by various agents, such as nuclear factor-kappa B (NF-κB), lipopolysaccharide (LPS), and adenosine triphosphate (ATP). The NLRP3 inflammasome facilitations the maturation of interleukin (IL)-1ß, a proinflammatory cytokine that is critically involved in the pathogenesis of atopic dermatitis (AD). Although the NLRP3 inflammasome clearly exacerbates AD symptoms such as erythema and pruritus, drugs for AD patients targeting the NLRP3 inflammasome are still lacking. Based on the previous findings that Mentha arvensis essential oil (MAEO) possesses strong anti-inflammatory and anti-AD properties through its inhibition of the ERK/NF-κB signaling pathway, we postulated that MAEO might be capable of modulating the NLRP3 inflammasome in AD. The aim of this research was to investigate whether MAEO affects the inhibition of NLRP3 inflammasome activation in murine bone marrow-derived macrophages (BMDMs) stimulated with LPS + ATP in vitro and in a murine model displaying AD-like symptoms induced by 2,4-dinitrochlorobenzene (DNCB) in vivo. We found that MAEO inhibited the expression of NLRP3 and caspase-1, leading to the suppression of NLRP3 inflammasome activation and IL-1ß production in BMDMs stimulated with LPS + ATP. In addition, MAEO exhibited efficacy in ameliorating AD symptoms in a murine model induced by DNCB, as indicated by the reduction in dermatitis score, ear thickness, transepidermal water loss (TEWL), epidermal thickness, and immunoglobulin E (IgE) levels. Furthermore, MAEO attenuated the recruitment of NLRP3-expressing macrophages and NLRP3 inflammasome activation in murine dorsal skin lesions induced by DNCB. Overall, we provide evidence for the anti-AD effects of MAEO via inhibition of NLRP3 inflammasome activation.

Assessment of organochlorine pesticides in the atmosphere of South Korea: spatial distribution, seasonal variation, and sources.

Organochlorine pesticides (OCPs) are widely used in certain countries. We determined atmospheric concentrations, distribution patterns, and seasonal variations of OCPs at four sites in South Korea for 1 year. Samples of 22 OCPs were collected using a high-volume air sampler, and measured via the isotope dilution method with HRGC/HRMS. In South Korea, pentachlorobenzene (PeCB), hexachlorocyclohexane (HCB), and endosulfan (EnSF) were dominant, accounting for > 87% of total OCPs. Spatial distributions showed significant differences and the highest levels were observed in Seosan (295.2 pg·m-3), indicating the compounding potential of diverse sources as Seosan has concentrated large-scale industrial complexes and agricultural activity (Seoul: 243.6 pg·m-3 > Jeju: 193.5 pg·m-3 > Baengnyeong: 178.2 pg·m-3). The isomeric ratios of OCPs in the South Korean atmosphere indicated that the dominant sources of HCB and dichlorodiphenyltrichloroethane were primarily used in the past; meanwhile, chlordane (CHL) and EnSFs were derived from recent material inputs. Seasonally, OCP concentrations largely peaked in summer with minimum values in winter. This apparent temperature dependence suggests the re-volatilization of accumulated chemicals into the atmosphere. Additionally, an air mass back trajectory indicated the influence of pollutants released from a reservoir through long-range atmospheric transport in the summer. In particular, restricted OCPs are primarily released into the atmosphere by inadvertent sources, such as industrial activities and volatilization from contaminated areas. Thus, severe OCP pollution in Korea is due to the mobile nature of the particles. These data can be useful for the continuous monitoring of long-range transported air pollutants that are transferred between countries.

Active Aging In Long-Term Care Facilities In Korea : Beyond The Lexical Meaning.

