Rcn1, the fission yeast homolog of human DSCR1, regulates arsenite tolerance independently from calcineurin.

Calcineurin (CN) is a conserved Ca2+/calmodulin-dependent phosphoprotein phosphatase that plays a key role in Ca2+ signaling. Regulator of calcineurin 1 (RCAN1), also known as Down syndrome critical region gene 1 (DSCR1), interacts with calcineurin and inhibits calcineurin-dependent signaling in various organisms. Ppb1, the fission yeast calcineurin regulates Cl--homeostasis, and Ppb1 deletion induces MgCl2 hypersensitivity. Here, we characterize the conserved and novel roles of the fission yeast RCAN1 homolog rcn1+. Consistent with its role as an endogenous calcineurin inhibitor, Rcn1 overproduction reproduced the calcineurin-null phenotypes, including MgCl2 hypersensitivity and inhibition of calcineurin signaling upon extracellular Ca2+ stimuli as evaluated by the nuclear translocation and transcriptional activation of the calcineurin substrate Prz1. Notably, overexpression of rcn1+ causes hypersensitivity to arsenite, whereas calcineurin deletion induces arsenite tolerance, showing a phenotypic discrepancy between Rcn1 overexpression and calcineurin deletion. Importantly, although Rcn1 deletion induces modest sensitivities to arsenite and MgCl2 in wild-type cells, the arsenite tolerance, but not MgCl2 sensitivity, associated with Ppb1 deletion was markedly suppressed by Rcn1 deletion. Collectively, our findings reveal a previously unrecognized functional collaboration between Rcn1 and calcineurin, wherein Rcn1 not only negatively regulates calcineurin in the Cl- homeostasis, but also Rcn1 mediates calcineurin signaling to modulate arsenite cytotoxicity.

Group IVA Phospholipase A2 in Collagen-Producing Cells Promotes High-Fat Diet-Induced Infiltration of Inflammatory Cells into the Liver by Upregulating the Expression of MCP-1.

Nonalcoholic steatohepatitis (NASH) is characterized by hepatic inflammation and fibrosis due to excessive fat accumulation. Monocyte chemoattractant protein-1 (MCP-1) is a key chemokine that infiltrates inflammatory cells into the liver during the development of NASH. Our previous studies demonstrated that a systemic deficiency of group IVA phospholipase A2 (IVA-PLA2), an enzyme that contributes to the production of lipid inflammatory mediators, protects mice against high-fat diet-induced hepatic fibrosis and markedly suppresses the CCl4-induced expression of MCP-1 in the liver. However, it remains unclear which cell types harboring IVA-PLA2 are involved in the elevated production of MCP-1. Hence, the present study assessed the types of cells responsible for IVA-PLA2-mediated production of MCP-1 using cultured hepatic stellate cells, endothelial cells, macrophages, and hepatocytes, as well as cell-type specific IVA-PLA2 deficient mice fed a high-fat diet. A relatively specific inhibitor of IVA-PLA2 markedly suppressed the expression of MCP-1 mRNA in cultured hepatic stellate cells, but the suppression of MCP-1 expression was partial in endothelial cells and not observed in monocytes/macrophages or hepatocytes. In contrast, a deficiency of IVA-PLA2 in collagen-producing cells (hepatic stellate cells), but not in other types of cells, reduced the high-fat diet-induced expression of MCP-1 and inflammatory cell infiltration in the liver. Our results suggest that IVA-PLA2 in hepatic stellate cells is critical for hepatic inflammation in the high-fat diet-induced development of NASH. This supports a potential therapeutic approach for NASH using a IVA-PLA2 inhibitor targeting hepatic stellate cells.

Bio-Metal Dyshomeostasis-Associated Acceleration of Aging and Cognitive Decline in Down Syndrome.

