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Mn-based alloys exhibit unique properties in the spintronics materials possessing perpendicular magnetic anisotropy (PMA) beyond the Fe and Co-based alloys. It is desired to figure out the quantum physics of PMA inherent to Mn-based alloys, which have never been reported. Here, the origin of PMA in ferrimagnetic Mn 3- δ Ga ordered alloys is investigated to resolve antiparallel-coupled Mn sites using x-ray magnetic circular and linear dichroism (XMCD/XMLD) and a first-principles calculation. We found that the contribution of orbital magnetic moments in PMA is small from XMCD and that the finite quadrupole-like orbital distortion through spin-flipped electron hopping is dominant from XMLD and theoretical calculations. These findings suggest that the spin-flipped orbital quadrupole formations originate from the PMA in Mn 3- δ Ga and bring the paradigm shift in the researches of PMA materials using x-ray magnetic spectroscopies.

Background: Herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, a variety of Japanese traditional herbal medicine ('Kampo') were examined for their potential anti-malarial activities., Methods: A comprehensive screening methods were designed to identify novel anti-malarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n = 96). The anti-malarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) strains of Plasmodium falciparum. The cytotoxicity was also evaluated using primary adult mouse brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo anti-malarial activity., Results: Out of 120 herbal extracts, Coptis rhizome showed the highest anti-malarial activity (IC 50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis rhizome also showed anti-malarial activities with IC 50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest anti-malarial activity (IC 50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. Finally, the herbal extract of Coptis rhizome and its major active compound coptisine chloride exhibited significant anti-malarial activity in mice infected with Plasmodium yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P < 0.05) for Coptis rhizome and from 81 to 89% (P < 0.01) for coptisine chloride., Conclusion: Coptis rhizome and its major active compound coptisine chloride showed promising anti-malarial activity against chloroquine-sensitive (3D7) and -resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus, Kampo herbal medicine is a potential natural resource for novel anti-malarial agents.

Purpose: The purpose of this study was to develop a novel quality assurance (QA) program to check the entire treatment chain of image-guided brachytherapy with dose distribution evaluation in a single setup and irradiation using a gel dosimeter., Methods and Materials: A polymer gel was used, and the readout was performed by magnetic resonance scanning. A CT-based treatment plan was generated using the Oncentra planning system (Elekta, Sweden), and irradiation was performed three times using an afterloading device with an Ir-192 source. The dose-response curve of the gel was created using 6-MV X-ray, which is independent of the source beams. Planar gamma images on a coronal plane along the source transport axis were calculated using the measured dose as a reference, and the calculated doses were used in several error simulations (no error; 2.0 or 2.5 mm systematic and random source dwell mispositioning; and dose error of 2%, 5%, 10%, and 20%)., Results: The dose-R 2 (spin-spin relaxation rate) conversion table revealed that the uncertainty and dose resolution of 6-MV X-ray were better than those of Ir-192 and also constant between the three measurements. With the 3%/1 mm criteria, there were statistically significant differences between each pair of settings except dose error of 2% and 5%., Conclusion: This work depicts a simple and efficient end-to-end test that can provide a clinically useful tool for QA of image-guided brachytherapy. In this QA program, air kerma strength and dwell position setting could also be verified. This test can also distinguish between different types of error., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: An increase in serum undercarboxylated osteocalcin concentrations suggests vitamin K deficiency. Clinical intervention studies suggested that the vitamin K supplementation might contribute to preventing bone loss in postmenopausal women. Evidence on the relationship between serum undercarboxylated osteocalcin (ucOC) levels and bone parameters of quantitative ultrasound (QUS) is limited. We examined the correlation between serum ucOC concentrations and bone status as measured by QUS among middle-aged and older Japanese men and women., Methods: The subjects were community-dwelling men (n = 358) and women (n = 503) aged ≥ 40 years in Japan. Heel QUS parameters, including the stiffness index, speed of sound, and broadband ultrasound attenuation, were measured. Serum ucOC concentrations were measured by electrochemiluminescence immunoassay. Grip strength was measured in the dominant hand. Information on alcohol drinking, current smoking, exercise, and menopause in women was collected., Results: Serum ucOC concentrations were significantly associated with age in both sexes. Serum ucOC concentrations in men were higher at ≥ 80 years than those in the age groups of 40-49, 50-59, and 60-69 years. Serum ucOC concentrations in women were higher in the age groups of 50-59 and 60-69 years than those at 40-49 years. Partial correlation analysis adjusting for covariates (age, body mass index, grip strength, alcohol drinking, current smoking, and exercise in men; age, body mass index, grip strength, alcohol drinking, current smoking, exercise, and menopause in women) showed that serum ucOC concentrations were negatively significantly correlated with all QUS parameters in women. Serum ucOC concentrations were not correlated with them in men., Conclusions: Vitamin K deficiency, evaluated with higher serum ucOC, was correlated with poor bone status in women.