The discourse of active aging, as introduced by the WHO, aims at optimizing older adults' opportunities for health, participation, and security that could eventually enhance their social integration and quality of life. Considering that even those with frailty could strive for active aging in the given circumstances, we examined the meaning of active aging in long-term care settings and care strategies to promote it based on the WHO's framework. We conducted interviews with a total of 35 participants. The interpretative analyses revealed that the activities taken place in LTCFs have various scopes depending on older adults' physical and cognitive functional ability, and it captures the forms of activities that go beyond its lexical meaning. By defining being "active," the present findings could contribute to an understanding of how the three elements of active aging can be carried out in LTCFs.

Nanostructural Perspective for Destabilization of Mg Hydride Using the Immiscible Transition Metal Mn.

Phase segregation in hydride-forming alloys may persist under the action of multiple hydrogenation/dehydrogenation cycles. We use this effect to destabilize metal hydrides in the immiscible Mg-Mn system. Here, in the MgxMn1-x thin films, the Mg and Mn domains are chemically segregated at the nanoscale. In Mn-rich compositions, the desorption pressure of hydrogen from MgH2 is elevated at a given temperature, indicating a thermodynamic destabilization. The increase in the desorption pressure of hydrogen reaches ∼2.5 orders in magnitude for x = 0.30 at moderate temperatures. Such large thermodynamic destabilization allows the MgH2 to reversibly absorb and desorb hydrogen even at room temperature. Our strategy to use immiscible elements for destabilization of MgH2 is effective and opens up the possibility for the development of advanced and low-cost hydrogen storage and supply systems.

Development of a rabbit monocyte activation test as an alternative to the rabbit pyrogen test and its application in the analysis of plasma-derived products.

The rabbit pyrogen test (RPT) is a safety test conducted as a part of mandatory requirements of regulatory agencies. RPT is currently performed for routine quality control (QC) by manufacturers and for national lot release of biological products, such as plasma-derived products. However, RPT involves the use of many rabbits, counter to the international efforts to minimize the use of animals in research. Furthermore, pyrogen amount cannot be discerned from the test results and the results may be considerably affected by various factors. Therefore, a need exists for substituting RPT with in vitro assays. As a viable alternative to RPT, we here established a rabbit monocyte activation test (RMAT) based on the human MAT in the European Pharmacopoeia. RMAT uses rabbit peripheral blood mononuclear cells as the source of monocytes instead of live animals. The test detected endotoxin, lipoteichoic acid, peptidoglycan, and zymosan with high sensitivity, showing high correlation with the in vivo RPT results. The results of RMAT and RPT testing of non-pyrogenic plasma-derived products were also consistent. Furthermore, RMAT showed satisfactory recovery rates in an interference test with product samples and spiked-in pyrogens. We conclude that RMAT could replace the existing RPT for routine QC.

Hydrogenation Properties of Mg83.3Cu7.2Y9.5 with Long Period Stacking Ordered Structure and Formation of Polymorphic γ-MgH2.

Nanosizing is known to affect the hydrogenation properties of magnesium. For this reason, the long period stacking ordered (LPSO) structures, made of the stacking of nanolayers of magnesium and nanolayers of Mg-A-B (with A = rare earth and B = transition metal), were herein considered. A Mg83.3Cu7.2Y9.5 LPSO compound with 18R structure was successfully synthesized. Its hydrogenation properties were investigated at temperatures between 150 and 400 °C. The X-ray diffraction (XRD) analysis indicates that the LPSO structure decomposes into magnesium hydride, yttrium hydride, and an intermetallic compound (Mg2Cu or MgCu2). The pressure composition (PC) isotherm for Mg83.3Cu7.2Y9.5 at 400 °C combined with XRD analysis allows one to understand the three-step hydrogenation pathway, detailed in this paper. At this hydrogenation temperature, the fully hydrogenated compound contains magnesium hydride exclusively crystallized in the most stable tetragonal structure (100% of α-MgH2 was formed). When the pristine LPSO was hydrogenated at lower temperature, the amount of α-MgH2 decreased, while its polymorphic structure, γ-MgH2, appeared. Finally, hydrogenation of Mg83.3Cu7.2Y9.5 at 150 °C led to the formation of γ-MgH2 with a high phase fraction (82% of γ-MgH2/MgH2). These results suggest that the crystallographic structure of the magnesium hydride can be controlled by the hydrogenation temperature of LPSO compounds.