Down syndrome (DS), which is caused by triplication of human chromosome 21 (Hsa21), exhibits some physical signs of accelerated aging, such as graying hair, wrinkles and menopause at an unusually young age. Development of early-onset Alzheimer's disease, which is frequently observed in adults with DS, is also suggested to occur due to accelerated aging of the brain. Several Hsa21 genes are suggested to be responsible for the accelerated aging in DS. In this review, we summarize these candidate genes and possible molecular mechanisms, and discuss the related key factors. In particular, we focus on copper, an essential trace element, as a key factor in the accelerated aging in DS. In addition, the physiological significance of brain copper accumulation in cognitive impairment is discussed. We herein provide our hypothesis on the copper dyshomeostasis-based pathophysiology of DS.

Deficiency of Group IVA Phospholipase A2 in Collagen-Producing Cells Alleviates the Aggravated Hepatic Fibrosis in High-Fat Diet-Fed Mice after Returning to a Normal Diet.

Hepatic fibrosis, a primary feature of non-alcoholic steatohepatitis (NASH), develops with inflammation and subsequent activation of hepatic stellate cells (HSCs), the main extracellular matrix-producing cells. Currently, no approved pharmacotherapy is available to treat hepatic fibrosis, even under dietary intervention. The activation of cultured HSCs has been shown to be attenuated by pharmacological inhibition of group IVA phospholipase A2 (IVA-PLA2), an enzyme initiating the generation of lipid proinflammatory mediators. We examined the potential utility of IVA-PLA2 of HSCs as a therapeutic target for hepatic fibrosis in NASH under dietary modification using collagen-producing cell-specific IVA-PLA2-conditional knockout mice fed a high-fat diet and then returned to a normal one. Apparent hepatic fibrosis and the accumulation of hepatic lipid droplets developed in the IVA-PLA2-conditional knockout mice on a high-fat diet for nine weeks to a similar degree as in control mice. Most of the lipid droplets disappeared five weeks after switching the diet back to a normal one in both genetic mice. In contrast, the hepatic fibrosis in control mice still progressed even after changing back to a normal diet. However, deficiency of IVA-PLA2 in collagen-producing cells alleviated the aggravated hepatic fibrosis under dietary modification. Our results revealed that the protective effects of an HSC-specific IVA-PLA2 deficiency on fibrogenesis appear after switching the diet from a high-fat one back to a normal one, supporting the promising beneficial effects of the inhibition of IVA-PLA2 on progressive hepatic fibrosis under dietary intervention in NASH treatment.

Plantainoside B in Bacopa monniera Binds to Aß Aggregates Attenuating Neuronal Damage and Memory Deficits Induced by Aß.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by dementia. The most characteristic pathological changes in AD brain include extracellular amyloid-ß (Aß) accumulation and neuronal loss. Particularly, cholinergic neurons in the nucleus basalis of Meynert are some of the first neuronal groups to degenerate; accumulating evidence suggests that Aß oligomers are the primary form of neurotoxicity. Bacopa monniera is a traditional Indian memory enhancer whose extract has shown neuroprotective and Aß-reducing effects. In this study, we explored the low molecular weight compounds from B. monniera extracts with an affinity to Aß aggregates, including its oligomers, using Aß oligomer-conjugated beads and identified plantainoside B. Plantainoside B exhibited evident neuroprotective effects by preventing Aß attachment on the cell surface of human induced pluripotent stem cell (hiPSC)-derived cholinergic neurons. Moreover, it attenuated memory impairment in mice that received intrahippocampal Aß injections. Furthermore, radioisotope experiments revealed that plantainoside B has affinity to Aß aggregates including its oligomers and brain tissue from a mouse model of Aß pathology. In addition, plantainoside B could delay the Aß aggregation rate. Accordingly, plantainoside B may exert neuroprotective effects by binding to Aß oligomers, thus interrupting the binding of Aß oligomers to the cell surface. This suggests its potential application as a theranostics in AD, simultaneously diagnostic and therapeutic drugs.

The accumulation of copper in the brain of Down syndrome promotes oxidative stress: possible mechanism underlying cognitive impairment.