Background: The amygdala can enhance emotional memory encoding as well as anxiogenesis via corticotropin-releasing factor neurons. However, the amygdala's explicit role in emotional encoding remains unclarified in humans. We examined how functional connectivity (FC) of amygdala subnuclei affects emotional encoding, considering its mechanism in which anxiety, attention, and cortisol conceivably participate., Methods: A total of 65 healthy humans underwent resting-state functional magnetic resonance imaging scans and saliva collection at 10 points in time over 2 days. FC analysis was performed for basolateral amygdala subnucleus (BLA) and centromedial amygdala subnucleus. We assessed attentional control via an emotional Stroop task and assessed emotional encoding via a facial identification task that examines how strongly a neutral face is memorized when accompanied by an emotional face (fearful, sad, or happy). FC and task performance were compared between high-anxious and non-high-anxious groups classified by anxious personality scores., Results: BLA connected with subgenual anterior cingulate cortex (sgACC) in proportion to the strength of fear-related encoding, whereas centromedial subnucleus connected with caudate nucleus for happy-related encoding. The high-anxious group showed more enhanced fear-related encoding but impaired happy-related encoding compared with the non-high-anxious group. BLA-sgACC FC was more intensified in the high-anxious group than in the non-high-anxious group; however, centromedial-caudate FC did not differ between them. Although emotional encoding was uncorrelated with either attentional control or cortisol, BLA-sgACC was positively correlated with cortisol increase after awakening., Conclusions: The study revealed that neural interactions of BLA, specifically with sgACC, might play a critical role in fear-related memory encoding, depending on the individual's level of anxiety. These findings aid in understanding the complicated mechanisms of emotional memory in anxiety disorders., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Cortisol is known to affect visuospatial memory through its major binding site in the brain, the hippocampus. The synchronization of neural activity between the hippocampus, prefrontal cortex (PFC), and visual cortex is presumed to be essential for the formation of visuospatial memory because of their visuospatial learning-dependent neuroplasticity. However, it remains unclear how hippocampal connectivity with the PFC and visual cortex is involved in the relationship between cortisol and visuospatial memory in humans. We thus investigated whether functional connectivity (FC) of the hippocampus, specifically its rostral and caudal subdivisions, mediates the relationship between visuospatial memory and endogenous cortisol. One-hundred sixty-six healthy young adults underwent standard neuropsychological tests to assess visuospatial construction (a complex figure copying test) and retrieval (the corresponding recall test) and collected their saliva at 6-time points across 2 consecutive days for measurement of daily cortisol concentrations (dCOR). Ninety of them received resting-state fMRI scans. Greater dCOR was significantly associated with better figure copying performance, but contrastingly with poorer figure recall. In proportion to dCOR, the rostral hippocampus (rHC) showed significantly increased FC with the PFC (including its dorsolateral and medial parts) and the inferior lateral occipital cortex (iLOC), while the caudal hippocampus had increased FC with the anterior middle temporal cortex. Of the cortisol-related hippocampal connectivity, the rHC-iLOC FC was specifically correlated with figure recall and showed complete mediation for the negative relationship of dCOR with figure recall. These results suggest that cortisol might have enhancing effects on visuospatial encoding as well as impairing effects on visuospatial retrieval, possibly due to its occupancy patterns of corticosteroid receptors. Cortisol's adverse effects on visuospatial retrieval might be explained through cortisol-related rostral hippocampal connectivity with the iLOC, which is a part of the extrastriate cortex implicated in visuospatial perception. Thorough dissection of hippocampal-prefrontal-extrastriate connectivity might facilitate the understanding of neural mechanisms underlying cortisol's contrasting effects on encoding (or consolidation) and retrieval of visuospatial information., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The National Program for Chagas disease was implemented in Bolivia in 2006, and it greatly decreased the number of infections through vector control. Subsequently, a treatment regimen of benznidazole (BNZ) was started in seropositive school-age children living in certified vector control areas., Methods and Findings: We conducted a 12-month follow-up study and seven blood samples were taken during and after the treatment. Serology, conventional diagnostic PCR (cPCR) and quantitative Real-time PCR (qPCR) were performed. Plasma Th1/Th2/Th17 cytokines levels were also determined. Approximately 73 of 103 seropositive children complied with BNZ, with three interruptions due to side effects. To evaluate each individual's treatment efficacy, the cPCR and qPCR values during the final 6 months of the follow-up period were observed. Among 57 children who completed follow-up, 6 individuals (11%) showed both cPCR(+) and qPCR(+) (non reactive), 24 (42%) cPCR(-) but qPCR(+) (ambiguous) and 27 (47%) cPCR(-) and qPCR(-) (reactive). Within 14 Th1/Th2/Th17 cytokines, IL-17A showed significantly higher levels in seropositive children before the treatment compared to age-matched seronegative children and significantly decreased to the normal level one-year after. Moreover, throughout the follow-up study, IL-17A levels were positively co-related to parasite counts detected by qPCR. At the 12 months' time point, IL-17A levels of non-reactive subjects were significantly higher than either those of reactive or ambiguous subjects suggesting that IL-17A might be useful to determine the reactivity to BNZ treatment., Conclusions: Plasma levels of IL-17A might be a bio-marker for detecting persistent infection of T. cruzi and its chronic inflammation., Competing Interests: The authors have declared that no conflict of interest exists.

The present study aimed to develop a denoising convolutional neural network metal artifact reduction hybrid reconstruction (DnCNN-MARHR) algorithm for decreasing metal objects in digital tomosynthesis (DT) for arthroplasty by using projection data. For metal artifact reduction (MAR), we implemented a DnCNN-MARHR algorithm based on a training network (mini-batch stochastic gradient descent algorithm with momentum) to estimate the residual reference (140 keV virtual monochromatic [VM]) and object (70 kV with metal artifacts) images. For this, we used projection data and subtracted the estimated residual images from the object images, involving hybrid and subjectively reconstructed image usage (back projection and maximum likelihood expectation maximization [MLEM]). The DnCNN-MARHR algorithm was compared with the dual-energy material decomposition reconstruction algorithm (DEMDRA), VM, MLEM, established and commonly used filtered back projection (FBP), and a simultaneous algebraic reconstruction technique-total variation (SART-TV) with MAR processing. MAR was compared using artifact index (AI) and texture analysis. Artifact spread functions (ASFs) for images that were out-of-plane and in-focus were evaluated using a prosthesis phantom. The overall performance of the DnCNN-MARHR algorithm was adequate with regard to the ASF, and the derived images showed better results, without being influenced by the metal type (AI was almost equal to the best value for the DEMDRA). In the ASF analysis, the DnCNN-MARHR algorithm generated better MAR compared with that obtained employing usual algorithms for reconstruction using MAR processing. In addition, comparison of the difference (mean square error) between DnCNN-MARHR and the conventional algorithm resulted in the smallest VM. The DnCNN-MARHR algorithm showed the best performance with regard to image homogeneity in the texture analysis. The proposed algorithm is particularly useful for reducing artifacts in the longitudinal direction, and it is not affected by tissue misclassification., Competing Interests: The authors have declared that no competing interests exist.

A female koala presented with hyperglycemia related to diabetes mellitus diagnosed at 9 years and treated with insulin. She presented with nasal hemorrhage, anemia, leukocytosis, and tachypnea at 10 years. A blood smear examination revealed scattered, atypical large myeloid cells and a clinical diagnosis of myelogenous leukemia was made. White blood cell count reached a maximum of 295 × 10 2 /µl, with evidence of severe regenerative anemia and thrombocytopenia. Grossly, systemic lymph node enlargement, fragile liver with hemorrhage, and bloody ascites were observed. Histopathologically, atypical myeloid cells, including myelocytic and metamyelocytic cells, were scattered in the vasculature and surrounding tissues throughout the organs. The patient was infected with a koala retrovirus, which might have caused the myelogenous leukemia.

Photopharmacology has attracted research attention as a new tool for achieving optical control of biomolecules, following the methods of caged compounds and optogenetics. We have developed an efficient photopharmacological inhibitor-azoMTX-for Escherichia coli dihydrofolate reductase (eDHFR) by replacing some atoms of the original ligand, methotrexate, to achieve photoisomerization properties. This fine molecular design enabled quick structural conversion between the active "bent" Z isomer of azoMTX and the inactive "extended" E isomer, and this property afforded quantitative control over the enzyme activity, depending on the wavelength of irradiating light applied. Real-time photoreversible control over enzyme activity was also achieved., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Osteoporosis in women is a serious health problem. The relationships between biochemical markers of bone turnover and bone mineral density (BMD) in women have been reported, but no study has examined relationships between tartrate-resistant acid phosphatase-5b (TRACP-5b) or bone-specific alkaline phosphatase (BAP) and bone mass measured by quantitative ultrasound (QUS) in Japanese post-menopausal women. Aim: To investigate the serum TRACP-5b and BAP levels and to determine their associations with the heel stiffness index measured by QUS in post-menopausal women. Subjects and methods: The subjects were 510 post-menopausal women who were invited to participate in periodic health examinations in 2011-2013 (the Unzen Study). The heel stiffness index (bone mass) was measured by QUS. Serum samples were collected and TRACP-5b and BAP levels were measured. Results: Multiple regression analysis showed that a higher log (TRACP-5b) was correlated with a lower stiffness index ( p  = 0.014) and log (BAP) was not correlated with stiffness index after adjusting for covariates ( p  = 0.136). Conclusion: Higher rates of bone resorption are associated with a lower stiffness index in Japanese post-menopausal women. These results may indicate that high bone resorption affects bone mass more than bone formation, resulting in a low bone mass.