Unveiling Nanoscale Compositional and Structural Heterogeneities of Highly Textured Mg0.7Ti0.3Hy Thin Films.

Thin films often exhibit fascinating properties, but the understanding of the underlying mechanism behind such properties is not simple. This is partially because of the limited structural information available. The hurdle in obtaining such information is especially high for textured thin films such as Mg-rich MgxTi1-x, a promising switchable smart coating material. Although these metastable thin films are seen as solid solution alloys by conventional crystallographic methods, their hydrogen-induced optical transition is hardly understood by a solid solution model. In this study, we collect atomic pair distribution function (PDF) data for a Mg0.7Ti0.3Hy thin film in situ on hydrogenation and successfully resolve TiH2 clusters of an average size of 30 Å embedded in the Mg matrix. This supports the chemically segregated model previously proposed for this system. We also observe the emergence of a previously unknown intermediate face-centered tetragonal phase during hydrogenation of the Mg matrix. This phase appears between Mg and MgH2 to reduce lattice mismatch, thereby preventing pulverization and facilitating rapid hydrogen uptake. This work may shed new light on the hydrogen-induced properties of Mg-rich MgxTi1-x thin films.

Metallurgical Synthesis of Mg2FexSi1-x Hydride: Destabilization of Mg2FeH6 Nanostructured in Templated Mg2Si.

Magnesium-based transition-metal hydrides are attractive hydrogen energy materials because of their relatively high gravimetric and volumetric hydrogen storage capacities combined with low material costs. However, most of them are too stable to release the hydrogen under moderate conditions. Here we synthesize the hydride of Mg2FexSi1-x, which consists of Mg2FeH6 and Mg2Si with the same cubic structure. For silicon-rich hydrides (x < 0.5), mostly the Mg2Si phase is observed by X-ray diffraction, and Mössbauer spectroscopy indicates the formation of an octahedral FeH6 unit. Transmission electron microscopy measurements indicate that Mg2FeH6 domains are nanometer-sized and embedded in a Mg2Si matrix. This synthesized metallographic structure leads to distortion of the Mg2FeH6 lattice, resulting in thermal destabilization. Our results indicate that nanometer-sized magnesium-based transition-metal hydrides can be formed into a matrix-forced organization induced by the hydrogenation of nonequilibrium Mg-Fe-Si composites. In this way, the thermodynamics of hydrogen absorption and desorption can be tuned, which allows for the development of lightweight and inexpensive hydrogen storage materials.

Interrogation of the Effect of Polymorphism of a Metal-Organic Framework Host on the Structure of Embedded Pd Guest Nanoparticles.

Metal-organic frameworks (MOFs) are very promising host materials for nanoscale guest materials. However, some MOFs such as MIL-53 are known to undergo phase transitions which can complicate the guest particle size control. In this study, Pd nanoparticles embedded in Al-MIL-53 were synthesised via (a) electrodeposition and (b) gas-phase reduction. A thorough structural investigation revealed that each synthesis method most likely favoured a different phase of Al-MIL-53, presenting the possibility of MOF phase selection as a technique for size control of embedded nanoparticles. For the first time, we hereby report the use of pair distribution function analysis to successfully investigate the structure and morphology of guest particles embedded in a MOF host.

Destabilizing the Dehydrogenation Thermodynamics of Magnesium Hydride by Utilizing the Immiscibility of Mn with Mg.