Individuals with Down syndrome (DS), which is caused by triplication of human chromosome 21 (Hsa21), show numerous characteristic symptoms, such as intellectual disability, an impaired cognitive function, and accelerated aging-like phenotypes. Enhanced oxidative stress is assumed to be implicated as a mechanism underlying many of these symptoms of DS. Some genes coded in Hsa21, such as App, Sod1, and Ets2, are suggested as being involved in the exacerbation of oxidative stress. In addition, enhanced oxidative stress has been recently shown to be caused by dyshomeostasis of the redox-active bio-metal copper in the brain of a mouse model of DS. This review aims to summarize the current knowledge on enhanced oxidative stress in DS and suggest a possible molecular mechanism underlying the cognitive impairment of DS mediated by enhanced oxidative stress.

Decrease in the T-box1 gene expression in embryonic brain and adult hippocampus of down syndrome mouse models.

Down syndrome (DS, Trisomy 21) is the most common genetic cause of delayed fetal brain development and postnatal intellectual disability. Although delayed fetal brain development might be involved in intellectual disability, no evidence of an association between these abnormal phenotypes has been shown. To identify molecules differentially expressed in both the prenatal forebrain and adult hippocampus of Ts1Cje mice, a mouse model of DS, we employed a transcriptomic analysis. In the present study, we conducted transcriptomic profiling of the hippocampus of adult Ts1Cje mice and compared the results with the previously obtained transcriptomic profile of the prenatal forebrain at embryonic day 14.5. Results showed that the Tbx1 mRNA expression was decreased at both life stages. In addition, the decreased expression of Tbx1 mRNA was confirmed in other DS mouse models, Dp(16)1Yey/+ and Ts1Rhr mice, which carry longer and shorter trisomic regions, respectively. Taken together, these findings suggest that Tbx1 may link the delayed fetal brain development and intellectual disability in DS.

Brain ventriculomegaly in Down syndrome mice is caused by Pcp4 dose-dependent cilia dysfunction.

Down syndrome is a leading cause of congenital intellectual disability caused by an additional copy of the chromosome 21. Patients display physiological and morphological changes affecting the brain and its function. Previously we showed that Ts1Cje and Ts2Cje, Down syndrome mouse models carrying overlapping trisomic segments of different length, show similar ventriculomegaly and neurogenesis dysfunction leading to the hypothesis of a cause-consequence relationship between these phenotypes. However, we here discovered that Ts1Rhr Down syndrome model, carrying an even shorter trisomic segment, was sufficient to trigger ventricular enlargement and ependymal cilia beating deficiency without affecting neurogenesis. We further found that Pcp4 gene on the Ts1Rhr trisomic segment is expressed in ependymal cells, and its resumption to two copies rescued both ventricular enlargement and cilia dysfunction in Ts1Rhr mice. This work underlines a Pcp4-dependent ciliopathy in Down syndrome brain affecting cerebrospinal fluid flow.

Antigen-specific airway IL-33 production depends on FcγR-mediated incorporation of the antigen by alveolar macrophages in sensitized mice.

Although interleukin (IL)-33 is a candidate for the aggravation of asthma, the mechanisms underlying antigen-specific IL-33 production in the lung are unclear. Therefore, we analysed the mechanisms in mice. Intra-tracheal administration of ovalbumin (OVA) evoked increases in IL-33 and IL-33 mRNA in the lungs of both non-sensitized and OVA-sensitized mice, and the increases in the sensitized mice were significantly higher than in the non-sensitized mice. However, intra-tracheal administration of bovine serum albumin did not increase the IL-33 level in the OVA-sensitized mice. Depletion of neither mast cells/basophils nor CD4+ cells abolished the OVA-induced IL-33 production in sensitized mice, suggesting that the antigen recognition leading to the IL-33 production was not related with either antigen-specific IgE-bearing mast cells/basophils or memory CD4+ Th2 cells. When a fluorogenic substrate-labelled OVA (DQ-OVA) was intra-tracheally administered, the lung cells of sensitized mice incorporated more DQ-OVA than those of non-sensitized mice. The lung cells incorporating DQ-OVA included B-cells and alveolar macrophages. The allergic IL-33 production was significantly reduced by treatment with anti-FcγRII/III mAb. Depletion of alveolar macrophages by clodronate liposomes significantly suppressed the allergic IL-33 production, whereas depletion of B-cells by anti-CD20 mAb did not. These results suggest that the administered OVA in the lung bound antigen-specific IgG Ab, and then alveolar macrophages incorporated the immune complex through FcγRII/III on the cell surface, resulting in IL-33 production in sensitized mice. The mechanisms underlying the antigen-specific IL-33 production may aid in development of new pharmacotherapies.