Background: Considerable progress has been made in dengue management, however the lack of appropriate predictors of severity has led to huge number of unwanted admissions mostly decided on the grounds of warning signs. Apoptosis related mediators, among others, are known to correlate with severe dengue (SD) although no predictive validity is established. The objective of this study was to investigate the association of plasma cell-free DNA (cfDNA) with SD, and evaluate its prognostic value in SD prediction at acute phase., Methods: This was a hospital-based prospective cohort study conducted in Vietnam. All the recruited patients were required to be admitted to the hospital and were strictly monitored for various laboratory and clinical parameters (including progression to SD) until discharged. Plasma samples collected during acute phase (6-48 h before defervescence) were used to estimate the level of cfDNA., Results: Of the 61 dengue patients, SD patients (n = 8) developed shock syndrome in 4.8 days (95% CI 3.7-5.4) after the fever onset. Plasma cfDNA levels before the defervescence of SD patients were significantly higher than the non-SD group (p = 0.0493). From the receiver operating characteristic (ROC) curve analysis, a cut-off of > 36.9 ng/mL was able to predict SD with a good sensitivity (87.5%), specificity (54.7%), and area under the curve (AUC) (0.72, 95% CI 0.55-0.88; p = 0.0493)., Conclusions: Taken together, these findings suggest that cfDNA could serve as a potential prognostic biomarker of SD. Studies with cfDNA kinetics and its combination with other biomarkers and clinical parameters would further improve the diagnostic ability for SD.

In a cavity quantum electrodynamics (QED) system, where atoms coherently interact with photons in a cavity, the eigenstates of the system are the superposition states of atoms and cavity photons, the so-called dressed states of atoms. When two cavities are connected by an optical fiber with negligible loss, the coherent coupling between the cavities gives rise to photonic normal modes. One of these normal modes is the fiber-dark mode, in which photons are delocalized in the two distant cavities. Here we demonstrate the setting of coupled-cavities QED, where two nanofiber cavity-QED systems are coherently connected by a meter-long low-loss channel in an all-fiber fashion. Specifically, we observe dressed states of distant atoms with delocalized photons of the fiber-dark normal mode. Our system will provide a platform for the study of delocalized atomic and photonic states, photonic many-body physics, and distributed quantum computation.

Rapid technological advances in high-dose-rate brachytherapy have led to a requirement for greater accuracy in treatment planning system calculations and in the verification of dose distributions. In high-dose-rate brachytherapy, it is important to measure the dose distribution in the low-dose region at a position away from the source in addition to the high-dose range in the proximity of the source. The aim of this study was to investigate the accuracy of a treatment plan designed for prostate cancer in the low-dose range using a normoxic N-vinylpyrrolidone-based polymer gel (VIPET gel) dosimeter containing inorganic salt as a sensitizer (iVIPET). The dose response was evaluated on the basis of the transverse relaxation rate (R 2 ) measured by magnetic resonance scanning. In the verification of the treatment plan, gamma analysis showed that the dose distributions obtained from the polymer gel dosimeter were in good agreement with those calculated by the treatment planning system. The gamma passing rate according to the 2%/2 mm criterion was 97.9%. The iVIPET gel dosimeter provided better accuracy for low doses than the normal VIPET gel dosimeter, demonstrating the potential to be a useful tool for quality assurance of the dose distribution delivered by high-dose-rate brachytherapy., (Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Objectives　This study aimed to explore the association of difficulties in activities of daily living (ADL) (activities related to bending, spine extension, standing endurance, and walking) with fear of falling among community-dwelling older adults.Methods　We recruited 642 older adults (men, n=267; women, n=375) aged 65 years and over. The mean age was 72.2±5.1 years. Fear of falling, falls in the previous year, pain (low back pain or knee pain), comorbidity, and cataracts were assessed using a self-administered questionnaire. ADL difficulties were assessed individually, such as activities related to bending (getting in or out the car, picking up a lightweight object, putting on socks or stockings, and lifting a 5 kg object from the floor), spine extension (reaching an object above your head), standing endurance (standing on your feet for 2 h), and walking (walking 100 m on a level surface, climbing 10 steps without stopping, and walking down 10 steps). The independent association between fear of falling and each ADL difficulties was assessed using logistic regression analysis.Results　Participants with fear of falling, compared with those without fear of falling, had an older age (74.8 and 71.6 in men, 73.3 and 71.0 in women, respectively; P<0.01), more falls in the previous year (21% and 9% in men, 28% and 11% in women, respectively; P<0.05), pain (80% and 61% in men, 82% and 64% in women, respectively; P<0.01), and comorbidity (23% and 15% in women, respectively; P<0.05). Multivariate logistic regression analysis identified each ADL difficulties except walking 100 m on a level surface as being independently associated with fear of falling after adjusting for age, body mass index, sex, falls in the previous year, pain, and comorbidity.Conclusion　ADL difficulties, such as activities related to bending, spine extension, standing endurance, and walking, except for walking 100 m on a level surface, were associated with fear of falling.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive deposition of droplets in hepatocytes. Patients with NAFLD can be at risk for nonalcoholic steatohepatitis, which can lead to hepatocellular carcinoma. Autophagy is a cellular pathway that is crucial for survival and homeostasis, and which protects against pathophysiological changes like obesity and cancer. We determined the expression of autophagy markers in preneoplastic hepatic lesions and the effects of an autophagy repressor chloroquine (CQ) or inducer amiodarone (AM) in a steatosis-related hepatocarcinogenesis model. Male F344 rats were fed a control diet or high fat diet (HFD), and subjected to initiation and promotion steps with N-nitrosodiethylamine injection at week 0 and a partial hepatectomy at week 3. Several HFD-fed rats were administered 0.1% CQ and 0.5% AM in their drinking water during week 2 and 8. CQ and AM did not improve HFD-induced obesity. AM, but not CQ, significantly decreased the number of glutathione S-transferase placental form-positive preneoplastic liver foci in the liver. Autophagosome markers LC3 and the LC3-binding protein p62 were heterogeneously expressed in the preneoplastic foci. CQ might inhibit autophagy by significantly increased p62/LC3 ratio, while AM might have a potential of inducing autophagy by showing an increased gene expression of the autophagy regulator, Atg5. These results suggest that preneoplastic lesions express autophagosome markers and that AM might decrease steatosis-related early hepatocarcinogenesis by potentially inducing autophagy in HFD-fed rats, while inhibition of autophagy by CQ did not alter the hepatocarcinogenesis. However, an immunohistochemical trial revealed a technical limitation in detecting autophagosome markers because there were variations in each preneoplastic lesion.

A magnetic nanolayer with a perpendicular magnetic easy axis and negligible magnetization is demonstrated. Even though a manganese metal is antiferromagnetic in bulk form, a few manganese monolayers grown on a paramagnetic ordered alloy template and capped by an oxide layer exhibit a strong perpendicular magnetic anisotropy field exceeding 19 T as well as a negligible magnetization of 25 kA/m. The nanolayer shows tunnel magnetoresistance. Moreover, the perpendicular magnetic anisotropy for the nanolayer can be reduced by applying an electric voltage. These findings will provide new insight into a creation of new nanolayer magnets.