Hydrogen storage is a key technology for the advancement of hydrogen and fuel cell power technologies in stationary and portable applications. MgH2, an example of a high-capacity hydrogen storage material, has two major material challenges for practical applications: slow hydrogen desorption kinetics and high hydrogen desorption temperature. Numerous studies have reported enhancements in kinetics but only a few in thermodynamics. Here, we present a simple but effective way to improve upon both the kinetic and thermodynamic aspects of desorption by utilizing the immiscibility of Mn, a non-hydrogen absorbing metal, with Mg. Mg0.25Mn0.75, prepared through ball milling MgH2 and Mn powders, is a nanocomposite where the nanometer-sized MgH2 domains are randomly embedded in a Mn matrix. This sample readily and reversibly absorbs and desorbs deuterium even at a temperature of 200 °C without the addition of any catalysts. This is nearly 180 °C lower than the typical operating temperature of conventional bulk Mg. Furthermore, at a given temperature, its deuterium desorption pressure is clearly elevated compared to that of pure Mg, indicating the destabilization of MgD2. The average crystallite size of MgD2 in deuterated Mg0.25Mn0.75 determined from X-ray diffraction data is around 9 nm. Nuclear magnetic resonance spectroscopy studies show that MgD2 domains are heavily strained and some of the D atoms are coordinated by a few Mn atoms, suggesting that a large number of lattice defects, including the partial substitution of Mg with Mn, are introduced during ball milling. Furthermore, the Mn matrix firmly locks nanosized MgD2, preventing the agglomeration of MgD2 below 250 °C. Our study suggests that a synergistic effect created by nanosizing, large lattice distortions, and robust interfaces between MgD2 and the Mn matrix can effectively and concurrently improve the kinetics and thermodynamics of MgD2 in Mg0.25Mn0.75. Our work demonstrates the possibility of utilizing the immiscibility of metals with Mg to synthesize a robust nanostructure that can alter the kinetics and stability of MgH2.

Relation Between Exercise Capacity and Extracardiac Conduit Size in Patients with Fontan Circulation.

Because Fontan circulation does not have a subpulmonary ventricle, the preload is limited. In Fontan circulation with extracardiac conduit, the size of conduit could be an important factor in determining the preload. We compared exercise capacity with each conduit size and tried to search for optimal conduit size in Fontan circulation. We reviewed the medical record of 677 patients with Fontan circulation. Patients who had other type Fontan circulation (Kawashima, atriopulmonary, lateral tunnel), SpO2 < 85%, protein losing enteropathy, results of inappropriate exercise test were excluded. As a result, 150 patients were enrolled and classified according to conduit size. We compared with their exercise capacity and analyzed correlation between exercise capacity and conduit size per body surface area (BSA). 97 Males were included and mean age was 17.5 ± 5.1 years old. In cardiac catheterization, central venous pressure (CVP) was 12.4 ± 2.5 mmHg and pulmonary vascular resistance was 1.2 ± 0.5 wu m2. In cardiopulmonary exercise test, predictive peak VO2 was 59.1 ± 9.7% and VE/VCO2 was 36.2 ± 6.9. In analysis using quadratic model, impacts of gender, age at Fontan operation, ventricular morphology, isomerism, and fenestration on exercise capacity were excluded and conduit size per BSA had a significant curved correlation with predictive peak VO2 and VE/VCO2. Our results showed that patients with about 12.5 mm/m2 conduit per BSA have the best exercise capacity. Patients with larger than smaller-sized conduit were found to be more attenuated in their ability to exercise.

Particulate matter increases beta-amyloid and activated glial cells in hippocampal tissues of transgenic Alzheimer's mouse: Involvement of PARP-1.

Exposure to air pollutants, such as particulate matter (PM), has been implicated in neurodegenerative disorders including Alzheimer's disease (AD). However, direct effects of PM on production of ß-amyloid (Aß), a key pathogenic molecule in AD, and its underlying mechanism are still elusive. Given PM's potential to induce oxidative stress in other tissues, we hypothesized that poly(ADP-ribose) polymerase (PARP-1) might be involved in PM-induced neurotoxicity. To address this, we used an ex vivo model of AD, the organotypic hippocampal slice tissue culture from old (12-14 months-of-age) triple transgenic 3xTg-AD mice. First, we observed that fine PM (aerodynamic diameter < 4 µm) can dose-dependently activate PARP-1 and decrease NAD+ levels in Neuro2A cells. PARP-1 activation did occur under concentrations of PM which did not affect cell viability. Next, we observed that direct treatment of PM increased Aß levels and activated glial cells in the ex vivo hippocampal tissues of 3xTg-AD mice. PM-induced glial activation was most prominent in CA1 region of the hippocampal tissue. Notably, we found that pharmacological inhibition of PARP-1 reversed both PM-induced Aß increase and glial activation, arguing the possible involvement of PARP-1 in PM-induced AD pathogenesis. Our findings suggest that PARP-1 might be a potential molecular target, responsible for mediating negative effects of PM on the brain. Modulating PARP-1 activity could be a promising approach to prevent or alleviate PM-related environmental neurotoxicity which could initiate AD pathogenesis.