Assessment of new functional units for agrivoltaic systems.

In agrivoltaic systems, photovoltaic (PV) modules are ground-mounted between crops replacing a part of greenhouse or are set below or above the cover film of greenhouse; these can provide solutions with respect to land competition and climate change mitigation. These systems have certain additional functions, namely, sunlight sharing, land sharing and power generation, as compared to the conventional agricultural production systems. These new functions are not adequately performed by traditionally used functional units (FUs), such as the mass- or the area-based FU, in agricultural life cycle assessment (LCA). Therefore, this study proposed new FUs for agrivoltaic systems, namely the modified area-based FU and the monetary-based FU. The modified area-based FU was derived by adding area covered by PV modules to the cultivated area addressing the function of land sharing. The monetary-based FU was derived by adding the prices of crops and electricity addressing the function of the system as a producer of differently valued market goods. The traditional area-based FU is based on the function of solar sharing because crop cultivation and power generation share the same sunlight falling on the same land. These new and traditional FUs were applied to a tomato greenhouse, with and without organic photovoltaics, as a case study of Japan. A combination of traditional and new FUs helps to maintain focus on crop production as the primary function of agricultural land and to better understand the environmental impacts of agrivoltaic systems. Finally, as the sharing of sunlight and land happen simultaneously, a method that addresses both these functions while reporting LCA results was considered.

The high matrix acquisition technique for imaging of atherosclerotic plaque inflammation in fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography with time-of-flight: Phantom study.

BACKGROUND: Motion artifact and partial volume effect caused underestimation of coronary plaque inflammation. This study evaluated the high matrix acquisition technique using time-of-flight (TOF) positron emission tomography/computed tomography for imaging of atherosclerotic plaque inflammation with fluorine-18 fluorodeoxyglucose in small and moving phantoms. METHODS AND RESULTS: All images were reconstructed using a conventional algorithm without TOF (4 × 4 × 4 mm3 voxel size) and a high matrix algorithm with TOF (2 × 2 × 2 mm3 voxel size). Microsphere phantoms of 10, 7.9, 6.2, 5.0, and 4.0 mm diameters were acquired in 3-dimensional list-mode for 30 minutes. A heart phantom mimicking cardiac motion consisted of a hot spot simulating a plaque (φ 4 mm, φ 2 mm) on the outside of the left ventricle. In the microsphere and heart phantom study, visual discrimination, maximum activity, and target-to-background ratio using the high matrix algorithm with TOF were better than those using the conventional algorithm without TOF. CONCLUSION: The high matrix algorithm with TOF improves detection of small targets in phantoms.

Group IVA phospholipase A(2) deficiency prevents CCl4-induced hepatic cell death through the enhancement of autophagy.

Group IVA phospholipase A2 (IVA-PLA2), which generates arachidonate, plays a role in inflammation. IVA-PLA2-deficiency reduced hepatotoxicity and hepatocyte cell death in mice that received a single dose of carbon tetrachloride (CCl4) without any inhibitory effects on CCl4-induced lipid peroxidation. An immunoblot analysis of extracts from wild-type mouse- and IVA-PLA2 KO mouse-derived primary hepatocytes that transiently expressed microtubule-associated protein 1 light chain 3B (LC3) revealed a higher amount of LC3-II, a typical index of autophagosome formation, in IVA-PLA2-deficient cells, suggesting the enhancement of constitutive autophagy. IVA-PLA2 may promote CCl4-induced cell death through the suppression of constitutive autophagy in hepatocytes.

ASB14780, an Orally Active Inhibitor of Group IVA Phospholipase A2, Is a Pharmacotherapeutic Candidate for Nonalcoholic Fatty Liver Disease.