In vivo multicolor imaging is important for monitoring multiple biomolecular or cellular processes in biology. 19 F magnetic resonance imaging (MRI) is an emerging in vivo imaging technique because it can non-invasively visualize 19 F nuclei without endogenous background signals. Therefore, 19 F MRI probes capable of multicolor imaging are in high demand. Herein, we report five types of perfluorocarbon-encapsulated silica nanoparticles that show 19 F NMR peaks with different chemical shifts. Three of the nanoprobes, which show spectrally distinct 19 F NMR peaks with sufficient sensitivity, were selected for in vivo multicolor 19 F MRI. The nanoprobes exhibited 19 F MRI signals with three colors in a living mouse. Our in vivo multicolor system could be utilized for evaluating the effect of surface functional groups on the hepatic uptake in a mouse. This novel multicolor imaging technology will be a practical tool for elucidating in vivo biomolecular networks by 19 F MRI., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A 79-year-old woman visited a hospital with coronary vasospastic angina and supraventricular tachycardia. Periodic inspection of echocardiography suggested a right atrial tumor which was not pointed out 6 months ago, but magnetic resonance imaging suggested a valve aneurysm. These findings were contradictory. We preoperatively diagnosed a cardiac tumor because of its new onset and mobility. Tumor resection and valve repair was planned in consideration of the risk of embolism. As a result, we finally diagnosed tricuspid valve aneurysm from the intraoperative findings and histopathological findings. We assumed that valve aneurysm was formed in the healing process of subclinical infective endocarditis. It was inferred that preoperative diagnosis of valve aneurysm is very difficult.

Activatable 19F MRI nanoprobes for sensing caspase-1 activity were developed. Tandem repetition of substrate peptide sequences improved the turn-on response of nanoprobes, allowing detection of caspase-1 activity by 19F MRI. In vivo immune response was successfully imaged using the new nanoprobe.

Introduction: Attentional bias modification (ABM) alleviates anxiety by moderating biased attentional processing toward threat; however, its neural mechanisms remain unclear. We examined how ABM changes functional connectivity (FC) and functional network measures, leading to anxiety reduction., Methods: Fifty-four healthy anxious individuals received either ABM or sham training for 1 month in a double-blind randomized controlled trial. Anxious traits, attentional control, and attentional bias were assessed. Thirty-five participants completed resting-state functional magnetic resonance imaging (MRI) scans before and after training., Results: ABM significantly mitigated an anxious traits regarding physical stress vulnerability (η 2  = 0.12, p = 0.009). As compared to sham training, ABM significantly strengthened FC between the pulvinar and transverse temporal gyrus along the temporoparietal junction (T = 3.90, FDR-corrected p = 0.010), whereas it decreased FC between the postCG and ventral fronto-parietal network (vFPN) regions such as the anterior insula and ventrolateral prefrontal cortex (all T ≤ - 3.19, FDR-corrected p ≤ 0.034). Although ABM diminished network measures of the postcentral gyrus (postCG) (all T ≤ - 4.30, FDR-corrected p ≤ 0.006), only the pulvinar-related FC increase was specifically correlated with anxiety reduction (r = - 0.46, p = 0.007)., Limitations: Per-protocol analysis and reduced sample size in MRI analysis., Conclusions: ABM might augment the pulvinar's control over vFPN to maintain endogenous attention to a behavioral goal, while diminishing the information exchanges of the postCG with vFPN to inhibit the capture of exogenous attention by potential threats. The pulvinar might play a critical role in ABM anxiolytic efficacy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The lack of an appropriate model has been a serious concern in dengue research pertinent to immune response and vaccine development. It remains a matter of impediment in dengue virus (DENV) studies when it comes to an in vitro model, which requires adequate quantity of dendritic cells (DC) with uniform characters. Other sources of DC, mostly monocyte derived DC (moDC), have been used despite their limitations such as quantity, proliferation, and donor dependent characters. Recent development of human iPS cells with consistent proliferation for long, stable, functional characteristics and desired HLA background has certainly offered added advantages. Therefore, we hypothesised that iPS derived cells would be a reliable alternative to the traditional DCs to be used with an in vitro DENV system. To develop a DENV infection and T cell activation model, we utilised iPS cells (HLA-A*24) as the source of DC. iPS-ML-DC was prepared and DENV infectivity was assessed apart from the major surface markers expression and cytokine production potential. Our iPS-ML-DC had major DC markers expression, DENV infection efficiency and cytokine production properties similar to that of moDC. Moreover, DENV infected iPS-ML-DC demonstrated the ability to activate HLA-matched T cell (but not mismatched) in vitro as evidenced by significantly higher proportion of IFN-γ + CD69 + T cells compared to non-infected iPS-ML-DC. This affirmed the antigen-specific T cell activation by iPS-ML-DC as a function of antigen presenting cells. To conclude, maturation potential, DENV infection efficiency and T cell activation ability collectively suggest that iPS-ML-DC serves as an attractive option of DC for use in DENV studies in vitro.

There is no definitive predictor of dengue severity, and this has led to a very large number of unnecessary hospitalizations worldwide. Although mast cell mediators are believed to a play role in dengue severity, the lack of precise kinetic data demands further research on early predictors. We enrolled 111 patients with confirmed dengue and 85 with "other febrile illness" (OFI) in a hospital-based prospective study in Vietnam. Dengue patients were classified as level 1, 2, or 3 based on the clinical intervention received. Blood samples were collected from each patient every day (pre- and post-defervescence) and after discharge. Plasma chymase, total IgE, and dengue-specific IgE were measured. Dengue-specific IgE levels showed an increasing trend during the course of illness and remained high even at post-discharge, although no significant difference was observed among severity levels. Total IgE showed no such trend. The specific IgE/total IgE ratio (S/T ratio) remained constantly higher in level 3 patients compared to other levels, with a significant difference at some time points. The S/T ratio of acute phase samples (before defervescence) tended to increase with increasing severity (level 1 < 2 < 3), and was significantly higher in level 3 patients than in level 1 and OFI patients. As an early predictor of severity allowing level 3 patients to be distinguished from other dengue patients, the S/T ratio achieved a sensitivity of 75% and specificity of 68%. We describe the kinetic profiles of IgEs, their ratio, and chymase levels at different severity levels. The S/T ratio was found to be associated with dengue severity, suggesting that it could potentially be used as an early predictor of severity.

Dengue virus (DENV) replication between mosquito and human hosts is hypothesized to be associated with viral determinants that interact in a differential manner between hosts. However, the understanding of inter-host viral determinants that drive DENV replication and growth between hosts is limited. Through the use of clinical isolates, we identified an amino acid variation of Ala, Met and Val at position 116 of DENV-1 NS4B. While the proportion of virus with the NS4B-116V variant remained constantly high in serial passages in a mosquito cell line, populations of the NS4B-116M and NS4B-116A variants became dominant after serial passages in mammalian cell lines. Using recombinant DENV-1 viruses, the Val to Ala or Met alteration at position NS4B-116 (rDENV-1-NS4B-116A and rDENV-1-NS4B-116M) resulted in enhanced virus growth in human cells in comparison to the clone with Val at NS4B-116 (rDENV-1-NS4B-116V). However, the reverse phenomenon was observed in a mosquito cell line. Additionally, in a human cell line, differential levels of IFN-α/β and IFN-stimulated gene expressions (IFIT3, IFI44L, OAS1) suggested that the enhanced viral growth was dependent on the ability of the NS4B protein to hamper host IFN response during the early phase of infection. Overall, we identified a novel and critical viral determinant at the pTMD3 of NS4B region that displayed differential effects on DENV replication and fitness in human and mosquito cell lines. Taken together, the results suggest the importance of the NS4B protein in virus replication and adaptation between hosts.