Response to hypomethylating agents improves long-term outcomes for lower-risk patients with myelodysplastic syndrome in case-matched cohorts.

Predictive factors for initiating hypomethylating agents' (HMAs) treatment and the survival benefit of HMAs for lower-risk myelodysplastic syndrome (LR-MDS) are still unknown. This study evaluated the factors affecting the use of HMAs and compared long-term outcomes between best supportive care (BSC) and HMA groups after matching baseline clinical factors. Data of 353 patients diagnosed with LR-MDS by International Prognostic Scoring System between October 1992 and July 2013 were retrospectively analyzed. HMAs were administered continuously until a clinical response or progression. HMAs were administered to 243 patients with median 45 days (range 0-7078 days) after diagnosis, while 110 patients were treated with BSC. HMAs were administered over a median of 5 cycles and overall response was achieved in 104 patients (42.8%). The cumulative incidence of HMA treatment increased in higher-risk groups by other risk scoring systems. Three-year overall survival (OS) rate was higher in BSC group (69.1%) than HMA responders (47.4%, p = 0.065) or HMA non-responders (46.3%, p = 0.005). Among 162 case-matched cohorts, 3-year OS rates were comparable between the BSC group (67.1%) and HMA responders (58.1%, p = 0.914), while that of HMA non-responder was low (32.2%, p < 0.001). In the case-matched cohorts, HMA non-responder were associated with inferior OS rate in the multivariate analysis (hazard ratio 3.01, p = 0.001). Higher-risk groups by other clinical risk scoring systems among IPSS lower-risk patients showed an increased incidence of using HMAs. The OS rate of HMA responders among case-matched cohorts showed an improved OS rate similar to the BSC group.

Structural Variation of Self-Organized Mg Hydride Nanoclusters in Immiscible Ti Matrix by Hydrogenation.

Hydrogenation of nonequilibrium alloys may form nanometer-sized metal hydride clusters, depending on the alloy compositions and hydrogenation conditions. Here in the Ti-rich compositions of the immiscible Mg-Ti system MgH2 clusters are embedded in a Ti-H matrix. Our previous works have indicated that the interface energy between the two metal hydrides reduces the stability of MgH2. The aim of our study is to obtain the structural information on the nanometer-sized clusters. Indeed, MgD2 clusters embedded in a face-centered-cubic (FCC) Ti-D matrix is found in Mg0.25Ti0.75D1.65 by means of 2H magic angle spinning nuclear magnetic resonance (MAS NMR). The atomic pair distribution function (PDF) analysis of neutron total scattering data suggests that the MgD2 clusters have an orthorhombic structure, which is different from a rutile-type body-centered-tetragonal (BCT) structure of α-MgD2 observed in the Mg-rich compositions. Our results suggest that we can tune the thermodynamics of hydrogen absorption and desorption in Mg-H using the interface energy effect and accompanying stress-induced structural change, which contributes to the substantial development of lightweight and inexpensive hydrogen storage materials.

Cholinesterase Inhibitor Donepezil Increases Mitochondrial Biogenesis through AMP-Activated Protein Kinase in the Hippocampus.