We have previously shown that high-fat cholesterol diet (HFCD)-induced fatty liver and carbon tetrachloride (CCl4)-induced hepatic fibrosis are reduced in mice deficient in group IVA phospholipase A2 (IVA-PLA2), which plays a role in inflammation. We herein demonstrate the beneficial effects of ASB14780 (3-[1-(4-phenoxyphenyl)-3-(2-phenylethyl)-1H-indol-5-yl]propanoic acid 2-amino-2-(hydroxymethyl)propane-1,3-diol salt), an orally active IVA-PLA2 inhibitor, on the development of fatty liver and hepatic fibrosis in mice. The daily coadministration of ASB14780 markedly ameliorated liver injury and hepatic fibrosis following 6 weeks of treatment with CCl4. ASB14780 markedly attenuated the CCl4-induced expression of smooth muscle α-actin (α-SMA) protein and the mRNA expression of collagen 1a2, α-SMA, and transforming growth factor-ß1 in the liver, and inhibited the expression of monocyte/macrophage markers, CD11b and monocyte chemotactic protein-1, while preventing the recruitment of monocytes/macrophages to the liver. Importantly, ASB14780 also reduced the development of fibrosis even in matured hepatic fibrosis. Additionally, ASB14780 also reduced HFCD-induced lipid deposition not only in the liver, but also in already established fatty liver. Furthermore, treatment with ASB14780 suppressed the HFCD-induced expression of lipogenic mRNAs. The present findings suggest that an IVA-PLA2 inhibitor, such as ASB14780, could be useful for the treatment of nonalcoholic fatty liver diseases, including fatty liver and hepatic fibrosis.

The reproducibility of time-of-flight PET and conventional PET for the quantification of myocardial blood flow and coronary flow reserve with (13)N-ammonia.

BACKGROUND: This study aimed to validate the reproducibility of quantitative analysis using time-of-flight (TOF) and conventional PET with (13)N-ammonia ((13)N-NH3). METHODS AND RESULTS: Phantom images were reconstructed with and without TOF, and recovery coefficients (RCs) and the percent contrast of each sphere over the percent background variability were assessed. In the clinical study, 21 subjects underwent dynamic (13)N-NH3 PET scanning under stress and rest conditions. The dynamic acquisition images and intra- and inter-observer reproducibility of myocardial blood flow (MBF) and coronary flow reserve (CFR) were compared between reconstructions (with and without TOF). In the phantom study, RCs and the percent contrast of each sphere over the percent background variability was improved with TOF. In the clinical study, the noise of blood pool and myocardial images with TOF was less than that without TOF. Territorial and global intra- and inter-observer reproducibility of MBF and CFR values was excellent. Although segmental intra- and inter-observer reproducibility was excellent, there were larger variations in apex and the segment near the right ventricle (RV) without TOF. These variations became inconspicuous with TOF. CONCLUSION: Visual image quality, RCs, and percent contrast over percent background variability with TOF were better than that without TOF. Excellent correlations and good agreements in quantitative values were observed. TOF improved the variation of segmental values.

Impact of time-of-flight on qualitative and quantitative analyses of myocardial perfusion PET studies using (13)N-ammonia.

BACKGROUND: The impact of time-of-flight (TOF) in myocardial perfusion (13)N-ammonia positron emission tomography (PET) is unclear. METHODS AND RESULTS: Twenty consecutive subjects underwent rest and adenosine stress (13)N-ammonia myocardial perfusion PET. Two sets of images were reconstructed using TOF-ordered subset expectation maximization (TOF-OSEM) and 3-dimensional row-action maximum likelihood algorithm (3D-RAMLA). Qualitative and quantitative analyses from the TOF-OSEM and 3D-RAMLA reconstructions were compared. Count profile curves revealed that TOF relatively increased the uptake of (13)N-ammonia at the lateral walls, and apical thinning was emphasized on the TOF images. Both segmental rest and stress myocardial blood flow (MBF) values were higher with TOF-OSEM use than with 3D-RAMLA use (rest MBF: 0.955 ± 0.201 vs 0.836 ± 0.185, P < .001; stress MBF: 2.149 ± 0.697 vs 2.058 ± 0.721, P < .001). The differentiation of MBF between reconstructions was more enhanced under rest conditions. Thus, segmental myocardial flow reserve (MFR) observed using TOF-OSEM reconstruction was lower than that observed using 3D-RAMLA (2.25 ± 0.57 vs 2.46 ± 0.75, P < .001). No remarkable differences were observed between segmental and territorial results. CONCLUSIONS: TOF increased lateral wall counts and emphasized apical thinning. Quantitatively, TOF reconstruction showed increased MBF, especially under relatively low perfusion conditions.