Administration of the diuretic, spironolactone (SR), can inhibit chronic liver diseases. We determined the effects of SR alone or in combination with the antioxidant α-glycosyl isoquercitrin (AGIQ) on hyperlipidemia- and steatosis-related precancerous lesions in high-fat diet (HFD)-fed rats subjected to a two-stage hepatocarcinogenesis model. Rats were fed with control basal diet or HFD, which was administered with SR alone or in combination with an antioxidant AGIQ in drinking water. An HFD increased body weight, intra-abdominal fat (adipose) tissue weight, and plasma lipids, which were reduced by coadministration of SR and AGIQ. SR and AGIQ coadministration also reduced hepatic steatosis and preneoplastic glutathione S-transferase placental form-positive foci, in association with decrease in NADPH oxidase (NOX) subunit p22phox-positive cells and an increase in active-caspase-3-positive cells in the foci. Hepatic gene expression analysis revealed that the coadministration of SR and AGIQ altered mRNA levels of lipogenic enzymes ( Scd1 and Fasn), antioxidant-related enzymes ( Catalase), NOX component ( P67phox), and anti-inflammatory transcriptional factor ( Pparg). Our results indicated that SR in combination with AGIQ had the potential of suppressing hyperlipidemia- and steatosis-related early hepatocarcinogenesis through the reduced expression of NOX subunits.

Using a laterally configured structure, we demonstrate modulation of the magnetization dynamics of an epitaxial Heusler ferromagnet, Fe 3 Si, by nonlocally injecting pure spin currents. From the ferromagnetic resonance signals, the effective Gilbert damping constant ([Formula: see text]) of the epitaxial Fe 3 Si nanomagnet is estimated to be  ∼0.003 at room temperature. By using the lateral and nonlocal spin injection, the [Formula: see text] value of the epitaxial Fe 3 Si nanomagnet can be modulated from 0.0034 to 0.0024. This study will open a way for control of the magnetization dynamics of high-performance ferromagnetic Heusler alloys due to pure spin currents even in laterally configured structures.

Oxidosqualene cyclase (OSC), a membrane-associated protein, is a key enzyme of sterol biosynthesis. Here we report a novel assay for OSC, involving reaction in aqueous solution, NMR quantification in organic solvent, and factor analysis of spectra. We evaluated one known and three novel inhibitors on OSC of Trypanosoma cruzi, a parasite causative of Chagas disease, and compared their effects on human OSC for selectivity. Among them, one novel inhibitor showed a significant parasiticidal activity.

Hydroxylated polychlorobiphenyls (OH-PCBs) are major metabolites of PCBs that are widely distributed in the environment. While the effects of penta- to hepta-chlorinated OH-PCBs on neuronal differentiation have been widely reported, those of lower chlorinated OH-PCBs have not been extensively studied. To investigate the effects of lower chlorinated OH-PCBs on neuronal development, we studied the effects of mono- to hexa-chlorinated OH-PCBs on PC12 cells. Morphological changes were examined using an automatic system IN Cell Analyzer. Seventeen of the 20 OH-PCBs investigated promoted neuronal elongation in an OH-PCB concentration-dependent manner, while three OH-PCB congeners suppressed neuronal elongation based on Dunnett's analysis. In particular, the top five OH-PCBs (4OH-PCB2, 4'OH-PCB3, 4'OH-PCB25, 4'OH-PCB68, and 4'OH-PCB159), which have hydroxyl groups at the para-position and chlorine substitutions at the 2, 4, or 3' positions, significantly promoted neuronal elongation. Moreover, these neuronal elongations were suppressed by U0126, and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was observed in PC12 cells treated with 4OH-PCB2, 4'OH-PCB25, and 4'OH-PCB159. Taken together, our results indicate that the effect of OH-PCB on neuronal development is not dependent on the number of chlorine groups but on the chemical structure, and the mitogen-activated kinase kinase (MEK)-ERK1/2 signaling pathway is involved in this process.

Highly sensitive imaging of enzymatic activities in the deep tissues of living mammals provides useful information about their biological functions and for developing new drugs; however, such imaging is challenging. 19 F magnetic resonance imaging (MRI) is suitable for noninvasive visualization of enzymatic activities without endogenous background signals. Although various enzyme-responsive 19 F MRI probes have been developed, most cannot be used for in vivo imaging because of their low sensitivity. Recently, we developed unique nanoparticles, called FLAMEs, that are composed of a liquid perfluorocarbon core and a robust silica shell, and demonstrated their outstanding sensitivity in vivo. Here, we report a highly functionalized nanoprobe, FLAME-DEVD 2, with an OFF/ON 19 F MRI switch for detecting caspase-3/7 activity based on the paramagnetic relaxation enhancement effect. To improve the cleavage efficiency of peptides by caspase-3, we designed a novel Gd 3+ complex-conjugated peptide, DEVD X ( X = 1, 2), which is a substrate peptide sequence tandemly repeated X times, and demonstrated that DEVD 2 showed faster cleavage kinetics than DEVD 1. By incorporating this novel concept into a signal activation strategy, FLAME-DEVD 2 showed a high 19 F MRI signal enhancement rate in response to caspase-3 activity. After intravenous injection of FLAME-DEVD 2 and an apoptosis-inducing reagent, caspase-3/7 activity in the spleen of a living mouse was successfully imaged by 19 F MRI. This imaging platform shows great potential for highly sensitive detection of enzymatic activities in vivo.

The rapid spread of strains of malaria parasites that are resistant to several drugs has threatened global malaria control. Hence, the aim of this study was to predict the antimalarial activity of chemical compounds that possess anti-hemozoin-formation activity as a new means of antimalarial drug discovery. After the initial in vitro anti-hemozoin-formation high-throughput screening (HTS) of 9,600 compounds, a total of 224 hit compounds were identified as hemozoin inhibitors. These 224 compounds were tested for in vitro erythrocytic antimalarial activity at 10 μM by using chloroquine-mefloquine-sensitive Plasmodium falciparum strain 3D7A. Two independent experiments were conducted. The physicochemical properties of the active compounds were extracted from the ChemSpider and SciFinder databases. We analyzed the extracted data by using Bayesian model averaging (BMA). Our findings revealed that lower numbers of S atoms; lower distribution coefficient (log D) values at pH 3, 4, and 5; and higher predicted distribution coefficient (ACD log D) values at pH 7.4 had significant associations with antimalarial activity among compounds that possess anti-hemozoin-formation activity. The BMA model revealed an accuracy of 91.23%. We report new prediction models containing physicochemical properties that shed light on effective chemical groups for synthetic antimalarial compounds and help with in silico screening for novel antimalarial drugs., (Copyright © 2018 American Society for Microbiology.)