OBJECTIVE: Donepezil, a widely prescribed drug for Alzheimer's disease (AD), is now considered to have multimodal actions beyond cholinesterase inhibition. We aimed to see whether donepezil enhances mitochondrial biogenesis and relevant signaling pathways since mitochondrial dysfunction is a key feature of the hypometabolic AD brain. METHODS: As a metabolic gauge, AMP-activated protein kinase (AMPK) was investigated as a tentative mediator of neurometabolic action of donepezil. Changes in phospho-AMPK levels, mitochondrial biogenesis, and ATP levels were measured upon donepezil treatment using neuroblastoma cells, primary cultured neurons and ex vivo hippocampal tissue of adult mice. RESULTS: Donepezil dose-dependently increased mitochondrial biogenesis and ATP levels as well as expression of PGC-1α and NRF-1 in neuroblastoma cells. Donepezil dose-dependently activated AMPK; however, inhibition of AMPK abolished the observed effects of donepezil, indicating that AMPK is a key mediator of donepezil's action. Notably, mitochondrial biogenesis upon donepezil treatment was mainly observed within dendritic regions of primary cultured hippocampal neurons. Levels of synaptic markers were also increased by donepezil. Finally, AMPK- dependent mitochondrial biogenesis by donepezil was confirmed in organotypic hippocampal tissue. CONCLUSIONS: Our findings indicate that AMPK/PGC-1α signaling is involved in beneficial actions of donepezil on neurometabolism. Pharmacological activation of AMPK might be a promising approach to counteract AD pathogenesis associated with brain hypometabolism.

Loss of RUNX3 expression promotes cancer-associated bone destruction by regulating CCL5, CCL19 and CXCL11 in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) frequently metastasizes to bone, which is associated with significant morbidity and a dismal prognosis. RUNX3 functions as a tumour suppressor in lung cancer and loss of expression occurs more frequently in invasive lung adenocarcinoma than in pre-invasive lesions. Here, we show that RUNX3 and RUNX3-regulated chemokines are linked to NSCLC-mediated bone resorption. Notably, the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio, an index of osteoclastogenic stimulation, was significantly increased in human osteoblastic cells treated with conditioned media derived from RUNX3-knockdown NSCLC cells. We aimed to identify RUNX3-regulated factors that modify the osteoblastic RANKL/OPG ratio and found that RUNX3 knockdown led to CCL5 up-regulation and down-regulation of CCL19 and CXCL11 in NSCLC cells. Tumour size was noticeably increased and more severe osteolytic lesions were induced in the calvaria and tibiae of mice that received RUNX3-knockdown cells. In response to RUNX3 knockdown, serum and tissue levels of CCL5 increased, whereas CCL19 and CXCL11 decreased. Furthermore, CCL5 increased the proliferation, migration, and invasion of lung cancer cells in a dose-dependent manner; however, CCL19 and CXCL11 did not show any significant effects. The RANKL/OPG ratio in osteoblastic cells was increased by CCL5 but reduced by CCL19 and CXCL11. CCL5 promoted osteoclast differentiation, but CCL19 and CXCL11 reduced osteoclastogenesis in RANKL-treated bone marrow macrophages. These findings suggest that RUNX3 and related chemokines are useful markers for the prediction and/or treatment of NSCLC-induced bone destruction.

Melting of Pb Charge Glass and Simultaneous Pb-Cr Charge Transfer in PbCrO3 as the Origin of Volume Collapse.

A metal to insulator transition in integer or half integer charge systems can be regarded as crystallization of charges. The insulating state tends to have a glassy nature when randomness or geometrical frustration exists. We report that the charge glass state is realized in a perovskite compound PbCrO3, which has been known for almost 50 years, without any obvious inhomogeneity or triangular arrangement in the charge system. PbCrO3 has a valence state of Pb(2+)(0.5)Pb(4+)(0.5)Cr(3+)O3 with Pb(2+)-Pb(4+) correlation length of three lattice-spacings at ambient condition. A pressure induced melting of charge glass and simultaneous Pb-Cr charge transfer causes an insulator to metal transition and ∼10% volume collapse.