Amyloid imaging with [(18)F]florbetapir in geriatric depression: early-onset versus late-onset.

BACKGROUND: We examined patients with mild cognitive impairment (MCI) with a history of geriatric depression (GD) and healthy controls (HC) to evaluate the effect of beta-amyloid (Aß) pathology on the pathology of GD by using [(18)F]florbetapir PET. METHODS: Thirty-three elderly patients (76.7 ± 4.2 years) and 22 healthy controls (HC; 72.0 ± 4.5 years, average ± SD) were examined by [(18)F]florbetapir positron emission tomography (PET) to quantify the standard uptake value ratio (SUVR) as the degree of amyloid accumulation, by MRI to determine the degree of atrophy, by Mini-Mental State Examination for cognitive functions, and by Geriatric Depression Scale for the severity of depression, and by Clinical Dementia Rating for activity of daily living (ADL). The cut-off value of 1.08 for SUVR was defined as Aß-positive. RESULTS: Of the patients and HC, 39.4% and 27.3%, respectively, were beta-amyloid-positive. The onset age of GD was significantly correlated with SUVR (r = 0.44, p < 0.01). Compared to patients without Aß (GD-Aß), patients with Aß (GD + Aß) did not differ in terms of age, cognitive function, severity of depression and ADL, and brain atrophy. GD + Aß had significantly older average ± SD age at onset of GD (73.6 ± 7.1 versus 58.7 ± 17.8, p < 0.01) and significantly shorter average ± SD time between onset of GD and PET scan day (3.1 ± 5.2 years versus 18.1 ± 18.6 years, p < 0.001) than GD-Aß. CONCLUSIONS: Our results showed that the rate of Aß positivity was higher in late-onset GD and that onset-age was associated with SUVR, suggesting that the later the onset of GD, the more Aß pathology affected its onset.

Comparison of imaging biomarkers for Alzheimer's disease: amyloid imaging with [18F]florbetapir positron emission tomography and magnetic resonance imaging voxel-based analysis for entorhinal cortex atrophy.

OBJECTIVE: We compared amyloid positron emission tomography (PET) and magnetic resonance imaging (MRI) in subjects clinically diagnosed with Alzheimer's disease (AD), mild cognitive impairment (MCI), and older healthy controls (OHC) in order to test how these imaging biomarkers represent cognitive decline in AD. METHODS: Fifteen OHC, 19 patients with MCI, and 19 patients with AD were examined by [(18)F]florbetapir PET to quantify the standard uptake value ratio (SUVR) as the degree of amyloid accumulation, by MRI and the voxel-based specific regional analysis system for AD to calculate z-score as the degree of entorhinal cortex atrophy, and by mini-mental state examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive component--Japanese version (ADAS-Jcog) for cognitive functions. RESULTS: Both cutoff values for measuring AD-like levels of amyloid (1.099 for SUVR) and entorhinal cortex atrophy (1.60 for z-score) were well differentially diagnosed and clinically defined AD from OHC (84.2% for SUVR and 86.7% for z-score). Subgroup analysis based on beta-amyloid positivity revealed that z-score significantly correlated with MMSE (r = -0.626, p < 0.01) and ADAS-Jcog (r = 0.691, p < 0.01) only among subjects with beta-amyloid. CONCLUSIONS: This is the first study to compare [(18)F]florbetapir PET and MRI voxel-based analysis of entorhinal cortex atrophy for AD. Both [(18)F]florbetapir PET and MRI detected changes in AD compared with OHC. Considering that entorhinal cortex atrophy correlated well with cognitive decline only among subjects with beta-amyloid, [18F]florbetapir PET makes it possible to detect AD pathology in the early stage, whereas MRI morphometry for subjects with beta-amyloid provides a good biomarker to assess the severity of AD in the later stage.