Ginsenoside Rh1 is one of major bioactive compounds extracted from red ginseng, which has been increasingly used for enhancing cognition and physical health worldwide. The objective of this study was to review the pharmacological effects of ginsenoside Rh1 in a systematic manner. We performed searches on eight electronic databases including MEDLINE (Pubmed), Scopus, Google Scholar, POPLINE, Global Health Library, Virtual Health Library, the System for Information on Grey Literature in Europe, and the New York Academy of Medicine Grey Literature Report to select the original research publications reporting the biological and pharmacological effects of ginsenoside Rh1 from in vitro and in vivo studies regardless of publication language and study design. Upon applying the inclusion and exclusion criteria, we included a total of 57 studies for our systemic review. Ginsenoside Rh1 exhibited the potent characteristics of anti-inflammatory, antioxidant, immunomodulatory effects, and positive effects on the nervous system. The cytotoxic effects of ginsenoside Rh1 were dependent on different types of cell lines. Other pharmacological effects including estrogenic, enzymatic, anti-microorganism activities, and cardiovascular effects have been mentioned, but the results were considerably diverged. A higher quality of evidence on clinical trial studies is highly recommended to confirm the consistent efficacy of ginsenoside Rh1., Competing Interests: All contributing authors declare no conflicts of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

The aim of the present study was to investigate the age-related patterns and the relationships between serum levels of tartrate-resistant acid phosphatase-5b (TRACP-5b) or bone-specific alkaline phosphatase (BAP), and the heel stiffness index measured by quantitative ultrasound (QUS) in 429 Japanese men, with special emphasis on 2 age groups (40-59 years and 60 years or over). The heel stiffness index (bone mass) was measured by QUS. Serum samples were collected, and TRACP-5b and BAP levels were measured. The stiffness index was significantly decreased with age. Log (TRACP-5b) was significantly increased with age, but Log (BAP) was stable. Generalized linear models showed that higher levels of Log (TRACP-5b) and Log (BAP) were correlated with a lower stiffness index after adjusting for covariates in men aged 60 years or over, but not in men aged 40 to 59 years. In conclusion, higher rates of bone turnover markers were associated with a lower stiffness index only in elderly men. These results may indicate a different mechanism of low bone mass among different age groups of men.

To determine the prevalence of fear of falling and associated factors among Japanese community-dwelling older adults.Cross-sectional study between 2011 and 2013.Community in which residents voluntarily attended a health examination.We recruited 844 older adults (male, n = 350; female, n = 494) aged 60 to 92 years from among those who presented at the health examination.We assessed fear of falling, falls in the previous year, pain, comorbidity, and cataracts. Five times chair stand time was applied as an indicator of physical performance.The prevalence of fear of falling was 26.9% and 43.3% among the men and women, respectively. Men and women who feared falling were older (P < .01), had longer 5 times chair stand time (P < .01), and more falls in the previous year (P < .05), pain (P < .01), and comorbidity (P < .05). Multivariate logistic regression analysis identified advanced age (odds ratios [OR], 1.57; 95% confidence interval [CI], 1.03-2.39), falls in the previous year (OR, 2.44; 95%CI, 1.29-4.64), and pain (OR, 1.82; 95%CI, 1.03-3.22) in men, and advanced age (OR, 1.59; 95%CI, 1.13-2.24), longer 5 times chair stand times (OR, 1.28; 95%CI, 1.04-1.59), falls in the previous year (OR, 2.59; 95%CI, 1.54-4.34), and pain (OR, 1.65; 95%CI, 1.06-2.55) in women as being independently associated with fear of falling.The prevalence of fear of falling was similar to previous reports. Advanced age, falls in previous year, and pain were associated with fear of falling in men. A longer 5 times chair stand time was also associated with fear of falling among older adult women. Maintenance of physical function and pain management might be important for older adults with fear of falling.

Mineralocorticoid receptor (MR)/NADPH oxidase (NOX) signaling is involved in the development of obesity, insulin resistance, and renal diseases; however, the role of this signaling on steatotic preneoplastic liver lesions is not fully elucidated. We determined the effects of the MR antagonist potassium canrenoate (PC) on MR/NOX signaling in hepatic steatosis and preneoplastic glutathione S-transferase placental form (GST-P)-positive liver foci. Rats were subjected to a two-stage hepatocarcinogenesis model and fed with basal diet or high fat diet (HFD) that was co-administered with PC alone or in combination with the antioxidant alpha-glycosyl isoquercitrin (AGIQ). PC reduced obesity and renal changes (basophilic tubules that expressed MR and p22phox) but did not affect blood glucose tolerance and non-alcoholic fatty liver disease activity score (NAS) in HFD-fed rats. However, the drug increased the area of GST-P-positive liver foci that expressed MR and p22phox as well as increased expression of NOX genes (p22phox, Poldip2, and NOX4). PC in combination with AGIQ had the potential of inhibiting the effects of PC on the area of GST-P-positive liver foci and the effects were associated with increasing expression of an anti-oxidative enzyme (Catalase). The results suggested that MR/NOX signaling might be involved in development of preneoplastic liver foci and renal basophilic changes in HFD-fed rats; however, the impacts of PC were different in each organ.

Single-molecule imaging (SMI) has been widely utilized to investigate biomolecular dynamics and protein-protein interactions in living cells. However, multicolor SMI of intracellular proteins is challenging because of high background signals and other limitations of current fluorescence labeling approaches. To achieve reproducible intracellular SMI, a labeling probe ensuring both efficient membrane permeability and minimal non-specific binding to cell components is essential. We developed near-infrared fluorescent probes for protein labeling that specifically bind to a mutant β-lactamase tag. By structural fine-tuning of cell permeability and minimized non-specific binding, SiRcB4 enabled multicolor SMI in combination with a HaloTag-based red-fluorescent probe. Upon addition of both chemical probes at sub-nanomolar concentrations, single-molecule imaging revealed the dynamics of TLR4 and its adaptor protein, TIRAP, which are involved in the innate immune system. Statistical analysis of the quantitative properties and time-lapse changes in dynamics revealed a protein-protein interaction in response to ligand stimulation.

[Purpose] This study aimed to evaluate the sustainability and efficacy of exercise intervention, as implemented by professionally trained volunteers, on the health-related quality of life among Japanese community-dwelling older females. [Subjects and Methods] We conducted a non-randomized observational prospective study of a six-month exercise intervention delivered by volunteers or health professionals. Health-related quality of life was scored using the Short Form 36 Health Survey before and after the intervention. Participants were classified into three groups, comprising those with improved health, maintained health, and reduced health. [Results] Among 127 Japanese community-dwelling females aged >65 years, 50 of 62 (80.6%) females involved in the intervention conducted by volunteers, and 55 of 65 (84.6%) females involved in the intervention conducted by health professionals, completed the six-month intervention program. Scoring revealed that interventions by both volunteers and health professionals had a maintaining or improving effect on scores in >70% of participants instead of an expected six-month aging decline. [Conclusion] Exercise intervention by trained volunteers was sustainable and effective for improving the health-related quality of life among Japanese community-dwelling older females. Professionally trained volunteers could benefit communities in helping older persons avoid the need for daily nursing care through promoting health activities.

The increasing resistance of malaria to drugs raise the need to new antimalarial agents. Antiplasmodial herbs and their active compounds are the most promising source the new antimalarial agents. This study aimed to identify the medicinal plants with very good in vitro antiplasmodial activities, with half-maximal inhibitory concentration (IC 50 )≤1μg/ml, and to determine trends in the process of screening their antiplasmodial activities. A total of 58 reports published in the English language were retrieved from the bibliographical databases. Screening and data extraction were performed by two independent reviewers. The herbs were categorized as very good, good, moderate and inactive if the IC 50 values were <0.1μg/ml, 0.1-1μg/ml, >1-5μg/ml and >5μg/ml respectively. We documented 752 medicinal plants belonging to 254 genera. The majority of the plants were reported from Africa followed by Asia. The traditional use for malaria treatment was the most common reason for the selection of the plants for investigation. About 80% of the plants experimented were reported to be inactive. Among plants identified as having very good to good antiplasmodial crude extracts are Harungana madagascariensis, Quassia africana, and Brucea javanica, while Picrolemma spruce, Aspidosperma vargasi, Aspidosperma desmanthum, and Artemisia annua were reported to have individual compound isolates with very good antiplasmodial activities. In conclusion, the number of plant species assessed so far is still small compared with the stock in nature's plant library. A mechanism of systematically approaching and exploring the untouched plant genera needs to be designed., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mg 2+ plays important roles in many physiological processes. However, the underlying molecular mechanisms, especially in the apoptotic pathway, remain unclear due to the diffusion of Mg 2+ probes, which hinders long-term imaging in specific organelles. We developed an immobilized Mg 2+ probe, MGH, which is covalently conjugated with the HaloTag protein in various organelles. HaloTag-coupled MGH enabled long-term imaging of intracellular local Mg 2+ dynamics for 24 h. To exploit this remarkable property, MGH was applied to the investigation of intracellular Mg 2+ dynamics during apoptosis. Time-lapse imaging revealed an increase in the Mg 2+ concentration after apoptotic cell shrinkage. Combined imaging analyses of intracellular Mg 2+ and ATP concentrations strongly suggested that this Mg 2+ concentration increase was caused by the dissociation of Mg 2+ from ATP, along with a decrease in the intracellular ATP concentration. Thus, this protein-coupled Mg 2+ probe could be a new chemical tool to elucidate intracellular Mg 2+ dynamics with high spatiotemporal resolution.

We previously found downregulation of ubiquitin-conjugating enzyme E2E 2 (UBE2E2) in GST-P-positive (+) proliferative lesions produced by tumor promotion from early hepatocarcinogenesis stages in rats. Here we investigated the role of UBE2E2 downregulation in preneoplastic lesions of the liver and other target organs produced by tumor promotion in rats. Increased number of UBE2E2-related ubiquitination target proteins, phosphorylated c-MYC, KDM4A and KMT5A, was found in the UBE2E2-downregulated GST-P + foci, compared with GST-P + foci expressing UBE2E2. However, p21 WAF1/CIP1 , another UBE2E2 target protein, did not increase in the positive cells. Furthermore, the numbers of PCNA + cells and γH2AX + cells were increased in UBE2E2-downregulated foci. These results suggest sustained activation of c-MYC and stabilization of KMT5A to result in c-MYC-mediated transcript upregulation and following KMT5A-mediated protein stabilization of PCNA in GST-P + foci, as well as KDM4A stabilization resulting in slowing down of DNA damage response in these lesions. Similar results were also observed in GST-P + foci produced by repeated treatment of rats with a hepatocarcinogen, thioacetamide, for 90days. Hepatocarcinogen treatment for 28 or 90days also increased the numbers of liver cells expressing UBE2E2-related ubiquitination target proteins, as well as PCNA + or γH2AX + cells. Conversely, UBE2E2 downregulation was lacking in PPARα agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs, suggestive of the loss of UBE2E2-related ubiquitination limited to hepatocarcinogenesis producing GST-P + proliferative lesions. Our results suggest that repeated hepatocarcinogen treatment of rats causes stabilization of UBE2E2-related ubiquitination target proteins in liver cells to promote carcinogenesis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We developed highly selective fluorescent Mg 2+ probes based on a novel tridentate Mg 2+ -selective chelator. The superior selectivity for Mg 2+ over Ca 2+ enabled the detection of intracellular Mg 2+ concentration changes without any response to Ca 2+ influx. The new probes are potential keys to elucidating intracellular Mg 2+ dynamics under conditions of extremely sharp Ca 2+ fluctuation.

We previously observed downregulation of mitochondrial oxidative phosphorylation-related protein, TMEM70, which is suggestive of disrupted cellular senescence, in GST-P-expressing (+) proliferative lesions from early hepatocarcinogenesis stages in rats. The present study investigated the immunohistochemical relationship between TMEM70 downregulation and cellular metabolic changes in carcinogenic processes, as well as the onset of the liver cell respiratory changes after repeated hepatocarcinogen treatment in rats. At the early hepatocarcinogenesis stage in a 2-stage model, GST-P+ preneoplastic lesions showing TMEM70 downregulation also downregulated the mitochondrial ATPase, ATPB, but upregulated glycolysis-related glucose transporter member 1 (GLUT1) and glucose-6-phosphate dehydrogenase, suggesting a metabolic shift from oxidative phosphorylation to glycolysis, known as the Warburg effect. Combined downregulation of TMEM70 and ATPB increased proliferation activity in GST-P+ preneoplastic lesions, suggesting cell proliferation facilitation by reducing mitochondrial respiration. Concurrent GLUT1-upregulation and TMEM70-downregulation increased nuclear phosphorylated c-MYC+ cells in GST-P+ preneoplastic lesions, suggesting c-MYC-mediated transcription facilitation to promote glycolysis and cell proliferation. The TMEM70-related metabolic shift was enhanced in GST-P+ neoplastic lesions, suggesting a contribution to tumor progression. Conversely, the TMEM70-related metabolic shift was lacking in peroxisome proliferator-activated receptor-α agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs. Transcript expression analysis following 28- and 90-day repeated hepatocarcinogen treatment showed downregulation of Tmem70 from day 28 and upregulation of Pkm and Myc at day 90, suggesting early onset of a catastrophic cellular senescence-related metabolic shift beginning from depressed mitochondrial respiration in the liver. These results suggest a contribution of TMEM70 downregulation to the Warburg effect, which directs tumor promotion and progression in GST-P+-linked hepatocarcinogenesis in rats., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The amygdala plays a critical role in emotion. Its functional coupling with the hippocampus and ventromedial prefrontal cortex extending to a portion of the anterior cingulate cortex (ACC) is implicated in anxiogenesis and hypothalamic-pituitary-adrenal (HPA) system regulation. However, it remains unclear how amygdala-centred functional connectivity (FC) affects anxiety and cortisol concentrations in everyday life. Here, we investigate the relationship between daily cortisol concentrations (dCOR) and amygdala-centred FC during emotional processing in forty-one healthy humans. FC analyses revealed that higher dCOR predicted strengthened amygdala-centred FC with the hippocampus and cerebellum, but inhibited FC with the supramarginal gyrus and a perigenual part of the ACC (pgACC) when processing fearful faces (vs. neutral faces). Notably, the strength of amygdala-hippocampus FC mediated the positive relationship between cortisol and anxiety, specifically when the effect of amygdala-pgACC FC, a presumptive neural indicator of emotional control, was taken into account. Individuals with diminished connectivity between the amygdala and pgACC during fear-related processing might be more vulnerable to anxiogenesis as it pertains to greater circulating cortisol levels in everyday life. Individual functional patterns of amygdala-hippocampal-pgACC connectivity might provide a key to understand the complicate link between cortisol and anxiety-related behaviors.