The Effect of Polyvinyl Alcohol Addition on the Optical Properties and Oxygen Detection Performance of Titanium Dioxide and Methylene Blue Nanocomposite Colorimetric Indicators.

In this study, we investigated the impact of polyvinyl alcohol (PVA) incorporation on the optical properties and oxygen detection performance of a titanium dioxide/methylene blue (TiO2/MB) nanocomposite colorimetric indicator for packaging applications. The nanocomposite was synthesized via mechanical milling of TiO2 nanoparticles with MB and citric acid. PVA, at varying concentrations (0, 3, 9, and 14 wt%), was introduced during the wet milling process to produce a homogeneous composite film. Spin coating was employed to fabricate TiO2/MB nanocomposite films for oxygen detection evaluation. The influence of PVA loading on the films' chemical functionalities and surface morphologies was assessed using Fourier-transform infrared spectroscopy (FTIR) and field-emission scanning electron microscopy (FE-SEM). The indicator's activation process, involving a color change between bleached and colored states, and its recovery time were monitored via optical imaging and UV-VIS-NIR spectrophotometry. The results revealed that a PVA content of 9 wt% yielded well-defined films with enhanced stability of the TiO2/MB nanocomposite's oxygen detection performance.

Suppression of Sleeping Beauty-induced Gliomagenicity in Ts1Cje Mice, a Model of Down Syndrome.

BACKGROUND/AIM: Individuals with Down syndrome (DS), attributed to triplication of human chromosome 21 (Hsa21), exhibit a reduced incidence of solid tumors. However, the prevalence of glioblastoma among individuals with DS remains a contentious issue in epidemiological studies. Therefore, this study examined the gliomagenicity in Ts1Cje mice, a murine model of DS. MATERIALS AND METHODS: We employed the Sleeping Beauty transposon system for the integration of human oncogenes into cells of the subventricular zone of neonatal mice. RESULTS: Notably, Sleeping Beauty-mediated de novo murine gliomagenesis was significantly suppressed in Ts1Cje mice compared to wild-type mice. In glioblastomas of Ts1je mice, we observed an augmented presence of M1-polarized tumor-associated macrophages and microglia, known for their anti-tumor efficacy in the early stage of tumor development. CONCLUSION: Our findings in a mouse model of DS offer novel perspectives on the diminished gliomagenicity observed in individuals with DS.

Group IVA phospholipase A2 participates in the progression of hepatic fibrosis.

Group IVA phospholipase A2 (IVA-PLA2) is an enzyme that intiates the arachidonic acid pathway and plays an important role in inflammation. We demonstrate that IVA-PLA2 deficiency suppresses lipid deposition in the liver, which was induced by administration of a high-fat and -cholesterol diet (HFCD) for 16 wk in mice. Herein, we performed 2-dimensional gel-based comparative proteomics to further define the suppressive effect of IVA-PLA2 deficiency on fatty liver formation. In comparisons among 4 groups, wild-type (WT)/normal diet (ND), IVA-PLA2-deficient knockout (KO)/ND, WT/HFCD, and KO/HFCD, 4 proteins, 3 of which are associated with hepatic fibrosis, were identified as molecules, of which altered expression by HFCD was suppressed in KO mice compared to WT mice. Therefore, we assessed the effect of IVA-PLA2 deficiency on hepatic fibrosis induced by HFCD or carbon tetrachloride (CCl4) in mouse models. Biochemical and histological analyses revealed that IVA-PLA2 deficiency markedly reduced overall collagen accumulation in the liver of HFCD- and CCl4-derived mouse models. We found that IVA-PLA2 deficiency prevented activation of hepatic stellate cells and infiltration of F4/80-positive macrophages without affecting other immunocytes such as CD8+ lymphocytes and natural killer cells. In summary, IVA-PLA2 deficiency attenuates not only lipid deposition in the liver but also hepatic fibrosis formation.