This study was performed to compare the exposure effects of N-methyl-N-nitrosourea (MNU), a cytocidal agent of proliferating cells, on rat hippocampal neurogenesis between developmental and postpubertal periods. Developmental exposure through maternal drinking water from gestational day 6 to day 21 after delivery on weaning decreased GFAP-immunoreactive (+) stem cells and increased immunoreactive cells indicative of subsequent progenitor and postmitotic immature neuronal populations, TUNEL + or p21 Cip1/Waf1+ stem/progenitor cells and COX2 + granule cells, on postnatal day (PND) 21. On PND 77 after cessation of developmental exposure, NeuN + postmitotic granule cells decreased in number. Postpubertal exposure by oral gavage for 28days decreased the numbers of all granule cell lineage populations and ARC + or COX2 + granule cells and increased the number of TUNEL + stem/progenitor cells. These results suggested that both developmental and postpubertal exposure caused apoptosis of stem/progenitor cells. However, developmental exposure increased COX2 expression to facilitate intermediate progenitor cell proliferation and increased neuronal plasticity. This effect was concurrent with the induction of p21 Cip1/Waf1 that causes cell cycle arrest of stem/progenitor cells in response to accumulating DNA damage on weaning, resulting in a subsequent reduction of postmitotic granule cells. In contrast, postpubertal exposure suppressed neuronal plasticity as evidenced by downregulation of ARC and COX2. The COX2 downregulation was responsible for the lack of facilitating stem/progenitor cell proliferation. Induction of apoptosis and the lack of cell proliferation facilitation may be responsible for the overall reduction of neurogenesis caused by postpubertal exposure. Thus, the disrupted pattern of hippocampal neurogenesis induced by MNU is different between developmental and postpubertal exposure., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: The purposes of the present study were to investigate risk factors for incident disability in activities of daily living (ADL) among middle-aged and older women, and to determine whether there are differences in risk factors according to age groups., Methods: The participants were 264 Japanese women aged 40 years and older. A self-administered questionnaire was used to survey participants about difficulty in carrying out selected basic and instrumental ADL at baseline and at follow up. ADL disability was defined as difficulty carrying out three or more ADL. Information on knee joint or back pain and comorbidities (heart disease, lung disease, stroke or diabetes mellitus) was obtained using a self-administered questionnaire at baseline. Physical performance measurements (grip strength, chair stand time, rapid walking speed and functional reach) were also carried out at baseline., Results: The prevalence of incident ADL disability was 44 (27.5%) in women aged 40-64 years, and 57 (54.8%) in women aged ≥65 years (P < 0.001). Multiple logistic regression analysis showed that decreased grip strength and having pain were significantly associated with a higher risk for incident ADL disability among women aged 40-64 years. For women aged ≥65 years, decreased rapid walking speed, having a comorbidity and having pain were associated with incident ADL disability., Conclusions: The present study showed that a different set of risk factors was associated with incident ADL disability among women aged 40-64 years and women aged ≥65 years. Age-specific screening and intervention strategies are necessary for effective prevention of incident ADL disability. Geriatr Gerontol Int 2017; 17: 1096-1101., (© 2016 Japan Geriatrics Society.)

Background: Numerous reported studies have shown that vertebral compression fractures are associated with impaired function or disability; however, few examined their association with objective measures of physical performance or functioning., Methods: We examined the association of vertebral compression fractures with physical performance measures in 556 Japanese women aged 40-89 years. Lateral spine radiographs were obtained and radiographic vertebral compression fractures were assessed by quantitative morphometry, defined as vertebral heights more than 3 SD below the normal mean. Measures of physical performance included walking speed, chair stand time and functional reach. Adjusted means of performance-based measures according to the number and severity of vertebral compression fractures were calculated using general linear modeling methods., Results: After adjusting for age, body mass index, back pain, number of painful joints, number of comorbidities and regular physical activities, the walking speed of women with two or more compression fractures (1.17 m/s) was significantly slower than that of women without compression fracture (1.24 m/s) (p = 0.03). Compared with women without compression fracture, chair stand time was longer in women with two or more compression fractures (p = 0.01), and functional reach was shorter (p = 0.01). No significant differences were observed in walking speed, chair stand time, or functional reach between women with one compression fracture and those without compression fracture., Conclusions: Having multiple vertebral compression fractures affects physical performance in community-dwelling Japanese women. Poor physical functioning may lead to functional dependence, accelerated bone loss, and increased risk for falls, injuries, and fractures. Preventing vertebral compression fracture is considered important for preserving the independence of older adults.

[This corrects the article DOI: 10.1039/C6SC04435B.].

Controlled release is one of the key technologies for medical innovation, and many stimulus-responsive nanocarriers have been developed to utilize this technology. Enzyme activity is one of the most useful stimuli, because many enzymes are specifically activated in diseased tissues. However, controlled release stimulated by enzyme activity has not been frequently reported. One of the reasons for this is the lack of versatility of carriers. Most of the reported stimulus-responsive systems involve a sophisticated design and a complicated process for the synthesis of stimulus-responsive nanocarrier components. The purpose of this study was to develop versatile controlled release systems triggered by various stimuli, including enzyme activity, without modifying the nanocarrier components. We developed two controlled release systems, both of which comprised a liposome as the nanocarrier and a membrane-damaging peptide, temporin L (TL), and its derivatives as the release-controllers. One system utilized branched peptides for proteases, and the other utilized phosphopeptides for phosphatases. In our systems, the target enzymes converted the non-membrane-damaging TL derivatives into membrane-damaging peptides and released the liposome inclusion. We demonstrated the use of our antimicrobial peptide-based controlled release systems for different enzymes and showed the promise of this technology as a novel theranostic tool.

The present study identified genes showing promoter region hypermethylation by CpG island microarrays in the liver of rats treated with hepatocarcinogen thioacetamide (TAA) for 28days. Among 47 hypermethylated genes, Hist1h2aa, Tmem70, Ube2e2, and Slk were confirmed to show hypermethylation by methylation-specific quantitative polymerase chain reaction (PCR) and pyrosequencing analyses as well as downregulation of transcript levels by real-time reverse transcription-PCR analysis in the livers of rats treated with TAA. All gene products of the 4 selected genes showed decreased immunoreactivity forming negative liver cell foci in a subpopulation of glutathione S-transferase placental form (GST-P) + foci in TAA-promoted rat livers in a two-stage hepatocarcinogenesis model. Among them, TMEM70 and UBE2E2 showed increased incidences of negative foci in GST-P + foci by promotion of all examined TAA, β-naphthoflavone, piperonyl butoxide, fenbendazole and phenobarbital, while HIST1H2AA and SLK did not respond to all promotive treatments. In the late stage of tumor promotion by TAA, the incidence of GST-P + proliferative lesions with downregulation of TMEM70 or UBE2E2 was higher in adenomas and carcinomas than liver cell foci. TMEM70 plays a role in mitochondrial oxidative phosphorylation, and UBE2E2 participates in the stabilization of cell cycle regulatory proteins. Therefore, our results indicate that aberrant epigenetic gene downregulation suggestive of a metabolic shift of cellular respiration from oxidative phosphorylation to glycolysis and aberrant cell cycle regulation facilitating cell proliferation from as early as 28days after hepatocarcinogen treatment contribute to tumor development., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)